#610357
Table of Contents
A number sign (#) is used with this entry because of evidence that autosomal dominant spastic paraplegia-30A (SPG30A) is caused by heterozygous mutation in the KIF1A gene (601255) on chromosome 2q37.
Heterozygous mutation in the KIF1A gene can also cause NESCAV syndrome (NESCAVS; 614255), which has some overlapping features with SPG30A, but is a more severe disorder.
Biallelic mutation in the KIF1A gene can cause autosomal recessive spastic paraplegia-30B (SPG30B; 620607) and hereditary sensory neuropathy type IIC (HSN2C; 614213).
Spastic paraplegia-30A (SPG30A) is a neurologic disorder characterized by onset of slowly progressive spastic paraplegia in the first or second decades of life. Affected individuals have unsteady spastic gait and hyperreflexia of the lower limbs. Most patients have a 'pure' form of the disorder, limited to spastic paraplegia, whereas some may have a 'complicated' form that includes mild cognitive dysfunction, learning disabilities, or behavioral abnormalities, peripheral axonal sensorimotor neuropathy, and urinary sphincter problems. The phenotypic features represent a spectrum of abnormalities of the central, peripheral, and autonomic nervous system (summary by Pennings et al., 2020).
For a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600).
Ylikallio et al. (2015) reported a father and son of Finnish origin with pure spastic paraplegia. They presented in the first years of life with toe walking, pes cavus, and spasticity of the lower extremities associated with hyperreflexia and extensor plantar responses. Both had normal cognitive development, although the son had some learning difficulties, and brain imaging in the son was normal.
Citterio et al. (2015) reported a large multigenerational Sicilian family (P7814) with SPG30. There were 11 reportedly affected individuals; clinical details and genetic studies were available for 4 patients. Three of these patients presented with frequent falls and gait instability in the first year of life, whereas the fourth, who presented at age 12, had a milder form of the disorder. Common features included lower limb spasticity with hyperreflexia and extensor plantar responses and pes cavus. Three patients had urinary symptoms, including 1 with distal sensory impairment. Table 1 indicated that all had normal cognition, and brain imaging, performed in 1 patient, was normal. However, in the supplementary material, the youngest affected child was reported to have mild psychomotor retardation (IQ of 68) at age 10.
Roda et al. (2017) reported 3 affected patients from a 3-generation family with pure SPG30. The proband was a 52-year-old man who showed abnormal gait and had frequent falls as a young child. His gait abnormalities were progressive, and he was nonambulatory as an adult. Additional features included scoliosis, foot eversion, and distal sensory impairment at the toes. His 35-year-old daughter had normal childhood development, but noticed trouble walking and running in her teenage years. She had a spastic gait with toe-walking. At age 6, her daughter showed a mildly spastic gait. All patients had hyperreflexia and extensor plantar responses; cognitive development and brain imaging were normal.
Pennings et al. (2020) reported 23 unrelated probands with a slowly progressive, mainly 'pure' form of SPG30 confirmed by genetic analysis. Eleven families were proven to have an inherited form of the disorder with familial segregation, 4 patients had a family history of the disorder but genetic material from affected family members was not available, 5 patients had proven de novo mutations, and 3 patients had sporadic disease without available parental DNA. The patients, who ranged in age from 3 to 66 years, had lower limb spasticity, hyperreflexia, and extensor plantar responses. The vast majority of patients had onset in childhood, but some had adult onset between 20 and 57 years. Additional common, but variable, features included lower limb weakness, distal sensory impairment of the lower limbs, and urinary sphincter problems. Brain imaging, when performed, was normal in most patients, but showed thin corpus callosum in 2. Two of the probands had mild cognitive impairment (IQ of 77 and 80). The patients were ascertained from a cohort of 347 patients with a similar disorder who underwent exome sequencing.
The transmission pattern of SPG30 in the families reported by Citterio et al. (2015), Roda et al. (2017), and Pennings et al. (2020) was consistent with autosomal dominant inheritance.
The heterozygous mutations in the KIF1A gene that were identified in some patients with SPG30 by Pennings et al. (2020) occurred de novo.
In a father and son of Finnish descent with pure autosomal dominant SPG30, Ylikallio et al. (2015) identified a heterozygous S69L mutation (601255.0014) in the KIF1A gene; the substitution affected a moderately conserved residue in the motor domain. The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, was found in both patients and was demonstrated to have occurred de novo in the father. The variant was not present in the 1000 Genomes Project or Exome Variant Server databases. Functional studies of the variant and studies of patient cells were not performed.
In 4 affected members of a multigenerational Sicilian family with autosomal dominant SPG30, Citterio et al. (2015) identified a heterozygous S69L mutation in the KIF1A gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed.
In 3 members of a 3-generation family with SPG30, Roda et al. (2017) identified a heterozygous S69L mutation in the KIF1A gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the ExAC database. Functional studies of the variant and studies of patient cells were not performed.
In 4 patients (patients 6, 8A, 8B, and 9), including 2 sibs, with SPG30, Nemani et al. (2020) identified heterozygous mutations in the KIF1A gene. Three patients carried the S69L mutation, whereas 1 had an R11Q mutation. Functional studies of the variants were not performed.
