Dihydrolipoamide Dehydrogenase Deficiency
A number sign (#) is used with this entry because dihydrolipoamide dehydrogenase deficiency (DLDD) is caused by homozygous or compound heterozygous mutation in the DLD gene (238331) on chromosome 7q31.
DescriptionDLD deficiency is an autosomal recessive metabolic disorder characterized biochemically by a combined deficiency of the branched-chain alpha-keto acid dehydrogenase complex (BCKDC), pyruvate dehydrogenase complex (PDC), and alpha-ketoglutarate dehydrogenase complex (KGDC). This is the result of E3 being a common component of all 3 mitochondrial multienzyme complexes. Clinically, affected individuals have lactic acidosis and neurologic deterioration due to sensitivity of the central nervous system to defects in oxidative metabolism. E3 deficiency is often associated with increased urinary excretion of alpha-keto acids, such as pyruvate (summary by Hong et al., 1996). E3 deficiency can also be associated with increased concentrations of branched-chain amino acids, as observed in maple syrup urine disease (MSUD; 248600), and is sometimes referred to as 'MSUD type III,' although patients with E3 deficiency have additional biochemical defects (Chuang and Shih, 2001; Robinson, 2001).
Clinical FeaturesRobinson et al. (1977) reported a male child, born of Caucasian first-cousin parents, who died at age 7 months with progressive neurologic deterioration and persistent metabolic acidosis. He was well until age 8 weeks, when he abruptly became ill with irregular labored respiration, increased muscle tone, bilateral optic atrophy, and metabolic acidosis. He had elevated blood pyruvate, lactate, alpha-ketoglutarate, and branched-chain amino acids, as well as occasional hypoglycemia. Thiamine therapy was of no benefit. Postmortem tissue analysis showed deficiency of the pyruvate dehydrogenase complex, and specifically of dihydrolipoyl dehydrogenase, or E3. Robinson et al. (1981) reported another similar case. The parents were normal in both cases, but the parents of 1 patient had decreased enzyme activity at about 30 to 42% of normal, supporting recessive inheritance. A primary deficiency of this enzyme had been suggested as the basic defect in Friedreich ataxia (229300), but Robinson et al. (1981) concluded that the deficiency in Friedreich ataxia is likely a secondary phenomenon.
In a case of E3 deficiency, Matalon et al. (1981) found that oral administration of lipoic acid resulted in almost complete clearance of abnormal organic aciduria and lactic and pyruvic acidemia, with clinical improvement. The patient had neonatal hypothermia, failure to thrive, and metabolic acidosis. In cultured fibroblasts, the E3 component was 23% of the control mean. Munnich et al. (1982) reported a 6-month-old girl with vomiting, hypotonia, and motor retardation who had combined chemical features of lactic acidosis, maple syrup urine disease, and ketoglutaric aciduria. E3 activity was reduced.
Sakaguchi et al. (1986) reported a patient with E3-deficient MSUD. In the first week of life, the patient's blood leucine was found to be 5 mg/dl, but the patient was left on a normal diet. At the age of 6 months, he exhibited hypotonia and minimal dystonic movements of the upper limbs. He had elevated plasma levels of pyruvate, alpha-ketoglutarate, and branched-chain amino acids and alpha-keto acids. Urinary excretion of these keto acids and their metabolites were also elevated. At 7 months of age, the patient was placed on a diet restricted in branched-chain amino acids, resulting in improvement of some biochemical and developmental parameters. The patient died at the age of 21 months, following a ketoacidotic episode. The total pyruvate dehydrogenase complex activity of the patient's cells was 10 to 30% that of control cells. Pyruvate dehydrogenase (E1) and dihydrolipoamide acetyltransferase (E2) activities were normal in the patient's muscle, but E3 activity was not detectable in either muscle or liver specimens obtained at autopsy.
