Search Results (25)

Mucopolysaccharidosis type I (MPS I) results in the accumulation of glycosaminoglycans (GAG) and, for the purposes of newborn screening, is differentiated into two forms: severe (Hurler syndrome) versus attenuated (encompassing Scheie and Hurler-Scheie syndromes). MPS I was added to the federal Recommended Uniform Screening Panel for newborn screening (NBS) in 2016, and as of December 2025, 45 of 54 programs in the United States (US) screen for MPS I. Within the newborn screening program, a second-tier analysis of GAG is thought to reduce false-positive rates, particularly through mitigating the detection of pseudodeficiency. However, there have been some concerns that the use of second-tier GAG analysis might inadvertently result in missed detection of attenuated cases. A survey of all US NBS programs was conducted requesting data on the total number of screen-positive NBS results for MPS I as well as the final diagnostic outcome from these results. Diagnostic outcomes after screening were classified as false-positive, pseudodeficiency, severe MPS I, attenuated MPS I, and MPS I of undetermined phenotype. Additionally, information on testing methodologies and dates of MPS I NBS implementation was collected. Responses were obtained from 32 NBS programs. The cohort of screening programs utilizing second-tier blood spot GAG determinations detected a higher proportion of severe cases than those not using this second-tier test (48% vs. 29%). The proportion of attenuated cases remained consistent between both groups (13% vs. 14%). The proportion of pseudodeficiency detection was only slightly lower in the cohort using second-tier GAG analysis (85% vs. 91%). Second-tier GAG analysis appears to reduce the detection of false-positive cases and improves the resolution of severe MPS I cases, though the proportion of pseudodeficiency was only slightly lower compared to the programs that do not use second-tier GAG analysis. Currently, the proportion of attenuated cases is comparable between the two cohorts, but the higher number of “undetermined phenotype” cases may eventually shift the balance toward states not using GAG analysis once the type is determined. Full article

Background/Objectives: To date, few studies have reported the use of neurophysiological testing to assess the long-term progression of functional changes in median and ulnar nerve conduction in children and adolescents with mucopolysaccharidosis (MPS). This case series study aimed to perform an electroneurographic (ENG) assessment of the median and ulnar nerves in three young patients with MPS treated with enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) over a five-year observation period. Methods: Bilateral electroneurography of the motor and sensory fibers in the median and ulnar nerves, recording compound muscle action potential (CMAP) and sensory nerve action potential (SNAP), was performed twice in 5-, 7-, and 19-year-old males at two time points: before and five years after the application of ERT and HSCT. Results: In three MPS patients with Hurler or Hunter syndrome, ENG studies similarly demonstrated decreased amplitudes and prolonged distal latencies in their CMAP recordings, confirming the bilateral progression of axonal degeneration and demyelinating changes in the distal parts of the median nerves. The SNAP recordings revealed more severe degenerative processes of similar types in the sensory fibers of the median nerves. Nerve conduction studies in the ulnar nerve fibers bilaterally revealed analogous pathologies, but with a lesser degree of progression. Conclusions: This study confirms the progression of axonal degeneration and demyelinating changes in the distal parts of the median nerves, which were associated with decreased amplitudes and prolonged distal latencies in the CMAP recordings of the MPS patients. More expressed degeneration processes of a similar type were found in the sensory fibers of the median nerves. Ulnar nerve pathologies of neural conduction are less advanced in patients with Hurler and Hunter syndromes. It seems advisable to implement neurophysiological diagnostics as soon as possible to specify surgical or conservative therapy, which is crucial for maintaining hand function in the case of progressive peripheral neuropathies in patients with MPS. The timing of the treatment and the patient’s age may be factors influencing the effectiveness of treatment. Full article

