ClinVar Genomic variation as it relates to human health

Spasticity (present) , Spastic paraplegia (present) , Urinary retention (present) , Brisk reflexes (present) , Impaired vibration sensation in the lower limbs (present) , Babinski sign (present) , Progressive spastic paraparesis (present) (less)

In affected members of 1 English and 4 Austrian families with Silver spastic paraplegia syndrome (SPG17; 270685), Windpassinger et al. (2004) identified heterozygosity for a 263A-G transition (c.263A-G, NM_032667) in the BSCL2 gene, resulting in an asn88-to-ser (N88S) mutation. The English family was the original one reported by Silver (1966). In affected members of 1 Italian, 1 English, and 8 Austrian families with autosomal dominant distal hereditary motor neuronopathy-13 (HMND13; 619112), they identified the N88S mutation. Auer-Grumbach et al. (2005) reported the phenotypic findings in 90 patients from 1 large Austrian family and 2 unrelated German families with the N88S mutation. There was considerable phenotypic variability, including asymptomatic nonpenetrance (4.4%), subclinical involvement (20%), distal spinal muscular atrophy characterized by prominent hand muscle involvement (31.1%), Silver syndrome (14.5%) with hand muscle involvement and spasticity, a Charcot-Marie-Tooth-like phenotype with distal muscle weakness and wasting of the lower limbs and sensory abnormalities (20%), and spastic paraparesis without hand involvement (10%). Auer-Grumbach et al. (2005) concluded that the N88S mutation causes a motor neuron disease affecting the upper motor neurons, lower motor neurons, or both. Hand muscle involvement was a frequent, although not regular, feature, and sensory involvement was usually not present. Genealogic studies of the Austrian kindred traced the disease to a common parent pair born in 1682. Van de Warrenburg et al. (2006) reported 2 Dutch families with multiple affected individuals carrying a heterozygous N88S mutation. The phenotype in both families overlapped between Silver syndrome and HMND13. Affected members in both families had foot and lower limb atrophy with slowly progressive hyperreflexia and extensor plantar responses without prominent spasticity. Hand involvement occurred in most patients and was restricted to interosseus muscles. Brusse et al. (2009) reported 12 members of a large 3-generation Dutch family with phenotypic overlap between Silver syndrome and distal HMND13 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), 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 between SNPs rs6500882 and rs7192086 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) identified a heterozygous N88S mutation in 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 clawed 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. His affected uncle also carried the mutation, as did his unaffected mother, suggesting incomplete penetrance. The mutation was identified by exome sequencing of the proband. The family was originally reported by Ionasescu et al. (1991) as having an X-linked form of CMT (302802). (less)

In affected members of 1 English and 4 Austrian families with Silver spastic paraplegia syndrome (SPG17; 270685), Windpassinger et al. (2004) identified heterozygosity for a 263A-G transition (c.263A-G, NM_032667) in the BSCL2 gene, resulting in an asn88-to-ser (N88S) mutation. The English family was the original one reported by Silver (1966). In affected members of 1 Italian, 1 English, and 8 Austrian families with autosomal dominant distal hereditary motor neuronopathy-13 (HMND13; 619112), they identified the N88S mutation. Auer-Grumbach et al. (2005) reported the phenotypic findings in 90 patients from 1 large Austrian family and 2 unrelated German families with the N88S mutation. There was considerable phenotypic variability, including asymptomatic nonpenetrance (4.4%), subclinical involvement (20%), distal spinal muscular atrophy characterized by prominent hand muscle involvement (31.1%), Silver syndrome (14.5%) with hand muscle involvement and spasticity, a Charcot-Marie-Tooth-like phenotype with distal muscle weakness and wasting of the lower limbs and sensory abnormalities (20%), and spastic paraparesis without hand involvement (10%). Auer-Grumbach et al. (2005) concluded that the N88S mutation causes a motor neuron disease affecting the upper motor neurons, lower motor neurons, or both. Hand muscle involvement was a frequent, although not regular, feature, and sensory involvement was usually not present. Genealogic studies of the Austrian kindred traced the disease to a common parent pair born in 1682. Van de Warrenburg et al. (2006) reported 2 Dutch families with multiple affected individuals carrying a heterozygous N88S mutation. The phenotype in both families overlapped between Silver syndrome and HMND13. Affected members in both families had foot and lower limb atrophy with slowly progressive hyperreflexia and extensor plantar responses without prominent spasticity. Hand involvement occurred in most patients and was restricted to interosseus muscles. Brusse et al. (2009) reported 12 members of a large 3-generation Dutch family with phenotypic overlap between Silver syndrome and distal HMND13 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), 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 between SNPs rs6500882 and rs7192086 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) identified a heterozygous N88S mutation in 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 clawed 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. His affected uncle also carried the mutation, as did his unaffected mother, suggesting incomplete penetrance. The mutation was identified by exome sequencing of the proband. The family was originally reported by Ionasescu et al. (1991) as having an X-linked form of CMT (302802). (less)