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Article

Overview of Neuro-Ophthalmic Findings in Leukodystrophies

by
Charlotte Maria Bettinger
1,
Simon Dulz
2,
Yevgeniya Atiskova
2,
Helena Guerreiro
3,
Gerhard Schön
4,
Philipp Guder
1,
Sarah Lena Maier
1,
Jonas Denecke
1 and
Annette E. Bley
1,*
1
Children’s Hospital, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
2
Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
3
Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
4
Center of Experimental Medicine, Institute for Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2024, 13(17), 5114; https://doi.org/10.3390/jcm13175114
Submission received: 9 July 2024 / Revised: 10 August 2024 / Accepted: 13 August 2024 / Published: 28 August 2024
(This article belongs to the Special Issue New Clinical Insights into Pediatric Neurology)
Browse Figures
Versions Notes

Abstract

:
Background: Leukodystrophies are a group of rare genetic diseases that primarily affect the white matter of the central nervous system. The broad spectrum of metabolic and pathological causes leads to manifestations at any age, most often in childhood and adolescence, and a variety of symptoms. Leukodystrophies are usually progressive, resulting in severe disabilities and premature death. Progressive visual impairment is a common symptom. Currently, no overview of the manifold neuro-ophthalmologic manifestations and visual impact of leukodystrophies exists. Methods: Data from 217 patients in the Hamburg leukodystrophy cohort were analyzed retrospectively for neuro-ophthalmologic manifestations, age of disease onset, and magnetic resonance imaging, visual evoked potential, and optical coherence tomography findings and were compared with data from the literature. Results: In total, 68% of the patients suffered from neuro-ophthalmologic symptoms, such as optic atrophy, visual neglect, strabismus, and nystagmus. Depending on the type of leukodystrophy, neuro-ophthalmologic symptoms occurred early or late during the course of the disease. Magnetic resonance imaging scans revealed pathologic alterations in the visual tract that were temporally correlated with symptoms. Conclusions: The first optical coherence tomography findings in Krabbe disease and metachromatic leukodystrophy allow retinal assessments. Comprehensive literature research supports the results of this first overview of neuro-ophthalmologic findings in leukodystrophies.

1. Introduction

Leukodystrophies (LDs) are a group of rare genetic neurodegenerative diseases characterized by a predominant involvement of the white matter of the central nervous system (CNS) [1,2,3]. All structural components of the white matter can be affected, including oligodendrocytes, astrocytes, microglia, axons, and blood vessels [3,4,5], resulting in dysfunctional synthesis and maintenance of myelin [1,6]. Hypomyelinating and demyelinating forms are distinguished according to myelin presentation over time [2,5,7].
Hypomyelinating leukodystrophies are usually caused by delayed and/or insufficient formation of myelin [2,8,9]. A typical hypomyelinating leukodystrophy is Pelizaeus–Merzbacher disease (PMD), and the appearance of the first symptoms occurs early after birth with developmental delay and nystagmus [2].
In demyelinating leukodystrophies, normal appearing myelin formation is followed by a loss of myelin, which leads to symptoms [2,10]. Classic demyelinating leukodystrophies are metachromatic leukodystrophy (MLD) and Krabbe disease (KD). In MLD, reduced activity of the enzyme arylsulfatase A leads to an accumulation of sulfatides in the central and peripheral nervous system, resulting in demyelination [11,12].
Clinical onset may occur at any age, from prenatal life to senescence [5,7], although many forms begin in infancy and affect clinically inconspicuous children until symptom onset [5,7]. Leukodystrophies are caused by different underlying pathomechanisms and lead to a broad spectrum of clinical symptoms. The clinical course is usually progressive, with extensive loss of motor and mental abilities, often leading to helplessness and premature death [1,2]. Initial symptoms often include an arrest of motor or cognitive development followed by further deterioration and regression. The most common neurological findings include motor deficits, which often manifest with a delay in reaching motor milestones [6,13,14]. Cognition is often affected during the course of the disease, especially in older patients, but deterioration of cognitive functions may also occur at disease onset. However, milder forms have also been described and are characterized by longer intervals of symptom stability or even improvement [2]. Most leukodystrophies are inherited in an autosomal recessive manner [6,15], although other modes of inheritance exist (autosomal dominant or X-linked) [15].
Neurodegenerative diseases are often associated with ocular and optic tract involvement [16,17,18,19]. Various manifestations range from the anterior eye, as noted in patients with cerebrotendinous xanthomatosis (CTX), who develop cataracts [20] via myopia in 4H syndrome to optic atrophy in various leukodystrophies [21].
Although ocular involvement has been described in numerous single reports of leukodystrophies [15], no broad observation of a large cohort of multiple leukodystrophies has been attempted thus far. A better understanding of visual impairment in leukodystrophy patients may have an impact on the clinical understanding of these diseases, may even facilitate earlier diagnosis [15], and may help to identify novel outcome measures in clinical trials.
Herein, we analyzed different neuro-ophthalmologic symptoms (NOSs) and correlated them with the presence of leukodystrophy and findings in the brain on MRI. We show the first findings of retinal nerve fiber layer imaging (RNFL) performed by optical coherence tomography (OCT) and the potential of this noninvasive imaging method for quantifying extracerebral neuronal tissue.

2. Materials and Methods

2.1. Data Extraction

The data of 349 patients with leukodystrophies were screened. The data of 217 patients with genetically and/or biochemically confirmed diagnoses of leukodystrophy from the Hamburg leukodystrophy cohort (HLC), Department of Pediatrics at the University Medical Center Hamburg-Eppendorf, Germany, who met the data protection criteria were analyzed retrospectively (informed consent according to PV3782, Ethics Committee of the Medical Association of Hamburg, Hamburg, Germany). The analyzed data records from international as well as German patients were anonymized and processed according to applicable regulations. The defined secondary outcome variables were age, sex, age at symptom onset, type of leukodystrophy, and survival.
For X-linked adrenoleukodystrophy (X-ALD) patients, only male patients of all ages were analyzed. Females with X-ALD were listed as others. For some analyses, LDs were grouped into demyelinating and hypomyelinating LDs. The following LDs were identified under demyelinating conditions: MLD, X-ALD, KD, Canavan disease (CD), Alexander disease (AxD), vanishing white matter disease (VWM), Aicardi–Goutières syndrome (AGS), and megalencephalic leukoencephalopathy with subcortical cysts (MLC). Under hypomyelinating LDs, we summarized the following: PMD and other less frequent leukodystrophies, such as 4H syndrome and X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD).
Clinical status was assessed using a retrospective review of neurological evaluations, neurodevelopmental assessments, and ophthalmological evaluations. The following neuro-ophthalmologic symptoms were defined as primary outcome variables, including the onset of the different neuro-ophthalmologic symptoms:
-
visual function (e.g., reduced visual acuity, contrast sensitivity, color discrimination, peripheral vision, and higher order visual processing);
-
eye movement disorders (EMD) (e.g., nystagmus, strabismus that was defined as any heterotropia at near and/or distance fixation);
-
fixational eye movement disorders (FEMD) (e.g., no ability to fix and follow or track objects);
-
pupillary light reflex (defined as either absent, delayed, or slowed); and
-
anterior and periocular segment findings (e.g., cataracts, ptosis, infections of the eye) and posterior segment findings (e.g., optic atrophy).
Normal as well as pathologic results were recorded.

2.2. MRI Analysis

MRI scans of patients with pathological neuroophthalmological findings were analyzed within a maximum of 1.5 years before or after the reported onset of neuro-ophthalmologic symptoms. T1W and T2W images as well as fluid-attenuated inversion recovery (FLAIR) images in the transverse and sagittal planes were used for the analysis. Brain MR images were acquired at different centers using numerous different scanners and distinct imaging protocols. Every examination included basic MRI sequences, which were used for review. Two independent experienced raters (HG and AB) evaluated these sequences with special attention to the visual tract, which consists of the optic nerve, the optic chiasm, the optic tract, the lateral geniculate nucleus, and the visual cortex in the occipital lobes [22]. Signal abnormalities were identified and recorded.

2.3. Optical Coherence Tomography and Retinal Nerve Fiber Measurement

OCT analysis was performed with a swept-source optical coherence tomography (SS-OCT) instrument (Topcon DRI OCT Triton Plus, Topcon Medical Inc., Tokyo, Japan). A circular peripapillary scan was performed in each eye, and retinal nerve fiber (RNFL) measurements (μm) were extracted from ImageNet 6 software (Topcon Medical Inc., Tokyo, Japan). One experienced rater (SD) evaluated the available OCT scans.

2.4. Visual Evoked Potential (VEP)

The results of the VEP examinations of the patients’ records were analyzed. If VEP was performed outside of our clinic, no information on the examination protocol was available. VEP findings were recorded and classified as “pathological” or “normal” without further specification. For simplification a pathological VEP was considered as neuro-ophthalmologic symptom. VEP examinations that were performed at our institution were performed using RetiPort (Roland Consult Stasche & Finger GmbH, Brandenburg an der Havel, Germany). For the device settings for pattern reversal VEP, the screen illumination was set to 50 cd/m2, the contrast was set to 100%, the pattern turnover ratio was set to 2/sec, and the sweep time was set to 300 ms. For the filter settings, the subfilter was set to 1 Hz. In the case of flash VEP, a 3 cd/s/m−2 flash stimulus with a flash rate of 1 Hz was used. All electrodes were applied according to the ISCEV guidelines [23].

2.5. Literature Review

To compare our data with data from the literature, a systematic analysis of the literature was conducted. The search strategy for the biomedical database MEDLINE via PubMed used a combination of key words (MeSH-terms) and free text (last searched May 15, 2022; the search strategy was as follows: ((“Leukodystrophy”[MeSh]) OR (“Leukoencephalopathies” [MeSh]) OR (“MLD”) OR (“Leukodystrophy, Metachromatic” [MeSh]) OR (“Canavan disease” [MeSh]) OR (“Krabbe disease” [MeSh]) OR (“Leukodystrophy, Globoid Cell” [MeSh]) OR (“Adrenoleukodystrophy” [MeSh]) OR (“ALD”) OR (“PMD”) OR (“Pelizaeus–Merzbacher disease” [MeSh]) OR (“VWM”) OR (“Vanishing white matter”) OR (“Alexander disease” [MeSh]) OR (“Aicardi–Goutières syndrome” [MeSh]) OR (“AGS”) OR (“MLC”) OR (“Megaleukoencephalopathy” [MeSh])) AND ((“Nystagmus, Pathologic”[MeSh]) OR (“Nystagmus, Congenital” [MeSh]) OR (“Optic Atrophy” [MeSh]) OR (“Strabismus” [MeSh]) OR (“Visual inattention”) OR (“Pupil disorders” [MeSh]) OR (“Eye movement” [MeSh]) OR (“Fixation, Ocular” [MeSh]) OR (“Visual Fields” [MeSh]) OR (“Vision, Ocular” [MeSh]) OR (“Pupillary reaction”) OR (“Pupillary response”) OR (“VEP”) OR (“Visual evoked potentials” [MeSh])).
The following databases were searched using free text combinations: EMBASE, ISI Web of Knowledge, Cochrane Central Register of Controlled Trials (CENTRAL), BioMed Central, and ScienceDirect (last searched 15 May 2022). No language restrictions were imposed. We additionally screened clinical trial registries, including WHO International Clinical Trials Registry and ClinicalTrials.gov, as well as the reference lists of the full texts of potentially relevant studies and review articles (last searched 15 May 2021). We searched for prospective and retrospective longitudinal observational studies investigating the association between leukodystrophies and the neuro-ophthalmologic symptoms. We also analyzed reviews, editorials, and commentaries. CB screened the identified articles and reviewed the full texts of the potentially relevant references. CB performed the data extraction and analysis. All references were managed and stored in EndNote 20 [24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132]. The literature search (Lit.) identified 529 possibly relevant references. Of these, 268 references were included for full-text evaluation. In total, we incorporated data from 168 publications into the analysis. Figure 1 provides an overview of the study selection process according to the PRISMA guidelines [133]. The flowchart shows the number of studies identified, excluded, and included, as well as the reasons for the exclusions.

2.6. Data Analysis

The data were analyzed in a Microsoft Excel Version 16.77 (23091003) spreadsheet. As descriptive statistics, arithmetic means and standard deviations are reported for the metric characteristics and counts, and proportions are reported for categorical variables.
For the analysis of time to symptom onset (FEMD, EMD, and visual function), the time between diagnosis and symptom onset was used. For patients without symptoms, the time between diagnosis and the last hospital visit was used. Statistical analyses were performed by the UKE Institute of Biometry and Statistics (GS) using the program R¹ (Version 3.4.3).

