Mutational study in the PDHA1 gene of 40 patients suspected of pyruvate dehydrogenase complex deficiency

Abstract

We screened for PDHA1 mutations in 40 patients with biochemically demonstrated PDHc deficiency or strong clinical suspicion, and found changes with probable pathological significance in 20. Five patients presented new mutations: p.A169V, c.932_938del, c.1143_1144 ins24, c.1146_1159dup and c.510-30G> A, this latter is a new undescribed cause of exon 6 skipping. Another four mutations have been found, and previously reported, in our patients: p.H113D, p.P172L, p.Y243del and p.Y369Q. Eleven patients presented seven known mutations: p.R127Q, p.I166I, p.A198T, p.R263G, p.R302C, p.R378C and c.1142_1145dup. The latter three were found in more than one unrelated patient: p.R302C was detected in a heterozygous girl and a mosaic male, p.R378C in two males and finally, c.1142_1145dup in three females; only one in 20 mothers was found to be a carrier (p.R263G). Apart from those 20 patients, the only alteration detected in one girl with clear PDHc and PDH-E1 deficiency was the silent change c.396A> C (p.R132R), and other eight PDHc deficient patients carry combinations of known infrequent polymorphisms that are overrepresented among our 20 unsolved patients. The importance of these changes on PDH activity is unclear. Investigations in the other PDHc genes are in course in order to elucidate the genetic defect in the unresolved patients.

Spectrum of neurological and survival outcomes in pyruvate dehydrogenase complex (PDC) deficiency: Lack of correlation with genotype

“…Furthermore, 22 of these 47 mutations are reported here for the first time, to our knowledge, and we do not have previously described clinical phenotypes for comparison. This high frequency of novel mutations of PDHA1 and the relatively low frequency of affected siblings or excessive spontaneous termination of pregnancies of mothers of affected children would be consistent with a high rate of de novo mutations, as has been previously suggested [14,11,17].…”

“…The relatively high frequency (36%) of mutations not found in this series of subjects who were known to be PDC-deficient by enzyme analysis has previously been reported [11,14], although most reports of PDC mutations do not include cases in which no mutation was found. This observation implies that standard genomic exon sequencing analysis, if negative, should not be the only test employed for suspected patients, since we estimate that would detect only approximately 2/3 of PDC deficient cases.…”

“…We presume that females with a substantial proportion of active X chromosomes bearing the normal allele would be relatively protected from the effects of a PDHA1 mutation on the other allele. As evidenced by the 2 asymptomatic heterozygous carriers out of 8 mothers of the subjects with PHDA1 mutations (tested by request for prenatal diagnosis), females with a PDHA1 mutation may be asymptomatic, which we attribute to favorable skewing of X-inactivation [13,11,14].…”

“…The other is a 12-year-old female, who is also functioning within the normal range of IQ. However, there is a large range of functional outcomes within reported cases with this same mutation, ranging from another normally functioning adult male to severely disabled females and fatal outcomes in infant males [10][11][12].…”

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

“…This neurometabolic disorder results in significant morbidity and mortality in children. The clinical presentation of PDC deficiency is variable and ranges from fatal congenital lactic acidosis and congenital brain abnormalities to relatively mild ataxia or neuropathy with normal cognitive function and long survival [1–3]. Among subjects with mutations in known PDC genes, this clinical heterogeneity is not correlated with genotype and occurs even with identical mutations [1–3].…”