Alpha-L-iduronidase deficiency: A novel mutation resulting in severe early presentation of Mucopolysaccharidosis type I and literature review of the molecular basis.

The IDUA gene (MIM 252800) provides instructions for producing alpha-L-iduronidase, which is essential for the breakdown of large sugar molecules called glycosaminoglycans (GAGs). Mutations in the IDUA gene have been found to cause Mucopolysaccharidosis type I (MPS I) (MIM 607014). This leads to the accumulation of GAGs within lysosomes causing many different organs and tissues to be dysfunctional. Deleted IDUA gene has not been reported in the literature, which showed to be associated with a severe phenotype in our proband case. We report a child from a consanguineous family who presented with severe cardiogenic shock attributed to dilated cardiomyopathy. He was also found to have hepatosplenomegaly, joint stiffness, hearing loss, corneal hazing, facial dysmorphism, and dilation of brain ventricles. Lysosomal storage disease particularly MPS I was suspected though it is considered to be an early atypical presentation. The diagnosis was achieved via gene mutation analysis which showed homozygous IDUA deletion of exon 9' to 3' in combination with a severe deficiency of alpha-L-iduronidase enzyme. A variant in the form of IDUA gene deletion may indicate an early severe phenotypic presentation of MPS I. Establishment of the diagnosis permits genetic counseling, prevents patients from undergoing unhelpful diagnostic procedures, and allows for accurate prognosis.

Endothelial Dysfunction and the Effect of Arginine and Citrulline Supplementation in Children and Adolescents With Mitochondrial Diseases.

BACKGROUND: In addition to the reduced energy production, characteristic of mitochondrial disorders, nitric oxide (NO) deficiency can occur as well. The NO produced by vascular endothelial cells relaxes vascular smooth muscles, resulting in vasodilation that maintains the patency of small blood vessels and promotes blood flow through microvasculature. Endothelial dysfunction due to inability of vascular endothelium to generate enough NO to maintain adequate vasodilation can result in decreased perfusion in the microvasculature of various tissues, contributing to many complications seen in individuals with mitochondrial diseases. The amino acids arginine and citrulline are NO precursors: increasing their concentrations could potentially restore NO production. METHODS: In this study, we assessed endothelial dysfunction in children and adolescents with mitochondrial diseases. We also investigated the effect of arginine and citrulline supplementation on endothelial dysfunction in these individuals. We used peripheral arterial tonometry to measure the reactive hyperemic index (RHI), which is low when there is endothelial dysfunction. RESULTS: The results demonstrated low RHI in individuals with mitochondrial diseases, indicating endothelial dysfunction. RHI increased with arginine or citrulline supplementation suggesting that supplementation with NO precursors can improve endothelial dysfunction by enhancing NO production. CONCLUSIONS: This study is the first one to use peripheral arterial tonometry methodology in mitochondrial diseases. The results of this study provide evidence for endothelial dysfunction in mitochondrial diseases and demonstrate that arginine or citrulline supplementation can alleviate the endothelial dysfunction, providing more evidence for the potential therapeutic utility of these amino acids in mitochondrial diseases.

A Novel Homozygous Missense Variant in the NAGA Gene with Extreme Intrafamilial Phenotypic Heterogeneity.

Schindler disease is a rare autosomal recessive lysosomal storage disorder caused by a deficiency in alpha-N-acetylgalactosaminidase (α-NAGA) activity due to defects in the NAGA gene. Accumulation of the enzyme's substrates results in clinically heterogeneous symptoms ranging from asymptomatic individuals to individuals with severe neurological manifestations. Here, a 5-year-old Emirati male born to consanguineous parents presented with congenital microcephaly and severe neurological manifestations. Whole genome sequencing revealed a homozygous missense variant (c.838C>A; p.L280I) in the NAGA gene. The allele is a reported SNP in the ExAC database with a 0.0007497 allele frequency. The proband's asymptomatic sister and cousin carry the same genotype in a homozygous state as revealed from the family screening. Due to the extreme intrafamilial heterogeneity of the disease as seen in previously reported cases, we performed further analyses to establish the pathogenicity of this variant. Both the proband and his sister showed abnormal urine oligosaccharide patterns, which is consistent with the diagnosis of Schindler disease. The α-NAGA activity was significantly reduced in the proband and his sister with 5.9% and 12.1% of the mean normal activity, respectively. Despite the activity loss, p.L280I α-NAGA processing and trafficking were not affected. However, protein molecular dynamic simulation analysis revealed that this amino acid substitution is likely to affect the enzyme's natural dynamics and hinders its ability to bind to the active site. Functional analysis confirmed the pathogenicity of the identified missense variant and the diagnosis of Schindler disease. Extreme intrafamilial clinical heterogeneity of the disease necessitates further studies for proper genetic counseling and management.

SYNJ1 gene associated with neonatal onset of neurodegenerative disorder and intractable seizure.

BACKGROUND: Synaptojanin 1 is encoded by the SYNJ1(MIM 604297) and plays a major role in phosphorylation and recycling of synaptic vesicles. Mutation of SYNJ1 is associated with two distinct phenotypes; a known homozygous missense mutation (p.Arg258Gln) associated with early-onset Parkinson disease (MIM 615530), whereas mutation with complete loss of SYNJ1 function result in a lethal neurodegenerative disease with intractable seizure and tauopathies (MIM 617389). METHODS: We report two related children from consanguineous family presented with intractable seizure, profound developmental delay, failure to thrive, acquired microcephaly, and hypotonia. The brain MRI is normal and EEG showed hypsarrhythmia. RESULT: The diagnosis was achieved via whole-genome sequencing which showed homozygous mutation in SYNJ1 (c.709C>T, p.Gln237*). CONCLUSION: A clinical pattern of neonatal-onset intractable seizure, profound developmental delay, muscular hypotonia, hypsarrhythmia, and no focal abnormality of brain MRI should prompt initiation of molecular genetic analysis of SYNJ1. Establishment of the diagnosis permits genetic counseling, prevents patients undergoing unhelpful diagnostic procedures and allows for accurate prognosis.