Succinic semialdehyde dehydrogenase deficiency of four Chinese patients and prenatal diagnosis for three fetuses.

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder that affects the degradation of γ-aminobutyric acid (GABA). Only a few cases of SSADH deficiency have been documented in mainland China and prenatal diagnosis has not been performed. SSADH deficiency in four patients (three girls and one boy) from four unrelated Chinese families was detected by selective screening at the age of 50days to 1year. Four patients were admitted due to intractable seizures and psychomotor retardation. Their urine 4-hydroxybutyric acid was significantly elevated. Seven mutations in their ALDH5A1 gene were identified, of which the following six were novel: c.127-128insGGCCC (p.Q43Rfs*50), [corrected] c.615delT (p.F206Sfs*5), c.1313T>C (p.L438P), c.1568C>T (p.S523F), 1383-2delA and a 0.15-Mb deletion harboring ALDH5A1. Only one mutation, c.820C>T, had been previously reported. Three mothers of Patients 1-3 underwent amniocentesis during their third pregnancy and the fetuses were not affected by SSADH deficiency. Normal development and urine organic acid levels of the infants confirmed the prenatal diagnosis after birth.

Familial 6p22.2 duplication associates with mild developmental delay and increased SSADH activity.

We present a family with mild developmental delay and a duplication (6)(p22.2). Array CGH analyses revealed this 0.7 Mb duplication in all three patients, spanning candidate genes ALDH5A1, DCDC2, and KIAA0319. Results were confirmed by MLPA analysis of the dyslexia genes DCDC2 and KIAA0319. Of interest, ALDH5A1 encodes succinate semialdehyde dehydrogenase (SSADH), an enzyme responsible for γ-amino-butyric acid (GABA) degradation. Inherited deficiency of SSADH results in accumulation of the neuromodulator γ-hydroxybutyrate (GHB), which likely contributes to some aspects of the neurological phenotype of SSADH deficiency (MIM #271980). Based on autosomal-recessive inheritance, we sequenced ALDH5A1 in all patients, which revealed no pathogenic mutations. SSADH enzyme studies in cultured white cells confirmed elevated SSADH activity, consistent with the duplication, whereas concentrations of SSA were slightly elevated in urine, suggesting oxidant stress. We speculate that the duplication (6)(p22.2) and corresponding hyperactive level of SSADH activity may have negative consequences for GABA metabolism and the role of SSADH in other metabolic sequences.