Pyruvate Dehydrogenase E3-Binding Protein Deficiency

A number sign (#) is used with this entry because pyruvate dehydrogenase E3-binding protein deficiency is caused by homozygous or compound heterozygous mutation in the PDHX gene (608769) on chromosome 11p13.

For a general phenotypic description and a discussion of genetic heterogeneity of pyruvate dehydrogenase deficiency, see 312170.

Clinical Features

Robinson et al. (1990) described 2 patients who had decreased activity of the pyruvate dehydrogenase (PDH) complex without observable reduction in the activities of enzymes E1 (300502/179060), E2 (608770), or E3 (238331). Western blot analysis showed that 1 patient appeared to be missing the component X protein, while the other had 2 distinct bands. The first patient, a male, was born of first-cousin parents and had a presumably identically affected older brother. Clinical features included hypotonia and severe psychomotor retardation. Blood ammonia, alanine, and pyruvate were slightly elevated, and blood lactate varied between 5.9 and 9.1 mM. The second patient was born to nonconsanguineous Japanese parents. Clinical impairment was relatively subtle; unsteady gait and difficulty running was first noted at age 3 years, and poor fine motor and gross motor coordination at age 5. Blood lactate and pyruvate were increased on numerous occasions. Computed tomography scanning at age 5.5 years showed bilateral basal ganglia lucencies and symmetrical lacunae in the area of the putamen. Because of the parental consanguinity, the authors suggested autosomal recessive inheritance.

Marsac et al. (1993) described 2 affected brothers, the offspring of first-cousin parents of Portuguese origin. Both were well at first, but progressive neurologic symptoms subsequently developed. The neurologic deterioration was consistent with Leigh syndrome (256000) in the older brother; he was very hypotonic with bilateral optic atrophy at the age of 5 years, and he died of respiratory insufficiency at the age of 6 years. The younger brother was less severely affected. Between the ages of 3 and 6 years, he was hospitalized because of developmental retardation. He walked at 8 years, developed spastic diplegia with ataxia at 11 years, and died suddenly of cardiopulmonary arrest at age 16 years after an infection with severe lactic acidosis and coma. The activity of the PDH complex was reduced to 10 to 20% of normal values in both cultured skin fibroblasts and skeletal muscle. Immunoblotting of skin fibroblast mitochondrial extracts showed a specific deficiency in the protein X component of the PDH complex but normal E1, E2, and E3 components.

Geoffroy et al. (1996) reported the clinical presentation, enzymatic analysis, and Western immunoblot analysis in a newborn girl with lactic acidemia as a result of a primary defect in the X component of the PDH complex.

De Meirleir et al. (1998) reported the fourth family in which an abnormal protein X was found. The proband had severe lactic acidosis and developmental delay. Immunochemical analysis with antibodies against the PDH complex demonstrated absence of component X protein. At birth, the infant was noted to be dysmorphic with trigonocephaly, a frontal metopic ridge, and a supranasal lipoma. He had hypertelorism, a thin upper lip, bilateral epicanthus and upward slant of the eyes, high palate, and pectus excavatum. He was developmentally delayed from birth, becoming severely quadriplegic and microcephalic. CT scan of the brain demonstrated partial frontal corpus callosum agenesis with dilated lateral ventricles.

Brown et al. (2002) reported 2 unrelated patients with component X deficiency. The first was well until day 15, when he presented with projectile vomiting and was found to have metabolic acidosis and hemolytic anemia. Lactic acidosis continued and development was delayed. The patient was alive at age 23 years, with mild delayed development and dystonia. The second patient was well until age 10 weeks, when she began to have tonic-clonic seizures that continued throughout the first year. Development was impaired, and when assessed at age 6, she had global developmental delay with particularly poor coordination. There were no signs of regression at the age of 7.5 years. Brown et al. (2002) noted that the clinical features were similar to those found in the more common pyruvate dehydrogenase E1-alpha subunit deficiency (312170); however, both patients had significant residual E1 enzyme activity in cultured fibroblasts and prolonged survival.

