Congenital lacticacidemia caused by lipoamide dehydrogenase deficiency with favorable outcome☆,☆☆,★
Section snippets
CASE REPORT
A 7-month-old boy was admitted because of refusal to eat and recurrent vomiting for 24 hours. He was the third child of nonconsanguineous Ashkenazi-Jewish parents. Two older sisters were healthy. He was born in another hospital after an uneventful pregnancy and delivery; birth weight was 4000 gm. He had an episode of tachypnea and vomiting 12 hours after birth, with a plasma lactate concentration of 7.0 mmol/L (normal, < 2.4 mmol/L) and total ketone bodies of 1.27 mmol/L (normal, < 0.24
METHODS
Plasma lactate levels were determined in 15 samples before therapy was started and in 66 samples during therapy. Urinary organic acids were identified with a Hewlett-Packard 5970 mass selective detector as previously described.6
In muscle homogenate, the activities of rotenone-sensitive NADH:ubiquinone oxidoreductase, antimycine-sensitive succinate:cytochrome c oxidoreductase, cytochrome c oxidase, citrate synthase, PDHC, the E1 subunit, LAD, and α-ketoglutarate dehydrogenase complex were
RESULTS
Mean plasma lactate concentrations were significantly lower after therapy (2.4 ± 0.9 mmol/L) than before (4.8 ± 2.1 mmol/L) (Figure).
On admission, urinary organic acid analysis revealed elevated lactic, β-hydroxybutyric, α-ketoglutaric, and α-ketoadipic acid levels (11.63, 1.47, 4.14, and 0.27 mol/mol creatinine, respectively). After introduction of therapy, only mild organic aciduria was found (0.18, 0.04, 0.94, and 0.15 mol/mol creatinine, respectively).
In muscle, PDHC activity was 0.51 mU/gm
DISCUSSION
Lipoamide dehydrogenase is one of the three catalytic proteins of the PDHC that converts pyruvate to acetyl-coenzyme A. LAD is also a component of two other α-keto acid dehydrogenase complexes: α-ketoglutarate dehy drogenase complex and branched-chain keto acid dehydrogenase complex. Thus a deficiency of LAD results in extensive metabolic disturbances, including lacticacidemia, Krebs cycle dysfunction with decreased NADH production, and impaired degradation of branched-chain amino acids.
Five
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Cited by (36)
The phenotypic spectrum of dihydrolipoamide dehydrogenase deficiency in Saudi Arabia
2021, Molecular Genetics and Metabolism ReportsCitation Excerpt :The variability is directly related to the effects of the mutation on the activity of the enzymatic complex [10]. To date, there is no effective treatment, although the effect of dietary supplements on disease progression and the episode severity has been reported in the literature [19–22]. We retrospectively reviewed the clinical and molecular diagnosis of 8 cases with a confirmed diagnosis of DLDD from four participating centers in Saudi Arabia to describe the phenotypic spectrum of this rare disease, which may help to establish a consensus on a treatment protocol for such cases in the future.
Organic Acids
2018, Volpe's Neurology of the NewbornDisorders of pyruvate metabolism
2013, Handbook of Clinical NeurologyCitation Excerpt :Progressively, hypotonia, psychomotor retardation, microcephaly, and spasticity occur. Some patients develop a typical picture of Leigh encephalopathy (Elpeleg et al., 1995, 1997; Grafakou et al., 2003; Hong et al., 2003). A clinical Reye-like picture with liver involvement and myopathy with myoglobinuria without mental retardation has been seen in Ashkenazi Jewish patients with an E3 deficiency (Shaag et al., 1999).
The spectrum of pyruvate dehydrogenase complex deficiency: Clinical, biochemical and genetic features in 371 patients
2012, Molecular Genetics and MetabolismCitation Excerpt :We found 159 full-length, peer-reviewed publications of 392 case reports of patients with PDC deficiency from the first reported case in 1970 [6]. A few papers reported complimentary details of the same patient [6,21,28,34,36,37,41,43,45,62,65,71,73,76,79,80,92,93,99,101,108,110,124]. Twenty-one cases were omitted from our analysis, owing to lack of explicit enzymological or molecular genetic confirmation of disease [10–20].
Thiamine and Parkinson's disease
2012, Journal of the Neurological SciencesCitation Excerpt :LAD-deficient mice have increased vulnerability to MPTP, malonate, and nitropionic acid neurotoxicity [35]. Congenital LAD deficiency has been found in muscles and fibroblasts; some patients have moderate motor impairment and respond well to thiamine treatment [36–38]. Furthermore, chromosome 7 is the location of genes for sporadic PD, LAD, and human thiamine pyrophosphokinase cDNA [39–41] and also regulates dopaminergic amacrine cell numbers in the mouse retina [42].
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From the Metabolic and Neuropediatric Units, Shaare-Zedek Medical Center, Jerusalem, Israel; the Department of Pediatrics, University Hospital, Nijmegen, The Netherlands; the Department of Pediatrics, Free University Hospital, Amsterdam, The Netherlands; the Department of Clinical Biochemistry, Hadassah Medical Center, Jerusalem, Israel; and the Department of Neurology, Columbia Presbyterian Medical Center, New York, New York.
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Reprint requests: Orly N. Elpeleg, MD, Metabolic Unit, Shaare-Zedek Medical Center, Jerusalem 91031, Israel.
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0022-3476/95/$3.00 + 09/22/60180