Hereditary ataxia
Gene: UCHL1
Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous UCHL1 variants have been reported, including 13 heterozygous loss-of-function variants (15 families) and a heterozygous inframe insertion (3 families) in PMID: 35986737. The affected individuals mainly presented with spasticity (24/31), ataxia (28/31), neuropathy (11/21), and optic atrophy (9/17), it was also noted in PMID: 35986737 that the condition onset in dominant cases was median 49 years (12-70 years) and in recessive was 7.5 years (2-10 years).Created: 17 Jan 2023, 2:55 p.m. | Last Modified: 17 Jan 2023, 3 p.m.
Panel Version: 1.314
Comment on mode of inheritance: In addition to previous reports of Spastic paraplegia 79, autosomal recessive (OMIM:615491), PMID: 35986737 reports a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy in cases with heterozygous loss of function UCHL1 variants.Created: 17 Jan 2023, 2:47 p.m. | Last Modified: 17 Jan 2023, 2:47 p.m.
Panel Version: 1.314
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Heterozygous loss of function variants have been reported to present with spasticity (24/31), ataxia (28/31), neuropathy (11/21) and optic atrophy (9/17) PMID: 35986737. Inheritance pattern can be extended to include autosomal dominant cases.Created: 13 Jan 2023, 3:34 p.m. | Last Modified: 13 Jan 2023, 3:34 p.m.
Panel Version: 1.313
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
spasticity; ataxia; neuropathy; optic atrophy
Publications
Variants in this GENE are reported as part of current diagnostic practice
Comment on list classification: Upgraded from Red to Green - ataxia and other cerebellar signs are a feature of this UCHL1-related neurodegenerative disorder. At least 4 unrelated families reported (PMIDs: 23359680; 28007905; 29735986; 32656641) with different biallelic variants, supported by functional and animal model data.Created: 11 May 2021, 10:12 a.m. | Last Modified: 11 May 2021, 10:12 a.m.
Panel Version: 1.219
Associated with relevant phenotype in OMIM (MIM# 615491) but is currently not listed in Gene2Phenotype.
- PMID: 23359680 (2013) - Three sibs born to consanguineous parents with an early-onset progressive neurodegenerative syndrome characterised by childhood-onset blindness, cerebellar ataxia, nystagmus, dorsal column dysfuction, and spasticity with upper motor neuron dysfunction. Homozygosity mapping followed by WES revealed a homozygous missense variant, (c.20A>C; p.Glu7Ala) in UCHL1 which segregated with the disorder. Some in vitro functional analysis of the variant showing near complete loss of UCHL1 hydrolase activity.
- PMID: 28007905 (2017) - Three sibs, born of unrelated Norwegian parents, with childhood-onset optic atrophy, followed by spasticity and ataxia due to comp het variants in UCHL1, c.533G>A (p.Arg178Gln) and c.647C>A (p.Ala216Asp), cosegregating with the phenotype. Functional evaluation of the variants indicates different functional consequences as the insoluble Ala216Asp variant led to LoF, whereas the Arg178Gln led to increased enzyme activity.
- PMID: 29735986 (2018) - Two sibs harbouring a homozygous splice-site variant (c.459+2T>C) in the UCHL1 gene who presented an early-onset neurodegenerative disorder characterised by SPG, optic atrophy, seizures, and facial dysmorphism. Clinical description does not include ataxia however both sibs displayed cerebellar signs such as dysarthria, nystagmus, tremors and gait impairment.
- PMID: 32656641 (2020) - Two sibs with a childhood-onset neurodegenerative disorder starting with motor DD and optic atrophy leading to progressive visual loss, cerebellar ataxia, spastic paraparesis, and motor neuropathy. Both sibs developed hypertrophic cardiomyopathy in their 30s and died of sudden cardiac death at age 43 and 40, respectively. WES identified a novel homozygous (c.627_629del; p.Gly210del) deletion in UCHL1. Their unaffected mother was heterozygous for the variant but the father was unavailable for genetic testing.
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UCHL1-deficient mice display axonal degeneration, progressive sensory motor ataxia, and premature death. UCHL1 is thought to have important roles in axonal repair after injury, axonal transport, and synaptic function (PMID: 11555633; 33159930)Created: 11 May 2021, 10:09 a.m. | Last Modified: 11 May 2021, 10:09 a.m.
Panel Version: 1.216
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Spastic paraplegia 79, autosomal recessive, OMIM:615491
Publications
Evidence (including functional) for a single variantCreated: 24 Nov 2015, 4:57 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Early onset ataxia and optic neuropathy
Publications
Variants in this GENE are reported as part of current diagnostic practice
Phenotypes for gene: UCHL1 were changed from Spastic paraplegia 79, autosomal recessive, OMIM:615491 to Spastic paraplegia 79B, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209; Spastic paraplegia 79A, autosomal dominant, OMIM:620221
Mode of inheritance for gene: UCHL1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: UCHL1 were set to 23359680; 28007905; 29735986; 32656641; 11555633; 33159930
Gene: uchl1 has been classified as Green List (High Evidence).
Phenotypes for gene: UCHL1 were changed from Early onset ataxia and optic neuropathy to Spastic paraplegia 79, autosomal recessive, OMIM:615491
Publications for gene: UCHL1 were set to PMID: 23359680
This gene has been classified as Red List (Low Evidence).
This gene has been classified as Red List (Low Evidence).
UCHL1 was created by jonathan.williams
UCHL1 was added to Hereditary ataxiapanel. Sources: Expert Review