Pyruvate Dehydrogenase E1-Alpha Deficiency

A number sign (#) is used with this entry because pyruvate dehydrogenase E1-alpha deficiency (PDHAD) is caused by mutation in the gene encoding the E1-alpha polypeptide (PDHA1; 300502) of the pyruvate dehydrogenase (PDH) complex, which maps to chromosome Xp22.

Description

Genetic defects in the pyruvate dehydrogenase complex are one of the most common causes of primary lactic acidosis in children. Most cases are caused by mutation in the E1-alpha subunit gene on the X chromosome. X-linked PDH deficiency is one of the few X-linked diseases in which a high proportion of heterozygous females manifest severe symptoms. The clinical spectrum of PDH deficiency is broad, ranging from fatal lactic acidosis in the newborn to chronic neurologic dysfunction with structural abnormalities in the central nervous system without systemic acidosis (Robinson et al., 1987; Brown et al., 1994).

Genetic Heterogeneity of Pyruvate Dehydrogenase Complex Deficiency

PDH deficiency can also be caused by mutation in other subunits of the PDH complex, including a form (PDHXD; 245349) caused by mutation in the component X gene (PDHX; 608769) on chromosome 11p13; a form (PDHBD; 614111) caused by mutation in the PDHB gene (179060) on chromosome 3p14; a form (PDHDD; 245348) caused by mutation in the DLAT gene (608770) on chromosome 11q23; a form (PDHPD; 608782) caused by mutation in the PDP1 gene (605993) on chromosome 8q22; and a form (PDHLD; 614462) caused by mutation in the LIAS gene (607031) on chromosome 4p14.

Clinical Features

In general, there are 2 major presentations of PDH deficiency, metabolic and neurologic, which occur at equal frequency. The metabolic form presents as severe lactic acidosis in the newborn period, usually leading to death. Patients with the neurologic presentation are hypotonic and lethargic, and develop seizures, mental retardation, and spasticity. They often have structural abnormalities in the central nervous system with minimal or absent metabolic abnormalities. Between these 2 extremes, there is a continuous spectrum of intermediate forms characterized by intermittent episodes of lactic acidosis associated with cerebellar ataxia. Many patients fit into the category of Leigh syndrome (256000) (Brown et al., 1994).

Blass et al. (1970) reported deficiency of pyruvate decarboxylase in an 8-year-old boy who had suffered 2 to 6 episodes of ataxia each year since the age of 16 months. Most attacks followed nonspecific febrile illness or other stresses. Choreoathetosis and cerebellar ataxia were present during the episodes, with mild clumsiness between episodes. Laboratory studies showed increased blood pyruvic acid, increased blood alanine, and a decreased activity of pyruvate decarboxylase (20% of normal). The father's fibroblasts and leukocytes showed partially defective pyruvate decarboxylase, and values in the mother were at the lower limit of normal. The patient of Blass et al. (1970) was reminiscent of a boy reported by Lonsdale et al. (1969) with intermittent ataxia and choreoathetosis precipitated by acute infections. Both patients showed conspicuous abnormalities of eye movement as in Wernicke-Korsakoff syndrome (277730). Thiamine in large doses appeared to benefit Lonsdale's patient.

Farrell et al. (1975) reported a 6-month-old infant with fatal congenital lactic acidosis and deficiency of pyruvate decarboxylase. Stromme et al. (1976) reported an infant with increased blood lactate, alanine, and serine. Fibroblasts cultured from skin showed a severe decrease in activity of the PDH complex (8% of normal) and the first enzyme of the complex (4% of normal).

Livingstone et al. (1984) described a family in which 5 males in 3 sibships had intermittent cerebellar ataxia and biochemical features of abnormal pyruvate metabolism. The patients were related through 3 presumed carrier females. Postmortem examination of 1 of the affected males, who died at age 50, showed neuropathologic findings suggestive of Leigh syndrome. There was cerebellar degeneration with a distribution suggestive of olivopontocerebellar atrophy, but the histologic appearance in tissues around the third ventricle and aqueduct was similar to those seen in Wernicke encephalopathy and in Leigh syndrome. There was no response to administration of thiamine. One of the affected males had recurrent episodes of ataxia and dysarthria beginning at the age of 3 years. Each attack lasted from 2 to 12 days and occurred every 3 to 4 months. Episodes were less severe and less frequent after the age of 14 years, and he was able to hold down a steady job as a laborer. In a teenaged affected male, elevated levels of fasting serum lactate and pyruvate were noted during recovery from a typical attack. At 10 years of age, his IQ was 65. One male died of pneumonia at the age of 5 years after recurrent attacks of hyperventilation and unsteadiness from the age of 3 years. Livingstone et al. (1984) observed at least a temporary favorable response to acetazolamide, and suggested that the basic defect might reside in the gene for the E1-alpha component of the pyruvate dehydrogenase complex.

