CLN8 Mutations Presenting with a Phenotypic Continuum of Neuronal Ceroid Lipofuscinosis—Literature Review and Case Report
Abstract
:1. Introduction
2. Materials and Methods
3. Results
3.1. Case Presentation
3.2. Molecular and Histological Testing
3.3. Follow-Up
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Type | Eponym | Original Reports | Age of Onset | Distinctive Clinical Features |
---|---|---|---|---|
Infantile | Haltia-Santavuori | Haltia and Santavuori [6] | 0–2 y | Rapid psychomotor deterioration, seizures, visual impairment, purposeless hand movements (Rett-like). Death around age 10 y [1]. |
Late-infantile | Jansky-Bielschowsky | Jansky [7] and Bielschowsky [8] | 2–4 y | Initially epilepsy, followed by cognitive deterioration, myoclonus, ataxia, vision impairment. Death by age 6–15 y. |
Juvenile | Batten, Batten-Spielmeyer-Vogt | Stengel [5], Batten [9], Spielmeyer [10] and Vogt [11] | 4–10 y | Initially rapidly progressive visual loss, followed by epilepsy. Death by age 30 y. |
Adult | Kufs (AR), Parry (AD) | Kufs [12], Boehme [13] | 15–50 y | Cognitive decline, ataxia, myoclonus, epilepsy, behavioral changes, no visual impairment |
Year/Phenotype | 1994/EPMR | 2000/EPMR | 2017/EPMR | 2001/vLINCL | 2006/vLINCL | 2010/vLINCL | 2010/vLINCL | 2010/vLINCL |
---|---|---|---|---|---|---|---|---|
Authors | Hirvasniemi et al. [20] | Ranta et al. [21] | Sahin et al. [24] | Mitchell et al. [22] | Cannelli et al. [28] | Reinhardt et al. [29] | Reinhardt et al. [29] | Reinhardt et al. [29] |
Nationality | Finnish | Turkish | Turkish | Turkish | Italian | German | Pakistani | Turkish |
No of cases, sex | 23, M(11), F(12) | 6 | 5, M(5) | 5 | 3, M(3) | 1, F(1) | 1, F(1) | 2, M(1), F(1) |
Mutation | Homoz. c.70C>G, p.(Arg24Gly) | (1) Homoz. c.789G>C, p.(Trp263Cys); (2) Homoz. c.610C>T, p.(Arg204Cys); (3) Comp. heteroz. c.789G>C, p.(Trp263Cys)+c.610C>T, p.(Arg204Cys) | Homoz. c.677T>C, p. (Leu226Pro) | (1) Homoz. c.610C>T, p.(Arg204Cys); (2) Comp. heteroz. c.46C>A, p.(Leu16Met)+ c.509C>T, p.(Thr170Met); (3) Homoz. c.88delG, p.(Ala30Leufs20) | (1) Comp. heteroz c.581A>G, p.(Gln194Arg) + c.66delG, p.(Ala30Leufs*20); (2) Comp. heteroz c.473A>G, p.(Tyr158Cys) +c.66delG, p.(Ile23Serfs*5); (3) Homoz. c.88G>C, p.(Ala30Pro) | Homoz. c.611G>T, p.(Arg204Leu) | Homoz. c.709G>A, p.(Gly237Arg) | Homoz. c.544-2566_590del2613, p.0 |
Infancy psychomotor development | Normal (20/23), Delayed (3/23) | N/A | Normal (5/5) | Delayed | Delayed | Normal | N/A | Delayed |
Age of symptoms onset‡ | 6.7 y (5–10) | 5.7 (3,5–7) | 8.4 y (8–10) | 3.5 (3–4) | 4.5 y (3,5–6) | 3.5 y | 4 y | 3.25 y (3–3,5) |
First symptoms‡ | Seizures | N/A | Seizures | Mixed | Seizures | Attention, sleep, speech disturbance | Ataxic gait | Seizures |
Epilepsy | Yes, GTCS (23/23), complex focal (7/23) | Yes (6/6) | Yes, GTCS (5/5) | Yes (4/4) | Yes, myoclonic (2/3), tonic-clonic (1/3) | Yes, absence | Yes, drop attacks | Yes, myoclonic and drop attacks |
Epilepsy onset | 6.7 y (5–10) | 6.2 y (3.5–8) | 8.4 y (8–10) | 3.5 y (3–4) | 4.5 y (3.5–6) | 4 y | 6,5 y | 3.25 y (3–3.5) |
Cognitive deterioration and onset | Yes (23/23), 2–5 y, after epilepsy onset | Yes (6/6) | Yes (5/5), 6.5 y (5–7y), after epilepsy onset | Yes | Yes | Yes, 3.5y | Yes, After ataxia onset | Yes, After epilepsy onset |
