Expanding the clinical spectrum of 3-phosphoglycerate dehydrogenase deficiency.

UNLABELLED: 3-Phosphoglycerate dehydrogenase (3-PGDH) deficiency is considered to be a rare cause of congenital microcephaly, infantile onset of intractable seizures and severe psychomotor retardation. Here, we report for the first time a very mild form of genetically confirmed 3-PGDH deficiency in two siblings with juvenile onset of absence seizures and mild developmental delay. Amino acid analysis showed serine values in CSF and plasma identical to what is observed in the severe infantile form. Both patients responded favourably to relatively low dosages of serine supplementation with cessation of seizures, normalisation of their EEG abnormalities and improvement of well-being and behaviour. These cases illustrate that 3-PGDH deficiency can present with mild symptoms and should be considered as a treatable disorder in the differential diagnosis of mild developmental delay and seizures. SYNOPSIS: we present a novel mild phenotype in patients with 3-PGDH deficiency.

Mutations in the urocanase gene UROC1 are associated with urocanic aciduria.

Urocanase is an enzyme in the histidine pathway encoded by the UROC1 gene. This report describes the first putative mutations, p.L70P and p.R450C, in the coding region of the UROC1 gene in a girl with urocanic aciduria presenting with mental retardation and intermittent ataxia. Computed (in silico) predictions, protein expression studies and enzyme activity assays suggest that none of the mutations can produce a fully functional enzyme. The p.L70P substitution, which probably implies the disruption of an alpha-helix in the N-terminus, would alter its properties and therefore, its function. The p.R450C change would render impossible any interaction between urocanase and its substrate and would loss its enzyme activity. Consequently, these studies suggest that both mutations could alter the correct activity of urocanase, which would explain the clinical and biochemical findings described in this patient.

Novel EBP gene mutations in Conradi-Hünermann-Happle syndrome.

BACKGROUND: Conradi-Hünermann-Happle syndrome [X-linked dominant chondrodysplasia punctata type 2 (CDPX2); MIM no. 302960] is an X-linked dominant disorder of cholesterol metabolism that causes a wide spectrum of skeletal abnormalities and linear ichthyosiform skin lesions. Mosaicism is probably responsible for the variability of the phenotype. OBJECTIVES: To describe new mutations in patients with variable manifestations of the disease. METHODS: We studied three patients with CDPX2. We performed mutation analysis of the EBP (formerly known as CDPX2) gene and gas chromatography-mass spectroscopy on serum of two patients. RESULTS: We found two novel (3G-->T and 419-422delTTCT) and one known mutation in the EBP gene. We demonstrated the presence of increased levels of dehydrocholesterol and 8(9)-cholestenol in the two patients with new mutations, confirming the diagnosis of CDPX2 and strongly suggesting that the mutations are indeed pathogenic. One patient had a very mild phenotype, presenting with linear alopecia and a mild symmetrical epiphyseal dysplasia. X-inactivation studies in peripheral blood of all patients showed skewing in only the most severely affected patient. CONCLUSIONS: The strong phenotypic variability in our patients suggests that there is no clear genotype-phenotype correlation.

Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder.

Congenital disorders of glycosylation (CDG) represent a group of inherited multiorgan diseases caused by defects in the biosynthesis of glycoproteins. We report on two dysmorphic siblings with severe liver disease who died at the age of a few weeks. Increased activities of lysosomal enzymes in plasma were found, though total sialic acid in plasma was strongly decreased. Isoelectric focusing of serum sialotransferrins showed a type 2-like CDG pattern. Some of the known CDG subtypes were excluded. O-Glycosylation was investigated by isoelectric focusing of apolipoprotein C-III, which showed increased fractions of hyposialylated isoforms. In a consecutive study a defect in the conserved oligomeric Golgi complex was established at the level of subunit COG-7, leading to disruption of multiple glycosylation functions of the Golgi. This report on patients with a new variant of CDG, due to a multiple Golgi defect, emphasizes in addition to sialotransferrins the importance of analysis of a serum O-linked glycoprotein, e.g. apolipoprotein C-III, in unclassified CDG-X cases.

Recurrent leg ulcers in a young man with hyperhomocysteinemia, factor V Leiden and impaired fibrinolysis.

We present a young male patient referred to our hospital with leg ulcers on both legs that were more than 3 years refractory to standard treatment with compression therapy. By thrombophilia screening factor V Leiden mutation, hyperhomocysteinemia and evidence for impaired fibrinolysis were found. Treatment with folic acid in combination with long-term oral anticoagulant therapy was added to non-elastic compression therapy. The leg ulcers showed slow improvement and complete healing within 3 years. During a 6-year follow-up period neither new thrombo-embolic events occurred nor recurrence of ulcerations. This case suggests a potential synergistic pathogenic role of factor V Leiden, hyperhomocysteinemia and impaired fibrinolysis in the development of postthrombotic syndrome and his sequelae. We postulate that increased formation of thrombi in the microcirculation of the skin in combination with ambulatory venous hypertension due to recurrent deep venous thrombosis might explain our observation.