Objective: The primary aim of this investigation is to describe a newly identified pathogenic variant within the SPG7 gene observed in a clinical presentation of spastic ataxia.

Background: Hereditary cerebellar ataxias and hereditary spastic paraplegias constitute two groups of genetically intricate and clinically diverse conditions, boasting an extensive catalog of over 70 documented genes and loci for each category (1). The SPG7 gene encodes paraplegin, a fundamental constituent of the m-AAA protease complex (2). Originally linked to uncomplicated and complex forms of hereditary spastic paraplegia accompanied by cerebellar atrophy, the SPG7 gene has emerged as aprevalent etiological factor contributing to undiagnosed cases of cerebellar ataxia and spastic ataxia (3).

Method: Assessment was conducted on a 22-year-old female presenting with a two-year history of dysarthria. The patient’s personal medical history unveiled a backdrop of childhood-onset ataxia. No pertinent family or perinatal antecedents were noted.Comprehensive physical examination disclosed a low-set right ear, bilateral gaze-evoked nystagmus, spastic-ataxic gait,marked spasticity graded as level 4, pes cavus, clonus and brisk tendon reflexes in the lower limbs, Hoffman and Tromner signs, in conjunction with dysarthria, dysdiadochokinesia and dysmetria. Pharmacotherapy consisting of tizanidine 1 mg and baclofen 10 mg, administered at 12-hour intervals, yielded negligible improvement.

Results: Neuroimaging via brain MRI exhibited hemispheric cerebellar atrophy, while laboratory analyses returned within normal parameters. Genetic sequencing via next-generation sequencing panels uncovered homozygosity for the SPG7 gene variant chr16:89,550,593 C>A (alternatively designated as c.1763C>A – ENST00000645818), culminating in the substitution of threonine at codon 588 with lysine (p.Thr588Lys).

Conclusion: To the best of our knowledge, this represents the first documented case of the chr16:89,550,593 C>A variant within the SPG7 gene in association with spastic ataxia. Elucidating the clinical profile of this patient serves to not only expand the genetic spectrum of SPG7-related disorders but also furnish profound insights into the intricate interplay between genotype and phenotype, juxtaposing the clinical manifestations of our case with antecedent reports.

References: 1. Parodi L, Fenu S, Barbier M, et al. Spastic paraplegia due to SPAST mutations is modified by the underlying mutation and sex. Brain. 2018;141(12):3331-3342. doi:10.1093/brain/awy2852.
2. Koppen M, Metodiev MD, Casari G, Rugarli EI, Langer T. Variable and tissue-specific subunit composition of mitochondrial m-AAA protease complexes linked to hereditary spastic paraplegia. Mol Cell Biol. 2007;27(2):758-767. doi:10.1128/MCB.01470-063.
3. Lallemant-Dudek P, Durr A. Clinical and genetic update of hereditary spastic paraparesis. Rev Neurol (Paris). 2021;177(5):550-556. doi:10.1016/j.neurol.2020.07.001

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MDS Abstracts - https://www.mdsabstracts.org/abstract/autosomal-recessive-spastic-ataxia-secondary-a-novel-spg7-gene-pathogenic-variant-a-case-report/