Cognitive outcome | Borderline (4/19), Mild (4/19), Moderate (5/19), Severe (6/19) | N/A | Mild (3), Moderate (1), Severe (1) | N/A | N/A | Severe | Severe | Severe |
Ataxia and onset | Yes (16/19), <30 y | yes (5/5), 8.2 y (4–12) | yes (5/5) | yes, 3.8 y (3.5–4) | yes | yes, 4 y | yes, 4 y | yes, 4 y |
Abnormal speech onset | N/A | 8.6 y (7–9) | 16 y (15–18) | N/A | N/A | 4 y | 5.5 y | 4 y |
Abnormal gait onset | <30 y | N/A | 14.6 y (14–16) | N/A | N/A | N/A | N/A | N/A |
Myoclonus and onset | No | Yes (4/4), 7.1 y (3.5–9) | No | Yes, 3.9 y (3–4.5) | Yes | Yes, 5 y | Yes, 5 y | Yes, 4 y |
Visual loss and onset | No or minor | Yes (6/6), 7.5 y (5–9) | No | Yes, 3.6 y (3–4) | Yes | Yes, 9 y | Yes, 7 y | Yes, 6 y |
Optic pathology | None | N/A | None | N/A | N/A | Retinal degeneration | Optic nerve atrophy | Retinal degeneration |
Progression rate | Slow | Rapid | Slow | Rapid | Rapid | Rapid | Rapid | Rapid |
EEG | Slow background, disappearance of sleep patterns, scanty interictal epileptiform activity | N/A | Normal | N/A | N/A | N/A | N/A | Generalized polyspike slow wave |
Cerebral MRI | Atrophy at later stages | N/A | Atrophy | N/A | Atrophy | Cortical atrophy | Atrophy, T2/FLAIR PV WM hyperintensivities | Atrophy, T2/FLAIR WM hyperintensivities |
Cerebellar atrophy | Yes | N/A | Yes | N/A | Yes | Yes | Yes | Yes |
Other | Behavioural difficulties in puberty (11/23) | N/A | N/A | N/A | Patients with deletions: earlier onset, myoclonus more prominent | N/A | Noise elicited myoclonus | N/A |
Year/Phenotype | 2012/vLINCL | 2012/vLINCL | 2016/vLINCL | 2018/vLINCL | 2020/vLINCL | 2015/cNCL | 2016/aLINCL | 2021/aLINCL |
Authors | Mahajnah et al. [30] | Allen et al. [31] | Katata et al. [32] | Gao et al. [33] | Alkhars et al. [34] | Kohan et al. [35] | Sanchez et al. [36] | Badura-Stronka et al. |
Nationality | Israeli/Arabian | Irish | Japanese | Chinese | Arabian | Argentinian | Hispanic | Polish |
No of cases, sex | 3, M(2), F(1) | 1, M(1) | 1, M(1) | 1, M(1) | 2, M(1), F(1) | 1, F(1) | 2, M(1), F(1) | 1, F(1) |
Mutation | Homoz. c.763C>G, p.(Gln255*) | Comp. heteroz. c.562_563delCT, p.(Leu188Valfs*58) + 8p23.3 terminal deletion | Homoz. c.620T>G, p.(Leu207Arg) | Comp. heteroz. c.298C>T, p.(Gln100*) + c.551G>A, p.(Trp184*) | (1) Homoz. c.699_700delGT, p.Phe234Profs12; (2) Homoz. c.(?_-1)_(5431_544-1)del | (rs143730802) + (rs587779411) | Comp. heteroz. c.200C>T, p.(Ala67Val) + CLN8 deletion | Homoz. c.531C>T, p.(Trp177Cys) |
Infancy psychomotor development | Normal | Delayed | Delayed | Normal | Normal (1/2), Delayed (1/2) | Delayed | Normal | Delayed |
Age of symptoms onset‡ | 5 y (4–6) | 4 y | 3 y | 4 y | 2 y | Congenital | 11.5 (7–16) | 5.5 y |
First symptoms‡ | Seizures (2/3), Mixed (1/3) | Ataxia | Seizures | Seizures | Seizures (1/2), Ataxia (1/2) | Seizures | Seizures (1/2), Visual (1/2) | Seizures |
Epilepsy | Yes, tonic-clonic | Yes | Yes, drop attacks, myoclonic | Yes | Yes, GTCS, myoclonic | Yes, GTCS | Yes, GTCS | Yes, GTCS, complex focal |
Epilepsy onset | 6.7 y (5–9) | 4.5 y | 3 y | 4 y | 1.5 y (1–2) | 3 y | 11.5 y (7–16) | 5.5 y |
