Objective: Spastic paraplegia type 55 (SPG55) is an autosomal recessive complicated HSP caused by homozygous mutation in the C12orf65 gene (613541) on chromosome 12q24. The severity of symptoms and progression rate are quite variable. We attempt to identify the new mutation of the C12orf65 gene in a Chinese HSP pedigree and explore the potential pathogenesis.

Background: Spastic paraplegia type 55 is rare reported in China, as an autosomal recessive complicated hereditary spastic paraplegia (HSP), resulting from homozygous mutations in the C12orf65 gene, which encodes a mitochondrial matrix protein. We attempt to identify the new mutation of the C12orf65 gene in a Chinese HSP pedigree and explore the potential pathogenesis.

Method: Here we presented a young patient in an autosomal recessive inheritance with optic atrophy, lower extremity spasticity and distal progressive peripheral neuropathy. DNA analysis was conducted for the patient and his family. Neurologic examination, funduscopic examination, nerve conduction, sural nerve biopsy was performed for the patient. Cell biology experiments were conducted in fibroblasts by skin biopsy from the patient.

Results: We detected a homozygous C12orf65 nonsense mutation (c.394C>T, p.R132X) in the patient. The novel truncated mutation of C12orf65 was first described in China. The clinical manifestation showed optic atrophy with reduced visual acuity, lower limb spasticity with hyperreflexia and anterior tibial muscle weakness and atrophy. Funduscopic examination showed that the optic nipples were pale in color and clear in borders, suggesting a significant atrophy of the optic nerve. Nerve conduction was consistent with a demyelinating sensory and motor neuropathy. A chronic predominantly hypomyelinating neuropathy were revealed by sural nerve biopsy. Through the cell biology experiments, we observed  LC3B, the protein crucial for autophagy, was up-regulated in fibroblasts from C12orf65-deficient patients and was normalized when treated by Dl-3-N-butylphthalide with 26 µM.

Conclusion: The novel nonsense mutation of C12orf65 could cause AR-HSP with optic atrophy, progressive distal lower extremity spasticity and bilateral lower limb muscle atrophy. The autophagy pathway may be involved in the pathogenesis of HSP 55.

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