3. Results

3.1. Patient Characteristics

The data of 217 patients with various leukodystrophies in the Hamburg leukodystrophy cohort (HLC) and 1153 patients from the literature search (LCC) were analyzed. The median age of disease onset of HLC patients was 7 months, varying from leukodystrophies with an early onset of 1 month as noted for PMD to leukodystrophies with a later onset as noted for X-ALD (median age of onset of 94 months). In the literature, the median age of onset of the disease was 6 months, ranging from 2 months for PMD to 83 months for X-ALD. A balanced sex distribution was observed in both cohorts, excluding patients with X-linked inherited leukodystrophies such as PMD, X-ALD, and H-SMD. Neuro-ophthalmologic symptoms occurred in 68% of HLC and 76% of LLC patients during the course of the disease. The occurrence of neuro-ophthalmologic symptoms depended on the type of leukodystrophy. In the HLC, patients with PMD (100%) and CD (100%) were most frequently affected by neuro-ophthalmologic symptoms, a tendency that was also observed in the LLC (PMD 98%, CD 83%). HLC patients with AxD (30%) and MLD (42%) were less frequently affected by neuro-ophthalmologic symptoms. In the LLC, the lowest prevalence was identified in patients with VWM (29%) and MLD (32%). Most neuro-ophthalmologic findings were progressive in patients that were observed over an extended period. Follow up time spans were 0–39 years with a median of 4.2 years (some patients only presented to us once).
An overview of the age at onset of the disease, the occurrence of neuro-ophthalmologic symptoms, and patient sex for different leukodystrophies is shown in Table 1.

3.2. Neuro-Ophthalmologic Disease Manifestations

The majority of leukodystrophy patients (68%) developed one or more than one (total sum of 366 neuro-ophthalmologic findings in the HLC) neuro-ophthalmologic symptoms during the course of the disease. Neuro-ophthalmologic symptoms occur early or late during the course of the disease. On average, if a leukodystrophy patient became symptomatic, the first description of neuro-ophthalmologic symptoms occurred within 6 months (range from 0 months to 33 years). Neuro-ophthalmologic symptoms were reported to be the first symptom of leukodystrophy in 26% of HLC patients (n = 38). In 8% (n = 12) of the patients, neuro-ophthalmologic symptoms were even reported to be present at birth, mainly in patients with PMD (n = 7) and CD (n = 4). The first neuro-ophthalmologic symptoms were reported to occur in the same month as disease onset in PMD and one month after disease onset in CD. Patients with AGS or KD were reported to suffer from neuro-ophthalmologic symptoms early in the course of the disease (4 and 5 months after disease onset, respectively). In those with X-ALD, neuro-ophthalmologic symptoms occurred 9 months after the onset of the disease. However, in other leukodystrophies, neuro-ophthalmologic symptoms were reported to occur rather late during the course of the disease, as were MLD (median 31 months), AxD (median 44 months), VWM (median 86 months) and MLC (median 100 months).
We differentiated neuro-ophthalmologic symptoms in all leukodystrophies by the kind of neuro-ophthalmic symptom. The most common were eye movement disorders (EMDs) in 30% and fixational eye movement disorders (FEMDs) in 15%, followed by posterior segment findings in 13%. The frequencies of all analyzed neuro-ophthalmologic symptoms are listed in Table 2.
In total, 1057 pathological findings were extracted from 1153 patients in the literature (LLC). As noted in the HLC, the most common findings were eye movement disorders (60%), followed by impaired visual function (21%) and posterior segment findings such as optic atrophy (14%), as shown in Table 2.
The neuro-ophthalmologic symptoms were differentiated according to the type of leukodystrophy and the type of the neuro-ophthalmologic symptom. Frequencies of specific neuro-ophthalmologic symptoms in the HLC and LLC are shown in Table 3.

3.2.1. EMD Nystagmus as an Early Sign of Hypomyelinating Leukodystrophies

The eye movement disorder nystagmus was the most common neuro-ophthalmologic symptoms in our analyzed leukodystrophy patients (28%). It occurred most frequently in PMD patients (100%), followed by CD patients (62%). The frequency of nystagmus is shown in Table 3. In 28% of patients, nystagmus was the first clinical sign of disease, and it was congenital in 18%. Considering only hypomyelinating forms of leukodystrophies (n = 26), nystagmus occurred in 77% of patients with a median of 0 months after disease onset (range 0 months to 20 years). In the demyelinating group (n = 191), only 21% of patients exhibited nystagmus with a median of 5 months after disease onset (range 0 months to 13 years). In 22% of patients, the nystagmus disappeared completely during the course of the disease, with a median age of 29 months (range 7 months to 15 years) after the first onset of nystagmus, regardless of the type of leukodystrophy. For 72% (569/790) of all LLC patients, nystagmus was reported. Among patients with nystagmus, 86% had a hypomyelinating form of leukodystrophy, and 14% had a demyelinating form of leukodystrophy.

3.2.2. EMD Strabismus

Strabismus was diagnosed in 18% of HLC patients, with a median age of onset of 8 months (range 0 months to 33 years) after disease onset. Patients with PMD (31%) were affected most frequently, followed by those with CD (26%) and other LDs, as shown in Table 3. In terms of hypomyelinating forms, 42% of patients showed strabismus with a median time span of 12 months after disease onset. In terms of demyelinating forms, 15% of patients developed strabismus with a median time span of 6 months after disease onset. Within the LLC, a total of 34% (68/202) of patients developed strabismus. The distribution of strabismus in the different forms of leukodystrophies is listed in Table 3. Among these patients who developed a strabismus, 9% had hypomyelination, and 91% had a demyelinating form of leukodystrophy.

3.2.3. Fixational Eye Movement Disorders (FEMD)

Twenty-five percent of HLC patients developed fixational eye movement disorders, with a median age of onset of 7 months (range 0 to 326) after disease onset. Patients with CD (56%) and AGS (44%) were affected most commonly. In LCC, 69% (24/35) of the patients were described to have a fixational eye movement disorder (further details in Table 3).

3.2.4. Visual Function

Impaired visual function was observed in 11% of all HLC patients, with a median age of onset of 18 months (range 0 to 432 months) after disease onset. Visual function impairment was most commonly reported in X-ALD (27%) and CD (21%) and less frequently in VWM (8%) and other forms of leukodystrophies (further details in Table 3). In the LLC, 53% (223/417) of patients had a deficit in visual function. In detail, of the patients who showed impaired visual function, 63% were patients with demyelinating leukodystrophies, and 29% were patients with hypomyelinating leukodystrophies.

3.2.5. Pupillary Light Reflex

A pathologic pupillary light reflex was less frequently reported in 14% (n = 31) of HLC patients, without major differences in patients with demyelination or hypomyelination. Median age of onset was 35 months (range 0 to 284) after disease onset. In the LLC, 39% (n = 28/72) were found to have a pathological light reaction. Further details of the occurrence of a pathological pupillary light reflex in the different forms of leukodystrophies of both cohorts are depicted in Table 3.

3.2.6. Anterior and Periocular Segment Findings

In the HLC, 11% (n = 23) had pathological findings of the anterior or periocular segment. The findings were inflammation of the anterior or periocular segment (hordeolum, blepharitis, and conjunctivitis) in 30% (n = 7) most frequently in patients with CD (n = 3) and MLD (n = 2), cataracts in 30% (n = 7) of patients with CTX (n = 2) and HCC (n = 1), and ptosis in 22% (n = 5) of patients with MLD (n = 2). Sparse LCC data did not allow for sufficient analysis.

3.2.7. Posterior Segment Findings as Optic Atrophy

Only 14% of HLC patients (n = 30) were reported to develop optic atrophy during the progression of the disease, with a median age of onset of 25 months (range 0 to 319 months) after disease onset. Patients with AGS (33%; n = 3/9) and PMD (31%, n = 4/13) were affected most frequently, followed by those with other LDs, as shown in Supplemental Table S1. Patients with hypomyelinating forms (35%; n = 9/26) were more often affected than patients with demyelinating forms (11%; n = 21/191). Among all patients identified by the literature search, 38% (145/385) developed optic atrophy during the course of the disease. Overall, 14% of patients with optic atrophy had hypomyelinating forms of leukodystrophy, and 86% had demyelinating forms of leukodystrophy.

3.3. VEP Results in Leukodystrophies

In total, 57 VEP results in 54 HLC symptomatic and pre-symptomatic patients were reported. Thirty-five patients showed pathological VEP findings (65%). A detailed analysis of all LD forms and percentages of pathologic VEP findings is shown in Table 4. In the group with hypomyelinating forms of leukodystrophies, pathological VEP findings were noted in 100% (n = 8/8) of patients, and in the group with demyelinating forms of leukodystrophies, it was found in 59% (n = 27/46) of patients. Patients exhibiting normal VEP findings had a median illness duration of 15 months, whereas those with pathological VEP findings demonstrated a significantly longer median illness duration of 26 months.
Almost all 35 patients with pathological VEP findings had at least one other neuro-ophthalmologic symptom. In total, the 35 patients with pathological VEP findings had 87 additional neuro-ophthalmologic findings. The most common were EMD (n = 29), followed by posterior segment findings (n = 16) and FEMD (n = 10). Normal VEP findings were initially observed in 22 patients. Three patients (1 MLD, 1 AxD, 1 MLC) developed pathological VEP findings during the course of the disease, leaving 19 patients with normal VEP findings during the observation of AxD (n = 2/3), KD (n = 3/4), X-ALD (n = 3/5), VWM (n = 2/4), and MLD (n = 8/19) patients. Patients with normal VEP findings had a median disease duration of 15 months.
In LLC patients, 66% (n = 52/79) had pathologic VEP results. Pathological VEP results occurred more frequently in hypomyelinating forms of leukodystrophy (83%; n = 15/18) than in demyelinating forms (61%; n = 37/61). More details are shown in Table 4.

3.4. OCT in Leukodystrophies

OCT was performed in 10 leukodystrophy patients (3 KD, 2 MLD, 2 X-ALD, 1 MLC, 1 4H syndrome, 1 CTX). The findings of nine patients were available for evaluation. Three patients showed abnormal thinning of the retinal nerve fiber layer on OCT, and six showed no abnormalities. The six patients with normal OCT findings (Figure 2, normal findings in a–d) were reported to be either early in their course of the disease or were suffering from a leukodystrophy with a late onset. One of the MLD patients has received an experimental treatment and has been symptom stable for years, and the one patient with proven X-ALD is presymptomatic for ccALD suffering only from Addison’s disease.
Two patients with KD and one patient with 4H syndrome showed abnormal thinning of the retinal nerve fiber layer (RNFL) on OCT (Figure 3). At the time of the OCT examination, optic atrophy was present in all three patients, which was diagnosed by inspection by an ophthalmologist. Neuro-ophthalmologic symptoms were detected in almost all patients with normal OCT results; in detail, two had cataracts, and three had refractive errors.

3.5. MRI Findings Correlate with Neuro-Ophthalmologic Findings

We analyzed 49 MRI scans of 49 patients for whom cranial MRI was performed 1.5 years before or after the onset of neuro-ophthalmologic symptoms. Patients were affected by the following neuro-ophthalmologic symptoms: EMD (n = 23), FEMD (n = 29), and pathological pupillary light reflex (n = 2). Five patients had two neuro-ophthalmologic symptoms at the time of evaluation. In-depth analysis of the visual tract was performed on T1W, T2W, and FLAIR cranial MR images.
The majority (n = 47/49) exhibited pathologic visual pathway effects on the brain (Figure 4), with effects on the periventricular parietooccipital white matter. Only two patients presented with age-appropriate MR images. Symptoms of these patients were a transient setting-sun phenomenon in an otherwise presymptomatic KD and strabismus in an X-ALD female conductor.
Myelin involvement of the parieto-occipital white matter and visual pathway was observed in all MRI images. Additional distinct findings were optic nerve kinking (increased tortuosity of the optic nerve) in eight patients (3 CD, 1 KD, 1 PMD, 1 X-ALD, 1 4H-syndrome, 1 Col4a1), optic nerve sheath dilatation/optic disc swelling in seven patients (1 CD, 3 KD, 1 VWM, 1 4H syndrome, 1 GM2) and optic atrophy in one patient (VWM), as shown in Figure 5.