Cognitive deterioration and onset | Yes, After epilepsy onset (2/3) | Yes, 4 y | Yes, N/A | Yes, 3 y, after epilepsy onset | Yes, 3 y, after epilepsy onset (1/2), Birth (1/2) | Yes, Birth | No, N/A | Yes, <2 y, after epilepsy onset |
Cognitive outcome | Profound (1/3), Moderate (1/3), Mild (1/3) | N/A | N/A | N/A | Severe | Severe | Excellent | Moderate |
Ataxia and onset | yes (1/3), 5 y, No (2/3) | yes, 4 y | yes, 4 y | yes, 7 y | yes, 2.5 y (1–4) | No | yes | yes, 6.6 y |
Abnormal speech onset | N/A | 4 y | N/A | 7 y | 3 y (1/2) | N/A | N/A | 3 y |
Abnormal gait onset | N/A | 4 y | 4 y | 7 y | 3 y (2-4) | Never achieved | N/A | 9.5 y |
Myoclonus and onset | Yes (1/3) | N/A | Yes, 5 y | N/A | Yes (2/2), 1.5 y (1–2) | Yes, 6 y | No | No |
Visual loss and onset | Yes, 6.5 y (6–7.5) | Yes, 5.5 y | Yes, 5 y | Yes, 7 y | Yes (2/2), 2.5 y (2–3) | N/A | Yes, 9 y (5–13) | Yes, 9.5 y |
Optic pathology | Retinal degeneration, Optic nerve atrophy (2/3) | Abnormal ERG | Retinal and macular | N/A | Optic nerve atrophy | N/A | Complex macular (1/2), Retinal and optic nerve atrophy (1/2) | Macular dystrophy, optic nerve atrophy |
Progression rate | Rapid (1/3), Slow (2/3) | Rapid | Rapid | Rapid | Rapid | Rapid | Slow | Slow |
EEG | Slow background (1/3), Multiple spikes and bursts of generalized spike-slow wave (1/3) | Slow background, complex focal seizures | Diffuse spikes and slow waves | Slow background, abundant generalized atypical spike-slow wave | Generalized slow background with polyspike epileptiform discharges | N/A | N/A | Progressive slowing, paroxysmal slow waves; generalized sharp-slow wave after 12 y |
Cerebral MRI | Diffuse atrophy (1/3), Mild atrophy (1/3), T2/FLAIR WM hyperintensivities (2/3) | T2/FLAIR posterior deep WM hyperintensivities | T2/FLAIR diffuse PV WM hyperintensivities | Diffuse atrophy | Diffuse atrophy (1/2) | N/A | N/A | T2/FLAIR WM hyperintensivities |
Cerebellar atrophy | Yes | Yes | Yes | Yes | Yes | Yes | N/A | Yes |
Other | Severily affected, rapid deterioration (1/3) | N/A | N/A | N/A | N/A | N/A | Polidactyly, ADHD (1/2) | Myoclonus on lamotrigine; hypersensitive to noise |
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Badura-Stronka, M.; Winczewska-Wiktor, A.; Pietrzak, A.; Hirschfeld, A.S.; Zemojtel, T.; Wołyńska, K.; Bednarek-Rajewska, K.; Seget-Dubaniewicz, M.; Matheisel, A.; Latos-Bielenska, A.; et al. CLN8 Mutations Presenting with a Phenotypic Continuum of Neuronal Ceroid Lipofuscinosis—Literature Review and Case Report. Genes 2021, 12, 956. https://doi.org/10.3390/genes12070956
Badura-Stronka M, Winczewska-Wiktor A, Pietrzak A, Hirschfeld AS, Zemojtel T, Wołyńska K, Bednarek-Rajewska K, Seget-Dubaniewicz M, Matheisel A, Latos-Bielenska A, et al. CLN8 Mutations Presenting with a Phenotypic Continuum of Neuronal Ceroid Lipofuscinosis—Literature Review and Case Report. Genes. 2021; 12(7):956. https://doi.org/10.3390/genes12070956
Chicago/Turabian StyleBadura-Stronka, Magdalena, Anna Winczewska-Wiktor, Anna Pietrzak, Adam Sebastian Hirschfeld, Tomasz Zemojtel, Katarzyna Wołyńska, Katarzyna Bednarek-Rajewska, Monika Seget-Dubaniewicz, Agnieszka Matheisel, Anna Latos-Bielenska, and et al. 2021. "CLN8 Mutations Presenting with a Phenotypic Continuum of Neuronal Ceroid Lipofuscinosis—Literature Review and Case Report" Genes 12, no. 7: 956. https://doi.org/10.3390/genes12070956