The spectrum of pyruvate dehydrogenase complex deficiency: Clinical, biochemical and genetic features in 371 patients

Abstract

Context Pyruvate dehydrogenase complex (PDC) deficiency is a genetic mitochondrial disorder commonly associated with lactic acidosis, progressive neurological and neuromuscular degeneration and, usually, death during childhood. There has been no recent comprehensive analysis of the natural history and clinical course of this disease. Objective We reviewed 371 cases of PDC deficiency, published between 1970 and 2010, that involved defects in subunits E1α and E1β and components E1, E2, E3 and the E3 binding protein of the complex. Data sources and extraction English language peer-reviewed publications were identified, primarily by using PubMed and Google Scholar search engines. Results Neurodevelopmental delay and hypotonia were the commonest clinical signs of PDC deficiency. Structural brain abnormalities frequently included ventriculomegaly, dysgenesis of the corpus callosum and neuroimaging findings typical of Leigh syndrome. Neither gender nor any clinical or neuroimaging feature differentiated the various biochemical etiologies of the disease. Patients who died were younger, presented clinically earlier and had higher blood lactate levels and lower residual enzyme activities than subjects who were still alive at the time of reporting. Survival bore no relationship to the underlying biochemical or genetic abnormality or to gender. Conclusions Although the clinical spectrum of PDC deficiency is broad, the dominant clinical phenotype includes presentation during the first year of life; neurological and neuromuscular degeneration; structural lesions revealed by neuroimaging; lactic acidosis and a blood lactate:pyruvate ratio≤20.

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

“…The spectrum of clinical manifestations in our cohort of patients is in line with previous reports (Barnerias et al 2010;Giribaldi et al 2012;Patel et al 2012). The high prevalence of feeding difficulties and lethargy soon after birth and the high prevalence of skeletal deformities are intriguing, as they have not been previously reported (Barnerias et al 2010;Patel et al 2012), possibly because they had not been directly associated with this diagnosis.…”

“…The proportion of thiamine-responsive patients in our cohort (4-5/19) is high in comparison with previous reports (Barnerias et al 2010;Patel et al 2012). This difference could be due to differing definitions of responsiveness, namely clinical, biochemical or other.…”

“…The high prevalence of feeding difficulties and lethargy soon after birth and the high prevalence of skeletal deformities are intriguing, as they have not been previously reported (Barnerias et al 2010;Patel et al 2012), possibly because they had not been directly associated with this diagnosis.…”

“…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).…”

“…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).…”