#600363
Table of Contents
A number sign (#) is used with this entry because of evidence that spastic paraplegia-6 (SPG6) is caused by heterozygous mutation in the NIPA1 gene (608145) on chromosome 15q11.
For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600).
Fink et al. (1995) reported a family in which hereditary spastic paraplegia had been diagnosed in 31 living subjects. The disorder developed insidiously with progressive gait disturbance at age 12 to 35 years. The unimodal distribution of age at onset of symptoms (mean 22.0 +/- 5.3 years) was similar to that of type I familial spastic paraplegia reported by Harding (1981), who found a mean age at onset of 20.5 +/- 17.9 years. Neurologic examination of affected subjects revealed hyperreflexia and spasticity in the lower limbs, weakness of hip flexion and ankle dorsiflexion, extensor plantar responses, diminished vibratory sense in the feet, and pes cavus. Muscle atrophy, when present, was noted only in the shins. Bladder disturbance was present in 3 affected subjects.
Reed et al. (2005) reported a large British family in which 14 members had spastic paraplegia inherited in an autosomal dominant pattern. The mean age at onset was 16.5 years (range 9 to 23), and most developed marked lower limb spasticity with hyperreflexia and extensor plantar responses. Mild bladder disturbances were also found, and most patients had pes cavus. Five affected individuals had generalized tonic-clonic seizures, and 3 developed a postural tremor in the upper limbs in their thirties.
In a large kindred extensively affected with autosomal dominant, uncomplicated familial spastic paraplegia, Fink et al. (1995) demonstrated linkage to a group of markers on chromosome 15q (maximum 2-point lod score = 9.70 at theta = 0.05); this locus was designate SPG6. Previous physical mapping of the microsatellite markers allowed Fink et al. (1995) to assign the SPG6 locus to 15q11.1. In this same family, Fink et al. (1996) observed obligate recombinants for polymorphisms immediately adjacent to the genes encoding the alpha-5 subunit of the GABA receptor (137142) and the beta-3 subunit of the GABA receptor (137192), excluding these as possible candidates.
Dube et al. (1997) referred to the chromosome 15-linked form of hereditary spastic paraplegia as SPG4a.
Rainier et al. (2003) analyzed a large kindred in which autosomal dominant hereditary spastic paraplegia mapped to the SPG6 locus (Fink et al., 1995) and found no evidence of genetic imprinting. Therefore, they analyzed as SPG6 candidates the 4 unique, nonimprinted, and highly evolutionarily conserved genes mapped proximal to the imprinted domain and within the pericentromeric region of 15q (Chai et al., 2003). In 28 SPG6 patients, Rainier et al. (2003) identified a mutation in the NIPA1 (608145.0001).
In affected members of a large British family with SPG6, Reed et al. (2005) identified a heterozygous mutation in the NIPA1 gene (608145.0004).
