No abstract

To date, epimutations reported in man have been somatic and erased in germlines. Here, we identify a cause of the autosomal recessive cblC class of inborn errors of vitamin B12 metabolism that we name “epi-cblC”. The subjects are compound heterozygotes for a genetic mutation and for a promoter epimutation, detected in blood, fibroblasts, and sperm, at the MMACHC locus; 5-azacytidine restores the expression of MMACHC in fibroblasts. MMACHC is flanked by CCDC163P and PRDX1, which are in the opposite orientation. The epimutation is present in three generations and results from PRDX1 mutations that force antisense transcription of MMACHC thereby possibly generating a H3K36me3 mark. The silencing of PRDX1 transcription leads to partial hypomethylation of the epiallele and restores the expression of MMACHC. This example of epi-cblC demonstrates the need to search for compound epigenetic-genetic heterozygosity in patients with typical disease manifestation and genetic heterozygosity in disease-causing genes located in other gene trios.

: type I (MIM 239500) results from the defect of the enzyme proline dehydrogenase (oxidase), which ensures the conversion of proline into ∆-1-pyrroline-5-carboxylate (P5C), the first step in the conversion from proline to glutamate, 4 and type II (MIM 239510) is the result of a defect of the P5C dehydrogenase/aldehyde dehydrogenase 4 enzyme and P5C is excreted in the urine. 5The phenotype of type II hyperprolinaemia is characterised by neurological manifestations including seizures and mental retardation.3 6 7 Although type I hyperprolinaemia was originally described in a kindred with a familial nephropathy, 1 2 the renal disease was subsequently shown to be coincidental and type I hyperprolinaemia has been considered to be a benign disorder which can be asymptomatic.3 Nevertheless, two studies have reported severe neurological manifestations (mental retardation, epilepsy) in two male children with type I hyperprolinaemia.8 9 While mutations of the ALDH4A1 gene, located on chromosome 1p36, have been identified in families with type II hyperprolinaemia, 10 the molecular basis of type I hyperprolinaemia has not been characterised until recently. We have recently identified in schizophrenic patients a heterozygous deletion and mutations of the PRODH gene, located on 22q11, which were associated with moderate hyperprolinaemia. We also found in two unrelated type I hyperprolinaemia children the same homozygous PRODH missense mutation.11 We now report the identification of a complete homozygous PRODH deletion in a child with type I hyperprolinaemia with severe neurological manifestations. CASE REPORTThe patient, a male, was the first child of healthy, consanguineous parents of Egyptian origin. At 4 years, he was referred for severe psychomotor delay, permanent hyperactivity, sleep disturbance with bruxism, and status epilepticus. Weight was 13 kg (−3 SD), length 95 cm (−2.5 SD), and head circumference 46 cm (−4 SD). There was no dysmorphism. Cerebral magnetic resonance imaging (MRI), performed at 4 years of age, showed normal myelination and no white matter abnormalities. Metabolic screening showed a very high level of plasma proline level (2246 µmol/l, n=133-227 µmol/l). Proline levels were also raised in urine (631 µmol/mmol creatinine, n<10 µmol/mmol creatinine) and cerebrospinal fluid (21 µmol/l, Key points• Type I hyperprolinaemia (MIM 239500) is a rare metabolic disorder which is biochemically characterised by a defect of the proline dehydrogenase (oxidase) enzyme involved in the conversion from proline to glutamate. Although type I hyperprolinaemia has been considered to be a benign disorder, severe neurological manifestations (mental retardation, epilepsy) have been reported in several affected subjects.• We identified, in a child with a severe form of type I hyperprolinaemia with severe psychomotor delay and status epilepticus associated with a very high level of plasma proline level (2246 µmol/l), a complete homozygous deletion of the PRODH gene located on chromosome 22q11. This 22q11 deletion, also removing...

Isolated complex I deficiency is a frequent cause of respiratory chain defects in childhood. In this study, we report our systematic approach with blue native PAGE (BN-PAGE) to study mitochondrial respiratory chain assembly in skin fibroblasts from patients with Leigh syndrome and CI deficiency. We describe five new NDUFS4 patients with a similar and constant abnormal BN-PAGE profile and present a meta-analysis of the literature. All NDUFS4 mutations that have been tested with BN-PAGE result in a constant and similar abnormal assembly profile with a complete loss of the fully assembled complex I usually due to a truncated protein and the loss of its canonical cAMP dependent protein kinase phosphorylation consensus site. We also report the association of abnormal brain MRI images with this characteristic BN-PAGE profile as the hallmarks of NDUFS4 mutations and the first founder NDUFS4 mutations in the North-African population.