Pyruvate dehydrogenase deficiency (ORPHA:765)
Pyruvate dehydrogenase deficiency (PDHD) is a rare neurometabolic disorder characterized by a wide range of clinical signs with metabolic and neurological components of varying severity. Manifestations range from often fatal, severe, neonatal lactic acidosis to later-onset neurological disorders. Six subtypes related to the affected subunit of the PDH complex have been recognized with significant clinical overlap: PDHD due to E1-alpha, E1-beta, E2 and E3 deficiency, PDHD due to E3-binding protein deficiency, and PDH phosphatase deficiency (see these terms).
Epidemiology
Exact prevalence is unknown but hundreds of cases have been reported.
Clinical description
PDHD may affect fetal development, with poor fetal weight gain and low birth weight being noted. Characteristic facial dysmorphism has only been described in some patients (narrow head, frontal bossing, wide nasal bridge, long philtrum and flared nostrils). Structural brain lesions are commonly observed, especially in females. Other patients develop symptoms soon after birth. Some have a primarily metabolic-type picture (potentially fatal lactic acidosis, occasionally with hyperammonemia, poor feeding, lethargy, tachypnea) and few neurological signs, while others have mainly neurological signs (developmental delay, growth retardation, poor acquisition or loss of motor milestones, hypotonia, seizures, ataxia and dystonia). Symptoms may occur in periods of stress or illness in the less severe, later-onset cases. Many patients have the characteristic clinical presentation, disease course and neuropathological changes of Leigh syndrome (see this term).
Etiology
PDHD is caused by a deficiency of one of the components of the PDH complex. The most common cause are mutations in the PDHA1 gene (Xp22.1), which encodes the E1-alpha subunit. Mutations in the genes for the other subunits have been described, but are far less frequent: E1-beta and E2 subunits (PDHB, DLAT); E3 binding protein (PDHX gene); and E3 and PDH phosphatase (DLD andPDP1).
Diagnostic methods
PDHD should be considered in cases of early-onset neurological disease and unexplained lactic acidosis, particularly if there are structural cerebral abnormalities. In many cases, lactate concentration in cerebrospinal fluid (CSF) is disproportionately increased compared to blood lactate. Definitive diagnosis is made by demonstrating abnormal enzyme function and immunochemical demonstration of a specific subunit deficiency.
Differential diagnosis
Differential diagnosis includes other causes of primary lactic acidosis (pyruvate carboxylase deficiency, defects of gluconeogenesis and a wide range of mitochondrial diseases). In patients presenting as Leigh syndrome, the differential diagnosis includes various forms of Complex I deficiency (see this term), cytochrome oxidase deficiency due to mutation in the SURF1 gene and a number of mitochondrial DNA mutations.
Antenatal diagnosis
Due to the severity of PDHD, prenatal diagnosis is requested in affected families (chorionic villi or amniocyte testing).
Genetic counseling
Most cases are due to mutations in the PDHA1 gene and are thus inherited as an X-linked dominant trait. As patients almost always have severe symptoms and greatly reduced life expectancy, most new cases are sporadic. Inheritance of all other forms of PDHD is autosomal recessive.
Management and treatment
Treatment is generally aimed at stimulating the PDH complex or providing an alternative energy source for the brain. Cofactor supplementation with thiamine, carnitine, and lipoic acid has been recommended. A very small number of patients with mutations in the PDHA1 gene are thiamine-responsive. A ketogenic diet may be indicated especially for those presenting with a dystonic disorder. Dichloroacetate has been used but significant side effects, such as peripheral neuropathy, may limit effectiveness. No treatment has an effect on preventing prenatal development of structural central nervous system anomalies.
Prognosis
Prognosis is variable but is generally poor (in terms of impact on development and life expectancy).

                            Last update: 
                            April 2012


                            - Expert reviewer(s): 
                            Dr Garry BROWN