Chai, J.-H., Locke, D. P., Greally, J. M., Knoll, J. H. M., Ohta, T., Dunai, J., Yavor, A., Eichler, E. E., Nicholls, R. D. Identification of four highly conserved genes between breakpoint hotspots BP1 and BP2 of the Prader-Willi/Angelman syndromes deletion region that have undergone evolutionary transposition mediated by flanking duplicons. Am. J. Hum. Genet. 73: 898-925, 2003. [PubMed: 14508708, images, related citations] [Full Text]
Dube, M.-P., Mlodzienski, M. A., Kibar, Z., Farlow, M. R., Ebers, G., Harper, P., Kolodny, E. H., Rouleau, G. A., Figlewicz, D. A. Hereditary spastic paraplegia: LOD-score considerations for confirmation of linkage in a heterogeneous trait. Am. J. Hum. Genet. 60: 625-629, 1997. [PubMed: 9042923, related citations]
Fink, J. K., Jones, S. M., Sharp, G. B., Lange, B. M., Otterud, B., Leppert, M. Hereditary spastic paraplegia linked to chromosome 15q: analysis of candidate genes. Neurology 46: 835-836, 1996. [PubMed: 8618696, related citations] [Full Text]
Fink, J. K., Sharp, G. B., Lange, B. M., Wu, C. B., Haley, T., Otterud, B., Peacock, M., Leppert, M. Autosomal dominant, familial spastic paraplegia, type I: clinical and genetic analysis of a large North American family. Neurology 45: 325-331, 1995. [PubMed: 7854534, related citations] [Full Text]
Fink, J. K., Wu, C. B., Jones, S. M., Sharp, G. B., Lange, B. M., Lesicki, A., Reinglass, T., Varvil, T., Otterud, B., Leppert, M. Autosomal dominant familial spastic paraplegia: tight linkage to chromosome 15q. Am. J. Hum. Genet. 56: 188-192, 1995. [PubMed: 7825577, related citations]
Harding, A. E. Hereditary 'pure' spastic paraplegia: a clinical and genetic study of 22 families. J. Neurol. Neurosurg. Psychiat. 44: 871-883, 1981. [PubMed: 7310405, related citations] [Full Text]
Rainier, S., Chai, J.-H., Tokarz, D., Nicholls, R. D., Fink, J. K. NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6). Am. J. Hum. Genet. 73: 967-971, 2003. [PubMed: 14508710, images, related citations] [Full Text]
Reed, J. A., Wilkinson, P. A., Patel, H., Simpson, M. A., Chatonnet, A., Robay, D., Patton, M. A., Crosby, A. H., Warner, T. T. A novel NIPA1 mutation associated with a pure form of autosomal dominant hereditary spastic paraplegia. Neurogenetics 6: 79-84, 2005. [PubMed: 15711826, related citations] [Full Text]
Alternative titles; symbols
SNOMEDCT: 732949006; ORPHA: 100988; DO: 0110811;
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
15q11.2 | Spastic paraplegia 6, autosomal dominant | 600363 | Autosomal dominant | 3 | NIPA1 | 608145 |
A number sign (#) is used with this entry because of evidence that spastic paraplegia-6 (SPG6) is caused by heterozygous mutation in the NIPA1 gene (608145) on chromosome 15q11.
For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600).
Fink et al. (1995) reported a family in which hereditary spastic paraplegia had been diagnosed in 31 living subjects. The disorder developed insidiously with progressive gait disturbance at age 12 to 35 years. The unimodal distribution of age at onset of symptoms (mean 22.0 +/- 5.3 years) was similar to that of type I familial spastic paraplegia reported by Harding (1981), who found a mean age at onset of 20.5 +/- 17.9 years. Neurologic examination of affected subjects revealed hyperreflexia and spasticity in the lower limbs, weakness of hip flexion and ankle dorsiflexion, extensor plantar responses, diminished vibratory sense in the feet, and pes cavus. Muscle atrophy, when present, was noted only in the shins. Bladder disturbance was present in 3 affected subjects.
Reed et al. (2005) reported a large British family in which 14 members had spastic paraplegia inherited in an autosomal dominant pattern. The mean age at onset was 16.5 years (range 9 to 23), and most developed marked lower limb spasticity with hyperreflexia and extensor plantar responses. Mild bladder disturbances were also found, and most patients had pes cavus. Five affected individuals had generalized tonic-clonic seizures, and 3 developed a postural tremor in the upper limbs in their thirties.
In a large kindred extensively affected with autosomal dominant, uncomplicated familial spastic paraplegia, Fink et al. (1995) demonstrated linkage to a group of markers on chromosome 15q (maximum 2-point lod score = 9.70 at theta = 0.05); this locus was designate SPG6. Previous physical mapping of the microsatellite markers allowed Fink et al. (1995) to assign the SPG6 locus to 15q11.1. In this same family, Fink et al. (1996) observed obligate recombinants for polymorphisms immediately adjacent to the genes encoding the alpha-5 subunit of the GABA receptor (137142) and the beta-3 subunit of the GABA receptor (137192), excluding these as possible candidates.
