title: Two patients with clinically distinct manifestation of pyruvate dehydrogenase deficiency due to mutations in PDHA1 gene.
abstract: The most common cause of pyruvate dehydrogenase complex (PDHc) deficiency is the deficit of the E1α-subunit. The aim of this study was to describe distinct course of the disease in two boys with mutations in PDHA1 gene and illustrate the possible obstacles in measurement of PDHc activity. Clinical data and metabolic profiles were collected and evaluated. PDHc and E1α-subunit activities were measured using radiometric assay. Subunits of PDHc were detected by Western blot. PDHA1 gene was analysed by direct sequencing. In patient 1, the initial hypotonia with psychomotor retardation was observed since early infancy. The child gradually showed symptoms of spasticity and arrest of psychomotor development. In patient 2, the disease manifested by seizures and hyporeflexia in the toddler age. The diagnosis was confirmed at the age of seven years after attacks of dystonia and clinical manifestation of myopathy with normal mental development. Brain MRI of both patients revealed lesions typical of Leigh syndrome. Enzymatic analyses revealed PDHc deficiency in isolated lymphocytes in the first but not in the second patient. The direct measurement of PDH E1-subunit revealed deficiency in this individual. In patient 1, a novel hemizigous mutation c.857C>T (Pro250Leu) was detected in the X-linked PDHA1 gene. Mutation c.367C>T (Arg88Cys) was found in patient 2. We present first two patients with PDHc deficit due to mutations in PDHA1 gene in the Czech Republic. We document the broad variability of clinical symptoms of this disease. We proved that normal PDHc activity may not exclude the disease.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Charles University, Prague, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Magner
authors.forename: K
authors.initials: K
authors.lastname: Vinšová
authors.forename: M
authors.initials: M
authors.lastname: Tesařová
authors.forename: Z
authors.initials: Z
authors.lastname: Hájková
authors.forename: H
authors.initials: H
authors.lastname: Hansíková
authors.forename: L
authors.initials: L
authors.lastname: Wenchich
authors.forename: P
authors.initials: P
authors.lastname: Ješina
authors.forename: V
authors.initials: V
authors.lastname: Smolka
authors.forename: T
authors.initials: T
authors.lastname: Adam
authors.forename: M
authors.initials: M
authors.lastname: Vaněčková
authors.forename: J
authors.initials: J
authors.lastname: Zeman
authors.forename: T
authors.initials: T
authors.lastname: Honzík
mesh_terms: D000293:Adolescent; D015153:Blotting, Western; D002648:Child; D006801:Humans; D008297:Male; D009154:Mutation; D030481:Pyruvate Dehydrogenase (Lipoamide) / Q000235:genetics*; D015325:Pyruvate Dehydrogenase Complex Deficiency Disease / Q000175:diagnosis / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D030481:Pyruvate Dehydrogenase (Lipoamide); C065640:pyruvate dehydrogenase E1alpha subunit