Lysosomal storage disorders (LSDs) are a group of rare inherited diseases caused by mutations in the genes encoding the proteins involved in normal lysosomal functions, leading to an accumulation of undegraded substrates within lysosomes. Among the most prominent clinical features are neurological impairment and neurodegeneration, arising from widespread cellular dysfunction. The development of powerful and reliable animal model systems that can in vivo recapitulate human LSD pathologies is critical for understanding disease mechanisms and advancing therapeutic strategies. In this study, we identified the Drosophila melanogaster orthologs of human LSD-related genes using the DIOPT tool and performed tissue-specific gene silencing along the brain–midgut axis via the use of GAL4/UAS and RNAi combined technologies. Transgenic fly models presented key features of human LSD pathologies, including significantly shortened lifespans and a progressive locomotor decline that serves as a measure for neuromuscular disintegration, following age- and sex-dependent patterns. These phenotypic parallels in pathology strongly support the functional relevance of the selected orthologs and underscore the value of Drosophila as a versatile in vivo model system for advanced LSD pathology research, offering state-of-the-art genetic tools for molecularly dissecting disease mechanisms and providing cutting-edge novel platforms for high-throughput genetic and/or pharmacological screening, moving towards development of new therapeutically beneficial drug-based regimens and mutant gene-rescue schemes. Full article

Accurate variant classification is crucial for newborn screening (NBS) to prevent missed diagnoses or unnecessary interventions. The IDUA gene variant denoted as c.250G>A (p.Gly84Ser) has been identified in individuals with positive NBS for Mucopolysaccharidosis Type I (MPS I). This variant has conflicting pathogenicity reports including one publication classifying this variant as associated with a severe MPS I phenotype; therefore, we aim to clarify the clinical significance of this variant by presenting a case series describing three individuals, each homozygous for c.250G>A (p.Gly84Ser), identified in Michigan and California. All patients in this case series had low alpha-iduronidase (IDUA) enzyme activity with normal or mildly elevated glycosaminoglycans (GAGs) in blood or urine not falling into the range or pattern seen for affected individuals. None of these patients have developed clinical features of MPS I during follow-up ranging up to 3.5 years of age. Review of functional and population data supports a pseudodeficiency effect, resulting in no need for treatment. Based on our experience with three patients all homozygous for c.250G>A (p.Gly84Ser), despite causing low in vitro IDUA activity, homozygosity for the IDUA gene variant denoted as c.250G>A (p.Gly84Ser), does not cause symptoms of MPS I and may represent a pseudodeficiency allele. Caution should be exercised in newborns with this variant to help reduce unnecessary interventions and alleviate the psychosocial and economic consequences of false-positive NBS results, particularly for the South Asian population. Full article

The potential association of congenital dermal melanocytosis as a marker for lysosomal storage disease in infancy is rarely studied. A few cases of congenital dermal melanocytosis in association with lysosomal storage diseases have been reported. GM1 gangliosidosis type 1 and Hurler syndrome are the most common underlying lysosomal disorders associated with dermal melanocytosis. We present two non-relative patients with Hurler’s Syndrome who exhibited cutaneous manifestations. Both cases had a recurrent genetic variant c.1045G>T (p.Asp349Tyr) in the IDUA gene, located in a highly conserved amino acid position. We encourage the role of cutaneous findings in early suspicion and detection of inborn errors of metabolism, as well as differential diagnoses in a newborn with this finding. Full article

MPS I (Mucopolysaccharidosis type I) is a rare lysosomal storage disease originating from the deficiency of the enzyme alpha-L-iduronidase, encoded by the IDUA gene, which impairs the degradation of glycosaminoglycans (GAGs) and diminishes biological functioning across several organs. Background: Out of the eleven MPS disorders, MPS I includes three syndromes, of which the first, named Hurler syndrome, affects the most. Methods: Several in silico tools were used, such as ConSurf (73 variants), Mutation Assessor (69 variants), PredictSNP, MAPP, PhDSNP, Polyphen-1, Polyphen-2, SIFT, SNAP, PANTHER, MetaSNP (24 variants); Missense 3D-DB (11 variants) and AlignGVGD (eight variants) for physicochemical properties; and I-Mutant, Mupro, CUPSAT, and INPS for stability predictions (four variants). Results: A molecular docking study was performed for the two variants: L238Q and P385R scored −7.22 and −7.05 kcal/mol, respectively, and the native scored −7.14 kcal/mol with IDR as the ligand. Molecular dynamics anticipated how these molecules fluctuate over a period of 100 nanoseconds. Conclusions: Alpha-L-iduronidase enzyme has a critical role in the lysosomal degradation of glycosaminoglycans. According to the comparative analysis of the three structures by MDS, P385R had the least stability in all aspects of the plots. Our study demonstrates that the mutation significantly alters protein stability and binding efficiency with the ligands. Full article

