Maple syrup urine disease (MSUD) is an autosomal recessive disorder associated with impaired metabolism of branched-chain amino acids (BCAA) leucine, isoleucine, and valine. Children with MSUD suffer from bouts of metabolic decompensation, which may lead to neurological damage. Liver transplantation from unrelated deceased donors has been considered curative. The natural history of the disease following transplantation using a haploidentical (obligate heterozygous) living donor is still unclear, although previously described as favorable. We describe acute metabolic crises in a 20-month-old child with MSUD type II. The first well-documented one occurred 5 months after a successful liver transplantation from his mother. The patient developed encephalopathy with progressive lethargy and seizures after an episode of gastroenteritis with dehydration. Plasma levels of leucine, isoleucine, and valine were markedly elevated and alloisoleucine was detected. He promptly responded to dialysis and BCAA-free dietetic management and subsequently could resume a normal diet. Since then he has had another symptomatic metabolic crisis with seizures. This case strongly suggests that some recipients of liver transplantation from a haploidentical parent possess limited capacity to oxidize BCAA at the time of catabolic stress and dehydration and remain at risk of severe metabolic crises. Thus, careful metabolic monitoring and prompt treatment post liver transplantation are still required to avoid neurological sequelae of MSUD, particularly if the donor is heterozygous for MSUD. Abbreviations BCAABranched-chain amino acids BCKDH Branched-chain keto acid dehydrogenase complex MSUD Maple syrup urine disease
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Background: Hearing loss (HL) is a heterogeneous condition that causes partial or complete hearing impairment. Hundreds of variants in >60 genes have been reported to be associated with Hereditary HL (HHL), variants of the GJB2 gene are the most common cause of congenital SNHL, with >100 variants reported.The HHL prevalence is thought to be high in the Arab population; however, the genetic epidemiology of HHL among Emirati populations is understudied.Aims: To shed light on the mutational spectrum of NSHL in Emirati patients seen in the genetic clinic over 10 years and to capture founder mutation(s) if any were identified. Methods: Retrospective chart review of all Emirati patients assessed by clinical geneticists due to NSHL during the period between January 2010 to December 2020. Genetic tests were done based on clinical phenotypes of the patient and family history including targeted mutation testing, next-generation sequencing, or whole-exome sequencing (solo or trio). The authors did literature reviews using PubMed for all previously reported articles related to NSHL genes from UAE.Results: A total of 162 patients with HL, were evaluated during the period between January 2010 to December 2020. There were 82 patients with NSHL, and only 72 patients who completed the genetic evaluations were included in this retrospective study. Among the studied group, 42 (51.2%) were males and 40 (48.78%) were females. The youngest patient was 2 years old and the oldest patient was 50 years old. Consanguinity was documented in 76 patients (92.68%). A total of 14 mutations reported here are novel (23/72 i.e., 31.9%). Twelve missense mutations, 6 nonsense mutations, 6 frameshift mutations, 2 in-frame deletion mutations, and 1 splice site mutation was found. Variants in the GJB2 gene are the most commonly identified cause of NSHL, with c.35delG being the most followed by c.506G > A. The second commonly found variant is c.934C > G (p.Arg312Gly) in the CDC14A gene, found in 9 patients. This was followed by variants in OTOF and SLC26A4 genes, found in 8 patients, respectively. Chromosomal microdeletions encompassing genes causing NSHL were found in 3 patients. No mitochondrial How to cite this article: Elsayed, O., & Al-Shamsi, A. (2022). Mutation spectrum of non-syndromic hearing loss in the UAE, a retrospective cohort study and literature review. Molecular Genetics & Genomic Medicine, 10, e2052.
Here, we delineate the phenotype of two siblings with a bi‐allelic frameshift variant in MMP15 gene with congenital cardiac defects, cholestasis, and dysmorphism. Genome sequencing analysis revealed a recently reported homozygous frameshift variant (c.1058delC, p.Pro353Glnfs*102) in MMP15 gene that co‐segregates with the phenotype in the family in a recessive mode of inheritance. Relative quantification of MMP15 mRNA showed evidence of degradation of the mutated transcript, presumably by nonsense mediated decay. Likewise, MMP15: p.Gly231Arg, a concurrently reported homozygous missense variant in another patient exhibiting a similar phenotype, was predicted to disrupt zinc ion binding to the MMP‐15 enzyme catalytic domain, which is essential for substrate proteolysis, by structural modeling. Previous animal models and cellular findings suggested that MMP15 plays a crucial role in the formation of endocardial cushions. These findings confirm that MMP15 is an important gene in human development, particularly cardiac, and that its loss of function is likely to cause a severe disorder phenotype.
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