: 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...