Hereditary ataxia with onset in adulthood

Gene: SLC25A46

Green List (high evidence)

Comment on classification of this gene: The rating for this gene should be GREEN, as this gene has been implicated in adult-onset ataxia, as identified from biallelic loss-of-function variants from at least 3 unrelated individuals and supported by results from animal models.

A study on patients from three North African families (Two siblings from Tunisian family and two unrelated Algerians) showed that the previously reported variant c.1018C>T/ p.Arg340Cys (displayed in Tunisian siblings and one Algerian patient) was associated with childhood onset, optic atrophy, gait and speech difficulties and wasting of the lower limbs, and the Algerian patient with the novel variant p.Trp160Ser did not present with optic atrophy, while all patients were presented with ataxia. Out of these one of the Tunisian siblings and both Algerian patients developed gait difficulties at juvenile/ adult stage with age of onset ranging from 14 to 23 (PMID:28558379).

Mouse models with loss-of-function mutation or lacking SLC25A46 gene manifest the main clinical features identified in patients such as ataxia, optic atrophy, cerebellar hypoplasia and peripheral neuropathy which were completely rescued by expression of human ortholog (PMID:28376086; PMID:28934388). The results suggest that the gene loss causes degeneration in neurons by affecting mitochondrial dynamics and energy production.

Loss-of-function in cultured cells and in zebrafish also led to increased mitochondrial connectivity, while severely affecting the development and maintenance of neurons in the zebrafish (PMID:26168012).

SLC25A46 has been associated with neuropathy, hereditary motor and sensory, type VIB in OMIM and Gene2Phenotype.

Created: 11 Dec 2022, 9:48 a.m. | Last Modified: 11 Dec 2022, 9:48 a.m.

Panel Version: 3.3

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Adult-onset ataxia; Cerebellar ataxia, MONDO:0000437; Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505

Publications

• 26168012
• 28376086
• 28558379
• 28934388

Red List (low evidence)

HMSN with ataxia as part of phenotype. More suited to another panel. Not on Ox or Shef.

Created: 27 Apr 2019, 7:39 p.m.

I don't know

As discussed with the GMS Neurology Specialist Test Group webex call 26th July 2019: The Specialist Test Group all agreed that there is enough evidence to rate this gene Green

Created: 1 Aug 2019, 3:43 p.m. | Last Modified: 1 Aug 2019, 3:43 p.m.

Panel Version: 1.188

Review and rating submitted by James Polke (Neurogenetics Laboratory, Institute of Neurology, London) on behalf of London North GLH for GMS Neurology specialist test group

Created: 27 Apr 2019, 8:55 p.m.

Review and rating from Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group.

Created: 15 Apr 2019, 10:21 a.m.

Green List (high evidence)

Multiple variants reported across papers - associated with a spectrum of disease and ataxia/cerebellar abnormalities a frequent part of phenotype. Also pontocerebellar hypoplasia in the most extreme of cases

Created: 15 Apr 2019, 10:06 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Hereditary motor and sensory neuropathy type VIB, 616505

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