Childhood onset hereditary spastic paraplegia

Gene: APOPT1

Green List (high evidence)

Comment on list classification: There is sufficient evidence available for the association of biallelic APOPT1 variants with childhood-onset spasticity (at least five unrelated cases). Hence, this gene can be promoted to green rating on this panel in the next GMS update.

Created: 28 Jul 2026, 5:34 p.m. | Last Modified: 28 Jul 2026, 5:34 p.m.

Panel Version: 9.6

The 'new-gene-name' tag has been added as the official HGNC gene symbol for APOPT1 is COA8.

Created: 28 Jul 2026, 5:33 p.m. | Last Modified: 28 Jul 2026, 5:33 p.m.

Panel Version: 9.5

PMID:25175347 (2014) reported a total of six patients from five unrelated families identified with biallelic variants in APOPT1 gene. There were six different variants identified from these patients and all but one were homozygous, and one individual had compound heterozygous variants. Across the six individuals with APOPT1 mutations, all show infantile or childhood‑onset mitochondrial disease with profound COX deficiency, a characteristic cavitating leukodystrophy on MRI predominantly affecting posterior cerebral white matter and corpus callosum, and evidence of peripheral neuropathy. Clinically, they range from acute neurometabolic decompensation with spastic tetraparesis, seizures and cognitive impairment to much milder phenotypes with preserved cognition, but all have a chronic, long‑surviving course with stabilization or partial recovery of motor function despite persistent structural white matter changes. All patients except one of the two siblings presented with spastic tetraparesis with onset in early childhood (2-5 years of age).

This gene has been associated with relevant phenotype in OMIM (MIM #619061, last accessed 28 July 2026), Gene2Phenotype (with 'definitive' rating on the DD and Eye panels) and in ClinGen (associated with 'definitive' rating for mitochondrial disease (MONDO:0044970) by Mitochondrial Diseases GCEP - https://search.clinicalgenome.org/CCID:004493)
Sources: Literature

Created: 28 Jul 2026, 5:29 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061; mitochondrial complex IV deficiency, nuclear type 17, MONDO:0033652; hereditary spastic paraplegia, MONDO:0019064

Publications

• 25175347