Spastic Paraplegia 74, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that autosomal recessive spastic paraplegia-74 (SPG74) is caused by homozygous mutation in the IBA57 gene (615316) on chromosome 1q42. One such family has been reported.

Description

Spastic paraplegia-74 is an autosomal recessive neurologic disorder characterized by onset of slowly progressive lower limb spasticity, optic atrophy, and peripheral neuropathy in the first decade (summary by Lossos et al., 2015).

For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).

Clinical Features

Lossos et al. (2015) reported a multigenerational, highly consanguineous Arab family in which 11 individuals had slowly progressive spastic paraplegia with optic atrophy and peripheral neuropathy. Symptoms first appeared in the first decade, manifest as gait impairment associated with mild to moderate spasticity, hyperreflexia of the knee, and extensor plantar responses. There was also distal sensory impairment, with loss of ankle reflexes, distal leg atrophy, and pes cavus. Funduscopic analysis showed optic atrophy and reduced visual acuity; brain imaging showed atrophy of the optic nerve. Nerve conduction studies in 4 patients showed reduced compound muscle action potentials and velocities with normal sensory conduction, indicating a primarily motor and axonal peripheral neuropathy. Cognition was normal.

Inheritance

The transmission pattern of SPG74 in the family reported by Lossos et al.(2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In affected members of a large consanguineous Arab family with SPG74, Lossos et al. (2015) identified a homozygous splice site mutation in the IBA57 gene (615316.0002). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. Patient lymphoblastoid cells showed a 90% decrease of IBA57 protein levels and a 30 to 40% reduction of mitochondrial respiratory chain complex I and II subunits and activities. Mitochondrial aconitase (ACO2; 100850) activity and lipoic acid synthesis were slightly decreased compared to controls. The findings were consistent with a hypomorphic mutation.