title: Dihydrolipoamide dehydrogenase (DLD) deficiency in a Spanish patient with myopathic presentation due to a new mutation in the interface domain.
abstract: We present a 32-year-old patient who, from age 7 months, developed photophobia, left-eye ptosis and progressive muscular weakness. At age 7 years, she showed normal psychomotor development, bilateral ptosis and exercise-induced weakness with severe acidosis. Basal blood and urine lactate were normal, increasing dramatically after effort. PDHc deficiency was demonstrated in muscle and fibroblasts without detectable PDHA1 mutations. Ketogenic diet was ineffective, however thiamine gave good response although bilateral ptosis and weakness with acidosis on exercise persisted. Recently, DLD gene analysis revealed a homozygous missense mutation, c.1440 A>G (p.I480M), in the interface domain. Both parents are heterozygous and DLD activity in the patient's fibroblasts is undetectable. The five patients that have been reported with DLD-interface mutations suffered fatal deteriorations. Our patient's disease is milder, only myopathic, more similar to that due to mutation p.G229C in the NAD(+)-binding domain. Two of the five patients presented mutations (p.D479V and p.R482G) very close to the present case (p.I480M). Despite differing degrees of clinical severity, all three had minimal clues to DLD deficiency, with occasional minor increases in α-ketoglutarate and branched-chain amino acids. In the two other patients, hypertrophic cardiomyopathy was a significant feature that has been attributed to moonlighting proteolytic activity of monomeric DLD, which can degrade other mitochondrial proteins, such as frataxin. Our patient does not have cardiomyopathy, suggesting that p.I480M may not affect the DLD ability to dimerize to the same extent as p.D479V and p.R482G. Our patient, with a novel mutation in the DLD interface and mild clinical symptoms, further broadens the spectrum of this enzyme defect.
authors.affiliation: Sección de Errores Congénitos del Metabolismo, Servicio de Bioquímica y Genética Molecular, Hospital Clínic, Instituto de Bioquímica Clínica, Barcelona, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: Quintana
authors.forename: Mercé
authors.initials: M
authors.lastname: Pineda
authors.forename: Aida
authors.initials: A
authors.lastname: Font
authors.forename: Maria Antonia
authors.initials: MA
authors.lastname: Vilaseca
authors.forename: Frederic
authors.initials: F
authors.lastname: Tort
authors.forename: Antonia
authors.initials: A
authors.lastname: Ribes
authors.forename: Paz
authors.initials: P
authors.lastname: Briones
mesh_terms: D000140:Acidosis, Lactic / Q000175:diagnosis / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001763:Blepharoptosis / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D019587:Dietary Supplements; D005260:Female; D020022:Genetic Predisposition to Disease; D040941:Heredity; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D019344:Lactic Acid / Q000097:blood / Q000652:urine; D008375:Maple Syrup Urine Disease / Q000175:diagnosis / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D008969:Molecular Sequence Data; D053580:Muscle Strength / Q000235:genetics; D018908:Muscle Weakness / Q000175:diagnosis / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D020795:Photophobia / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics; D017434:Protein Structure, Tertiary; D015325:Pyruvate Dehydrogenase Complex Deficiency Disease / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics; D013030:Spain; D013831:Thiamine / Q000627:therapeutic use; D008063:Thioctic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000172:deficiency / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D019344:Lactic Acid; C007409:dihydrolipoamide; D008063:Thioctic Acid; D013831:Thiamine