Hereditary neuropathy or pain disorder

Gene: PDHA1

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 24 Feb 2025, 5:02 p.m. | Last Modified: 24 Feb 2025, 5:02 p.m.

Panel Version: 6.148

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

Green List (high evidence)

Comment on list classification: As reviewed by Alexander Rossor, there is sufficient evidence available for the association of this gene with syndromic neuropathy and hence this gene can be promoted to green rating in the next GMS update.

Created: 26 Oct 2024, 6:08 p.m. | Last Modified: 26 Oct 2024, 6:08 p.m.

Panel Version: 5.93

PMID:33661577 reported a 12-year-old boy with lethal neuropathy and and was identified with a de novo variant in PDHA1 gene (p.Ser390LysfsTer33) that is clinically significant for Leigh Syndrome. PDCD is known a biochemical pathway in individuals with Leigh Syndrome.

PMID:3669341 reported a 21-year-old patient with sensory-motor polyneuropathy and was identified with a hemizygous PDHA1 variant (p.Arg88Cys). This variant has previously been described in five patients with similar phenotype.

PMID:38497591 reported the identification of seven female PDHA1 carriers from five different families. They all had signs of peripheral axonal neuropathy, four presented with stroke-like episodes including two with Leigh-like lesions, and three had facial stigmata.

This gene has been associated with relevant phenotypes in both OMIM (MIM #312170) and Gene2Phenotype (with 'definitive' rating on the DD panel).

Created: 26 Oct 2024, 6:04 p.m. | Last Modified: 26 Oct 2024, 6:04 p.m.

Panel Version: 5.89

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, OMIM:312170

Publications

• 33661577
• 36693417
• 38497591

I don't know

This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.

Created: 6 Dec 2019, 8:24 p.m. | Last Modified: 6 Dec 2019, 8:24 p.m.

Panel Version: 0.63

Comment on list classification: Gene included in a list of complex neuropathy syndrome genes recommended to be downgraded for R78 panel (list submitted by Alex Rossor 15th July 2019)

Created: 6 Dec 2019, 8:21 p.m. | Last Modified: 6 Dec 2019, 8:21 p.m.

Panel Version: 0.61

Rating and review submitted on behalf of James Polke (Neurogenetics Laboratory,Institute of Neurology, London), on behalf of London North GLH for GMS Neurology specialist test group.

Created: 9 May 2019, 5 p.m.

Red List (low evidence)

Can cause neuropathy but not in isolation ie complex phenotype

Created: 29 Apr 2019, 9:20 a.m.

Green List (high evidence)

Variants in this GENE are reported as part of current diagnostic practice

Comment on list classification: Green review, and a current diagnostic for this reviewer. Is a confirmed DD gene for X-linked Leigh syndrome.

Created: 4 May 2016, 12:03 p.m.

Green List (high evidence)

PN in multiple unrelated individuals and therefore should be includedin R78 panel

Created: 20 Oct 2024, 10:25 a.m. | Last Modified: 20 Oct 2024, 10:25 a.m.

Panel Version: 5.19

Episodic lactic acidosis, cerebellar ataxia, neurodevelopmental delay and clinical features resembling Leigh syndrome, neuropathy reported (NCV not reported)

Created: 9 Dec 2015, 8:50 a.m.

Phenotypes
peripheral neuropathy; Leigh syndrome

Publications

• 38497591: 36693417: 20002125

Leigh syndrome

Created: 8 Dec 2015, 3:06 p.m.