Robinson and Sherwood (1984) found that 18 of 23 patients with congenital lactic acidemia had a defect in the first component of the PDH complex. Ten cases had facial dysmorphism consisting of a narrow head, wide nasal bridge and flared nostrils, and microcephaly. Two patients had agenesis of the corpus callosum. In a study of 30 patients with defect in the PDH complex E1 component Robinson et al. (1987) found that residual activity of the PDH complex ranged from 1.6% to 69.5% of controls. Seven patients died before 6 months of age, and another 5 before 2 years of age. Sixteen of the surviving patients and the 5 who died before age 2 had psychomotor retardation, and 17 children had structural damage of the central nervous system, ranging from cerebral atrophy to cystic lesions in the cortex, basal ganglia, and brainstem resembling Leigh syndrome.

Evans (1984) reported episodic weakness in pyruvate decarboxylase deficiency. Brown et al. (1988) reported 6 patients with early onset of neurologic symptoms, gross cerebral changes, and increased levels of pyruvate and lactate in cerebrospinal fluid. Although the patients appeared to have a defect in pyruvate metabolism as evidenced by deficient pyruvate dehydrogenase activity in cultured fibroblasts, systemic acidosis was not a problem clinically and blood pyruvate and lactate concentrations were only slightly raised. Brown et al. (1988) termed this form of the disorder 'cerebral' lactic acidosis.

Kerr et al. (1988) described 2 brothers who had E1 deficiency in liver, skeletal muscle, and heart. The pyruvate dehydrogenase complex showed about 30% activity in kidney. The second (E2) and third (E3) components of the complex were normal. PDH activity was less than 10% of controls in lymphocytes, but normal in skin fibroblasts. Kerr et al. (1988) considered the possibility of X-linked inheritance because these patients and 4 other similarly affected patients with absence of both E1 subunits were male and because the mother, but not the father, had reduced enzyme activity in her lymphocytes. The fact that the maternal grandmother and great-grandmother had normal lymphocyte pyruvate dehydrogenase activity suggested that the mutation had originated with the mother of the brothers. The clinical course was as severe as in the usual cases, but the neuropathologic findings of Leigh syndrome were not found. Kerr et al. (1988) noted that if the activity of pyruvate dehydrogenase had not been found to be very low in lymphocytes, the defect could easily have been overlooked because of the normal activity in fibroblasts. In the patients reported by Kerr et al. (1988), Wexler et al. (1992) identified a mutation in the PDHA1 gene (300502.0008).

Matthews et al. (1993) reported an infant with a clinical diagnosis of Leigh syndrome. He was delivered by cesarean section at 36 weeks because of worsening preeclampsia and a breech presentation, and was limp and apneic on delivery. He showed little growth or development and died at about 13 weeks. Pathologic findings were consistent with subacute necrotizing encephalomyelopathy, and deficiency of the pyruvate dehydrogenase complex was demonstrated enzymatically.

Dahl and Brown (1994) described a male infant with E1-alpha deficiency who died suddenly at the age of 18 months after becoming acutely ill with an intercurrent viral illness. Marked spongiform change was found in the globus pallidus and less extensive degenerative change in the dentate nucleus and surrounding white matter. He had previously been found to have developmental delay and biochemical evidence of compensated metabolic acidosis with mild elevation of the blood lactate and pyruvate concentrations. A mutation was identified in the PDHA1 gene (300502.0012).

Takakubo et al. (1995) reported a 10-month-old male with E1-alpha deficiency who presented with intermittent divergent squint. A half brother had died at age 33 months with autopsy-confirmed Leigh syndrome after a progressive neurologic illness that began with ocular symptoms. No other neurologic abnormalities were found in the proband, and blood lactate and pyruvate levels were within normal limits. However, cerebrospinal fluid lactate and pyruvate levels were markedly raised, and cultured skin fibroblasts showed PDH complex activity of 28% and PDHA1 activity of 23% of normal control mean. A mutation in the PDHA1 gene (300502.0017) was found in the proband, an affected brother, and the mildly affected mother.

