Hereditary neuropathy or pain disorder

Gene: APOPT1

Green List (high evidence)

Comment on list classification: There are four unrelated patients with biallelic APOPT1 variants and presenting with neuropathy. Hence, this gene can be promoted to green rating on this panel in the next GMS update.

Created: 28 Jul 2026, 5:12 p.m. | Last Modified: 28 Jul 2026, 5:12 p.m.

Panel Version: 8.28

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

Created: 28 Jul 2026, 5:11 p.m. | Last Modified: 28 Jul 2026, 5:11 p.m.

Panel Version: 8.27

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. Sensorimotor polyneuropathy was reported in three of the six patients.

PMID:38098475 (2023) reported two female siblings from an Italian family with mitochondrial myopathy. Patient 1 presented with generalised epilepsy and retinitis pigmentosa at 10 years of age. She had cramps and myalgia after exercise and bilateral hearing loss since early adulthood. Last neurological examination (52 years of age) showed bilateral ptosis, muscle weakness, peripheral neuropathy, mild dysarthria, dysphonia and cognitive impairment. Muscle biopsy had shown the presence of ragged-red fibers. Patient 2 presented with fatigability, myalgia, and hearing loss. Neurological examination showed ptosis and muscle weakness. Muscle biopsy displayed a diffuse reduction of COX activity staining and ragged-red fibers. Both sisters presented secondary amenorrhea. A novel homozygous variant in COA8 (APOPT1) was identified via whole-exome sequencing in the probands (c.170_173dupGACC, p.Pro59fs).

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)

Created: 28 Jul 2026, 11:54 a.m. | Last Modified: 28 Jul 2026, 5:08 p.m.

Panel Version: 8.26

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; peripheral neuropathy, MONDO:0005244

Publications

• 25175347
• 38098475

Green List (high evidence)

Sources: Expert list

Created: 19 Apr 2026, 10:03 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
25175347; 38098475Encephalopathic episodes; loss of developmental milestones; seizures; spasticity; cavitating leukodystrophy

Publications

• 25175347
• 38098475