title: Familial 6p22.2 duplication associates with mild developmental delay and increased SSADH activity.
abstract: 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.
authors: Department of Pathology, Haartman Institute, University of Helsinki, Finland. linda.siggberg@helsinki.fi
authors: Linda
authors: L
authors: Siggberg
authors: Aki
authors: A
authors: Mustonen
authors: Robert
authors: R
authors: Schuit
authors: Gajja S
authors: GS
authors: Salomons
authors: Birthe
authors: B
authors: Roos
authors: K Michael
authors: KM
authors: Gibson
authors: Cornelis
authors: C
authors: Jakobs
authors: Jaakko
authors: J
authors: Ignatius
authors: Sakari
authors: S
authors: Knuutila
mesh_terms: D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D058674:Chromosome Duplication; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D002658:Developmental Disabilities / Q000201:enzymology / Q000235:genetics*; D005190:Family; D005260:Female; D006801:Humans; D007962:Leukocytes; D008297:Male; D050644:Succinate-Semialdehyde Dehydrogenase / Q000378:metabolism / Q000652:urine*; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D005680:gamma-Aminobutyric Acid; C493643:ALDH5A1 protein, human; D050644:Succinate-Semialdehyde Dehydrogenase