In 3 males born to first-cousin Algerian parents and presenting with hypotonia, metabolic acidosis, and hyperlactatemia immediately after birth, Bonnefont et al. (1992) described a 'new' inborn error of the tricarboxylic acid cycle, alpha-ketoglutarate dehydrogenase. Neurologic deterioration resulted in death at about 30 months of age. In a review of the patients reported by Bonnefont et al. (1992), Odievre et al. (2005) noted that 1 of the patients had hypertrophic cardiomyopathy. The patients showed lack of accumulation of branched-chain amino acids or pyruvate, but KGDC activity was markedly deficient. In fibroblasts derived from these patients, Odievre et al. (2005) identified a homozygous mutation in the DLD gene (R447G; 238331.0012). E3 activity was about 20% of controls, and residual activity of the PDC and BCKDC were 63% and 56% of controls, respectively, which was likely sufficient to prevent accumulation of pyruvate and branched-chain amino acids.
Craigen (1996) described a 6-month-old female infant who presented with hypotonia, ketolactic acidosis, and an MRI of the brain that showed subacute necrotizing encephalomyelopathy consistent with Leigh syndrome (LS; 256000). Enzymatic analysis demonstrated deficiency of lipoamide dehydrogenase. Treatment with lipoic acid and later with dichloroacetate led to a significant but transient decline in serum lactate levels, but no clinical improvement. Hong et al. (1996) also studied the patient reported by Craigen (1996). She had developmental delay, hypotonia, metabolic acidosis, transient neonatal hypoglycemia, and poor sucking. Plasma amino acid analysis in the patient initially showed increased branched-chain amino acids, and urinary organic acid analysis showed mild to moderate increases of lactic, 2-hydroxybutyric, 3-hydroxybutyric, alpha-ketoglutaric, and 3-hydroxyisovaleric acids. She died at age 28 months. Activities of the PDC and E3 in patient lymphocytes were 26% and 2% of control values, respectively, and in patient fibroblasts were 11% and 14%, respectively. KGDC activity in fibroblasts was 20%. Corresponding values in the clinically unaffected parents were about 50% of normal, except for KGDC, which was normal. These findings suggested that a partial reduction in E3 is not rate-limiting for KGDC activity in fibroblasts. Glycine was also not increased in the patient.
Shany et al. (1999) reported a 9-month-old girl of Muslim origin with a severe neurodegenerative form of DLDD. She presented on the third day of life with apathy, poor feeding, and lethargy. Laboratory studies showed hypoglycemia and severe lactic acidosis, but normal levels of branched-chain keto acids and alpha-ketoglutarate. Muscle biopsy showed no activity of the pyruvate dehydrogenase complex, severely decreased activity of the alpha-ketoglutarate dehydrogenase complex (2%), and decreased DLD activity at 15% of controls. Each unaffected parent had about 50% reduced DLD protein activity. The patient had recurrent episodes of metabolic acidosis, often triggered by infection. Clinical features included microcephaly, lack of psychomotor development, blindness, deafness, hypotonia, brisk reflexes, and mild hypertrophic cardiomyopathy.
Hong et al. (2003) described 4 patients with DLD deficiency. Two were a sister and brother, born of consanguineous Palestinian Arab Muslim parents. The sister died in infancy during an episode of repeated vomiting associated with encephalopathy. Two earlier-born sibs had died under similar circumstances. Her brother had recurrent episodes of vomiting associated with encephalopathy from age 8 months. Examination at age 10 years showed generalized muscle weakness and wasting, ataxic gait, hepatomegaly, and lactic acidemia. He was treated with riboflavin, coenzyme Q, biotin, and carnitine. Six years later, he was functioning well at a normal school, but had slight ataxia and intention tremor. The 2 other patients, both of Ashkenazi Jewish descent, had a severe form of E3 deficiency. One had repeated episodes of hypoglycemia and was in a persistent vegetative state at age 4 years; he died soon after. A girl had recurrent episodes of repeated vomiting and acidosis since infancy; she died of hepatic failure at age 5 years. All 4 patients, including the Arab sibs, were homozygous for a G229C mutation (238331.0006) that is a founder allele among Ashkenazi Jews. All patients had decreased levels of the E3 protein (range, 35-68% of controls) and decreased E3 activity (8 to 33% of controls). Hong et al. (2003) emphasized the favorable outcome in the 1 child treated with riboflavin and additional supplements.