4. Discussion

This study describes the occurrence and frequency of different neuro-ophthalmologic symptoms in 217 patients with different leukodystrophies in a leukodystrophy cohort and compares them with data from 1153 patients reported in the literature. We further report the heterogeneity of the occurrence of the neuro-ophthalmologic symptoms in relation to the timing of the first disease symptom in patients with different types of leukodystrophies. We describe the corresponding findings of ophthalmologic and other diagnostic methods, such as MRI, VEP, and OCT. In two patients with Krabbe disease and one patient with 4H syndrome, we report a previously unpublished abnormal thinning of the retinal nerve fiber layer observed in OCT imaging.
Neuro-ophthalmologic symptoms are common findings in leukodystrophies. In our cohort, 68% of our patients were reported to suffer from neuro-ophthalmologic symptoms, compared to 76% in the literature cohort. The occurrence of neuro-ophthalmologic symptoms was 100% in patients with PMD and CD in our cohort and was also very frequent feature in patients in the literature with PMD (98%) and CD (83%). In 26% of our cohort, neuro-ophthalmologic symptoms were among the first symptoms of the disease, especially in patients suffering from PMD and CD. Hence, the majority of neuro-ophthalmologic symptoms occurs secondarily during the course of the disease. Some symptoms occurred usually earlier in the course of the disease, such as EMD (median nystagmus 0 months and strabismus 8 months after disease onset) and FEMD (median 7 months after disease onset). Other neuro-ophthalmologic symptoms occurred later during the course of the disease as optic atrophy occurred at a median of 25 months after disease onset and pathologic light response at a median of 35 months after disease onset. These finding may support development of specific treatments according to affected functions during the course of the disease.
Interestingly, we found that the most common neuro-ophthalmologic symptoms in leukodystrophy patients (30% in our cohort, 60% in the literature) were eye movement disorders. Among these patients, nystagmus was most common (54%) and appeared at disease onset in our cohort, predominantly in patients with hypomyelinating leukodystrophies, including PMD, as reported previously [13]. Nystagmus in general, as an eye movement disorder, may reflect the interruption of visual input, which is important for optimal eye movement [135]. It is frequently observed in children with cortical and subcortical visual disorders and might be associated with severe visual disturbances and inability to fix and track objects [136]. Nystagmus is not solely related to neuro-ophthalmic pathologies, but it can also be observed in diseases of the vestibular apparatus or central nervous regions such as those of the brainstem [137] and as a sequel of intoxications and metabolic disorders [138]. It is not yet understood why nystagmus occurs predominantly in hypomyelinating forms of leukodystrophies. It is possible that the disruption of early myelinating structures (as for example infratentorial structures) might be related to the higher occurrence.
The optic tract crosses the brain and is dependent on the degree of myelination. In our patients with hypomyelinating leukodystrophies, 100% of the VEP findings were abnormal, and 83% of the VEP findings in the literature group with hypomyelinating leukodystrophies were abnormal, reflecting insufficient myelination of the optical tract/optic pathway. The occurrence of nystagmus in 100% of our PMD patients appears conclusive with this finding. Interestingly, none of our PMD patients reported suffering from a visual function deficit. Since VEPs reflect the sum of the functions of the retina, the visual pathway, and the processing of visual stimuli by the brain, these findings mainly represent a pathology of the visual pathway or visual cortex in LD [139]. We hypothesize that nearly all patients with leukodystrophy exhibit pathological VEP during the progression of the illness. Due to their age and disabilities, these patients are usually unable to communicate visual symptoms or participate in standardized tests, so the VEP serves as a surrogate parameter for the duration or stage of the disease [140].
It is also not understood why, regardless of whether it is a hypomyelination or a demyelinating form of leukodystrophy, in 22% of HLC patients, the nystagmus disappeared completely over the course of the disease, with a median of 29 months (range 7 months to 15 years) after onset. Patients with hypomyelinating leukodystrophies, such as PMD or 4H syndrome, often gain further developmental milestones over time before a regression is noted. Atrophy is often described to occur after some time, often years, in hypomyelinating leukodystrophies, such as PMD [141] We assume that this partial, at least functional, maturation may also affect the nystagmus positively.
In demyelinating leukodystrophies, we rather assume that the initial affection of structures causes neuronal imbalances that lead to the nystagmus. Further degeneration with almost complete loss of myelinated structures and progressive atrophy may affect the symptoms of nystagmus, leading to blindness with regression of nystagmus due to more unspecific oculomotor problems. Further research with prospective assessments, such as ophthalmologic examination, MRI, and VEP, may support elucidation of the pathogenesis of nystagmus in different LDs and in general.
The second most common eye movement disorder in our cohort was strabismus (18%), with a median onset of 8 months after disease onset. In our cohort, strabismus was most common in hypomyelinating LDs, as in PMD. Forty-two percent of patients showed strabismus with a median time span of 12 months after disease onset. However, in demyelinating forms, 15% of patients developed strabismus with a median time span of 6 months after disease onset. A specific correlation to one or more of the involved neurologic systems that are important for eye movement coordination in the brainstem, such as cranial nerve nuclei, the supraoculomotor area, the medial longitudinal fasciculus, and paramedian pontine formation [142], was not possible according to our retrospective MRI analyses. In the literature cohort, 34% of patients developed strabismus. Among these patients, 9% had a hypomyelinating form of leukodystrophy, and 91% had a demyelinating form of leukodystrophy.
Visual function deficits in patients with leukodystrophies have also been reported but are less common, with only 11% in our cohort and 53% in the literature. We assume that the composition of our cohort with a greater percentage of patients in their early disease course might explain this discrepancy as well as the method used for the literature search, as an association between leukodystrophy and visual deficits was explicitly sought.
Abnormalities in pupillary light reflexes according to clinical examination were less frequent in our cohort (14%) than in the literature cohort (39%). As abnormal myelination usually affects the nerve conduction velocity, we assume that subtle changes in the reaction time of pupillary light reflexes might be persistent but would need more sensitive methods, such as pupillometry. This topic is subject to further research.
Pathologic findings of the anterior and periocular segments occurred in 11% of our cohort. Inflammation, such as blepharitis, conjunctivitis, or hordoleum, was most common in patients with Canavan disease (42%, n = 3/7). Prospective studies are necessary to reveal potential causes, such as reduced blinking frequencies, in children with CD. As previously published, cataracts were present in patients with CTX [20].
Analysis of 54 patients with VEP revealed a pathologic finding in the majority of the reported examinations (65%), which is in line with the results in the LCC where 66% also showed pathological VEP findings (52 of 79 patients). When grouped by hypomyelinating and demyelinating forms of leukodystrophies, pathological VEP findings were noted in 100% (n = 8/8) of our cohort in the group with hypomyelinating leukodystrophies (83% in LCC) and in 59% (n = 27/46) of our cohort in the group with demyelinating forms of leukodystrophies (61% in LCC).
Involvement of the optic nerve during disease progression is a known feature of leukodystrophies. As an example in MLD, histopathological findings have revealed metachromatic deposits in retinal ganglion cells, optic nerves, and ciliary nerves [143]. Optic atrophy is mainly described later during the disease course [2]. We believe the normal VEP results in 19 patients can be attributed to the early timing of the examinations, conducted at a median of 15 months after disease onset.
The discrepancies in the frequency of ophthalmologic findings between HLC and LLC data might be explained by the selection of studies or articles based on predefined search criteria and keywords. There might be an overestimation of the incidence in the literature as reported cases are often more severely affected or have a longer follow-up time. In our cohort, there are many cases who are still early in the course of the disease, for whom we suspect that neuro-ophthalmologic symptoms may still occur during the course of the disease. A follow-up would be useful and would provide information about the actual differences in frequency. A prospective systematic evaluation based on research would allow a significant reduction in this bias.
In our study, the OCT data of 9 patients with leukodystrophy were analyzed. Six patients with MLD (n = 2), X-ALD (n = 2), CTX (n = 1), or MLC (n = 1) and normal OCT findings were not in an advanced stage of the disease or suffered from a slowly progressive form of leukodystrophy. Three patients, two with KD and one with 4H syndrome, showed abnormal thinning of the retinal nerve fiber layer (RNFL). All patients with pathologic OCT presented at a progressed stage of disease and presented optic atrophy when OCT was performed. Interestingly, no reports of abnormal RNFL thinning in Krabbe disease or 4H syndrome patients, including one adult Krabbe patient without abnormal OCT findings [144], have been published to date. As the thickness of the RNFL is thought to reflect the integrity of the unmyelinated axons of the anterior visual pathway and the CNS white matter, future studies need to analyze the impact of OCT as a surrogate marker for disease progression. We did not observe hyperreflective retinal spots in the three pathologic OCT results of Krabbe and 4H syndrome patients, which are thought to be related to microglia activation [145]. Due to the limited number of patients who underwent OCT, we assumed that retinal changes might correlate with the degree of progression reflecting later stages of the disease. Further research should evaluate retinal involvement in leukodystrophies using OCT. This may impact decisions in the development of new treatments as not all application routes for CNS treatments might have effects on the retina.
MRI provides information on the extent and cause of white matter involvement in the brain [15,16,17]. In general, white matter involvement in LDs is bilateral and symmetric [146]. Characteristic MRI patterns are known for some LDs, which may contribute to the correct diagnosis [15]. For example, MLD patients show a distinct pattern of demyelination, which is also called the “stripe sign” or the “leopard skin sign” with stripes and patches [147]. There is also a common MRI pattern in X-ALD patients with symmetrical involvement of the parieto-occipital or frontal white matter and the adjacent part of the corpus callosum [146].
As we analyzed cerebral MRI within +/− 1.5 years before or after the reported onset of neuro-ophthalmologic symptoms, most MRIs revealed abnormal findings of the visual tract in the HLC. Most commonly, bilateral demyelination of the occipital white matter was found, whereas abnormalities of the optic nerves were second most common.
Eight patients showed optic nerve kinking on MRI, which, to our knowledge, has not been previously described in leukodystrophies. These patients suffer from CD, KD, PMD, X-ALD, 4H syndrome, and Col4a1. In the literature, optic nerve kinking has for example been reported in optic nerve gliomas, neurofibromatosis 1 [148,149], and aneurysms [150]. Seiff et al. cited the high water content in myxomatous tissue as a possible explanation for kink formation [151]. The pathophysiology of optic nerve kinking in LDs has yet be solved and may be the focus of future MRI studies. The small number of patients with an MRI analysis may affect the generalizability of the results. The selection criteria were independent of leukodystrophy, gender, age of onset, and disease severity. We therefore assume that this group represents our cohort well.
However, this study has limitations given the relatively small sample size of the individual leukodystrophies. In addition, data collection was only retrospective, and the length and intervals of the follow-up periods varies considerably. Reports of neuro-ophthalmologic and other clinical symptoms were part of the clinical examinations and not performed on a systematic prospective basis. Currently, for most leukodystrophies, there is no curative treatment available. As palliative care is the main treatment for most patients, complete and regular assessments with MRI, VEP, OCT and ophthalmologic examinations are not done as part of routine clinical care given the health system costs and patient burden. Systematic prospective studies within a research setting would allow a deeper understanding of NOS in leukodystrophies and may allow more targeted development of treatments.
Further follow-up studies should investigate the occurrence of neuro-ophthalmologic symptoms and the possible improvement of existing symptoms over a longer period of time with or without therapy. This is of interest as the evaluation of individual therapies is still discussed and the development of new treatment approaches is ongoing.
It must be taken into account that the disease stage of LD is important for the pathology of the optical tract, particularly in the case of demyelinating LD. The results therefore represent a longitudinal section of the course of the disease after diagnosis and should not be used as absolute frequencies of occurrence in the corresponding diseases. The collection of these data in the respective final stage of the diseases would therefore be expected to be associated with considerably higher figures.

5. Conclusions

Leukodystrophies remain one of the most devastating inherited neurological disorders in children and young adults. Our results demonstrate the importance of ophthalmic assessments as neuro-ophthalmologic symptoms are common in leukodystrophies and contribute to the burden of disease. An MRI scan of the brain is an appropriate tool to reveal pathologic alterations in the visual tract that are temporally correlated with symptoms. The first OCT findings in Krabbe and 4H syndrome patients demonstrate retinal findings. Further research needs to evaluate occurrence of retinal involvement in leukodystrophies.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/jcm13175114/s1, Table S1: Optic atrophy in the literature cohort.

Author Contributions

A.E.B., J.D. and C.M.B. designed the study. C.M.B. performed data extraction and chart analysis. G.S. performed statistical analyses. C.M.B., A.E.B., S.L.M. and P.G. wrote the manuscript. C.M.B., A.E.B. and H.G. evaluated MRI findings. S.D. and Y.A. performed ophthalmological assessments in some patients and reviewed ophthalmological examination in charts. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the support of the non-profit association Freundeskreis UKE für Kinder mit Demenz e.V. (https://fk-kindermitdemenz.de) accessed on 15 January 2022.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Medical Association of Hamburg, Germany for studies involving humans (PV3782, approved on 7 November 2011 and 4 September 2020). Informed consent was obtained from all living subjects involved in the study.

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study. Patient consent was waived if patients were deceased.