Naito et al. (1997) reported a boy with PDHAD born at term to healthy, consanguineous parents. At age 4 months, he showed developmental delay. He had increased blood lactate and pyruvate as well as basal ganglia lesions on MRI, consistent with Leigh syndrome. His older brother had shown a similar disorder, with hypotonia, mental retardation, lactic acidemia, and basal ganglia lesions. The brothers died at ages 6 and 4 years from respiratory failure. The index patient showed some clinical improvement with thiamine therapy.

De Meirleir et al. (1998) reported a 3-year-old boy and a younger sister with E1-alpha deficiency caused by mutation in the PDHA1 gene (300502.0019). The boy showed general hypotonia during development, and from the age of 3 months had several episodes of ptosis lasting 1 to 2 days. These episodes became more frequent between 15 and 17 months of age and were associated with swallowing disturbances and hypotonia, paralysis of lateral gaze, and tachypnea. Metabolic acidosis was found. He had 2 episodes of acute ataxia with weakness between the ages 2 and 3 years. MRI of the brain demonstrated bilateral pallidal lesions and demyelinating pons lesions. The more severely affected younger sister presented from birth with severe hypotonia and dysmorphia and by the age of 10 months developed spastic quadriplegia with areflexia and severe mental retardation.

Okajima et al. (2006) reported a 7-year-old boy with E1-alpha deficiency resulting from somatic mosaicism for a splice site mutation in the PDHA1 gene. The diagnosis was difficult due to the relatively mild and nonspecific features. He presented at age 6 months with moderately delayed motor development and was subsequently found to have intermittent elevated blood lactate on several occasions. Other biochemical studies and brain MRI were normal. At 18 months, he had mild microcephaly, mild global developmental delay, central hypotonia, and mild spasticity of the lower extremities. He spoke his first words at 14 months and walked at 24 months. Repeat measurements showed increased CSF lactate and pyruvate, and the correct diagnosis was made. At age 6 years, he had cognitive impairment, showed some repetitive automatisms, poor attention span, hyperactivity, and mild hypotonia. Total PDC activity was significantly decreased in fibroblasts and skeletal muscle, but normal in lymphocytes. Detailed genetic, biochemical, and Western blot analysis of buccal cells, hair, lymphoblasts, and fibroblasts showed a mixed species of mutant and normal E1-alpha, with corresponding variable activity and immunoreactivity, all consistent with somatic mosaicism.

Heterozygous Females

Dahl et al. (1992) described 3 female patients with pyruvate dehydrogenase deficiency due to mutation in the PDHA1 gene (300502.0009). Two of the patients demonstrated typical features of the disorder with severe neurologic dysfunction, degenerative changes, and developmental anomalies in the brain, together with variable lactic acidosis. Both had manifestations from early after birth; 1 died at 5 months and the other at 17 years. The third patient, an adult who was the mother of the 17-year-old, had delayed development. She did not walk until 4 years of age and could not spell until she was 20. She had epilepsy which was reasonably controlled with medication. The mother had 4 brothers, all of normal intelligence. Dahl et al. (1992) suggested that she may have been a mosaic for an early somatic mutation.

Matthews et al. (1994) reported 2 female patients with early-onset encephalopathy and lactic acidosis who had PDH activity in the normal range. One had mild dysmorphic features, antimongoloid slant of the eyes, a broad philtrum, and microcephaly. There was generalized brain atrophy, ventriculomegaly, and a frontoparietal cystic lesion. The X-inactivation pattern in the fibroblasts was 80 to 20. This was the third child of consanguineous parents; a previous male infant had died with severe developmental delay and lactic acidosis. The second patient was hypotonic with marked developmental delay, cerebral atrophy, and extensor infantile spasms at 2 months of age. X-inactivation pattern was 70 to 30. The authors noted that PDH activity was well within the normal range in both girls and the diagnosis was only possible by DNA studies, which identified mutations in the PDHA1 gene (300502.0015; 300502.0016).

Shevell et al. (1994) described 3 infant girls with PDH complex deficiency. MRI revealed hypoplasia, particularly of the posterior part of the corpus callosum, as well as global white matter loss without heterotopias. Phosphorus magnetic resonance spectroscopy (MRS) of muscle revealed abnormally low phosphorylation potentials. Proton MRS of the brain demonstrated a large increase in signals of lactic acid and decrease of the relative signal intensity of N-acetylaspartate. The authors proposed that cerebral dysgenesis and cerebral lactic acidemia should suggest PDH complex deficiency.

