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Dihydrolipoamide dehydrogenase (DLD) deficiency in a Spanish patient with myopathic presentation due to a new mutation in the interface domain
Author(s) -
Quintana Ester,
Pineda Mercé,
Font Aida,
Vilaseca Maria Antonia,
Tort Frederic,
Ribes Antonia,
Briones Paz
Publication year - 2010
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-010-9169-4
Subject(s) - frataxin , ptosis , dihydrolipoamide dehydrogenase , missense mutation , cardiomyopathy , medicine , endocrinology , chronic progressive external ophthalmoplegia , muscle weakness , mutation , biology , mitochondrial myopathy , surgery , genetics , pyruvate dehydrogenase complex , biochemistry , mitochondrial dna , gene , heart failure , enzyme , iron binding proteins , transferrin
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.