Spastic Paraplegia 76, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that autosomal recessive hereditary spastic paraplegia-76 (SPG76) is caused by homozygous or compound heterozygous mutation in the CAPN1 gene (114220) on chromosome 11q13.

Description

Spastic paraplegia-76 is an autosomal recessive neurologic disorder characterized by young-adult onset of slowly progressive spasticity of the lower limbs resulting in gait difficulties. Most affected individuals have upper limb involvement and additional features such as foot deformities and dysarthria. Cognition is unaffected (summary by Gan-Or et al., 2016).

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

Clinical Features

Gan-Or et al. (2016) reported 3 families, 2 consanguineous Moroccan families and 1 nonconsanguineous North American family, with spastic paraplegia. The clinical features of 8 patients were reported in detail. The average age at onset was 28.5 years (range 19 to 39); all affected individuals had spasticity and hyperreflexia of the lower limbs, 7 had hyperreflexia of the upper limbs, 6 had dysarthria, and 3 had ataxia. Six patients had foot deformities, including pes cavus or pes valgus, 2 had abnormal bladder function, and 2 had distal sensory impairment. The motor impairment was mild to moderate, and 2 patients had started using a cane to aid in walking. There were no other neurologic abnormalities.

Inheritance

The transmission pattern of SPG76 in the families reported by Gan-Or et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In affected members of 3 unrelated families with SPG76, Gan-Or et al. (2016) identified homozygous or compound heterozygous mutations in the CAPN1 gene (114220.0001-114220.0004). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. One of the mutations was a missense mutation, whereas the others were nonsense, frameshift, or splice site mutations. Functional studies of the variants and studies of patient cells were not performed, but knockdown of the Capn1 gene in animal models resulted in disruption of neuronal patterning and neurodegeneration (see ANIMAL MODEL).

Animal Model

Gan-Or et al. (2016) found that RNAi knockdown of the Capn1 gene in C. elegans resulted in neurodegeneration of GABAergic motor neurons and an age-dependent paralysis phenotype. Loss of Capn1 in Drosophila led to locomotor defects, axonal abnormalities, and age-dependent negative geotaxis. The axons appeared to have larger diameters and increased levels of acetylated tubulin. Morpholino knockdown of capn1a in zebrafish resulted in disruption of brain development, particularly of branchiomotor neuron migration and positioning, as well as disorganization of the microtubule network with abnormal accumulation of axonal acetylated tubulin as well as depletion of acetylated tubulin. These animal models supported a neuroprotective role of Capn1.