Dube et al. (1997) referred to the chromosome 15-linked form of hereditary spastic paraplegia as SPG4a.
Rainier et al. (2003) analyzed a large kindred in which autosomal dominant hereditary spastic paraplegia mapped to the SPG6 locus (Fink et al., 1995) and found no evidence of genetic imprinting. Therefore, they analyzed as SPG6 candidates the 4 unique, nonimprinted, and highly evolutionarily conserved genes mapped proximal to the imprinted domain and within the pericentromeric region of 15q (Chai et al., 2003). In 28 SPG6 patients, Rainier et al. (2003) identified a mutation in the NIPA1 (608145.0001).
In affected members of a large British family with SPG6, Reed et al. (2005) identified a heterozygous mutation in the NIPA1 gene (608145.0004).
Chai, J.-H., Locke, D. P., Greally, J. M., Knoll, J. H. M., Ohta, T., Dunai, J., Yavor, A., Eichler, E. E., Nicholls, R. D. Identification of four highly conserved genes between breakpoint hotspots BP1 and BP2 of the Prader-Willi/Angelman syndromes deletion region that have undergone evolutionary transposition mediated by flanking duplicons. Am. J. Hum. Genet. 73: 898-925, 2003. [PubMed: 14508708] [Full Text: https://doi.org/10.1086/378816]
Dube, M.-P., Mlodzienski, M. A., Kibar, Z., Farlow, M. R., Ebers, G., Harper, P., Kolodny, E. H., Rouleau, G. A., Figlewicz, D. A. Hereditary spastic paraplegia: LOD-score considerations for confirmation of linkage in a heterogeneous trait. Am. J. Hum. Genet. 60: 625-629, 1997. [PubMed: 9042923]
Fink, J. K., Jones, S. M., Sharp, G. B., Lange, B. M., Otterud, B., Leppert, M. Hereditary spastic paraplegia linked to chromosome 15q: analysis of candidate genes. Neurology 46: 835-836, 1996. [PubMed: 8618696] [Full Text: https://doi.org/10.1212/wnl.46.3.835]
Fink, J. K., Sharp, G. B., Lange, B. M., Wu, C. B., Haley, T., Otterud, B., Peacock, M., Leppert, M. Autosomal dominant, familial spastic paraplegia, type I: clinical and genetic analysis of a large North American family. Neurology 45: 325-331, 1995. [PubMed: 7854534] [Full Text: https://doi.org/10.1212/wnl.45.2.325]
Fink, J. K., Wu, C. B., Jones, S. M., Sharp, G. B., Lange, B. M., Lesicki, A., Reinglass, T., Varvil, T., Otterud, B., Leppert, M. Autosomal dominant familial spastic paraplegia: tight linkage to chromosome 15q. Am. J. Hum. Genet. 56: 188-192, 1995. [PubMed: 7825577]
Harding, A. E. Hereditary 'pure' spastic paraplegia: a clinical and genetic study of 22 families. J. Neurol. Neurosurg. Psychiat. 44: 871-883, 1981. [PubMed: 7310405] [Full Text: https://doi.org/10.1136/jnnp.44.10.871]
Rainier, S., Chai, J.-H., Tokarz, D., Nicholls, R. D., Fink, J. K. NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6). Am. J. Hum. Genet. 73: 967-971, 2003. [PubMed: 14508710] [Full Text: https://doi.org/10.1086/378817]
Reed, J. A., Wilkinson, P. A., Patel, H., Simpson, M. A., Chatonnet, A., Robay, D., Patton, M. A., Crosby, A. H., Warner, T. T. A novel NIPA1 mutation associated with a pure form of autosomal dominant hereditary spastic paraplegia. Neurogenetics 6: 79-84, 2005. [PubMed: 15711826] [Full Text: https://doi.org/10.1007/s10048-004-0209-9]
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