Neurodegenerative disorders, adult onset

Gene: PSMF1

Green List (high evidence)

Comment on list classification: There are 10 individuals from 8 unrelated families reported in literature with biallelic PSMF1 variants (mostly missense) and early-onset Parkinson disease. Of those, 6 individuals had disease onset at 18-48 years. Hence, this gene can be promoted to Green on Neurodegenerative disorders, adult onset.

Created: 4 Nov 2026, 2:30 p.m. | Last Modified: 4 Nov 2026, 2:30 p.m.

Panel Version: 9.29

PMID: 41986367 Magrinelli et al., 2026
Report of 18 unrelated families of European, Asian and African ancestry with 25 affected subjects harbouring biallelic PSMF1 missense and loss-of-function variants. Consanguinity was reported in 11/18 families. Probands’ parents were healthy. Patient phenotypes ranged from early-onset PD to perinatal lethality with neurological manifestations.
In 8 families, 10 individuals presented with early-onset Parkinson disease. 5 individuals had disease onset at age 18 years or under, 4 others were aged 19-29 years, and 1 individual had disease onset at 48 years. These individuals harboured homozygous missense variants, or comp het homozygous + LoF.
In 4 families the presentation consisted of miscellaneous movement disorders, encompassing parkinsonism, moderate-to-severe pyramidal tract signs, ataxia or a combination thereof, with mild-to-moderate intellectual disability, epilepsy and cognitive decline. Cerebellar malformations/atrophy were noted on MRI in 4 individuals. Age of onset was under 12 years of age for this subgroup. All 4 probands were homozygous for splice variants in PSMF1.
Finally, in 4 families, the core phenotype was arthrogryposis, with poor feeding, respiratory insufficiency, corpus callosum malformations and early lethality. Biallelic LoF variants are thought to cause this most severe presentation.
Functional evidence: Drosophila and mouse models showed age-dependent motor impairment, brain-wide mitochondrial membrane depolarization and dopaminergic neurodegeneration in aged flies, and diffuse gliosis in mice.

PSMF1 is associated with Parkinson disease 27, autosomal recessive early-onset, OMIM:621693, AR Arthrogryposis multiplex congenita 8, neurogenic type, OMIM:621695, and Neurodegeneration, childhood-onset, with movement disorders, cognitive decline, and brain abnormalities, OMIM:621694, and AR (OMIM accessed 4th Nov 2026).
Sources: Literature

Created: 4 Nov 2026, 2:25 p.m. | Last Modified: 4 Nov 2026, 3:03 p.m.

Panel Version: 9.29

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Parkinson disease 27, autosomal recessive early-onset, OMIM:621693; young-onset Parkinson disease, MONDO:0017279

Publications

• 41986367