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

Brain. 2012 Oct;135(Pt 10):2994-3004. doi: 10.1093/brain/aws224. Epub 2012 Sep 10.

Abstract

Spastic paraplegia type 7 is an autosomal recessive neurodegenerative disorder mainly characterized by progressive bilateral lower limb spasticity and referred to as a form of hereditary spastic paraplegia. Additional disease features may also be observed as part of a more complex phenotype. Many different mutations have already been identified, but no genotype-phenotype correlations have been found so far. From a total of almost 800 patients referred for testing, we identified 60 patients with mutations in the SPG7 gene. We identified 14 previously unreported mutations and detected a high recurrence rate of several earlier reported mutations. We were able to collect detailed clinical data for 49 patients, who were ranked based on a pure versus complex phenotype, ataxia versus no ataxia and missense versus null mutations. A generally complex phenotype occurred in 69% of all patients and was associated with a younger age at onset (trend with P = 0.07). Ataxia was observed in 57% of all patients. We found that null mutations were associated with the co-occurrence of cerebellar ataxia (trend with P = 0.06). The c.1409 G > A (p.Arg470Gln) mutation, which was found homozygously in two sibs, was associated with a specific complex phenotype that included predominant visual loss due to optical nerve atrophy. Neuropathology in one of these cases showed severe degeneration of the optic system, with less severe degeneration of the ascending tracts of the spinal cord and cerebellum. Other disease features encountered in this cohort included cervical dystonia, vertical gaze palsy, ptosis and severe intellectual disability. In this large Dutch cohort, we seem to have identified the first genotype-phenotype correlation in spastic paraplegia type 7 by observing an association between the cerebellar phenotype of spastic paraplegia type 7 and SPG7 null alleles. An overlapping phenotypic presentation with its biological counterpart AFG3L2, which when mutated causes spinocerebellar ataxia type 28, is apparent and possibly suggests that abnormal levels of the SPG7 protein impact the function of the mitochondrial ATPases associated with diverse cellular activities-protease complex (formed by SPG7 and AFG3L2) in the cerebellum. In addition, a missense mutation in exon 10 resulted in predominant optical nerve atrophy, which might suggest deleterious interactions of this SPG7 variant with its substrate OPA1, the mutated gene product in optic atrophy type 1. Functional studies are required to further investigate these interactions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATPases Associated with Diverse Cellular Activities
  • Angiopoietin-Like Protein 6
  • Angiopoietin-like Proteins
  • Angiopoietins / genetics*
  • Cerebellar Ataxia / genetics
  • Cerebellar Ataxia / physiopathology
  • Cohort Studies
  • Genetic Association Studies*
  • Genotype
  • Humans
  • Metalloendopeptidases / genetics*
  • Mutation / genetics*
  • Netherlands
  • Optic Nerve Diseases / genetics
  • Optic Nerve Diseases / physiopathology
  • Phenotype
  • Spastic Paraplegia, Hereditary / genetics*
  • Spastic Paraplegia, Hereditary / physiopathology

Substances

  • ANGPTL6 protein, human
  • Angiopoietin-Like Protein 6
  • Angiopoietin-like Proteins
  • Angiopoietins
  • Metalloendopeptidases
  • SPG7 protein, human
  • ATPases Associated with Diverse Cellular Activities