Dey et al. (2003) reported an affected infant born to related parents. The child had severe hypotonia, respiratory distress, and abnormal ocular movements. Brain MRI showed large subependymal cysts and a thin corpus callosum. Activity of the pyruvate dehydrogenase complex was reduced to 23% of control. She died at 35 days of age.

Ramadan et al. (2004) reported 2 sisters from a family of Syrian descent and a brother and sister from a Kuwaiti family with E3-binding protein deficiency confirmed by genetic analysis. In the Syrian family, 1 child presented in the neonatal period with persistent vomiting and failure to thrive. At age 7 months, she was found to have delayed development and lactic acidosis. By age 4 years, she had a wide-based gait, generalized hypertonia, delayed mental development, and thinning of the corpus callosum on brain MRI. Her younger sister was found to have increased serum lactate at age 15 days and later showed delayed development. At age 14 months, she could stand with support and had no speech. Neither had dysmorphic features. In the Kuwaiti family, both children presented in infancy with delayed development and were found to have lactic acidosis. Brain MRI showed thin corpus callosum and cerebral atrophy; 1 had necrotic changes in the basal ganglia. Both had generalized hypotonia. One was bedridden with no speech at age 5 years; the other could understand simple commands at age 3 years and 7 months. The index patients in each family had reduced PDC activity in cultured fibroblasts and no detectable immunoreactive E3 protein.

Mine et al. (2007) reported a 25-year-old man with pyruvate dehydrogenase E3-binding protein (E3BP) deficiency confirmed by genetic analysis. Clinically, the patient showed psychomotor delay associated with spastic diplegia and dysarthria at age 3 years. At 7 years, he had recurrent acute dystonic posturing, which disappeared with a ketogenic diet. Serum lactate was normal, but CSF lactate and pyruvate were increased. Brain MRI showed atrophic corpus callosum and hyperintensities in the putamen. PDH complex activity in fibroblasts and lymphocytes was 19% and 30% of normal values, respectively. Western blot analysis detected no E3BP.

Ivanov et al. (2014) described the clinical manifestations of 20 patients from the Roma population in Bulgaria who were homozygous for the R446X mutation in the PDHX gene (608769.0011). Fifteen of 20 presented with lactic acidosis crisis in the first days or months of life, while 5 presented with delayed psychomotor development and/or seizures in infancy. Eight of 19 patients from whom data were available had hypoplasia or aplasia of the corpus callosum, and 5 of 19 had periventricular cysts. Four developed ventricular dilatation. Patients developed severe growth restriction with microcephaly. IQ was less than 30 for the vast majority. Most had spastic diplegia and quadriparesis, and 1 patient manifested axial hypotonia. The majority developed seizures in the neonatal period or later in infancy.

Diagnosis

Prenatal Diagnosis

Rouillac et al. (1999) described the results of the first prenatal diagnosis based on the PDX1 gene. The heterozygous mother of an affected child reported by Geoffroy et al. (1996) in whom a large homozygous deletion (78del85; 608769.0001) in the PDX1 gene was found by Aral et al. (1997), requested prenatal diagnosis during a subsequent pregnancy. The fetus was found to be heterozygous for the deletion, and had inherited the mother's normal allele.

Molecular Genetics

In 4 patients with neonatal lactic acidemia and component X deficiency, Aral et al. (1997) identified 2 different homozygous mutations in the PDHX gene (608769.0001 and 608769.0002). One other patient had no PDHX mRNA expression.

In 2 unrelated patients with pyruvate dehydrogenase E3-binding protein deficiency, Brown et al. (2002) identified mutations in the PDHX gene (608769.0004 and 608769.0005).

In a 25-year-old man with pyruvate dehydrogenase E3-binding protein deficiency, Mine et al. (2007) identified compound heterozygosity for 2 mutations in the PDHX gene (608769.0007 and 608769.0008). One of the mutations was a large deletion resulting from a retrotranspositional insertion of a full-length LINE-1 element, a novel mechanism causing human genetic disease.

Najmabadi et al. (2011) performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arabic) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. In family 8500234, in which the parents were first cousins, they found that all 3 children with intellectual disability, microcephaly, and ataxia had a homozygous mutation in the PDHX gene (608769.0010). The parents had 1 unaffected child.