Prepair 1000+

Gene: PDHA1

Green List (high evidence)

Onset in infancy or early childhood (OMIM).

Variants in this gene are known to have variable expressivity which has been detailed by PMID: 22142326.
- Neonatal lactic acidosis predominates in males, in whom the degree of residual pyruvate dehydrogenase complex (PDHC) activity depends on the PDHA1 mutation.
- Very severe mutations are not found in males, probably because they are embryonically lethal.
- In heterozygous females, the residual PDHC activity is related to both the mutation and the random pattern of X‐inactivation, with variable expression of the mutant and normal genes in different tissues.
- Females can also present a severe clinical picture, with early‐onset microcephaly, spastic quadriplegia, severe epilepsy, and cortical/subcortical atrophy.
- In the milder form, individuals may show intercurrent clinical and biochemical normalization, despite persistence of neuroradiological and electrophysiological findings. Some late‐onset childhood variants respond to thiamine supplementation.

Created: 16 Jan 2025, 8:54 p.m. | Last Modified: 16 Jan 2025, 8:54 p.m.

Panel Version: 1.1064

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
Pyruvate dehydrogenase E1-alpha deficiency MIM#312170

Publications

• 22142326

Green List (high evidence)

Reports of familial recurrence suggest that some females are mildly or not clinically affected and just have reproductive risk of severely affected males/females.

Created: 17 Aug 2022, 6:40 a.m. | Last Modified: 17 Aug 2022, 6:40 a.m.

Panel Version: 0.131

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Pyruvate dehydrogenase E1-alpha deficiency (MIM#312170)

I don't know

Well-established gene disease association however condition shows XLD inheritance with a high proportion of females affected. Complete loss-of-function variants are embryonic lethal in males. Phenotype is highly variable

Does not fit with scope of testing (AR/XLR) - consider for exclusion

Created: 14 Jul 2022, 11:12 p.m. | Last Modified: 14 Jul 2022, 11:12 p.m.

Panel Version: 0.49

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
Pyruvate dehydrogenase E1-alpha deficiency (MIM#312170)

Publications

• 28584645
• 22142326