Data Availability Statement

The data presented in this study are not available in a more detailed form due to data protection reasons.

Acknowledgments

We want to thank all patients and their families who support our leukodystrophy studies. We thank Alfried Kohlschütter who established the leukodystrophy clinic at Kinder-UKE.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Raymond, G.V. Leukodystrophy: Basic and Clinical. In Neurodegenerative Diseases: Pathology, Mechanisms, and Potential Therapeutic Targets; Beart, P., Robinson, M., Rattray, M., Maragakis, N.J., Eds.; Springer International Publishing: Cham, Switzerland, 2017; pp. 365–382. [Google Scholar] [CrossRef]
  2. van der Knaap, M.S.; Bugiani, M. Leukodystrophies: A proposed classification system based on pathological changes and pathogenetic mechanisms. Acta Neuropathol. 2017, 134, 351–382. [Google Scholar] [CrossRef] [PubMed]
  3. Kevelam, S.H.; Steenweg, M.E.; Srivastava, S.; Helman, G.; Naidu, S.; Schiffmann, R.; Blaser, S.; Vanderver, A.; Wolf, N.I.; van der Knaap, M.S. Update on Leukodystrophies: A Historical Perspective and Adapted Definition. Neuropediatrics 2016, 47, 349–354. [Google Scholar] [CrossRef] [PubMed]
  4. Bugiani, M.; van der Knaap, M.S. Childhood white matter disorders: Much more than just diseases of myelin. Acta Neuropathologica 2017, 134, 329–330. [Google Scholar] [CrossRef] [PubMed]
  5. Vanderver, A.; Prust, M.; Tonduti, D.; Mochel, F.; Hussey, H.M.; Helman, G.; Garbern, J.; Eichler, F.; Labauge, P.; Aubourg, P.; et al. Case definition and classification of leukodystrophies and leukoencephalopathies. Mol. Genet. Metab. 2015, 114, 494–500. [Google Scholar] [CrossRef]
  6. Kohlschütter, A.; Eichler, F. Childhood leukodystrophies: A clinical perspective. Expert. Rev. Neurother. 2011, 11, 1485–1496. [Google Scholar] [CrossRef]
  7. Costello, D.J.; Eichler, A.F.; Eichler, F.S. Leukodystrophies: Classification, diagnosis, and treatment. Neurologist 2009, 15, 319–328. [Google Scholar] [CrossRef]
  8. Torii, T.; Yamauchi, J. Molecular Pathogenic Mechanisms of Hypomyelinating Leukodystrophies (HLDs). Neurol. Int. 2023, 15, 1155–1173. [Google Scholar] [CrossRef]
  9. Wolf, N.I.; Ffrench-Constant, C.; van der Knaap, M.S. Hypomyelinating leukodystrophies—Unravelling myelin biology. Nat. Rev. Neurol. 2021, 17, 88–103. [Google Scholar] [CrossRef]
  10. Köhler, W.; Curiel, J.; Vanderver, A. Adulthood leukodystrophies. Nat. Rev. Neurol. 2018, 14, 94–105. [Google Scholar] [CrossRef]
  11. van Rappard, D.F.; Boelens, J.J.; Wolf, N.I. Metachromatic leukodystrophy: Disease spectrum and approaches for treatment. Best. Pract. Res. Clin. Endocrinol. Metab. 2015, 29, 261–273. [Google Scholar] [CrossRef]
  12. Patil, S.A.; Maegawa, G.H. Developing therapeutic approaches for metachromatic leukodystrophy. Drug Des. Devel. Ther. 2013, 7, 729–745. [Google Scholar] [CrossRef] [PubMed]
  13. Parikh, S.; Bernard, G.; Leventer, R.J.; van der Knaap, M.S.; van Hove, J.; Pizzino, A.; McNeill, N.H.; Helman, G.; Simons, C.; Schmidt, J.L.; et al. A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies. Mol. Genet. Metab. 2015, 114, 501–515. [Google Scholar] [CrossRef]
  14. Ashrafi, M.R.; Tavasoli, A.R. Childhood leukodystrophies: A literature review of updates on new definitions, classification, diagnostic approach and management. Brain Dev. 2017, 39, 369–385. [Google Scholar] [CrossRef]
  15. Ashrafi, M.R.; Amanat, M.; Garshasbi, M.; Kameli, R.; Nilipour, Y.; Heidari, M.; Rezaei, Z.; Tavasoli, A.R. An update on clinical, pathological, diagnostic, and therapeutic perspectives of childhood leukodystrophies. Expert. Rev. Neurother. 2020, 20, 65–84. [Google Scholar] [CrossRef] [PubMed]
  16. Davidsdottir, S.; Cronin-Golomb, A.; Lee, A. Visual and spatial symptoms in Parkinson’s disease. Vision. Res. 2005, 45, 1285–1296. [Google Scholar] [CrossRef] [PubMed]
  17. Jasse, L.; Vukusic, S.; Durand-Dubief, F.; Vartin, C.; Piras, C.; Bernard, M.; Pélisson, D.; Confavreux, C.; Vighetto, A.; Tilikete, C. Persistent visual impairment in multiple sclerosis: Prevalence, mechanisms and resulting disability. Mult. Scler. 2013, 19, 1618–1626. [Google Scholar] [CrossRef] [PubMed]
  18. Urwyler, P.; Nef, T.; Killen, A.; Collerton, D.; Thomas, A.; Burn, D.; McKeith, I.; Mosimann, U.P. Visual complaints and visual hallucinations in Parkinson’s disease. Park. Relat. Disord. 2014, 20, 318–322. [Google Scholar] [CrossRef]
  19. Bowen, M.; Edgar, D.F.; Hancock, B.; Haque, S.; Shah, R.; Buchanan, S.; Iliffe, S.; Maskell, S.; Pickett, J.; Taylor, J.P.; et al. Health Services and Delivery Research. In The Prevalence of Visual Impairment in People with Dementia (the PrOVIDe Study): A Cross-Sectional Study of People Aged 60–89 Years with Dementia and Qualitative Exploration of Individual, Carer and Professional Perspectives; NIHR Journals Library: Southampton, UK, 2016. [Google Scholar]
  20. Kohlschütter, A.; Bley, A.; Brockmann, K.; Gärtner, J.; Krägeloh-Mann, I.; Rolfs, A.; Schöls, L. Leukodystrophies and other genetic metabolic leukoencephalopathies in children and adults. Brain Dev. 2010, 32, 82–89. [Google Scholar] [CrossRef]
  21. Vaphiades, M.S.; Brodsky, M.C. Pediatric optic atrophy. Int. Ophthalmol. Clin. 2012, 52, 17–28. [Google Scholar] [CrossRef]
  22. Mehra, D.; Moshirfar, M. Neuroanatomy, Optic Tract. In StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2021. [Google Scholar]
  23. Odom, J.V.; Bach, M.; Brigell, M.; Holder, G.E.; McCulloch, D.L.; Mizota, A.; Tormene, A.P.; International Society for Clinical Electrophysiology of Vision. ISCEV standard for clinical visual evoked potentials: (2016 update). Doc. Ophthalmol. 2016, 133, 1–9. [Google Scholar] [CrossRef]
  24. Ji, H.; Li, D.; Wu, Y.; Zhang, Q.; Gu, Q.; Xie, H.; Ji, T.; Wang, H.; Zhao, L.; Zhao, H.; et al. Hypomyelinating disorders in China: The clinical and genetic heterogeneity in 119 patients. PLoS ONE 2018, 13, e0188869. [Google Scholar] [CrossRef]
  25. Srivastava, S.; Butala, A.; Mahida, S.; Richter, J.; Mu, W.; Poretti, A.; Vernon, H.; VanGerpen, J.; Atwal, P.S.; Middlebrooks, E.H.; et al. Expansion of the clinical spectrum associated with AARS2-related disorders. Am. J. Med. Genet. A 2019, 179, 1556–1564. [Google Scholar] [CrossRef] [PubMed]
  26. Goebel, H.H.; Busch-Hettwer, H.; Bohl, J. Ultrastructural study of the retina in late infantile metachromatic leukodystrophy. Ophthalmic Res. 1992, 24, 103–109. [Google Scholar] [CrossRef]
  27. Johal, J.; Castro Apolo, R.; Johnson, M.W.; Persch, M.R.; Edwards, A.; Varade, P.; Yacoub, H. Adult polyglucosan body disease: An acute presentation leading to unmasking of this rare disorder. Hosp. Pract. 2022, 50, 244–250. [Google Scholar] [CrossRef]
  28. Ishihara, K.; Horibe, Y.; Ohno, H.; Sugie, M.; Shiota, J.; Nakano, I.; Kawamura, M. A clinicopathological study of young-onset dementia: Report of 2 autopsied cases. Brain Nerve 2011, 63, 1117–1123. [Google Scholar]
  29. Giroud, M.; Gouyon, J.B.; Chaumet, F.; Cinquin, A.M.; Chevalier-Nivelon, A.; Alison, M.; Dumas, R. A case of progressive familial encephalopathy in infancy with calcification of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Childs Nerv. Syst. 1986, 2, 47–48. [Google Scholar] [CrossRef]
  30. Viguera-Elías, D.; de la Iglesia-Nagore, I.; Toledo-Gotor, C.; Domínguez-Garrido, E.; Poch-Olivé, M.L. Aicardi-Goutieres syndrome: A family case due to alteration of the RNASEH2B gene. Rev. Neurol. 2021, 72, 407–409. [Google Scholar] [CrossRef] [PubMed]
  31. Nishri, D.; Edvardson, S.; Lev, D.; Leshinsky-Silver, E.; Ben-Sira, L.; Henneke, M.; Lerman-Sagie, T.; Blumkin, L. Diagnosis by whole exome sequencing of atypical infantile onset Alexander disease masquerading as a mitochondrial disorder. Eur. J. Paediatr. Neurol. 2014, 18, 495–501. [Google Scholar] [CrossRef] [PubMed]
  32. Pfeffer, G.; Abegg, M.; Vertinsky, A.T.; Ceccherini, I.; Caroli, F.; Barton, J.J. The ocular motor features of adult-onset alexander disease: A case and review of the literature. J. Neuroophthalmol. 2011, 31, 155–159. [Google Scholar] [CrossRef]
  33. Namekawa, M.; Takiyama, Y.; Honda, J.; Shimazaki, H.; Sakoe, K.; Nakano, I. Adult-onset Alexander disease with typical “tadpole” brainstem atrophy and unusual bilateral basal ganglia involvement: A case report and review of the literature. BMC Neurol. 2010, 10, 21. [Google Scholar] [CrossRef] [PubMed]
  34. Martidis, A.; Yee, R.D.; Azzarelli, B.; Biller, J. Neuro-ophthalmic, radiographic, and pathologic manifestations of adult-onset Alexander disease. Arch. Ophthalmol. 1999, 117, 265–267. [Google Scholar] [CrossRef]
  35. Nikam, R.M.; Gripp, K.W.; Choudhary, A.K.; Kandula, V. Imaging phenotype of multiple mitochondrial dysfunction syndrome 2, a rare BOLA3-associated leukodystrophy. Am. J. Med. Genet. A 2018, 176, 2787–2790. [Google Scholar] [CrossRef] [PubMed]
  36. Edvardson, S.; Kose, S.; Jalas, C.; Fattal-Valevski, A.; Watanabe, A.; Ogawa, Y.; Mamada, H.; Fedick, A.M.; Ben-Shachar, S.; Treff, N.R.; et al. Leukoencephalopathy and early death associated with an Ashkenazi-Jewish founder mutation in the Hikeshi gene. J. Med. Genet. 2016, 53, 132–137. [Google Scholar] [CrossRef]
  37. Pretegiani, E.; Rosini, F.; Dotti, M.T.; Bianchi, S.; Federico, A.; Rufa, A. Visual system involvement in CADASIL. J. Stroke Cerebrovasc. Dis. 2013, 22, 1377–1384. [Google Scholar] [CrossRef]
  38. Gowda, V.K.; Bhat, M.D.; Srinivasan, V.M.; Prasad, C.; Benakappa, A.; Faruq, M. A case of Canavan disease with microcephaly. Brain Dev. 2016, 38, 759–762. [Google Scholar] [CrossRef] [PubMed]
  39. Drenckhahn, A.; Schuelke, M.; Knierim, E. Leukodystrophy with multiple beaded periventricular cysts: Unusual cranial MRI results in Canavan disease. J. Inherit. Metab. Dis. 2015, 38, 983–984. [Google Scholar] [CrossRef] [PubMed]
