The spectrum of pyruvate oxidation defects in the diagnosis of mitochondrial disorders

Abstract

Pyruvate oxidation defects (PODs) are among the most frequent causes of deficiencies in the mitochondrial energy metabolism and represent a substantial subset of classical mitochondrial diseases. PODs are not only caused by deficiency of subunits of the pyruvate dehydrogenase complex (PDHC) but also by various disorders recently described in the whole pyruvate oxidation route including cofactors, regulation of PDHC and the mitochondrial pyruvate carrier. Our own patients from 2000 to July 2014 and patients identified by a systematic survey of the literature from 1970 to July 2014 with a pyruvate oxidation disorder and a genetically proven defect were included in the study (n=628). Of these defects 74.2% (n=466) belong to PDHC subunits, 24.5% (n=154) to cofactors, 0.5% (n=3) to PDHC regulation and 0.8% (n=5) to mitochondrial pyruvate import. PODs are underestimated in the field of mitochondrial diseases because not all diagnostic centres include biochemical investigations of PDHC in their routine analysis. Cofactor and transport defects can be missed, if pyruvate oxidation is not measured in intact mitochondria routinely. Furthermore deficiency of the X-chromosomal PDHA1 can be biochemically missed depending on the X-inactivation pattern. This is reflected by an increasing number of patients diagnosed recently by genetic high throughput screening approaches. PDHC deficiency including regulation and import affect mainly the glucose dependent central and peripheral nervous system and skeletal muscle. PODs with combined enzyme defects affect also other organs like heart, lung and liver. The spectrum of clinical presentation of PODs is still expanding. PODs are a therapeutically interesting group of mitochondrial diseases since some can be bypassed by ketogenic diet or treated by cofactor supplementation. PDHC kinase inhibition, chaperone therapy and PGC1α stimulation is still a matter of further investigations.

Enzymatic testing sensitivity, variability and practical diagnostic algorithm for pyruvate dehydrogenase complex (PDC) deficiency

“…The molecular etiologies for the remainder were either unknown or not reported to CIDEM. About 78% (70/90) of the genetically-resolved subjects had a pathogenic mutation in PDHA1 , a number comparable to the 74–90% observed by others [1,2,14]. Forty-nine percent (91/186) and 51% (95/186) were female and male, respectively, and 36% (33/91) and 39% (37/95) of females and males, respectively, had an identified pathogenic PDHA1 mutation.…”

Mitochondrial energy generation disorders: genes, mechanisms, and clues to pathology

“…Additional genes responsible for mitochondrial disorders affect mitochondrial and cellular metabolism, including components of the PDC and TCA cycle, enzymes involved in toxic compound metabolism, and carrier proteins involved in metabolite and cofactor transport across cellular and mitochondrial membranes (19,54). We have elected not to include genes involved in other metabolic pathways, such as mitochondrial fatty acid oxidation, in which secondary inhibition of OXPHOS function may result from altered metabolite concentrations or cellular signaling pathways (55).…”

“…Other genes that could be classified into several categories include DNAJC19 (protein import and cardiolipin homeostasis) (59) and MECR (mitochondrial fatty acid synthesis and synthesis of the cofactor lipoic acid) (54,60). Similarly, although considered a member of the carrier family, SLC25A46 localizes to the mitochondrial outer membrane where it functions in mitochondrial cristae architecture and ER/mitochondrial contacts implicated in lipid transfer (61).…”

Complex genetic findings in a female patient with pyruvate dehydrogenase complex deficiency: Null mutations in the PDHX gene associated with unusual expression of the testis-specific PDHA2 gene in her somatic cells

“…The actual flow-chart used in most laboratories for molecular characterization of PDC deficiency involves initially sequencing of the coding regions of PDHA1, and if this is normal, subsequently sequencing all the other genes encoding the several subunits as well as the synthesis of respective cofactors [33]. The multiple genetic alterations in this case might not be detected if we had followed such procedure.…”