Cameron et al. (2006) reported 2 second-cousin Ashkenazi Jewish boys with DLD deficiency. They had different genotypes and variable severity. One presented on the second day of life with metabolic acidosis and seizures, and showed episodes of myocardial and hepatic dysfunction, but had a relatively mild course of recurrent encephalopathy up to 8.5 years of age. The other presented at age 14 months with developmental delay, hypotonia, weakness, and microcephaly, and had multiple episodes of decompensation. Both patients had decreased activities of the KGDH (25% and 44%, respectively) and BCKDH (58% and 62%, respectively) complexes, but PDH complex activity was at the low end of normal (69% and 59%, respectively). DLD activity was decreased in both patients.
Clinical Variability
Shaag et al. (1999) studied 13 patients with E3 deficiency originating from 7 Ashkenazi Jewish families. The disease course was highly variable, with a variable age at onset. Some patients had few neurologic sequelae and long survival. Two patients presented immediately after birth, 9 around age 2 years, and 2 as adults. All had recurrent episodes of vomiting, abdominal pain, and hepatomegaly, usually associated with neurologic signs during the episodes. Episodes were associated with lactic acidosis, abnormal liver enzymes, and prolonged prothrombin time. Biochemical anomalies, such as increased branched-chain amino acids and increased alpha-ketoacids, were not commonly found. The 2 patients who presented neonatally had residual neurologic damage with attention deficit-hyperactivity disorder, mild ataxia, motor incoordination, muscle hypotonia, and weakness. Nine patients who presented in early childhood or as adults suffered from exertional fatigue between episodes of decompensation but were otherwise asymptomatic and showed normal psychomotor development. Two patients died because of intractable metabolic acidosis and multiorgan failure. In all patients E3 activity was reduced to 8 to 21% of the control value in muscle or lymphocytes. In 4 patients tested, the E3 protein in muscle was reduced to 20 to 60% of control. Eleven patients were homozygous for a founder mutation in the DLD gene (G229C; 238331.0006) and 2 were compound heterozygous for G229C and a 1-bp insertion (238331.0003). Shaag et al. (1999) concluded that the phenotype associated with G229C is milder than that associated with other genotypes. However, the phenotype did not appear to be associated with residual enzyme activity.
InheritanceThe transmission pattern of DLD deficiency in the families reported by Shaag et al. (1999) was consistent with autosomal recessive inheritance.
Molecular GeneticsIn a patient with dihydrolipoyl dehydrogenase deficiency reported by Sakaguchi et al. (1986), Liu et al. (1993) demonstrated compound heterozygosity for 2 missense mutations in the DLD gene (238331.0001 and 238331.0002).
In a female infant with E3 deficiency previously reported by Craigen (1996). Hong et al. (1996) identified compound heterozygosity for 2 mutations in the DLD gene (238331.0003 and 238331.0004).
In 2 second-cousin Ashkenazi Jewish patients with DLD deficiency, Cameron et al. (2006) identified compound heterozygosity for 2 mutations in the DLD gene. Both patients carried an I47T mutation (238331.0013) on 1 allele; on the other allele, one had a G229C mutation (238331.0006) and the other had an E375K (238331.0009) mutation. All of the parents were unaffected and heterozygous for 1 of the mutations.
Population GeneticsAmong 13 affected patients from 7 Ashkenazi Jewish families with LAD deficiency, Shaag et al. (1999) identified a founder mutation (G229C; 238331.0006) in the DLD gene in 12 of 14 mutated alleles. The other 2 alleles had a previously identified insertion mutation (238331.0003).