  40. Gowda, V.K.; Bharathi, N.K.; Bettaiah, J.; Bhat, M.; Shivappa, S.K. Canavan Disease: Clinical and Laboratory Profile from Southern Part of India. Ann. Indian. Acad. Neurol. 2021, 24, 347–350. [Google Scholar] [CrossRef] [PubMed]
  41. Karimzadeh, P.; Jafari, N.; Nejad Biglari, H.; Rahimian, E.; Ahmadabadi, F.; Nemati, H.; Nasehi, M.M.; Ghofrani, M.; Mollamohammadi, M. The Clinical Features and Diagnosis of Canavan’s Disease: A Case Series of Iranian Patients. Iran. J. Child. Neurol. 2014, 8, 66–71. [Google Scholar]
  42. Guo, Z.; Lu, T.; Peng, L.; Cheng, H.; Peng, F.; Li, J.; Lu, Z.; Chen, S.; Qiu, W. CLCN2-related leukoencephalopathy: A case report and review of the literature. BMC Neurol. 2019, 19, 156. [Google Scholar] [CrossRef]
  43. Riedhammer, K.M.; Stockler, S.; Ploski, R.; Wenzel, M.; Adis-Dutschmann, B.; Ahting, U.; Alhaddad, B.; Blaschek, A.; Haack, T.B.; Kopajtich, R.; et al. De novo stop-loss variants in CLDN11 cause hypomyelinating leukodystrophy. Brain 2021, 144, 411–419. [Google Scholar] [CrossRef] [PubMed]
  44. Orcesi, S.; La Piana, R.; Uggetti, C.; Tonduti, D.; Pichiecchio, A.; Pasin, M.; Viselner, G.; Comi, G.P.; Del Bo, R.; Ronchi, D.; et al. Spinal cord calcification in an early-onset progressive leukoencephalopathy. J. Child. Neurol. 2011, 26, 876–880. [Google Scholar] [CrossRef] [PubMed]
  45. Pant, D.C.; Dorboz, I.; Schluter, A.; Fourcade, S.; Launay, N.; Joya, J.; Aguilera-Albesa, S.; Yoldi, M.E.; Casasnovas, C.; Willis, M.J.; et al. Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy. J. Clin. Invest. 2019, 129, 1240–1256. [Google Scholar] [CrossRef]
  46. Fiumara, A.; Barone, R.; Arena, A.; Filocamo, M.; Lissens, W.; Pavone, L.; Sorge, G. Krabbe leukodystrophy in a selected population with high rate of late onset forms: Longer survival linked to c.121G>A (p.Gly41Ser) mutation. Clin. Genet. 2011, 80, 452–458. [Google Scholar] [CrossRef] [PubMed]
  47. Harbord, M.G.; Finn, J.P.; Hall-Craggs, M.A.; Brett, E.M.; Baraitser, M. Early onset leukodystrophy with distinct facial features in 2 siblings. Neuropediatrics 1989, 20, 154–157. [Google Scholar] [CrossRef]
  48. Calame, D.G.; Hainlen, M.; Takacs, D.; Ferrante, L.; Pence, K.; Emrick, L.T.; Chao, H.T. EIF2AK2-related Neurodevelopmental Disorder With Leukoencephalopathy, Developmental Delay, and Episodic Neurologic Regression Mimics Pelizaeus-Merzbacher Disease. Neurol. Genet. 2021, 7, e539. [Google Scholar] [CrossRef] [PubMed]
  49. Uhlenberg, B.; Schuelke, M.; Rüschendorf, F.; Ruf, N.; Kaindl, A.M.; Henneke, M.; Thiele, H.; Stoltenburg-Didinger, G.; Aksu, F.; Topaloğlu, H.; et al. Mutations in the gene encoding gap junction protein alpha 12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease. Am. J. Hum. Genet. 2004, 75, 251–260. [Google Scholar] [CrossRef] [PubMed]
  50. Bugiani, M.; Al Shahwan, S.; Lamantea, E.; Bizzi, A.; Bakhsh, E.; Moroni, I.; Balestrini, M.R.; Uziel, G.; Zeviani, M. GJA12 mutations in children with recessive hypomyelinating leukoencephalopathy. Neurology 2006, 67, 273–279. [Google Scholar] [CrossRef] [PubMed]
  51. Owczarek-Lipska, M.; Mulahasanovic, L.; Obermaier, C.D.; Hörtnagel, K.; Neubauer, B.A.; Korenke, G.C.; Biskup, S.; Neidhardt, J. Novel mutations in the GJC2 gene associated with Pelizaeus-Merzbacher-like disease. Mol. Biol. Rep. 2019, 46, 4507–4516. [Google Scholar] [CrossRef]
  52. Kammoun Jellouli, N.; Salem, I.H.; Ellouz, E.; Louhichi, N.; Tlili, A.; Kammoun, F.; Triki, C.; Fakhfakh, F. Molecular confirmation of founder mutation c.-167A>G in Tunisian patients with PMLD disease. Gene 2013, 513, 233–238. [Google Scholar] [CrossRef]
  53. Yalcinkaya, C.; Erturk, O.; Tuysuz, B.; Yesil, G.; Verbeke, J.I.; Keyser, B.; Stuhrmann, M.; Steinemann, D.; Sistermans, E.A.; van der Knaap, M.S. A novel GJC2 mutation associated with hypomyelination and Müllerian agenesis syndrome: Coincidence or a new entity? Neuropediatrics 2012, 43, 159–161. [Google Scholar] [CrossRef]
  54. Mercimek-Mahmutoglu, S.; van der Knaap, M.S.; Baric, I.; Prayer, D.; Stoeckler-Ipsiroglu, S. Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). Report of a new case. Neuropediatrics 2005, 36, 223–226. [Google Scholar] [CrossRef] [PubMed]
  55. Miyake, N.; Wolf, N.I.; Cayami, F.K.; Crawford, J.; Bley, A.; Bulas, D.; Conant, A.; Bent, S.J.; Gripp, K.W.; Hahn, A.; et al. X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1. Neurogenetics 2017, 18, 185–194. [Google Scholar] [CrossRef] [PubMed]
  56. Helman, G.; Zerem, A.; Almad, A.; Hacker, J.L.; Woidill, S.; Sase, S.; LeFevre, A.N.; Ekstein, J.; Johansson, M.M.; Stutterd, C.A.; et al. Further Delineation of the Clinical and Pathologic Features of HIKESHI-Related Hypomyelinating Leukodystrophy. Pediatr. Neurol. 2021, 121, 11–19. [Google Scholar] [CrossRef] [PubMed]
  57. Otero-Dominguez, E.; Gomez-Lado, C.; Fuentes-Pita, P.; Dacruz, D.; Barros-Angueira, F.; Eiris-Punal, J. [Hypomyelinating leukodystrophy type 6. Clinical and neuroimaging key features in the detection of a new case]. Rev. Neurol. 2018, 67, 339–342. [Google Scholar] [PubMed]
  58. Numata, Y.; Gotoh, L.; Iwaki, A.; Kurosawa, K.; Takanashi, J.; Deguchi, K.; Yamamoto, T.; Osaka, H.; Inoue, K. Epidemiological, clinical, and genetic landscapes of hypomyelinating leukodystrophies. J. Neurol. 2014, 261, 752–758. [Google Scholar] [CrossRef]
  59. Bassani, R.; Pareyson, D.; D’Incerti, L.; Di Bella, D.; Taroni, F.; Salsano, E. Pendular nystagmus in hypomyelinating leukodystrophy. J. Clin. Neurosci. 2013, 20, 1443–1445. [Google Scholar] [CrossRef]
  60. Blumkin, L.; Lev, D.; Watemberg, N.; Lerman-Sagie, T. Hypomyelinating leukoencephalopathy with paroxysmal tonic upgaze and absence of psychomotor development. Mov. Disord. 2007, 22, 226–230. [Google Scholar] [CrossRef]
  61. Hamanaka, K.; Miyatake, S.; Zerem, A.; Lev, D.; Blumkin, L.; Yokochi, K.; Fujita, A.; Imagawa, E.; Iwama, K.; Nakashima, M.; et al. Expanding the phenotype of IBA57 mutations: Related leukodystrophy can remain asymptomatic. J. Hum. Genet. 2018, 63, 1223–1229. [Google Scholar] [CrossRef]
  62. Alfadhel, M.; Nashabat, M.; Alrifai, M.T.; Alshaalan, H.; Al Mutairi, F.; Al-Shahrani, S.A.; Plecko, B.; Almass, R.; Alsagob, M.; Almutairi, F.B.; et al. Further delineation of the phenotypic spectrum of ISCA2 defect: A report of ten new cases. Eur. J. Paediatr. Neurol. 2018, 22, 46–55. [Google Scholar] [CrossRef]
  63. Alaimo, J.T.; Besse, A.; Alston, C.L.; Pang, K.; Appadurai, V.; Samanta, M.; Smpokou, P.; McFarland, R.; Taylor, R.W.; Bonnen, P.E. Loss-of-function mutations in ISCA2 disrupt 4Fe-4S cluster machinery and cause a fatal leukodystrophy with hyperglycinemia and mtDNA depletion. Hum. Mutat. 2018, 39, 537–549. [Google Scholar] [CrossRef]
  64. Toldo, I.; Nosadini, M.; Boscardin, C.; Talenti, G.; Manara, R.; Lamantea, E.; Legati, A.; Ghezzi, D.; Perilongo, G.; Sartori, S. Neonatal mitochondrial leukoencephalopathy with brain and spinal involvement and high lactate: Expanding the phenotype of ISCA2 gene mutations. Metab. Brain Dis. 2018, 33, 805–812. [Google Scholar] [CrossRef] [PubMed]
  65. Itoh, M.; Dai, H.; Horike, S.I.; Gonzalez, J.; Kitami, Y.; Meguro-Horike, M.; Kuki, I.; Shimakawa, S.; Yoshinaga, H.; Ota, Y.; et al. Biallelic KARS pathogenic variants cause an early-onset progressive leukodystrophy. Brain 2019, 142, 560–573. [Google Scholar] [CrossRef] [PubMed]
  66. Ardissone, A.; Tonduti, D.; Legati, A.; Lamantea, E.; Barone, R.; Dorboz, I.; Boespflug-Tanguy, O.; Nebbia, G.; Maggioni, M.; Garavaglia, B.; et al. KARS-related diseases: Progressive leukoencephalopathy with brainstem and spinal cord calcifications as new phenotype and a review of literature. Orphanet J. Rare Dis. 2018, 13, 45. [Google Scholar] [CrossRef] [PubMed]
  67. Laxdal, T.; Hallgrimsson, J. Krabbe’s globoid cell leucodystrophy with hydrocephalus. Arch. Dis. Child. 1974, 49, 232–235. [Google Scholar] [CrossRef] [PubMed]
  68. Bascou, N.; DeRenzo, A.; Poe, M.D.; Escolar, M.L. A prospective natural history study of Krabbe disease in a patient cohort with onset between 6 months and 3 years of life. Orphanet J. Rare Dis. 2018, 13, 126. [Google Scholar] [CrossRef]
  69. Bussière, M.; Kotylak, T.; Naik, K.; Levin, S. Optic nerve enlargement associated with globoid cell leukodystrophy. Can. J. Neurol. Sci. 2006, 33, 235–236. [Google Scholar] [CrossRef]
  70. Roy, P.; Chidambaranathan, S.; Ramesh, S. Krabbe disease--a case report. J. Indian. Med. Assoc. 2005, 103, 548–550. [Google Scholar]
  71. Arvidsson, J.; Hagberg, B.; Månsson, J.E.; Svennerholm, L. Late onset globoid cell leukodystrophy (Krabbe’s disease)--Swedish case with 15 years of follow-up. Acta Paediatr. 1995, 84, 218–221. [Google Scholar] [CrossRef]
  72. Bascou, N.A.; Beltran-Quintero, M.L.; Escolar, M.L. Pathogenic Variants in GALC Gene Correlate With Late Onset Krabbe Disease and Vision Loss: Case Series and Review of Literature. Front. Neurol. 2020, 11, 563724. [Google Scholar] [CrossRef]
  73. Lossos, A.; Elazar, N.; Lerer, I.; Schueler-Furman, O.; Fellig, Y.; Glick, B.; Zimmerman, B.E.; Azulay, H.; Dotan, S.; Goldberg, S.; et al. Myelin-associated glycoprotein gene mutation causes Pelizaeus-Merzbacher disease-like disorder. Brain 2015, 138, 2521–2536. [Google Scholar] [CrossRef]
  74. Roda, R.H.; FitzGibbon, E.J.; Boucekkine, H.; Schindler, A.B.; Blackstone, C. Neurologic syndrome associated with homozygous mutation at MAG sialic acid binding site. Ann. Clin. Transl. Neurol. 2016, 3, 650–654. [Google Scholar] [CrossRef] [PubMed]
  75. Scmidt-Sidor, B.; Szymańska, K.; Lewandowska, E.; Mierzewska, H.; Wierzba-Bobrowicz, T.; Pasennik, E.; Stepień, T. Infantile mitochondrial leucodystrophy—A case report. Folia Neuropathol. 2005, 43, 186–190. [Google Scholar] [PubMed]
  76. Shian, W.J.; Chi, C.C.; Mak, S.C.; Tzeng, G.Y. Late infantile form metachromatic leukodystrophy: Report of one case. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi 1992, 33, 286–293. [Google Scholar]
