SPG7 and Hereditary Spastic Paraplegia 7

Hereditary spastic paraplegia 7 (HSP7) is an autosomal recessive neurodegenerative disorder caused by biallelic variants in SPG7, which encodes the mitochondrial m-AAA protease subunit paraplegin. Affected individuals present with progressive lower limb spasticity often accompanied by cerebellar ataxia, dysarthria, and ophthalmoplegia. SPG7 testing should be included in the diagnostic workup of adult-onset spastic-ataxic syndromes given its prevalence in multiple populations.

Genetic analyses across diverse cohorts have identified 42 probands with biallelic SPG7 variants in a British ancestry cohort (PMID:30533525), 21 Spanish patients (PMID:34500365), and 60 Dutch patients (PMID:22964162), consistently demonstrating autosomal recessive inheritance. The variant spectrum includes missense (e.g., c.1529C>T (p.Ala510Val)), nonsense, splice-site, frameshift, and large deletions. Founder alleles such as p.His701Pro in Norway were shown by haplotype analysis to underlie 4 of 6 families (PMID:26756429).

Segregation studies confirm recessive transmission in multiple families. A Japanese pedigree with homozygous c.1192C>T (p.Arg398Ter) exhibited two affected siblings (PMID:27081526), while a Cypriot family with a novel homozygous p.Thr588Met variant had five affected members (PMID:35096021). Additional sib pairs and consanguineous kindreds provide robust co-segregation evidence.

The phenotypic spectrum ranges from pure spastic paraparesis (HP:0001258) to complex presentations with cerebellar ataxia (HP:0001251), progressive external ophthalmoplegia (HP:0000590), parkinsonism, dystonia, and cognitive impairment. MRI often reveals cerebellar atrophy and dentate nucleus T2 hyperintensity correlating with genotype (PMID:32161564; PMID:31433872).

Functional data support a loss-of-function mechanism. Yeast complementation assays showed impaired proteolytic activity for variants including p.Gly349Ser and p.Ala510Val (PMID:20186691). Muscle biopsies from SPG7 patients revealed multiple mitochondrial DNA deletions and combined respiratory chain deficiencies (PMID:24466038). Patient-derived cells harboring p.Ala510Val display mitochondrial fragmentation, reduced oxidative phosphorylation, and increased oxidative stress (PMID:32973427).

Although predominantly recessive, heterozygous SPG7 variants such as p.Ala510Val are enriched in hereditary spastic paraplegia and amyotrophic lateral sclerosis cohorts, suggesting potential dominant or digenic contributions in select cases (PMID:33598982; PMID:32447552). Reports of epistasis between SPG7 and AFG3L2 further highlight complex inheritance patterns.

In summary, a strong body of genetic and experimental evidence links biallelic SPG7 variants to hereditary spastic paraplegia 7. Additional animal models and longitudinal natural history studies extend beyond scoring but reinforce clinical utility. Key Take-home: SPG7 genetic testing is essential for accurate diagnosis and management of spastic-ataxic syndromes.

References

• Human genome variation • 2015 • Predominant cerebellar phenotype in spastic paraplegia 7 (SPG7). PMID:27081526
• PLoS One • 2014 • Spastic paraplegia type 7 is associated with multiple mitochondrial DNA deletions. PMID:24466038
• Neurology: Genetics • 2018 • Novel genotype-phenotype and MRI correlations in a large cohort of patients with SPG7 mutations. PMID:30533525
• Journal of the Neurological Sciences • 2021 • Clinical and genetic characteristics of 21 Spanish patients with biallelic pathogenic SPG7 mutations. PMID:34500365
• Brain: a Journal of Neurology • 2012 • Genotype-phenotype correlations in spastic paraplegia type 7: a study in a large Dutch cohort. PMID:22964162
• European Journal of Neurology • 2016 • A founder mutation p.H701P identified as a major cause of SPG7 in Norway. PMID:26756429
• Human Mutation • 2010 • Functional evaluation of paraplegin mutations by a yeast complementation assay. PMID:20186691
• Movement Disorders • 2019 • Parkinsonism and spastic paraplegia type 7: Expanding the spectrum of mitochondrial Parkinsonism. PMID:31433872
• Frontiers in Neuroscience • 2020 • Mitochondrial Function in Hereditary Spastic Paraplegia: Deficits in SPG7 but Not SPAST Patient-Derived Stem Cells. PMID:32973427
• Journal of Neurology • 2020 • SPG7 mutations in amyotrophic lateral sclerosis: a genetic link to hereditary spastic paraplegia. PMID:32447552
• BMC Neurology • 2022 • A novel compound heterozygous SPG7 variant is associated with progressive spastic ataxia and persecutory delusions found in Chinese patients: two case reports. PMID:35637455
• Frontiers in Genetics • 2021 • A Novel SPG7 Gene Pathogenic Variant in a Cypriot Family With Autosomal Recessive Spastic Ataxia. PMID:35096021
• Frontiers in Neurology • 2020 • Cerebello-Cortical Alterations Linked to Cognitive and Social Problems in Patients With Spastic Paraplegia Type 7: A Preliminary Study. PMID:32161564

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