Spastic Paraplegia 17, Autosomal Dominant

A number sign (#) is used with this entry because spastic paraplegia-17 (SPG17) is caused by heterozygous mutation in the BSCL2 gene (606158) on chromosome 11q12.

Distal spinal muscular atrophy type VA (DSMAVA, or HMN5A; 600794), which is characterized by muscle weakness and wasting confined predominantly to the hands without spasticity, is an allelic disorder with an overlapping phenotype.

Clinical Features

Silver (1966) reported 2 families with spastic paraplegia with amyotrophy of the hands inherited in an autosomal dominant pattern. In the larger family with more affected members, age at onset of gait abnormalities was 8 to 40 years and of hand involvement 14 to 60 years. Both lower limb spasticity and amyotrophy of intrinsic hand muscles were present in most affected individuals. All had weakness of intrinsic hand muscles, with severe amyotrophy most marked in the thenar eminence. There was also mild impairment of vibration sense in the lower limbs of older individuals.

Van Gent et al. (1985) reported a large kinship with an autosomal dominant disorder characterized by amyotrophy of predominantly upper limb muscles and mild pyramidal features. Sensory changes were noted in older patients. The authors noted the variation in the clinical phenotype, which had features of distal spinal muscular atrophy, pure pyramidal syndromes, and peroneal muscular atrophy with pyramidal features.

Windpassinger et al. (2003) reported 4 related Austrian families in which 19 members had mild to severe lower limb spasticity and/or distal muscle weakness and wasting of the upper and occasionally the lower limbs. Six members had very mild disease. Onset of symptoms varied widely (11-63 years), and gait disturbance was the predominant sign in 9 persons. Nine patients had uni- or bilateral wasting of the small hand muscles which was preferentially distributed to the thenar and dorsalis interosseus I muscles; 3 of these patients also had gait abnormalities. Almost all patients had foot deformities and brisk lower limb reflexes. Babinski sign was present in the patients with spastic gait. Sensation was usually normal, except for mildly reduced vibration in some. Median motor nerve conduction velocities were normal or mildly reduced. Windpassinger et al. (2003) noted the broad phenotypic variation and also suggested incomplete penetrance of the disorder.

Bruyn et al. (1993) reported the cases of 2 sibs, a brother and sister with nonconsanguineous parents, with what they interpreted to be autosomal recessive spastic paraparesis and severe amyotrophy of distal limb muscles. Amyotrophy began in the first decade. Spasticity was more pronounced than paraparesis. Severe wasting of the thenar and hypothenar eminences was accompanied by amyotrophy below the knees and pedes cavi. The patients had experienced unnecessary distress from an early diagnosis of amyotrophic lateral sclerosis. Both Silver (1966) and Bruyn et al. (1993) noted that recessive inheritance of a similar disorder had been reported by Ormerod (1904) and Holmes (1905).

Van de Warrenburg et al. (2006) reported 2 unrelated Dutch families with overlapping Silver syndrome and distal motor neuropathy. The first family contained 5 affected individuals spanning 3 generations. All presented with pes cavus and foot of leg muscle weakness and atrophy between 11 and 26 years of age. There was slow progression, with gradually evolving lower limb hypertonia and hyperreflexia with extensor plantar responses without prominent spasticity. Two patients also developed weakness and atrophy of the first dorsal interosseus and abductor pollicis brevis muscles without involvement of the hypothenar muscles. In the second family, there were multiple affected individuals spanning 3 generations. Age at onset was before age 20 years. About half of the patients presented with foot or leg muscle weakness and atrophy, whereas the other half presented with hand muscle weakness and atrophy. Most developed hyperreflexia with extensor plantar responses; spasticity was observed in older patients. Affected members of both families carried the same BSCL2 mutation (N88S; 606158.0013). Van de Warrenburg et al. (2006) emphasized the phenotypic variability and incomplete penetrance of some symptoms.