Mitral annular calcification (MAC) is usually considered an incidental, benign, age-related finding without serious complications in patients evaluated for cardiovascular or pulmonary disease with imaging studies that may result in mitral regurgitation or stenosis when severe. Therefore, it is usually not considered a significant alteration. However, there is accumulating evidence that it is associated with a higher risk of cardiovascular events, such as atherosclerotic coronary artery disease, aortic artery disease, carotid artery disease, peripheral artery disease, stroke, atrial fibrillation, atrioventricular and/or intraventricular conduction disturbance, systemic embolization, infective endocarditis, heart failure and mortality. The presence of MAC also significantly influences the outcome of mitral valve transcatheter and surgical interventions. Several conditions may predispose to MAC. MAC is strongly related to cardiovascular risk factors, such as hypertension, diabetes, smoking and cardiovascular atherosclerosis, and inflammation may also play a role in the pathogenesis of MAC. Also, conditions that increase mitral valve stress, such as hypertension, aortic stenosis and hypertrophic cardiomyopathy, predispose to accelerated degenerative calcification of the mitral annulus area. Congenital disorders, e.g., Marfan syndrome and Hurler syndrome, are also associated with MAC, due to an intrinsic abnormality of the connective tissue composing the annulus. Full article

Mucopolysaccharidosis type I (MPS-I) is an autosomal recessive, progressive, multisystem hereditary lysosomal storage disease (LSD), which is characterized by the gradual accumulation of dermatan sulphate (DS), heparan sulphate (HS), and glycosaminoglycans (GAGs) in all organs and tissues due to the deficiency of the enzyme α-L-hyduronidase. The multisystem clinical manifestations of varying severities of MPS-I are present in two forms—the “severe form of MPS I” (Hurler type) and the “attenuated form of MPS-I” (Hurler–Scheie or Scheie type). These forms represent the entire case history of the disease. The three phenotypes share common symptoms, including musculoskeletal abnormalities, facial dysmorphisms, hernias, short stature, finger stiffness, carpal tunnel syndrome, and corneal opacities. Abnormalities affecting the internal organs include hepatomegaly, splenomegaly, and valvulopathy. There is some evidence to suggest a similarity and overlap with the clinical symptoms of MPS-I, particularly in cases of another rare LSD that is autosomal and recessively inherited—l’α-mannosidosis. This disorder has been observed to result from a dysfunction of the corresponding α-mannosidase enzyme, which has been shown to lead to the accumulation of mannose-rich N-linked oligosaccharides. This review compares the phenotypic similarities and molecular differences between mucopolysaccharidosis type I (MPS-I) and α-mannosidosis. We review genotype–phenotype correlations, diagnostic difficulties, and the applicability of artificial intelligence for the assistance of differential diagnosis, with the goal of facilitating the earlier and more accurate diagnosis of these rare lysosomal storage diseases. Full article

