Objective: To report a new late-onset autosomal recessive spastic paraplegia caused by heterozygous mutations in the AFG3L2 and SPG7 genes.

Background: The hereditary spastic paraplegias (HSP) are a clinically heterogeneous group of disorders characterized by progressive lower extremity spasticity and weakness. Paraplegin is a mitochondrial protein and subunit of the mitochondrial matrix protease (m-AAA protease), which is mutated in SPG7 and causes an autosomal recessive HSP. AFG3L2 encodes another subunit of the m-AAA protease which is highly expressed in Purkinje cells. Pathogenic variants generally cause juvenile to early-adult onset autosomal dominant spinocerebellar ataxia, SCA28. AFG3L2 and paraplegin complex and interact with each other and can modulate disease presentation.

Methods: At age 48, the patient developed a slowly progressive spastic paraparesis with occasional falls and some bladder dysfunction. On examination 6 years into her disease, she had a mild lower extremity predominant spastic paraparesis with no evidence of cerebellar ataxia. She has no family history of spasticity or cerebellar ataxia.

Results: Brain MRI revealed isolated mild cerebellar atrophy. Exome sequencing revealed a heterozygous A510V mutation [c.1529C>T,p.Ala510Val] in the SPG7 gene and a heterozygous Y616C variant likely mutation [c.1847A>G,p.Tyr616Cys] in the AFG3L2 gene. She inherited the A510V mutation in the SPG7 gene from her mother and the Y616C mutation in the AFG3L2 gene from her father. Both parents are neurologically healthy.

Conclusions: Paraplegin is incapable of self-assembly into homo-oligomers and requires AFG3L2 for function. In addition, although most ALFG3L2 mutations cause autosomal dominant ataxia, the Y616C variant produces a severe phenotype of spastic-ataxia-neuropathy syndrome (SPAX-5), but only in the homozygous state (autosomal recessive inheritance). Functional studies have revealed impaired oligomerization with both the AFG3L2 protein and paraplegin. Therefore, our hypothesis is that in this patient, the AFG3L2 mutation in combination with the presence of a single mutated SPG7 allele produced an affected phenotype resembling SPG7 as result of synergistic partial loss-of-function effect and impaired protein interaction of both alleles.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/hereditary-spastic-paraplegia-caused-by-heterozygous-afg3l2-and-spg7-mutations/