Brusse et al. (2009) reported 12 members of a large 3-generation Dutch family with phenotypic overlap between Silver syndrome and distal HMN5 who carried a heterozygous N88S mutation. The phenotype was variable, and the distribution of muscle weakness and atrophy included predominantly the feet (in 4), the hands (in 1), or both upper and lower extremities (in 4). Three individuals showed evidence of pyramidal features, including spasticity, hyperreflexia, and extensor plantar responses. Severity of the disease ranged from adolescent patients with disabling muscle weakness to an elderly patient with only mild weakness of the ankle dorsiflexors and bilateral pes cavus. Brusse et al. (2009) noted the extreme phenotypic variability associated with the N88S mutation in their family and in those reported by Auer-Grumbach et al. (2005) and van de Warrenburg et al. (2006), who also carried the N88S mutations, and suggested the presence of other genetic or environmental factors. In their family, Brusse et al. (2009) used genomewide linkage analysis to identify a candidate disease modifier on chromosome 16p13.3-p13.12 that was shared by all 12 affected individuals (maximum lod score of 3.28). One family member without the N88S mutation but with the chromosome 16p haplotype showed mild electrophysiologic abnormalities. Brusse et al. (2009) postulated that a locus on chromosome 16p may contain a disease modifier in their family.

Chaudhry et al. (2013) reported a man with SPG17. He had onset of weakness of the hands and feet at around 12 years of age. Examination at age 14 showed distal weakness and wasting with claw hands and flat feet, extensor plantar responses, mild tremor, and distal sensory impairment. The disorder was slowly progressive, and he remained ambulatory with orthotics at age 36. Exome sequencing revealed a heterozygous mutation in the BSCL2 gene (N88S; 606158.0013). His affected uncle also carried the mutation, as did his unaffected mother, suggesting incomplete penetrance. The family was originally reported by Ionasescu et al. (1991) as having an X-linked form of CMT (302802).

Mapping

In 2 large multigeneration families with Silver syndrome, 1 of which had been reported by Silver (1966), Patel et al. (2001) excluded linkage to known loci for spastic paraplegia. In another report on the same families, Patel et al. (2001) found that the family reported by Silver (1966) was linked to chromosome 11q12-q14, whereas the other family did not show linkage to 11q, indicating genetic heterogeneity. Recombination events positioned the locus, which the authors designated 'SPG17,' to a 13-cM interval flanked by markers D11S1765 and D11S4136 (lod score greater than 3.0). Haplotype construction revealed that each of the 14 affected family members and 4 unaffected family members had inherited an identical region, indicating reduced penetrance.

In 4 related Austrian families with typical Silver syndrome, Windpassinger et al. (2003) found linkage to 11q12-q14. Haplotype analysis in affected individuals indicated a common ancestor in the 4 families. By recombination analysis in affected individuals, the Silver spastic paraplegia syndrome candidate gene interval was reduced from 13 to 5.9 cM and placed between markers D11S1765 and D11S987. By sequence analysis in affected individuals, 8 functional and positional candidate genes were excluded.

Molecular Genetics

In affected members of 1 English and 4 Austrian families with Silver syndrome, Windpassinger et al. (2004) identified heterozygosity for an asn88-to-ser mutation in the BSCL2 gene (N88S; 606158.0013). The English family was the original one reported by Silver (1966). Eight related Austrian families with DSMAV had the same mutation. In affected members of a Belgian family and a Brazilian family with Silver syndrome, Windpassinger et al. (2004) identified heterozygosity for a ser90-to-leu mutation (S90L; 606158.0014).

Irobi et al. (2004) reviewed the molecular genetics of the distal motor neuropathies.

Pathogenesis

By in vitro functional expression analysis, Ito and Suzuki (2007) demonstrated that the N88S and S90L mutations in the BSCL2 gene disrupt glycosylation of the seipin protein. Overexpressed mutant seipin was highly ubiquitinated and degraded by the proteasome, and improper glycosylation exacerbated endoplasmic reticulum (ER) retention. Mutant proteins activated the unfolded protein response (UPR), resulting in apoptotic cell death through ER stress. Ito and Suzuki (2007) concluded that the N88S and S90L mutations, which result in motor neuron disease, have a gain-of-function effect, resulting in conformational protein changes, activation of the UPR, cell death, and neurodegeneration. Ito and Suzuki (2009) provided a review.