Nonsense mutations are genetic mutations that create premature termination codons (PTCs), leading to truncated, defective proteins in diseases such as cystic fibrosis, neurofibromatosis type 1, Dravet syndrome, Hurler syndrome, Beta thalassemia, inherited bone marrow failure syndromes, Duchenne muscular dystrophy, and even cancer. These mutations can also trigger a cellular surveillance mechanism known as nonsense-mediated mRNA decay (NMD) that degrades the PTC-containing mRNA. The activation of NMD can attenuate the consequences of truncated, defective, and potentially toxic proteins in the cell. Since approximately 20% of all single-point mutations are disease-causing nonsense mutations, it is not surprising that this field has received significant attention, resulting in a remarkable advancement in recent years. In fact, since our last review on this topic, new examples of nonsense suppression approaches have been reported, namely new ways of promoting the translational readthrough of PTCs or inhibiting the NMD pathway. With this review, we update the state-of-the-art technologies in nonsense suppression, focusing on novel modalities with therapeutic potential, such as small molecules (readthrough agents, NMD inhibitors, and molecular glue degraders); antisense oligonucleotides; tRNA suppressors; ADAR-mediated RNA editing; targeted pseudouridylation; and gene/base editing. While these various modalities have significantly advanced in their development stage since our last review, each has advantages (e.g., ease of delivery and specificity) and disadvantages (manufacturing complexity and off-target effect potential), which we discuss here. Full article

Congenital dermal melanocytosis (DM) represents a common birthmark mainly found in children of Asian and darker skin phototype descent, clinically characterized by an oval blue-grey macule or macules, commonly located on the lumbosacral area. In rare DM cases, when presenting with diffuse macules persisting during the first years of life, it could represent a cutaneous feature of mucopolysaccharidoses (MPS). Extensive congenital DM is actually associated with Hurler syndrome (MPS type I) and Hunter syndrome (MPS type II), although several reports also described this association with MPS type VI and other lysosomal storage disorders (LySD), including GM1 gangliosidosis, mucolipidosis, Sandhoff disease, and Niemann–Pick disease. Here, we present the case of a two-year-old boy presenting with extensive dermal melanocytosis, generalized hypertrichosis, and chronic itch, harboring a heterozygous variant of uncertain significance, NM_152419.3: c.493C>T (p.Pro165Ser), in the exon 4 of HGSNAT gene, whose mutations are classically associated with MPS IIIC, also known as Sanfilippo syndrome. This is the first report that highlights the association between extensive congenital DM and MPS type IIIC, as well as a pathogenetic link between heterozygous LySD carrier status and congenital DM. We speculate that some cases of extensive congenital DM could be related to heterozygous LySD carriers, as a manifestation of a mild clinical phenotype. Full article

Introduction: Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease present in 1:100,000 newborns. Variants in the IDUA (alpha-L-iduronidase) gene decrease the enzyme activity for glycosaminoglycans metabolism. MPS I patients exhibit clinical manifestations that fall on the Hurler, Hurler–Scheie, and Scheie syndrome spectrum. Case presentation: We present a male Mexican patient with respiratory exacerbations requiring recurrent hospitalizations. He showed macrocephaly, coarse facies, hepatomegaly, umbilical hernia, and dorsal kyphosis. The sequencing of the IDUA gene revealed the following genotype: c.46_57del12/c.1205G>A. He received combined therapy with hematopoietic stem cell transplantation and enzyme replacement. Mexican case reports were analyzed to estimate the prevalence of the associated genetic variants. Conclusion: Despite the challenges of managing this rare disease in Mexico, our patient benefited from the combined therapy. The discrete clinical manifestations and prompt evaluation by a geneticist were crucial in establishing a diagnosis, enabling an early intervention by a multidisciplinary team. The combination of ERT before and after HSCT provided health benefits to our patient. Full article

Mucopolysaccharidosis I-Hurler (MPS I-H) is caused by the loss of α-L-iduronidase, a lysosomal enzyme that degrades glycosaminoglycans. Current therapies cannot treat many MPS I-H manifestations. In this study, triamterene, an FDA-approved, antihypertensive diuretic, was found to suppress translation termination at a nonsense mutation associated with MPS I-H. Triamterene rescued enough α-L-iduronidase function to normalize glycosaminoglycan storage in cell and animal models. This new function of triamterene operates through premature termination codon (PTC) dependent mechanisms that are unaffected by epithelial sodium channel activity, the target of triamterene’s diuretic function. Triamterene represents a potential non-invasive treatment for MPS I-H patients carrying a PTC. Full article