  77. Beerepoot, S.; Wolf, N.I.; Wehner, K.; Bender, B.; van der Knaap, M.S.; Krägeloh-Mann, I.; Groeschel, S. Acute-onset paralytic strabismus in toddlers is important to consider as a potential early sign of late-infantile Metachromatic Leukodystrophy. Eur. J. Paediatr. Neurol. 2022, 37, 87–93. [Google Scholar] [CrossRef] [PubMed]
  78. Kori, A.A.; Robin, N.H.; Jacobs, J.B.; Erchul, D.M.; Zaidat, O.O.; Remler, B.F.; Averbuch-Heller, L.; Dell’Osso, L.F.; Leigh, R.J.; Zinn, A.B. Pendular nystagmus in patients with peroxisomal assembly disorder. Arch. Neurol. 1998, 55, 554–558. [Google Scholar] [CrossRef] [PubMed]
  79. Hosseini Bereshneh, A.; Hosseipour, S.; Rasoulinezhad, M.S.; Pak, N.; Garshasbi, M.; Tavasoli, A.R. Expanding the clinical and neuroimaging features of NKX6-2-related hereditary spastic ataxia type 8. Eur. J. Med. Genet. 2020, 63, 103868. [Google Scholar] [CrossRef]
  80. Dorboz, I.; Aiello, C.; Simons, C.; Stone, R.T.; Niceta, M.; Elmaleh, M.; Abuawad, M.; Doummar, D.; Bruselles, A.; Wolf, N.I.; et al. Biallelic mutations in the homeodomain of NKX6-2 underlie a severe hypomyelinating leukodystrophy. Brain 2017, 140, 2550–2556. [Google Scholar] [CrossRef]
  81. Chelban, V.; Alsagob, M.; Kloth, K.; Chirita-Emandi, A.; Vandrovcova, J.; Maroofian, R.; Davagnanam, I.; Bakhtiari, S.; AlSayed, M.D.; Rahbeeni, Z.; et al. Genetic and phenotypic characterization of NKX6-2-related spastic ataxia and hypomyelination. Eur. J. Neurol. 2020, 27, 334–342. [Google Scholar] [CrossRef]
  82. Fu, H.; Wang, Q.; Liu, H. Novel Mutations in NPC1 are Associated with Pelizaeus-Merzbacher-Like Disease: A Case Report. Int. J. Gen. Med. 2021, 14, 797–803. [Google Scholar] [CrossRef]
  83. Bae, E.Y.; Yi, Y.; Lim, H.H.; Lee, J.M.; Lee, B.; Kim, S.Y.; Kim, Y.M. First Case of Peroxisomal D-bifunctional Protein Deficiency with Novel HSD17B4 Mutations and Progressive Neuropathy in Korea. J. Korean Med. Sci. 2020, 35, e357. [Google Scholar] [CrossRef]
  84. Poll-The, B.T.; Gootjes, J.; Duran, M.; De Klerk, J.B.; Wenniger-Prick, L.J.; Admiraal, R.J.; Waterham, H.R.; Wanders, R.J.; Barth, P.G. Peroxisome biogenesis disorders with prolonged survival: Phenotypic expression in a cohort of 31 patients. Am. J. Med. Genet. A 2004, 126, 333–338. [Google Scholar] [CrossRef]
  85. Wang, C.; Li, J. Subacute onset leukodystrophy and visual-spatial disorders revealing phenylketonuria combined with homocysteinmia in adulthood: A case report. Medicine 2018, 97, e9801. [Google Scholar] [CrossRef] [PubMed]
  86. Liu, Y.H.; Zhang, H.F.; Jin, J.Y.; Wei, Y.Q.; Wang, C.Y.; Fan, L.L.; Liu, L. Case Report: A Homozygous Mutation (p.Y62X) of Phospholipase D3 May Lead to a New Leukoencephalopathy Syndrome. Front. Aging Neurosci. 2021, 13, 671296. [Google Scholar] [CrossRef] [PubMed]
  87. Nicita, F.; Aiello, C.; Vasco, G.; Valeriani, M.; Stregapede, F.; Sancesario, A.; Armando, M.; Bertini, E. Expanding the Clinical and Mutational Spectrum of the PLP1-Related Hypomyelination of Early Myelinated Structures (HEMS). Brain Sci. 2021, 11, 93. [Google Scholar] [CrossRef]
  88. Velasco Parra, H.M.; Maradei Anaya, S.J.; Acosta Guio, J.C.; Arteaga Diaz, C.E.; Prieto Rivera, J.C. Clinical and mutational spectrum of Colombian patients with Pelizaeus Merzbacher Disease. Colomb. Med. 2018, 49, 182–187. [Google Scholar] [CrossRef]
  89. Najafi, K.; Kariminejad, R.; Hosseini, K.; Moshtagh, A.; Abbassi, G.M.; Sadatian, N.; Bazrgar, M.; Kariminejad, A.; Kariminejad, M.H. Familial Case of Pelizaeus-Merzbacher Disorder Detected by Oligoarray Comparative Genomic Hybridization: Genotype-to-Phenotype Diagnosis. Case Rep. Genet. 2017, 2017, 2706098. [Google Scholar] [CrossRef]
  90. Chen, Y.C.; Liang, W.C.; Su, Y.N.; Jong, Y.J. Pelizaeus-Merzbacher disease, easily misdiagnosed as cerebral palsy: A report of a three-generation family. Pediatr. Neonatol. 2014, 55, 150–153. [Google Scholar] [CrossRef]
  91. Shimojima, K.; Mano, T.; Kashiwagi, M.; Tanabe, T.; Sugawara, M.; Okamoto, N.; Arai, H.; Yamamoto, T. Pelizaeus-Merzbacher disease caused by a duplication-inverted triplication-duplication in chromosomal segments including the PLP1 region. Eur. J. Med. Genet. 2012, 55, 400–403. [Google Scholar] [CrossRef] [PubMed]
  92. Kim, S.J.; Yoon, J.S.; Baek, H.J.; Suh, S.I.; Bae, S.Y.; Cho, H.J.; Ki, C.S. Identification of proteolipid protein 1 gene duplication by multiplex ligation-dependent probe amplification: First report of genetically confirmed family of Pelizaeus-Merzbacher disease in Korea. J. Korean Med. Sci. 2008, 23, 328–331. [Google Scholar] [CrossRef]
  93. Nezu, A. Neurophysiological study in Pelizaeus-Merzbacher disease. Brain Dev. 1995, 17, 175–181. [Google Scholar] [CrossRef]
  94. Gao, Z.J.; Jiang, Q.; Chen, Q.; Xu, K.M.; Liu, Z.Q.; Chen, X.B.; Chen, X.L. Clinical manifestation and gene analyses of 15 patients with intellectual disability or developmental delay complicated with congenital nystagmus. Zhonghua Er Ke Za Zhi 2017, 55, 824–829. [Google Scholar] [CrossRef] [PubMed]
  95. Tewari, V.V.; Mehta, R.; Sreedhar, C.M.; Tewari, K.; Mohammad, A.; Gupta, N.; Gulati, S.; Kabra, M. A novel homozygous mutation in POLR3A gene causing 4H syndrome: A case report. BMC Pediatr. 2018, 18, 126. [Google Scholar] [CrossRef] [PubMed]
  96. Uygun, Ö.; Gündüz, T.; Eraksoy, M.; Kürtüncü, M. Adult-onset 4H leukodystrophy: A case presentation and review of the literature. Acta Neurol. Belg. 2020, 120, 1461–1462. [Google Scholar] [CrossRef]
  97. Rezaei, Z.; Hosseinpour, S.; Ashrafi, M.R.; Mahdieh, N.; Alizadeh, H.; Mohammadpour, M.; Khosroshahi, N.; Amanat, M.; Tavasoli, A.R. Hypomyelinating Leukodystrophy with Spinal Cord Involvement Caused by a Novel Variant in RARS: Report of Two Unrelated Patients. Neuropediatrics 2019, 50, 130–134. [Google Scholar] [CrossRef] [PubMed]
  98. Mendes, M.I.; Green, L.M.C.; Bertini, E.; Tonduti, D.; Aiello, C.; Smith, D.; Salsano, E.; Beerepoot, S.; Hertecant, J.; von Spiczak, S.; et al. RARS1-related hypomyelinating leukodystrophy: Expanding the spectrum. Ann. Clin. Transl. Neurol. 2020, 7, 83–93. [Google Scholar] [CrossRef] [PubMed]
  99. Acharya, B.S.; Ritwik, P.; Velasquez, G.M.; Fenton, S.J. Medical-dental findings and management of a child with infantile Refsum disease: A case report. Spec. Care Dentist. 2012, 32, 112–117. [Google Scholar] [CrossRef]
  100. Llaci, L.; Ramsey, K.; Belnap, N.; Claasen, A.M.; Balak, C.D.; Szelinger, S.; Jepsen, W.M.; Siniard, A.L.; Richholt, R.; Izat, T.; et al. Compound heterozygous mutations in SNAP29 is associated with Pelizaeus-Merzbacher-like disorder (PMLD). Hum. Genet. 2019, 138, 1409–1417. [Google Scholar] [CrossRef]
  101. Simons, C.; Dyment, D.; Bent, S.J.; Crawford, J.; D’Hooghe, M.; Kohlschütter, A.; Venkateswaran, S.; Helman, G.; Poll-The, B.T.; Makowski, C.C.; et al. A recurrent de novo mutation in TMEM106B causes hypomyelinating leukodystrophy. Brain 2017, 140, 3105–3111. [Google Scholar] [CrossRef]
  102. Ikemoto, S.; Hamano, S.I.; Kikuchi, K.; Koichihara, R.; Hirata, Y.; Matsuura, R.; Hiraide, T.; Nakashima, M.; Inoue, K.; Kurosawa, K.; et al. A recurrent TMEM106B mutation in hypomyelinating leukodystrophy: A rapid diagnostic assay. Brain Dev. 2020, 42, 603–606. [Google Scholar] [CrossRef]
  103. Yan, H.; Kubisiak, T.; Ji, H.; Xiao, J.; Wang, J.; Burmeister, M. The recurrent mutation in TMEM106B also causes hypomyelinating leukodystrophy in China and is a CpG hotspot. Brain 2018, 141, e36. [Google Scholar] [CrossRef]
  104. Yan, H.; Helman, G.; Murthy, S.E.; Ji, H.; Crawford, J.; Kubisiak, T.; Bent, S.J.; Xiao, J.; Taft, R.J.; Coombs, A.; et al. Heterozygous Variants in the Mechanosensitive Ion Channel TMEM63A Result in Transient Hypomyelination during Infancy. Am. J. Hum. Genet. 2019, 105, 996–1004. [Google Scholar] [CrossRef]
  105. Stam, A.H.; Kothari, P.H.; Shaikh, A.; Gschwendter, A.; Jen, J.C.; Hodgkinson, S.; Hardy, T.A.; Hayes, M.; Kempster, P.A.; Kotschet, K.E.; et al. Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations. Brain 2016, 139, 2909–2922. [Google Scholar] [CrossRef] [PubMed]
  106. Purnell, S.M.; Bleyl, S.B.; Bonkowsky, J.L. Clinical exome sequencing identifies a novel TUBB4A mutation in a child with static hypomyelinating leukodystrophy. Pediatr. Neurol. 2014, 50, 608–611. [Google Scholar] [CrossRef] [PubMed]
  107. Joyal, K.M.; Michaud, J.; van der Knaap, M.S.; Bugiani, M.; Venkateswaran, S. Severe TUBB4A-Related Hypomyelination With Atrophy of the Basal Ganglia and Cerebellum: Novel Neuropathological Findings. J. Neuropathol. Exp. Neurol. 2019, 78, 3–9. [Google Scholar] [CrossRef] [PubMed]
  108. Barros, S.R.; Parreira, S.C.R.; Miranda, A.F.B.; Pereira, A.M.B.; Campos, N.M.P. New Insights in Vanishing White Matter Disease: Isolated Bilateral Optic Neuropathy in Adult Onset Disease. J. Neuroophthalmol. 2018, 38, 42–46. [Google Scholar] [CrossRef] [PubMed]
  109. Khorrami, M.; Khorram, E.; Yaghini, O.; Rezaei, M.; Hejazifar, A.; Iravani, O.; Yazdani, V.; Riahinezhad, M.; Kheirollahi, M. Identification of a Missense Variant in the EIF2B3 Gene Causing Vanishing White Matter Disease with Antenatal-Onset but Mild Symptoms and Long-Term Survival. J. Mol. Neurosci. 2021, 71, 2405–2414. [Google Scholar] [CrossRef]
  110. Powers, J.M.; Schaumburg, H.H. Adreno-leukodystrophy (sex-linked Schilder’s disease). A pathogenetic hypothesis based on ultrastructural lesions in adrenal cortex, peripheral nerve and testis. Am. J. Pathol. 1974, 76, 481–491. [Google Scholar]
  111. Battaglia, A.; Harden, A.; Pampiglione, G.; Walsh, P.J. Adrenoleucodystrophy: Neurophysiological aspects. J. Neurol. Neurosurg. Psychiatry 1981, 44, 781–785. [Google Scholar] [CrossRef]
  112. Zgorzalewicz-Stachowiak, M.; Stradomska, T.J.; Bartkowiak, Z.; Galas-Zgorzalewicz, B. Cerebral childhood and adolescent X-linked adrenoleukodystrophy. Clinical presentation, neurophysiological, neuroimaging and biochemical investigations. Folia Neuropathol. 2006, 44, 319–326. [Google Scholar]