Lissens et al. (1999) reported 2 unrelated girls with PDH deficiency caused by 2 different mutations in the PDHA1 gene (300502.0020; 300502.0021). Both patients had spastic quadriplegia, severe mental retardation, and microcephaly. One patient presented at the age of 5 months with infantile spasms. Lactate levels in blood and cerebrospinal fluid were increased, with a normal lactate/pyruvate ratio. Brain MRI at the age of 13 years revealed asymmetric irregular ventricular enlargement, abnormally steep angle of the Sylvian fissures, normal myelination, an intact corpus callosum, and a normal-sized cerebellum. In the second patient, MRI of the brain showed cortical atrophy of both cerebral hemispheres and cerebellum, a partial agenesis of the corpus callosum, and dilatation of the lateral and third ventricles. Both patients had low PDH activity, but normal amounts of all subunits on Western blotting. Blood lactate and pyruvate levels were increased, with a normal lactate/pyruvate ratio. X-inactivation studies in fibroblast DNA showed that the second patient had an almost completely skewed inactivation pattern.

Biochemical Features

With a polyclonal antibody, Wicking et al. (1985) identified absence of the E1 alpha-subunit in a patient with severe neonatal lactic acidosis and structural alteration of the E1 protein in another patient with severe brain damage associated with less severe lactic acidosis. Birch-Machin et al. (1988) described an infant with severe pyruvate dehydrogenase deficiency who had low concentrations of both the alpha and beta subunits of E1 in immunochemical studies of liver and skeletal muscle mitochondrial fractions.

Using both specific antibodies to pyruvate dehydrogenase and cDNAs coding for its 2 alpha and beta subunits, Wexler et al. (1988) characterized 11 patients with PDH deficiency. Three different patterns were found: 7 patients had immunologically detectable cross-reactive material for the alpha and beta proteins of PDH; 2 patients had no detectable cross-reactive protein for either subunit, but had normal amounts of mRNA for both subunits; and 2 patients had no detectable cross-reactive proteins with diminished amounts of the alpha subunit mRNA only. The results indicated that loss of PDH activity may be associated with either absent or catalytically inactive proteins or with decreased mRNA. When mRNA for 1 of the subunits is lacking, both protein subunits are absent, suggesting that a mutation affecting the expression of one of them causes the remaining uncomplexed subunit to be unstable.

In a patient with intermittent ataxia, a disorder of pyruvate metabolism, and an X-linked pattern of inheritance, Bindoff et al. (1989) found immunochemical evidence for E1 deficiency in skeletal muscle mitochondria.

Diagnosis

Brown et al. (1994) reviewed all aspects of PDH deficiency, including prenatal diagnosis and treatment. They noted that the biochemical abnormalities may be minimal and easily overlooked, especially when the patient has extensive structural defects in the brain. The variable manifestations of the disorder in heterozygous females is largely determined by differences in the pattern of X inactivation, and there are considerable difficulties in establishing the diagnosis when it is based on measurements of enzyme activity and immunoreactive protein.

In a significant number of patients with biochemical evidence of a defect in the E1-alpha component of the pyruvate dehydrogenase complex, it is not possible to identify a mutation in the gene coding regions. Brown et al. (1997) developed a method to screen for E1-alpha gene defects based on complementation of the enzyme deficiency in transformed fibroblast cell lines following transfection and expression of the normal cDNA. Using this system, cell lines from patients with a variety of different defined mutations in the PDHA1 gene showed restoration of enzyme activity. A number of patients were identified in whom deficient enzyme activity was not restored by expression of the normal cDNA, indicating that an alternative explanation for the enzyme defect must be sought.

Clinical Management

Falk et al. (1976) reported successful treatment of PDH deficiency with a ketogenic diet.

McCormick et al. (1985) reported the successful use of sodium benzoate in a neonate with hyperammonemia associated with congenital lactic acidosis caused by a partial deficiency of the E1 component of the PDH complex. The authors noted that this biochemical disturbance had not previously been observed in PDH deficiency.