Mucopolysaccharidosis type I (MPS I) is a rare inherited lysosomal disorder caused by deficiency of the α-L-iduronidase enzyme, resulting in the progressive accumulation of glycosaminoglycans (GAGs), which interfere with the normal function of multiple tissues and organs. The clinical phenotype includes characteristic facial features, hepatosplenomegaly, dysostosis multiplex, umbilical and inguinal hernias, progressive cognitive deficits with corresponding hydrocephalus, and neuropathology. Untreated children do not survive into the second decade. The common cardiac phenotype seen in MPS I and other MPS types includes valve thickening and dysfunction, conduction abnormalities, coronary artery disease, and cardiomyopathy—usually seen later in the disease course. A 15-month-old ex-35-weeker who presented with cardiomyopathy and left ventricular failure at the age of three weeks is presented here. Early evaluation and diagnosis with the help of newborn screening (NBS), followed by treatment with enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT), resulted in improvement of his cardiopulmonary status. In MPS I, an early cardiac phenotype is uncommon. Based on the evidence from the literature review for early neonatal cardiac phenotype, we propose that all infants with abnormal newborn screening for MPS I should receive cardiac screening with echocardiogram and NT-proB-type natriuretic peptide (BNP) during the initial evaluation. Full article

Mucopolysaccharidoses (MPS) are a family of genetic diseases associated with a deficiency of alpha-L iduronidase, which causes a lack of catabolism of glycosaminoglycans (GAGs). Therefore, the accumulation of GAGs determines a wide spectrum of symptoms, typically found in a few syndromes like Hurler syndrome (HS). Among other specific manifestations, craniofacial abnormalities are crucial for the characterization of this syndrome. Ameloblastoma is a rare, benign, slow-growing, odontogenic tumor usually located in the mandible. Clear risk factors for the development of ameloblastoma remain unknown, but black patients have a fivefold increased risk. Clinically, it is characterized by a painless, variable-sized jaw swelling. Although classified as a benign tumor, ameloblastoma often has a severe clinical outcome. The most common type of ameloblastoma is the solid/multicystic/conventional one. A computed tomography scan (CT) with and without contrast is the gold standard for evaluating this kind of neoplasia. Conservative or radical surgery is the mainstay of treatment. In this case report, we described an unusual clinical assessment of conventional ameloblastoma interesting the posterior left mandible of a 35-month-old child affected by HS. This case represented a suggestive challenge both from a diagnostic and a therapeutic point of view. The patient was disease-free at 2 years’ follow-up. Full article

Deficit of the IDUA (α-L-iduronidase) enzyme causes the lysosomal storage disorder mucopolysaccharidosis type I (MPS I), a rare pediatric neurometabolic disease, due to pathological variants in the IDUA gene and is characterized by the accumulation of the undegraded mucopolysaccharides heparan sulfate and dermatan sulfate into lysosomes, with secondary cellular consequences that are still mostly unclarified. Here, we report a new fruit fly RNAi-mediated knockdown model of a IDUA homolog (D-idua) displaying a phenotype mimicking some typical molecular features of Lysosomal Storage Disorders (LSD). In this study, we showed that D-idua is a vital gene in Drosophila and that ubiquitous reduction of its expression leads to lethality during the pupal stage, when the precise degradation/synthesis of macromolecules, together with a functional autophagic pathway, are indispensable for the correct development to the adult stage. Tissue-specific analysis of the D-idua model showed an increase in the number and size of lysosomes in the brain and muscle. Moreover, the incorrect acidification of lysosomes led to dysfunctional lysosome-autophagosome fusion and the consequent block of autophagy flux. A concomitant metabolic drift of glycolysis and lipogenesis pathways was observed. After starvation, D-idua larvae showed a quite complete rescue of both autophagy/lysosome phenotypes and metabolic alterations. Metabolism and autophagy are strictly interconnected vital processes that contribute to maintain homeostatic control of energy balance, and little is known about this regulation in LSDs. Our results provide new starting points for future investigations on the disease’s pathogenic mechanisms and possible pharmacological manipulations. Full article