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Introduction <p><i>SPG7</i> mutations are typically associated with autosomal recessive hereditary spastic paraplegia (HSP). However, evidence suggests that the p.A510V variant may also be pathogenic in heterozygous form, often manifesting as late-onset cerebellar ataxia with variable clinical features.</p> Methods <p>We report the case of a 72-year-old woman presenting with progressive gait instability and cerebellar signs. The diagnostic workup included neurological, neurophysiological, radiological, and genetic assessments.</p> Results <p>Neurological examination revealed gaze-evoked nystagmus, dysarthria, limb dysmetria, and gait ataxia. MRI showed cerebellar atrophy, predominantly involving the vermis. Electrophysiological studies revealed a length-dependent sensory axonal neuropathy. Genetic analysis via NGS detected a heterozygous c.1529C &gt; T (p.A510V) variant in <i>SPG7</i>; no second pathogenic allele or large deletions were identified. Screening for trinucleotide repeat expansions in the most common spinocerebellar ataxias yielded negative results. Segregation analysis was not feasible. The patient remained clinically stable at two-year follow-up.</p> Discussion <p>This case contributes to the limited but growing evidence supporting a role for heterozygous <i>SPG7</i> p.A510V in late-onset cerebellar ataxia without spasticity. Our findings highlight the importance of considering <i>SPG7</i> in the differential diagnosis of sporadic ataxias, even in the absence of a clear recessive inheritance pattern.</p>

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SPG7 p.A510V heterozygosity as a cause of adult-onset cerebellar ataxia without spasticity: longitudinal evidence from a sporadic case

  • 期刊论文

  • 发表日期：

    2025年8月18日

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  • Simone Aloisio,
  • Martina De Riggi,
  • Adriana Martini,
  • Sofia Grandolfo,
  • Daniele Birreci,
  • Luca Angelini,
  • Giulia Paparella,
  • Stefano Gambardella,
  • Matteo Bologna

摘要

Introduction

SPG7 mutations are typically associated with autosomal recessive hereditary spastic paraplegia (HSP). However, evidence suggests that the p.A510V variant may also be pathogenic in heterozygous form, often manifesting as late-onset cerebellar ataxia with variable clinical features.

Methods

We report the case of a 72-year-old woman presenting with progressive gait instability and cerebellar signs. The diagnostic workup included neurological, neurophysiological, radiological, and genetic assessments.

Results

Neurological examination revealed gaze-evoked nystagmus, dysarthria, limb dysmetria, and gait ataxia. MRI showed cerebellar atrophy, predominantly involving the vermis. Electrophysiological studies revealed a length-dependent sensory axonal neuropathy. Genetic analysis via NGS detected a heterozygous c.1529C > T (p.A510V) variant in SPG7; no second pathogenic allele or large deletions were identified. Screening for trinucleotide repeat expansions in the most common spinocerebellar ataxias yielded negative results. Segregation analysis was not feasible. The patient remained clinically stable at two-year follow-up.

Discussion

This case contributes to the limited but growing evidence supporting a role for heterozygous SPG7 p.A510V in late-onset cerebellar ataxia without spasticity. Our findings highlight the importance of considering SPG7 in the differential diagnosis of sporadic ataxias, even in the absence of a clear recessive inheritance pattern.