Pyruvate dehydrogenase complex deficiency: four neurological phenotypes with differing pathogenesis

Abstract

Aim To describe the phenotype and genotype of pyruvate dehydrogenase complex (PDHc) deficiency. Method Twenty‐two participants with enzymologically and genetically confirmed PDHc deficiency were analysed for clinical and imaging features over a 15‐year period. Results Four groups were identified: (1) those with neonatal encephalopathy with lactic acidosis (one male, four females; diagnosis at birth); (2) those with non‐progressive infantile encephalopathy (three males, three females; age at diagnosis 2–9mo); (3) those with Leigh syndrome (eight males; age at diagnosis 1–13mo); and (4) those with relapsing ataxia (three males; 18–30mo). Seventeen mutations involved PDHA1 (a hotspot was identified in exons 6, 7, and 8 in seven males with Leigh syndrome or recurrent ataxia). Mutations in the PDHX gene (five cases) were correlated with non‐progressive encephalopathy and long‐term survival in four cases. Interpretation Two types of neurological involvement were identified. Abnormal prenatal brain development resulted in severe non‐progressive encephalopathy with callosal agenesis, gyration anomalies, microcephaly with intrauterine growth retardation, or dysmorphia in both males and females (12 cases). Acute energy failure in infant life produced basal ganglia lesions with paroxysmal dystonia, neuropathic ataxia due to axonal transport dysfunction, or epilepsy only in males (11 cases). The ketogenic diet improved only paroxysmal dysfunction, providing an additional argument in favour of paroxysmal energy failure.

Thiamine-Responsive and Non-responsive Patients with PDHC-E1 Deficiency: A Retrospective Assessment

“…We did not consider biochemical improvement in the definition of responsiveness to thiamine because values of lactate and pyruvate range broadly, are inconsistent and can be influenced by a variety of factors, as has been well documented previously (Chariot et al 1994). Moreover, lack of correlation between lactate and pyruvate concentrations and clinical outcome has been shown in previous studies on treatment of patients with PDHC deficiency (Barnerias et al 2010). …”

“…Four main neurological presentations have been reported: neonatal encephalopathy with lactic acidosis, non-progressive infantile encephalopathy, Leigh syndrome and relapsing ataxia (Robinson et al 1987;Brown et al 1988Brown et al , 1989aBarnerias et al 2010;Patel et al 2012). The majority of patients have a mutation located in the PDHA1 gene encoding the E1a subunit, which is located on the X chromosome (Robinson and Sherwood 1984;McKay et al 1986;Wicking et al 1986;Brown et al 1989b;Lissens et al 2000).…”

“…It leads to decreased blood lactate and pyruvate concentrations and provides an alternative source of energy in the form of ketones (Wexler et al 1997) and has been shown to be helpful in reducing childhood onset epilepsy and paroxysmal dystonia (Barnerias et al 2010). However, its efficacy has been variable (Weber et al 2001).…”

“…However, its efficacy has been variable (Weber et al 2001). The administration of thiamine is an additional treatment that can potentially be effective, given its role as a cofactor (as TPP) of the enzyme-complex activity (Di Rocco et al 2000;Lee et al 2006;Barnerias et al 2010;Giribaldi et al 2012).…”

“…Thus, it is likely that not all patients are correctly diagnosed and therefore the exact prevalence of PDHC deficiency is not known (Barnerias et al 2010;Patel et al 2012). Moreover, thiamineresponsive patients might be missed, because enzyme analysis is usually performed with high TPP concentrations and will not show a decreased PDHC enzyme activity in these patients (Di Rocco et al 2000;Naito et al 2002a;Lee et al 2006).…”