  113. Sakurai, K.; Ohashi, T.; Shimozawa, N.; Joo-Hyun, S.; Okuyama, T.; Ida, H. Characteristics of Japanese patients with X-linked adrenoleukodystrophy and concerns of their families from the 1st registry system. Brain Dev. 2019, 41, 50–56. [Google Scholar] [CrossRef]
  114. Iinuma, K.; Haginoya, K.; Handa, I.; Kojima, A.; Fueki, N.; Aikawa, J.; Ito, M.; Hatazawa, J.; Ido, T. Computed tomography, magnetic resonance imaging, positron emission tomography and evoked potentials at early stage of adrenoleukodystrophy. Tohoku J. Exp. Med. 1989, 159, 195–203. [Google Scholar] [CrossRef]
  115. Turón-Viñas, E.; Pineda, M.; Cusí, V.; López-Laso, E.; Del Pozo, R.L.; Gutiérrez-Solana, L.G.; Moreno, D.C.; Sierra-Córcoles, C.; Olabarrieta-Hoyos, N.; Madruga-Garrido, M.; et al. Vanishing white matter disease in a spanish population. J. Cent. Nerv. Syst. Dis. 2014, 6, 59–68. [Google Scholar] [CrossRef]
  116. Traboulsi, E.I.; Maumenee, I.H. Ophthalmologic manifestations of X-linked childhood adrenoleukodystrophy. Ophthalmology 1987, 94, 47–52. [Google Scholar] [CrossRef] [PubMed]
  117. Jang, Y.C.; Mun, B.R.; Choi, I.S.; Song, M.K. Rehabilitative management of an infant with Pelizaeus-Merzbacher disease: A case report. Medicine (Baltimore) 2020, 99, e20110. [Google Scholar] [CrossRef]
  118. Ueda, A.; Shimbo, H.; Yada, Y.; Koike, Y.; Yamagata, T.; Osaka, H. Pelizaeus-Merzbacher disease can be a differential diagnosis in males presenting with severe neonatal respiratory distress and hypotonia. Hum. Genome Var. 2018, 5, 18013. [Google Scholar] [CrossRef]
  119. Lu, Y.; Shimojima, K.; Sakuma, T.; Nakaoka, S.; Yamamoto, T. A novel PLP1 mutation F240L identified in a patient with connatal type Pelizaeus-Merzbacher disease. Hum. Genome Var. 2017, 4, 16044. [Google Scholar] [CrossRef] [PubMed]
  120. Masliah-Planchon, J.; Dupont, C.; Vartzelis, G.; Trimouille, A.; Eymard-Pierre, E.; Gay-Bellile, M.; Renaldo, F.; Dorboz, I.; Pagan, C.; Quentin, S.; et al. Insertion of an extra copy of Xq22.2 into 1p36 results in functional duplication of the PLP1 gene in a girl with classical Pelizaeus-Merzbacher disease. BMC Med. Genet. 2015, 16, 77. [Google Scholar] [CrossRef]
  121. Xie, H.; Feng, H.; Ji, J.; Wu, Y.; Kou, L.; Li, D.; Ji, H.; Wu, X.; Niu, Z.; Wang, J.; et al. Identification and functional study of novel PLP1 mutations in Chinese patients with Pelizaeus-Merzbacher disease. Brain Dev. 2015, 37, 797–802. [Google Scholar] [CrossRef]
  122. Shimojima, K.; Okumura, A.; Ikeno, M.; Nishimura, A.; Saito, A.; Saitsu, H.; Matsumoto, N.; Yamamoto, T. A de novo TUBB4A mutation in a patient with hypomyelination mimicking Pelizaeus-Merzbacher disease. Brain Dev. 2015, 37, 281–285. [Google Scholar] [CrossRef]
  123. Naseebullah; Siddiqui, M.; Saeed, S.; Chaudary, Y. A rare case of Palizaeus Merzbacher Disease in a female patient diagnosed radiologically. J. Pak. Med. Assoc. 2014, 64, 1313–1314. [Google Scholar] [PubMed]
  124. Karimzadeh, P.; Ahmadabadi, F.; Aryani, O.; Houshmand, M.; Khatami, A. New mutation of pelizaeus--merzbacher-like disease; a report from iran. Iran. J. Radiol. 2014, 11, e6913. [Google Scholar] [CrossRef]
  125. Rikitake, M.; Kaga, K. Development of speech and hearing of two children with Pelizaeus-Merzbacher disease presenting only waves I and II of the auditory brainstem response. Acta Otolaryngol. 2012, 132, 563–569. [Google Scholar] [CrossRef] [PubMed]
  126. Shimojima, K.; Inoue, T.; Hoshino, A.; Kakiuchi, S.; Watanabe, Y.; Sasaki, M.; Nishimura, A.; Takeshita-Yanagisawa, A.; Tajima, G.; Ozawa, H.; et al. Comprehensive genetic analyses of PLP1 in patients with Pelizaeus-Merzbacher disease applied by array-CGH and fiber-FISH analyses identified new mutations and variable sizes of duplications. Brain Dev. 2010, 32, 171–179. [Google Scholar] [CrossRef] [PubMed]
  127. Kibe, T.; Miyahara, J.; Yokochi, K.; Iwaki, A. A novel PLP mutation in a Japanese patient with mild Pelizaeus-Merzbacher disease. Brain Dev. 2009, 31, 248–251. [Google Scholar] [CrossRef] [PubMed]
  128. Wang, J.M.; Wu, Y.; Wang, H.F.; Deng, Y.H.; Yang, Y.L.; Qin, J.; Li, X.Y.; Wu, X.R.; Jiang, Y.W. Proteolipid protein 1 gene mutation in nine patients with Pelizaeus-Merzbacher disease. Chin. Med. J. 2008, 121, 1638–1642. [Google Scholar] [CrossRef]
  129. Wolf, N.I.; Cundall, M.; Rutland, P.; Rosser, E.; Surtees, R.; Benton, S.; Chong, W.K.; Malcolm, S.; Ebinger, F.; Bitner-Glindzicz, M.; et al. Frameshift mutation in GJA12 leading to nystagmus, spastic ataxia and CNS dys-/demyelination. Neurogenetics 2007, 8, 39–44. [Google Scholar] [CrossRef]
  130. Kaga, K.; Tamai, F.; Kodama, M.; Kodama, K. Three young adult patients with Pelizaeus-Merzbacher disease who showed only waves I and II in auditory brainstem responses but had good auditory perception. Acta Otolaryngol. 2005, 125, 1018–1023. [Google Scholar] [CrossRef]
  131. Golomb, M.R.; Walsh, L.E.; Carvalho, K.S.; Christensen, C.K.; DeMyer, W.E. Clinical findings in Pelizaeus-Merzbacher disease. J. Child. Neurol. 2004, 19, 328–331. [Google Scholar] [CrossRef]
  132. Hobson, G.M.; Davis, A.P.; Stowell, N.C.; Kolodny, E.H.; Sistermans, E.A.; de Coo, I.F.; Funanage, V.L.; Marks, H.G. Mutations in noncoding regions of the proteolipid protein gene in Pelizaeus-Merzbacher disease. Neurology 2000, 55, 1089–1096. [Google Scholar] [CrossRef]
  133. Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D.G.; The, P.G. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLOS Med. 2009, 6, e1000097. [Google Scholar] [CrossRef]
  134. Page, M.J.; McKenzie, J.E.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Akl, E.A.; Brennan, S.E.; et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. bmj 2021, 372. [Google Scholar]
  135. Leigh, R.J.; Zee, D.S. Eye movements of the blind. Invest. Ophthalmol. Vis. Sci. 1980, 19, 328–331. [Google Scholar] [PubMed]
  136. Brodsky, M.C.; Fray, K.J.; Glasier, C.M. Perinatal cortical and subcortical visual loss: Mechanisms of injury and associated ophthalmologic signs. Ophthalmology 2002, 109, 85–94. [Google Scholar] [CrossRef] [PubMed]
  137. Mallinson, A.I.; Longridge, N.S.; Dunn, H.G.; McCormick, A.Q. Vestibular studies in Pelizaeus-Merzbacher disease. J. Otolaryngol. 1983, 12, 361–364. [Google Scholar]
  138. Strupp, M.; Hüfner, K.; Sandmann, R.; Zwergal, A.; Dieterich, M.; Jahn, K.; Brandt, T. Central oculomotor disturbances and nystagmus: A window into the brainstem and cerebellum. Dtsch. Arztebl. Int. 2011, 108, 197–204. [Google Scholar] [CrossRef]
  139. Creel, D.J. Visually evoked potentials. Handb. Clin. Neurol. 2019, 160, 501–522. [Google Scholar] [CrossRef]
  140. Heinen, F.; Müller-Felber, W. Evozierte Potenziale im Kindesalter. In Evozierte Potenziale, Neurovegetative Diagnostik, Okulographie; Buchner, H., Ed.; Georg Thieme Verlag KG: Stuttgart, Germany, 2005. [Google Scholar]
  141. Magnetic Resonance of Myelination and Myelin Disorders, 3rd ed. AJNR Am. J. Neuroradiol. 2006, 27, 947–948.
  142. Kang, S.L.; Shaikh, A.G.; Ghasia, F.F. Vergence and Strabismus in Neurodegenerative Disorders. Front. Neurol. 2018, 9, 299. [Google Scholar] [CrossRef]
  143. Libert, J.; Van Hoof, F.; Toussaint, D.; Roozitalab, H.; Kenyon, K.R.; Green, W.R. Ocular findings in metachromatic leukodystrophy. An electron microscopic and enzyme study in different clinical and genetic variants. Arch. Ophthalmol. 1979, 97, 1495–1504. [Google Scholar] [CrossRef] [PubMed]
  144. Wang, Y.; Wang, S.Y.; Li, K.; Zhu, Y.L.; Xia, K.; Sun, D.D.; Ai, W.L.; Fu, X.M.; Ye, Q.R.; Li, J.; et al. Adult-onset Krabbe disease presenting with progressive myoclonic epilepsy and asymmetric occipital lesions: A case report. Front. Neurol. 2022, 13, 1010150. [Google Scholar] [CrossRef]
  145. Vujosevic, S.; Parra, M.M.; Hartnett, M.E.; O’Toole, L.; Nuzzi, A.; Limoli, C.; Villani, E.; Nucci, P. Optical coherence tomography as retinal imaging biomarker of neuroinflammation/neurodegeneration in systemic disorders in adults and children. Eye 2022, 37, 203–219. [Google Scholar] [CrossRef]
  146. van der Knaap, M.S. Magnetic resonance in childhood white-matter disorders. Dev. Med. Child. Neurol. 2001, 43, 705–712. [Google Scholar] [CrossRef]
  147. Cheon, J.E.; Kim, I.O.; Hwang, Y.S.; Kim, K.J.; Wang, K.C.; Cho, B.K.; Chi, J.G.; Kim, C.J.; Kim, W.S.; Yeon, K.M. Leukodystrophy in children: A pictorial review of MR imaging features. Radiographics 2002, 22, 461–476. [Google Scholar] [CrossRef]
  148. Imes, R.K.; Hoyt, W.F. Magnetic resonance imaging signs of optic nerve gliomas in neurofibromatosis 1. Am. J. Ophthalmol. 1991, 111, 729–734. [Google Scholar] [CrossRef]
  149. Viglianesi, A.; Messina, M.; Chiaramonte, R.; Meli, G.A.; Meli, L.; Chiaramonte, I.; Pero, G. An interpretation of optic nerve tortuosity. A case report. Neuroradiol. J. 2009, 22, 381–385. [Google Scholar] [CrossRef]
  150. Misra, M.; Mohanty, A.B.; Rath, S. Giant aneurysm of internal carotid artery presenting features of retrobulbar neuritis. Indian J. Ophthalmol. 1991, 39, 28–29. [Google Scholar]
  151. Seiff, S.R.; Brodsky, M.C.; MacDonald, G.; Berg, B.O.; Howes, E.L., Jr.; Hoyt, W.F. Orbital optic glioma in neurofibromatosis. Magnetic resonance diagnosis of perineural arachnoidal gliomatosis. Arch. Ophthalmol. 1987, 105, 1689–1692. [Google Scholar] [CrossRef]
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Figure 1. PRISMA 2020 flow diagram. Source: [134].
Figure 1. PRISMA 2020 flow diagram. Source: [134].
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Figure 2. Diagrammatic map revealing the OCT examination of a patient with metachromatic leukodystrophy, showing regular peripapillary retinal nerve fiber layer (RNFL) thickness in the right eye measured by spectral domain OCT (SD-OCT). (a) The appearance of the right optic nerve. (b) Transverse image of the RNFL. (c) Segmentation of the RNFL. Each area is colour coded to indicate whether the thickness of the nerve fiber layer is in the normal range (green) or out of range (yellow or red). (d) RNFL thickness map of the right eye. The different coloured areas in the background represent reference areas (normal distributions). The black line represents the measured thickness of the patient’s nerve fiber layer. This curve can be used to recognize whether the thickness in certain areas is within (green area) or outside (red area) the normal range.
