Hereditary ataxia with onset in adulthood

Gene: NPTX1

Green List (high evidence)

Comment on list classification: As reviewed by Jenna Ridley, there are eight unrelated families identified with four different heterozygous missense variants in NPTX1 gene. Seven families were reported with late-onset ataxia, whereas it is early-onset in the six-year-old girl reported in PMID:35560436. There is also functional evidence available for the two variants reported in PMID:34788392.

This gene has been associated with relevant phenotype in OMIM (MIM #620158).

Hence, this gene should be promoted to green rating in the next GMS update.

Created: 25 Apr 2025, 3:40 p.m. | Last Modified: 25 Apr 2025, 3:44 p.m.

Panel Version: 7.23

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Spinocerebellar ataxia 50, OMIM:620158

Publications

• 34788392
• 35285082
• 35288776
• 35560436

Green List (high evidence)

Eight unrelated families/cases reported with heterozygous missense variants with cerebellar ataxia, oculomotor apraxia, downbeat nystagmus, cognitive impairment reminiscent of cerebellar cognitive affective syndrome, myoclonic tremor and mild cerebellar vermian atrophy on brain imaging.
One of these cases is childhood onset.

PMID:34788392 reported a large multigenerational family with late onset slowly progressive cerebellar ataxia (along with other clinical manifestations) in which 9 members and 6 additional patients from four families harboured c.1165G>A p.(Gly389Arg) variant. Unaffected individuals that were tested did not harbour the variant. An additional patient from another unrelated family harboured c.980A>G p.(Glu327Gly) variant. Functional work undertaken also support pathogenicity for these variants.

PMID:35285082 reported a male patient with slowly progressive late-onset ataxia with c.428G>T p.(Arg143Leu).

PMID: 35288776 report a 58-year-old woman from one of the families reported by Coutelier et al. (2022) (family LUEB01) who presented with oculomotor apraxia at 43 years of age. Her visual disturbances were progressive and severe, with an inability to initiate horizontal saccades or smooth pursuit eye movements. She did not have nystagmus or oculomotor cerebellar signs. Functional MRI studies showed abnormally reduced structural connectivity within the defined oculomotor network of each hemisphere (intrahemispheric dysfunction).

Please note that PMID:35560436 reported a six years old girl with early-onset ataxia with c.1109A>G p.(Gln370Arg)

Only missense variants appear to be reported for this gene.
Sources: Literature

Created: 21 Feb 2025, 11:30 a.m. | Last Modified: 21 Feb 2025, 11:31 a.m.

Panel Version: 7.8

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Spinocerebellar ataxia 50, OMIM:620158

Publications

• 34788392
• 35285082
• 35288776
• 35560436

Mode of pathogenicity
Other

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