Novel mutations in NPHS1 are a rare cause of congenital nephrotic syndrome

Congenital Nephrotic Syndrome (CNS) is an autosomal recessive disorder most commonly caused by mutations in NPHS1 which encodes the nephrin protein. It is characterized by massive proteinuria, hypoalbuminemia and gross edema in the neonatal period. This report describes two male siblings of mixed Filipino and German descent who both presented in the neonatal period with CNS. Sequencing of NPHS1 demonstrated a previously unreported novel heterozygous mutation in exon 11 denoted c.1437C>G (p.Y479X). This mutation creates a premature stop codon which is very likely to result in a truncated protein or loss of protein production, and it is therefore likely disease- causing. Additionally a previously unreported novel heterozygous large deletion encompassing exons 25, 26, 27, 28 and 29 of the NPHS1 gene was detected by qPCR. This mutation is very likely to result in loss of protein production, and it is therefore likely disease-causing. We note that long deletions are particularly rare in CNS [4,5], and this could be due to the lack of clinically available testing for deletions in NPHS1 – at this time deletion/duplication analysis is not clinically available in the US. In summary, this report describes two siblings affected with previously undescribed mutations in NPHS1 which are a cause of CNS

Mutations in the complex III assembly factor tetratricopeptide 19 gene TTC19 are a rare cause of Leigh syndrome

We report a patient with Leigh syndrome shown to have two previously undescribed truncating mutations in the TTC19 gene. Our patient is a 4-year-old boy with global developmental delay, language regression at 13 months, and brain MRI showing T2 high-signal lesions involving the putamen, caudate body, and the brainstem, which appear to be progressing. Molecular testing showed our patient is heterozygous for two previously undescribed mutations in the TTC19 gene, c.577G>A (p.Trp186Stop) and c.964_967delGGCT (p.Gly322MetfsX8), both of which are predicted to cause loss of protein function due to either protein truncation or nonsense-mediated mRNA decay. TTC19 encodes tetratricopeptide 19 (TTC19) and is thought to be a complex III (CIII) assembly factor that is embedded on the inner mitochondrial membrane as part of two high-molecular-weight complexes, one of which coincides with CIII. The initial presentations of previously described patients with TTC19 mutations are heterogeneous and can be from childhood to adulthood. In summary, TTC19 mutations have been shown to affect CIII complex function, which results in a heterogeneous clinical phenotype including Leigh syndrome

Expanding the Clinical Phenotype of HDAC8 Mutations

No abstract available

Haemodialysis is an effective treatment in acute metabolic decompensation of maple syrup urine disease

Acute metabolic decompensation in maple syrup urine disease can occur during intercurrent illness and is a medical emergency. A handful of reports in the medical literature describe the use of peritoneal dialysis and haemodialysis as therapeutic inventions. We report the only patient from our centre to have haemodialysis performed in this setting. Combined with dietary BCAA restriction and calorific support, haemodialysis allows rapid reduction in plasma leucine concentrations considerably faster than conservative methods

Biomarkers for Evidence of Mitochondrial Dysfunction in Cobalamin C Disease

No abstract available

Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance

Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for approximately 5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS