A GPHN point mutation leading to molybdenum cofactor deficiency.

To the Editor : Molybdenum cofactor deficiency (MoCoD, MIM 252150) is an autosomal recessive and rare metabolic disease (1). Absence of the cofactor inactivates sulphite oxidase activity thereby resulting via elevated sulphite levels in severe and progressive neurological damage. Affected patients are found worldwide and usually come to clinical attention by intractable seizures with a prominent opisthotonus. Diagnostic hallmarks are elevated sulphite levels in fresh urine samples and low uric acid levels due to simultaneous deficiency of the cofactor-dependent xanthine dehydrogenase. Typically, the patients are severely retarded and die within early childhood. Most of the disease-causing mutations are found in the gene MOCS 1 (type A deficiency, MIM 603707) followed by mutations in MOCS 2 (type B deficiency, MIM 603708) (2). To date, only one mutation has been described in the gene GPHN (type C deficiency, MIM 603930) (3). The GPHN gene product gephyrin has a still bewildering dual function in cofactor synthesis as well as synaptic receptor clustering (4). The formerly described mutation was a frameshift deletion affecting the G domain of the protein responsible for adenylating molybdopterin as well as the E domain required for molybdenum insertion by simultaneous hydrolysis of the adenyl bondage. Absence of both domains and activities, respectively, leaves the molybdopterin unmodified and subject to non-enzymatic molybdenum insertion by high concentrations of inorganic molybdate, which is prohibited by the adenyl activation (3). This null mutation was identified post-mortem in a Danish patient who deceased 3 days after birth. The patient described here is the second child of healthy first cousin parents of Algerian origin. Her 4-year-old brother is unaffected and there is no family history of the disease. She was born after a normal pregnancy at 39 weeks of gestation with a weight of 3.640 kg, a height of 52 cm and a head circumference of 35 cm. Ten hours after birth, she developed global hypotonia with feeding difficulties. At day 2, generalized seizures Table 1. Metabolic findings in the patient