Figure 2. Diagrammatic map revealing the OCT examination of a patient with metachromatic leukodystrophy, showing regular peripapillary retinal nerve fiber layer (RNFL) thickness in the right eye measured by spectral domain OCT (SD-OCT). (a) The appearance of the right optic nerve. (b) Transverse image of the RNFL. (c) Segmentation of the RNFL. Each area is colour coded to indicate whether the thickness of the nerve fiber layer is in the normal range (green) or out of range (yellow or red). (d) RNFL thickness map of the right eye. The different coloured areas in the background represent reference areas (normal distributions). The black line represents the measured thickness of the patient’s nerve fiber layer. This curve can be used to recognize whether the thickness in certain areas is within (green area) or outside (red area) the normal range.
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Figure 3. Diagrammatic map revealing the OCT examination of a patient with Krabbe disease, showing superior RNFL thinning in the right eye. (a) The appearance of the right optic nerve. (b) Transverse image of the RNFL. (c) Segmentation of the RNFL. Each area is colour coded to indicate whether the thickness of the nerve fiber layer is in the normal range (green) or out of range (yellow or red). (d) RNFL thickness map of the right eye. The different coloured areas in the background represent reference areas (normal distributions). The black line represents the measured thickness of the patient’s nerve fiber layer. This curve can be used to recognize whether the thickness in certain areas is within (green area) or outside (red area) the normal range.
Figure 3. Diagrammatic map revealing the OCT examination of a patient with Krabbe disease, showing superior RNFL thinning in the right eye. (a) The appearance of the right optic nerve. (b) Transverse image of the RNFL. (c) Segmentation of the RNFL. Each area is colour coded to indicate whether the thickness of the nerve fiber layer is in the normal range (green) or out of range (yellow or red). (d) RNFL thickness map of the right eye. The different coloured areas in the background represent reference areas (normal distributions). The black line represents the measured thickness of the patient’s nerve fiber layer. This curve can be used to recognize whether the thickness in certain areas is within (green area) or outside (red area) the normal range.
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Figure 4. Pathological brain MRI findings of selected patients with myelin involvement of the visual pathway.
Figure 4. Pathological brain MRI findings of selected patients with myelin involvement of the visual pathway.
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Figure 5. Pathological findings of the optic nerves.
Figure 5. Pathological findings of the optic nerves.
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Table 1. Occurrence of neuro-ophthalmologic symptoms, median age of onset of the disease, and patient sex in different leukodystrophy forms in the HLC and LLC.
Table 1. Occurrence of neuro-ophthalmologic symptoms, median age of onset of the disease, and patient sex in different leukodystrophy forms in the HLC and LLC.
Sex Sex *
Diseasen/n HLC (%)Median AO in MonthsmfDiseasen/n LLC (%) *Median AO in Months *mf
Total148/217 (68%)712889Total831/1090 (76%)6655219
MLD21/50
(42%)		632624MLD39/122
(32%)		241512
CD34/34
(100%)		21717CD29/35
(83%)		72111
KD14/25
(56%)		51213KD47/86
(55%)		113731
X-ALD13/22
(59%)		94220X-ALD32/47
(68%)		83610
PMD13/13
(100%)		1130PMD285/291 (98%)225411
VWM7/12
(58%)		2566VWM7/24
(29%)		30813
AxD3/10
(30%)		1355AxD4/6
(67%)		823
AGS6/9
(67%)		563AGS2/3
(67%)		430
MLC2/5
(40%)		1141MLC1/1
(100%)		510
Others27/37
(73%)		41720others385/475 (81%)3253138
HLC = Hamburg leukodystrophy cohort, LLC = literature leukodystrophy cohort, AO = age of onset of the disease, MLD = metachromatic leukodystrophy, CD = Canavan disease, KD = Krabbe disease, X-ALD = X-linked adrenoleukodystrophy, PMD = Pelizaeus–Merzbacher disease, VWM = vanishing white matter disease, AxD = Alexander disease, AGS = Aicardi–Goutières syndrome, MLC = megalencephalic leukoencephalopathy with subcortical cysts, others = less frequent leukodystrophies. * Clinical data on the occurrence of neuro-ophthalmologic symptoms could be determined for 1090/1153 patients. Clinical data on sex could be determined for 874/1153 patients. Clinical data on age of onset of the disease could be determined for 654/1153 patients.
Table 2. Frequency of different neuro-ophthalmologic symptoms in leukodystrophy patients of the HLC and LLC related to the total number of pathologic findings.
Table 2. Frequency of different neuro-ophthalmologic symptoms in leukodystrophy patients of the HLC and LLC related to the total number of pathologic findings.
n/n HLC (%)n/n LLC (%)
Total NOS3661057
EMD111/366 (30%)637/1057 (60%)
Fixational eye movement55/366 (15%)24/1057 (2%)
Posterior segment findings47/366 (13%)145/1057 (18%)
Refractive errors37/366 (10%)not specified
Pathological light reflex36/366 (10%)28/1057 (3%)
Visual function23/366 (6%)223/1057 (21%)
Anterior and periocular segment findings23/366 (6%)not specified
HLC = Hamburg leukodystrophy cohort, LLC = literature leukodystrophy cohort, NOS = neuro-ophthalmologic symptom, EMD = eye movement disorders.
Table 3. Occurrence of specific neuro-ophthalmologic symptoms in absolute numbers and percentages in different leukodystrophies in the HLC and LLC.
Table 3. Occurrence of specific neuro-ophthalmologic symptoms in absolute numbers and percentages in different leukodystrophies in the HLC and LLC.
Nystagmus (EMD) Strabismus (EMD) FEMD Visual Function Pathological Light Reflex
n/n HLC (%)n/n LLC (%)n/n HLC (%)n/n LLC (%)n/n HLC (%)n/n LLC (%)n/n HLC (%)n/n LLC (%)n/n HLC (%)n/n LLC (%)
Total60/217
(28%)		569/790 (72%)40/217
(18%)		68/202
(34%)		55/217
(25%)		24/35
(69%)		23/217
(11%)		223/417 (53%)31/217
(14%)		28/72
(39%)
PMD13/13
(100%)		273/276 (99%)4/13
(31%)		3/11
(27%)		2/13
(15%)		1/1
(100%)		0/13
(0%)		24/94
(26%)		1/13
(8%)		not specified
CD21/34
(62%)		9/15
(60%)		9/34
(26%)		not specified19/34
(56%)		7/17
(41%)		7/34
(21%)		14/14
(100%)		7/34
(21%)		1/1
(100%)
VWM3/12
(25%)		1/1
(100%)		2/12
(17%)		not specified2/12
(17%)		not specified1/12
(8%)		1/1
(100%)		1/12
(8%)		1/1
(100%)
AGS2/9
(22%)		2/3
(67%)		2/9
(22%)		not specified4/9
(44%)		1/1
(100%)		0/9
(0%)		not specified3/9
(33%)		not specified
AxD2/10
(20%)		4/4
(100%)		0/10
(0%)		1/1
(100%)		0/10
(0%)		not specified0/10
(0%)		not specified1/10
(10%)		not specified
KD4/25
(16%)		13/112
(12%)		3/25
(12%)		5/35
(14%)		7/25
(28%)		2/2
(100%)		2/25
(8%)		59/108
(44%)		4/25
(16%)		20/34
(59%)
X-ALD1/22
(5%)		4/4
(100%)		5/22
(23%)		19/43
(44%)		6/22
(27%)		not specified6/22
(27%)		36/57
(63%)		1/22
(5%)		not specified
MLD2/50
(4%)		3/3
(100%)		5/50
(10%)		17/63
(27%)		7/50
(14%)		not specified1/50
(2%)		not specified11/50
(22%)		not specified
MLC0/5
(0%)		not specified0/5
(0%)		not specified0/5
(0%)		not specified0/5
(0%)		not specified0/5
(0%)		not specified
others12/37
(32%)		260/372 (70%)10/37
(27%)		23/49
(47%)		7/37
(19%)		13/14
(93%)		6/37
(16%)		89/143
(63%)		2/37
(5%)		6/36
(17%)
HLC = Hamburg leukodystrophy cohort, LLC = literature leukodystrophy cohort, EMD = eye movement disorder, FEMD = fixational deficit, MLD = metachromatic leukodystrophy, CD = Canavan disease, KD = Krabbe disease, X-ALD = X-linked adrenoleukodystrophy, PMD = Pelizaeus–Merzbacher disease, VWM = vanishing white matter disease, AxD = Alexander disease, AGS = Aicardi–Goutières syndrome, MLC = megalencephalic leukoencephalopathy with subcortical cysts, others = less frequent leukodystrophies.
Table 4. Fraction of pathological VEP findings in patients with different leukodystrophies.
Table 4. Fraction of pathological VEP findings in patients with different leukodystrophies.
n/n HLC (%)n/n LLC (%)
Total35/54 (65%)52/79 (66%)
PMD4/4 (100%)13/16 (81%)
AGS1/1 (100%)not specified
MLC2/2 (100%)1/1 (100%)
CD4/5 (80%)1/3 (33%)
MLD11/19 (58%)9/12 (75%)
VWM2/4 (50%)not specified
X-ALD2/5 (40%)3/5 (60%)
AxD1/3 (33%)0/2 (0%)
KD1/4 (25%)23/37 (62%)
others7/7 (100%)2/3 (66%)
HLC = Hamburg leukodystrophy cohort, LLC = literature leukodystrophy cohort, PMD = Pelizaeus–Merzbacher disease, AGS = Aicardi–Goutières syndrome, MLC = megalencephalic leukoencephalopathy with subcortical cysts, CD = Canavan disease, MLD = metachromatic leukodystrophy, VWM = vanishing white matter disease, X-ALD = X-linked adrenoleukodystrophy, AxD = Alexander disease, KD = Krabbe disease, others = less frequent leukodystrophies.
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Bettinger, C.M.; Dulz, S.; Atiskova, Y.; Guerreiro, H.; Schön, G.; Guder, P.; Maier, S.L.; Denecke, J.; Bley, A.E. Overview of Neuro-Ophthalmic Findings in Leukodystrophies. J. Clin. Med. 2024, 13, 5114. https://doi.org/10.3390/jcm13175114

AMA Style

Bettinger CM, Dulz S, Atiskova Y, Guerreiro H, Schön G, Guder P, Maier SL, Denecke J, Bley AE. Overview of Neuro-Ophthalmic Findings in Leukodystrophies. Journal of Clinical Medicine. 2024; 13(17):5114. https://doi.org/10.3390/jcm13175114

Chicago/Turabian Style

Bettinger, Charlotte Maria, Simon Dulz, Yevgeniya Atiskova, Helena Guerreiro, Gerhard Schön, Philipp Guder, Sarah Lena Maier, Jonas Denecke, and Annette E. Bley. 2024. "Overview of Neuro-Ophthalmic Findings in Leukodystrophies" Journal of Clinical Medicine 13, no. 17: 5114. https://doi.org/10.3390/jcm13175114

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