SNOMEDCT: 771469002; ORPHA: 313772; DO: 0050944;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 18p11.21 | Spastic ataxia 5, autosomal recessive | 614487 | Autosomal recessive | 3 | AFG3L2 | 604581 |
A number sign (#) is used with this entry because of evidence that autosomal recessive spastic ataxia-5 (SPAX5) is caused by homozygous or compound heterozygous mutation in the AFG3L2 gene (604581) on chromosome 18p11.
Heterozygous mutation in the AFG3L2 gene can cause autosomal dominant spinocerebellar ataxia-28 (SCA28; 610246) and optic atrophy-12 (OPA12; 618977).
Spastic ataxia-5 (SPAX5) is an autosomal recessive neurodegenerative disorder characterized by early-onset spasticity resulting in significantly impaired ambulation, cerebellar ataxia, oculomotor apraxia, dystonia, and myoclonic epilepsy (summary by Pierson et al., 2011).
For a discussion of genetic heterogeneity of spastic ataxia, see SPAX1 (108600).
Pierson et al. (2011) reported 2 brothers, born of consanguineous Hispanic parents from Colombia, with early-onset spinocerebellar ataxia with spasticity and myoclonic epilepsy. Their disease courses were similar, although the younger sib had a more severe phenotype and died of pneumonia at age 13 years. The older brother developed spastic gait at age 2 years and eventually lost the ability to ambulate independently, whereas the younger brother never acquired independent ambulation. Both developed progressive myoclonic epilepsy associated with generalized tonic-clonic seizures at age 8 years. This was followed by progressive dysarthria, dysphagia, motor degeneration, and lower extremity weakness with distal muscle atrophy. The older brother showed dysmetria, dysdiadochokinesia, ataxic dysarthria, ptosis, oculomotor apraxia, and dystonic movements. Cognition was normal. Brain MRI showed moderate cerebellar atrophy, and nerve conduction studies showed an axonal sensorimotor neuropathy of the lower extremities. Electron microscopy of skeletal muscle showed misplaced mitochondria associated with large lipid droplets, and there was decreased mtDNA copy number. Both parents were without neurologic complaints and had normal neurologic and ophthalmological exams, although the mother had mild cerebellar atrophy on brain imaging.
Franchino et al. (2024) reported a girl (patient 2) with SPAX5 who had gait instability and ataxia at 3 years of age. A brain MRI showed abnormal signal in the globus pallidus and the cerebellar peduncles. She developed progressive dysmetria, dysarthria, and pyramidal signs. At 6 years of age, she had seizures and myoclonic bursts.
Clinical Variability
Muona et al. (2015) reported 2 Italian patients, not known to be related, who presented with severe progressive myoclonus at age 10 years after normal early development. One patient had a single tonic-clonic seizure, ataxia, and mild cognitive decline. He was wheelchair-bound at age 22 years. The other patient had a single tonic-clonic seizure at age 22, ataxia, and mild cognitive impairment. She became wheelchair-bound at age 48 years. Neither patient had early spasticity or neuropathy. Muona et al. (2015) noted that the phenotype in these 2 patients was not as severe as that reported by Pierson et al. (2011).
Caporali et al. (2020) reported 2 unrelated patients (families 6 and 11) with SPAX5 associated with optic atrophy. They had impaired vision, color vision deficits, photophobia, pale optic discs, and decreased thickness of the retinal nerve fiber layer. These patients also had ataxia, spasticity, myoclonus, chorea, dystonia, and cerebellar signs. The report expanded the phenotypic spectrum associated with biallelic AFG3L2 mutations. Molecular studies identified compound heterozygous mutations in the AFG3L2 gene (604581.0014-604581.0015, 604581.0018-604581.0019).
The transmission pattern of spastic ataxia in the family reported by Pierson et al. (2011) was consistent with autosomal recessive inheritance.
By whole-exome sequencing in 2 brothers with early-onset spastic ataxia, Pierson et al. (2011) identified a homozygous mutation in the AFG3L2 gene (Y616C; 604581.0010). Both parents, who were heterozygous carriers of the mutation, were without neurologic complaints and had normal neurologic and ophthalmologic exams, although the mother had mild cerebellar atrophy on brain imaging. In vitro functional expression studies in yeast showed that Y616C was a hypomorphic allele, resulting in decreased activity of the homooligomeric enzyme, but not in complete inhibition. The Y616C mutant protein also showed impaired ability to assemble with itself or with paraplegin (SPG7; 602783) in protease complexes, resulting in low levels of functionally active protease complexes and a functional paraplegin defect. The report expanded the phenotype associated with AFG3L2 mutations and was reminiscent of a combined SCA28/SPG7 (607259) phenotype with some features of a mitochondrial disorder.
In 2 unrelated Italian patients with a variant of SPAX5 presenting as severe progressive myoclonus and ataxia, Muona et al. (2015) identified a homozygous missense mutation in the AFG3L2 gene (M625I; 604581.0011). Functional studies of the variant were not performed. The patients were ascertained from a cohort of 84 individuals with progressive myoclonic epilepsy who underwent exome sequencing.
In an 8-year-old girl (patient 2) with SPAX5, Franchino et al. (2024) identified compound heterozygous mutations in the AFG3L2 gene (M625I, 604581.0011; c.245dup, 604581.0020). Fibroblasts from the patient showed reduced protein expression of AFG3L2, reduced TMRM fluorescence, and decreased mitochondrial membrane potential. Activation of OMA1 was detected in patient cells, evidenced by reduced OMA1 and OPA1 protein content. To test if the OMA1-mediated integrated stress response (ISR) was mediated through DELE1, DELE1 was silenced in patient fibroblasts, which resulted in slowed growth and reduced phosphorylation of eIF2-alpha (603907) compared to controls.
Caporali, L., Magri, S., Legati, A., Del Dotto, V., Tagliavini, F., Balistreri, F., Nasca, A., La Morgia, C., Carbonelli, M., Valentino, M. L., Lamantea, E., Baratta, S., and 19 others. ATPase domain AFG3L2 mutations alter OPA1 processing and cause optic neuropathy. Ann. Neurol. 88: 18-32, 2020. [PubMed: 32219868] [Full Text: https://doi.org/10.1002/ana.25723]
Franchino, C. A., Brughera, M., Baderna, V., De Ritis, D., Rocco, A., Seneca, S., Regal, L., Podini, P., D'Antonio, M., Toro, C., Quattrini, A., Scalais, E., Maltecca, F. Sustained OMA1-mediated integrated stress response is beneficial for spastic ataxia type 5. Brain 147: 1043-1056, 2024. [PubMed: 37804316] [Full Text: https://doi.org/10.1093/brain/awad340]
Muona, M., Berkovic, S. F., Dibbens, L. M., Oliver, K. L., Maljevic, S., Bayly, M. A., Joensuu, T., Canafoglia, L., Franceschetti, S., Michelucci, R., Markkinen, S., Heron, S. E., and 39 others. A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. Nature Genet. 47: 39-46, 2015. [PubMed: 25401298] [Full Text: https://doi.org/10.1038/ng.3144]
Pierson, T. M., Adams, D., Bonn, F., Martinelli, P., Cherukuri, P. F., Teer, J. K., Hansen, N. F., Cruz, P., Mullikin, J. C., Blakesley, R. W., Golas, G., Kwan, J., and 9 others. Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases. PLoS Genet. 7: e1002325, 2011. Note: Electronic Article. [PubMed: 22022284] [Full Text: https://doi.org/10.1371/journal.pgen.1002325]