Genotype-phenotype correlations in spastic paraplegia type 7: a study in a large Dutch cohort

Area of Science:

• Neurogenetics
• Molecular Neurology
• Clinical Genetics

Background:

• Spastic paraplegia type 7 (SPG7) is an autosomal recessive neurodegenerative disorder causing progressive lower limb spasticity.
• While numerous SPG7 mutations exist, genotype-phenotype correlations remain elusive.
• SPG7 mutations can present with complex phenotypes beyond spasticity.

Purpose of the Study:

• To investigate genotype-phenotype correlations in SPG7.
• To identify specific SPG7 mutations associated with distinct clinical features.
• To explore potential pathomechanisms involving SPG7 protein function.

Main Methods:

• Genetic analysis of SPG7 in a cohort of 800 patients, identifying 60 with mutations.
• Detailed clinical data collection and phenotyping for 49 patients.
• Neuropathological examination in a patient with a specific SPG7 mutation.

Main Results:

• Identified 14 novel SPG7 mutations and confirmed recurrence of known mutations.
• A complex phenotype was observed in 69% of patients, often with earlier onset.
• SPG7 null mutations correlated with cerebellar ataxia (P=0.06), and a specific missense mutation (c.1409 G > A) was linked to optic nerve atrophy and visual loss.

Conclusions:

• The first genotype-phenotype correlation for SPG7 is established, associating null alleles with cerebellar ataxia.
• A specific SPG7 missense mutation is linked to optic nerve atrophy, suggesting interactions with OPA1.
• Findings suggest SPG7's role in mitochondrial proteases and potential implications for spinocerebellar ataxia type 28.