SPG7 – Primary Lateral Sclerosis

Autosomal recessive variants in SPG7, encoding the mitochondrial m-AAA protease paraplegin, have been implicated in Primary Lateral Sclerosis (PLS), a rare motor neuron disease characterized by progressive upper motor neuron dysfunction with spasticity, bulbar signs, and a normal electromyogram. While SPG7 is a well-established cause of recessive hereditary spastic paraplegia, recent reports extend its phenotypic spectrum to adult-onset PLS ([PMID:27123479], [PMID:31117107]).

In a European family with five PLS-affected individuals, exome sequencing identified compound heterozygous SPG7 missense variants c.2084T>C (p.Leu695Pro) and c.2228T>C (p.Ile743Thr) segregating under an autosomal recessive model. Seahorse metabolic analyses demonstrated impaired mitochondrial respiratory capacity in patient-derived cells under low-glucose conditions, supporting a loss-of-function mechanism. Parents and heterozygous siblings remained asymptomatic, consistent with recessive inheritance ([PMID:27123479]).

A Chinese adult-onset PLS family harbored a homozygous c.2219A>G (p.Tyr740Cys) variant in SPG7 that fully cosegregated with spasticity and limb weakness in multiple affected relatives. In silico predictions classified p.Tyr740Cys as deleterious to paraplegin structure, reinforcing its pathogenicity ([PMID:31117107]).

Prospective molecular screening of 41 clinically definite PLS patients identified rare SPG7 mutations in 3 cases (7%), while whole-exome sequencing of 139 PLS patients revealed 10 likely pathogenic SPG7 variants (7%) assigned to a pure HSP-like subgroup. These cohort data implicate SPG7 variants in a subset of PLS, meriting inclusion in PLS diagnostic gene panels ([PMID:27066542], [PMID:37133535]).

Functional assays in yeast complementation and patient cells have consistently shown that SPG7 mutations disrupt m-AAA protease activity, leading to impaired protein quality control, altered OPA1 processing, mitochondrial network fragmentation, and reduced oxidative phosphorylation. These mechanistic insights align with vulnerability of upper motor neurons in PLS.

Collectively, multiple independent families, cohort studies, and convergent functional evidence support a moderate clinical validity for SPG7 in PLS. Genetic testing for SPG7 should be considered in adult-onset PLS cases—especially with familial clustering—to inform diagnosis, genetic counseling, and potential therapeutic strategies.

Key take-home: Recessive SPG7 variants can underlie a PLS phenotype; targeted genetic analysis enhances diagnostic yield and guides patient management.

References

• Neurology. Genetics • 2016 • Compound heterozygote mutations in SPG7 in a family with adult-onset primary lateral sclerosis. PMID:27123479
• European neurology • 2019 • Exome Sequencing Identifies a Mutation (Y740C) in Spastic Paraplegia 7 Gene Associated with Adult-Onset Primary Lateral Sclerosis in a Chinese Family. PMID:31117107
• Neurology. Genetics • 2015 • Phenotypic and molecular analyses of primary lateral sclerosis. PMID:27066542
• Journal of neurology • 2023 • Genetic characterization of primary lateral sclerosis. PMID:37133535

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