Fouque et al. (2003) investigated the underlying mechanism for the differential response to dichloroacetate (DCA), a structural pyruvate analog, in fibroblasts from 3 PDHC-deficient patients with very low levels of PDHC activity, unstable polypeptides, and different mutations in the E1-alpha subunit: 2 point mutations and a deletion mutation. Cell lines with the point mutations responded to treatment, whereas the cell line with the deletion did not. Fouque et al. (2003) concluded that mutations that retain catalytic activity may be DCA responsive due to increased E1-alpha subunit stability and that DCA may be useful as an adjunct to ketogenic and thiamine treatment.

Thiamine-Responsive Pyruvate Dehydrogenase Deficiency

Lonsdale et al. (1969), Brunette et al. (1972), and Wick et al. (1977) reported patients who benefited from thiamine.

Naito et al. (1994) reported a patient with thiamine-responsive deficiency of the PDH complex, resulting from a reduced affinity of the PDHC for thiamine pyrophosphate (TPP). Naito et al. (1998) reported on the characteristics of 13 patients with thiamine-responsive lactic acidemia and examined the activity of the PDH complex to sodium dichloroacetate (DCA), known as an activator of PDHC. Three groups were identified according to PDHC activity in cell culture: 2 patients had very low PDHC activity, which was not increased by DCA but was increased at high TPP concentrations; 5 patients displayed below normal PDHC activity, which was increased by DCA and by high TPP concentrations; and 6 patients had normal PDHC activity at low and high TPP concentrations, which was increased by DCA. The authors concluded that PDHC deficiency in the patients of the first 2 groups was due to a decreased affinity of PDHC for TPP.

Naito et al. (2002) reported 2 unrelated male patients with thiamine-responsive E1-alpha deficiency. Both boys had onset of weakness, hypotonia, and gait instability at an early age, and had mutations in the PDHA1 gene (300502.0012 and 300502.0023). Analysis of cultured lymphoblastoid cells from the patients showed a decrease in E1 affinity for TPP and a significant increase in PDH complex and E1 activity in response to high TPP concentrations. With thiamine therapy, both patients showed clinical improvement in blood lactate and pyruvate concentrations and in neurologic symptoms.

Inheritance

Benke et al. (1982) suggested the existence of an X-linked recessive form of Leigh syndrome on the basis of their observation of affected half brothers (with different fathers), a sex ratio of M1.83:F1.0 in reported cases, and a reported excess of male sibs in reported familial cases. For example, Montpetit et al. (1971) reported a family in which 2 of 4 brothers were affected; their mother had a brother who died at 2.7 years with spastic quadriplegia and another brother who died at 8 months following a viral illness and convulsions. Kissach et al. (1974) described 2 affected brothers who had 2 maternal uncles, aged 47 and 49 years, with nystagmus, chorea, and hypercapnia, and, in 1, intermittent coma.

Molecular Genetics

In a male patient with lactic acidosis and decreased pyruvate dehydrogenase E1 activity, Endo et al. (1989) identified a 4-bp deletion in the PDHA1 cDNA (300502.0001). In a female patient with PDH deficiency and decreased levels of the E1-alpha subunit, Dahl et al. (1990) identified a 7-bp deletion in the PDHA1 gene (300502.0002). The authors noted that the severity of the deficiency in affected females is largely dependent on the X-chromosome inactivation patterns in the brain.

Dahl et al. (1992) cataloged 20 different mutations, including deletions, insertions, and point mutations. Twelve of the 20 mutations occurred in exons 10 and 11 of this 11-exon gene. Four of the mutations were seen in unrelated patients.

In a male infant with PDHAD presenting as acute Leigh syndrome, Matthews et al. (1993) identified a point mutation in the PDHA1 gene (D258A; 300502.0011).

In a review of the literature, Matthews et al. (1994) noted that most of the reported mutations in the E1-alpha gene were unique. The sex ratio of PDH E1-alpha deficiency was approximately 1:1, but almost all of the missense mutations had been identified in males and almost all of the deletions or insertions had been found in females. Matthews et al. (1994) speculated that insertions and deletions in hemizygous males may cause intrauterine death.

In a boy who presented with Leigh syndrome, Naito et al. (1997) identified a mutation in the PDHA1 gene (R263G; 300502.0022). His unaffected mother was heterozygous for the mutation. Functional studies of cells from the patient and his mother showed decreased affinity of the pyruvate dehydrogenase complex, and the E1 subunit in particular, for thiamine pyrophosphate, a necessary coenzyme. Naito et al. (1997) suggested that variable expression of pyruvate dehydrogenase complex deficiencies may depend on surrounding concentrations of thiamine and thiamine pyrophosphate.