Spastic Paraplegia 79, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that autosomal recessive spastic paraplegia-79 (SPG79) is caused by by homozygous or compound heterozygous mutation in the UCHL1 gene (191342) on chromosome 4p13.

Description

SPG79 is an autosomal recessive progressive neurologic disorder characterized by onset of spastic paraplegia and optic atrophy in the first decade of life. Additional features are variable, but may include peripheral neuropathy, cerebellar ataxia, and cognitive impairment (summary by Rydning et al., 2017).

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

Clinical Features

Nyberg-Hansen and Refsum (1972) reported 2 brothers, born of unrelated Norwegian parents, with onset of progressive lower and upper limb spasticity in early childhood, followed by onset of progressive visual failure, myopia, and optic atrophy at age 10 years. Features included hyperreflexia, ankle clonus, extensor plantar responses, and intention tremor in the upper limbs. One patient had pes planus and pectus carinatum, and the other had pes cavus. An older sister was similarly affected. Rydning et al. (2017) reported follow-up of this family. The brothers became wheelchair-bound at age 55. At age 62, they had pronounced spasticity with contractures of all joints in the lower limbs, tetraparesis most pronounced in the lower limbs, generalized fasciculations, gaze-evoked horizontal nystagmus, and reduced superficial and dorsal column sensibility. Their sister showed signs of late-onset cerebellar ataxia without spasticity. She also had nystagmus, disrupted saccades, facial myokymia, and reduced sensation. Electrophysiologic studies of the brothers showed an axonal sensorimotor neuropathy. Brain imaging of all patients showed optic atrophy; only 1 of the brothers had mild cerebellar atrophy. Cognitive function was normal in all patients.

Bilguvar et al. (2013) reported a consanguineous Turkish family in which 3 of 6 sibs had a neurodegenerative disorder with onset in early childhood. The affected children had normal early development, but developed progressive visual loss around age 5 years. Physical examination in childhood showed optic atrophy, nystagmus, cerebellar ataxia, and spasticity of the lower limbs with hyperreflexia and extensor plantar responses. IQ was mildly decreased (71 and 74) in 2 patients examined. One patient had seizures with 3.5- to 4-Hz spike activity on EEG. As young adults, the patients were blind and had cerebellar ataxia with an inability to stand without assistance, nystagmus, titubation, spasticity, and decreased vibration and position sense due to dorsal column dysfunction. Nerve conduction velocities were normal, but muscles showed myokymic activity. One patient had myotonia. Ophthalmologic examination showed optic atrophy with decreased visual evoked potentials and normal electroretinogram. Brain imaging showed cerebral and cerebellar atrophy.

Inheritance

The transmission pattern of SPG79 in the family reported by Bilguvar et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 sibs, born of consanguineous Turkish parents, with SPG79, Bilguvar et al. (2013) identified a homozygous missense mutation in the UCHL1 gene (E7A; 191342.0003). The mutation, which was found by homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies in E. coli showed that the E7A mutant protein had decreased binding to ubiquitin and significantly decreased (less than 10%) hydrolase activity compared to wildtype. The clinical features resembled those of the Uchl1-null mouse (Yamazaki et al., 1988). Bilguvar et al. (2013) noted that neither parent, each of whom was heterozygous for the mutation, had evidence of Parkinson disease. The findings indicated the importance of UCHL1 in the maintenance of nervous system integrity.

In 3 sibs, including a pair of monozygotic twin brothers, born of unrelated Norwegian parents, with SPG79, Rydning et al. (2017) identified compound heterozygous missense mutations in the UCHL1 gene: R178Q (191342.0004) and A216D (191342.0005). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies in E. coli showed that the R178Q mutation resulted in a 4-fold increase in enzyme activity compared to controls. Expression of the A216D mutation resulted in inclusion bodies, containing presumably misfolded, aggregated proteins, so activity assays of this mutant were not possible. Patient fibroblasts showed decreased levels of the UCHL1 protein, at about 25 to 35% of controls, and consisted only of the R178Q mutant; the A216D mutant protein was not detected in patient cells, suggesting that it is degraded. Rydning et al. (2017) noted that the patients did not have cognitive dysfunction, and speculated that the nonsoluble A216D protein results in reduction of UCHL1 function and contributes to neurodegeneration, whereas the increased enzymatic activity of R178Q many compensate and even protect cognitive function.

Animal Model

The gracile axonal dystrophy (gad) mouse is an autosomal recessive mutant that shows sensory ataxia at an early age, followed by motor ataxia later (Yamazaki et al., 1988). Pathologically, the mutant is characterized by 'dying-back' type axonal degeneration and formation of spheroid bodies in nerve terminals. Pathologic observations in the human have associated brain aging and neurodegenerative diseases with progressive accumulation of ubiquitinated protein conjugates. In gad mice, accumulation of amyloid beta-protein and ubiquitin-positive deposits occur retrogradely along the sensory and motor nervous systems. Suh et al. (1995) showed that the gad mutation is located on mouse chromosome 5. Saigoh et al. (1999) found that the gad mutation is caused by an in-frame deletion including exons 7 and 8 of the Uchl1 gene, encoding the ubiquitin carboxy-terminal hydrolase selectively expressed in the nervous system and testis. The gad allele encodes a truncated Uchl1 protein lacking a segment of 42 amino acids containing a catalytic residue. Since this protein is thought to stimulate protein degradation by generating free monomeric ubiquitin, the gad mutation appears to affect protein turnover. The findings suggested that altered function of the ubiquitin system directly causes neurodegeneration. The gad mouse provides a useful model for investigating human neurodegenerative disorders.