One pedigree with four patients has been recently described with mitochondrial DNA depletion and mutation in SUCLA2 gene leading to succinyl-CoA synthase deficiency. Patients had a Leigh-like encephalomyopathy and deafness but besides the presence of lactic acidosis, the profile of urine organic acid was not reported. We have studied 14 patients with mild 'unlabelled' methylmalonic aciduria (MMA) from 11 families. Eight of the families are from the Faroe Islands, having a common ancestor, and three are from southern Italy. Since the reaction catalysed by succinyl-CoA synthase in the tricarboxylic acid (TCA) cycle represents a distal step of the methylmalonic acid pathway, we investigated the SUCLA2 gene as a candidate gene in our patients. Genetic analysis of the gene in the 14 patients confirmed the defect in all patients and led to the identification of three novel mutations (p.Gly118Arg; p.Arg284Cys; c.534 + 1G --> A). The defect could be convincingly shown at the protein level and our data also confirm the previously described mitochondrial DNA depletion. Defects in SUCLA2 can be found at the metabolite level and are defined by mildly elevated methylmalonic acid and C4-dicarboxylic carnitine concentrations in body fluids in association with variable lactic acidosis. Clinically the diagnosis should be considered in patients with early/neonatal onset encephalomyopathy, dystonia, deafness and Leigh-like MRI abnormalities mainly affecting the putamen and the caudate nuclei. The frequency of the mutated allele in the Faroese population amounted to 2%, corresponding with an estimated homozygote frequency of 1 : 2500. Our data extend knowledge on the genetic defects causing MMA. Our patients present with an early infantile Leigh-like encephalomyopathy with deafness, and later on a progressive dystonia. Mild MMA, lactic acidosis and specific abnormalities in the carnitine ester profile are the biochemical hallmarks of the disease. In view of the frequency of the mutated allele on the Faroe Islands, measures become feasible to prevent the occurrence of the disease on the islands. We confirm and extend the findings on this inborn error of metabolism in the TCA cycle that must be carefully investigated by accurate metabolite analyses.

Cerebellar hypoplasia and slowly progressive ophthalmological symptoms are common features in patients with congenital disorders of glycosylation type I. In a group of patients with congenital disorders of glycosylation type I with unknown aetiology, we have previously described a distinct phenotype with severe, early visual impairment and variable eye malformations, including optic nerve hypoplasia, retinal coloboma, congenital cataract and glaucoma. Some of the symptoms overlapped with the phenotype in other congenital disorders of glycosylation type I subtypes, such as vermis hypoplasia, anaemia, ichtyosiform dermatitis, liver dysfunction and coagulation abnormalities. We recently identified pathogenic mutations in the SRD5A3 gene, encoding steroid 5α-reductase type 3, in a group of patients who presented with this particular phenotype and a common metabolic pattern. Here, we report on the clinical, genetic and metabolic features of 12 patients from nine families with cerebellar ataxia and congenital eye malformations diagnosed with SRD5A3-congenital disorders of glycosylation due to steroid 5α-reductase type 3 defect. This enzyme is necessary for the reduction of polyprenol to dolichol, the lipid anchor for N-glycosylation in the endoplasmic reticulum. Dolichol synthesis is an essential metabolic step in protein glycosylation. The current defect leads to a severely abnormal glycosylation state already in the early phase of the N-glycan biosynthesis pathway in the endoplasmic reticulum. We detected high expression of SRD5A3 in foetal brain tissue, especially in the cerebellum, consistent with the finding of the congenital cerebellar malformations. Based on the overlapping clinical, biochemical and genetic data in this large group of patients with congenital disorders of glycosylation, we define a novel syndrome of cerebellar ataxia associated with congenital eye malformations due to a defect in dolichol metabolism.

Key Points 5hmC levels vary considerably in patients with AML. High levels of 5hmC independently correlate with inferior overall survival in AML.