Citterio, A., Arnoldi, A., Panzeri, E., Merlini, L., D'Angelo, M. G., Musumeci, O., Toscano, A., Bondi, A., Martinuzzi, A., Bresolin, N., Bassi, M. T. Variants in KIF1A gene in dominant and sporadic forms of hereditary spastic paraparesis. J. Neurol. 262: 2684-2690, 2015. [PubMed: 26410750, related citations] [Full Text]
Nemani, T., Steel, D., Kaliakatsos, M., DeVile, C., Ververi, A., Scott, R., Getov, S., Sudhakar, W., Male, A., Mankad, K., Genomics England Research Consortium, Muntoni, F., Reilly, M. M., Kurian, M. A., Carr, L., Munot, P. KIF1A-related disorders in children: a wide spectrum of central and peripheral nervous system involvement. J. Peripher. Nerv. Syst. 25: 117-124, 2020. [PubMed: 32096284, related citations] [Full Text]
Pennings, M., Schouten, M. I., van Gaalen, J., Meijer, R. P. P., de Bot, S. T., Kriek, M., Saris, C. G. J., van den Berg, L. H., van Es, M. A., Zuidgeest, D. M. H., Elting, M. W., van de Kamp, J. M., and 12 others. KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia. Europ. J. Hum. Genet. 28: 40-49, 2020. [PubMed: 31488895, images, related citations] [Full Text]
Roda, R. H., Schindler, A. B., Blackstone, C. Multigeneration family with dominant SPG30 hereditary spastic paraplegia. Ann. Clin. Transl. Neurol. 4: 821-824, 2017. [PubMed: 29159194, related citations] [Full Text]
Ylikallio, E., Kim, D., Isohanni, P., Auranen, M., Kim, E., Lonnqvist, T., Tyynismaa, H. Dominant transmission of de novo KIF1A motor domain variant underlying pure spastic paraplegia. Europ. J. Hum. Genet. 23: 1427-1430, 2015. [PubMed: 25585697, images, related citations] [Full Text]
Alternative titles; symbols
SNOMEDCT: 763377006; ORPHA: 101010; DO: 0110781;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q37.3 | Spastic paraplegia 30, autosomal dominant | 610357 | Autosomal dominant | 3 | KIF1A | 601255 |
A number sign (#) is used with this entry because of evidence that autosomal dominant spastic paraplegia-30A (SPG30A) is caused by heterozygous mutation in the KIF1A gene (601255) on chromosome 2q37.
Heterozygous mutation in the KIF1A gene can also cause NESCAV syndrome (NESCAVS; 614255), which has some overlapping features with SPG30A, but is a more severe disorder.
Biallelic mutation in the KIF1A gene can cause autosomal recessive spastic paraplegia-30B (SPG30B; 620607) and hereditary sensory neuropathy type IIC (HSN2C; 614213).
Spastic paraplegia-30A (SPG30A) is a neurologic disorder characterized by onset of slowly progressive spastic paraplegia in the first or second decades of life. Affected individuals have unsteady spastic gait and hyperreflexia of the lower limbs. Most patients have a 'pure' form of the disorder, limited to spastic paraplegia, whereas some may have a 'complicated' form that includes mild cognitive dysfunction, learning disabilities, or behavioral abnormalities, peripheral axonal sensorimotor neuropathy, and urinary sphincter problems. The phenotypic features represent a spectrum of abnormalities of the central, peripheral, and autonomic nervous system (summary by Pennings et al., 2020).
For a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600).
Ylikallio et al. (2015) reported a father and son of Finnish origin with pure spastic paraplegia. They presented in the first years of life with toe walking, pes cavus, and spasticity of the lower extremities associated with hyperreflexia and extensor plantar responses. Both had normal cognitive development, although the son had some learning difficulties, and brain imaging in the son was normal.
Citterio et al. (2015) reported a large multigenerational Sicilian family (P7814) with SPG30. There were 11 reportedly affected individuals; clinical details and genetic studies were available for 4 patients. Three of these patients presented with frequent falls and gait instability in the first year of life, whereas the fourth, who presented at age 12, had a milder form of the disorder. Common features included lower limb spasticity with hyperreflexia and extensor plantar responses and pes cavus. Three patients had urinary symptoms, including 1 with distal sensory impairment. Table 1 indicated that all had normal cognition, and brain imaging, performed in 1 patient, was normal. However, in the supplementary material, the youngest affected child was reported to have mild psychomotor retardation (IQ of 68) at age 10.
Roda et al. (2017) reported 3 affected patients from a 3-generation family with pure SPG30. The proband was a 52-year-old man who showed abnormal gait and had frequent falls as a young child. His gait abnormalities were progressive, and he was nonambulatory as an adult. Additional features included scoliosis, foot eversion, and distal sensory impairment at the toes. His 35-year-old daughter had normal childhood development, but noticed trouble walking and running in her teenage years. She had a spastic gait with toe-walking. At age 6, her daughter showed a mildly spastic gait. All patients had hyperreflexia and extensor plantar responses; cognitive development and brain imaging were normal.
Pennings et al. (2020) reported 23 unrelated probands with a slowly progressive, mainly 'pure' form of SPG30 confirmed by genetic analysis. Eleven families were proven to have an inherited form of the disorder with familial segregation, 4 patients had a family history of the disorder but genetic material from affected family members was not available, 5 patients had proven de novo mutations, and 3 patients had sporadic disease without available parental DNA. The patients, who ranged in age from 3 to 66 years, had lower limb spasticity, hyperreflexia, and extensor plantar responses. The vast majority of patients had onset in childhood, but some had adult onset between 20 and 57 years. Additional common, but variable, features included lower limb weakness, distal sensory impairment of the lower limbs, and urinary sphincter problems. Brain imaging, when performed, was normal in most patients, but showed thin corpus callosum in 2. Two of the probands had mild cognitive impairment (IQ of 77 and 80). The patients were ascertained from a cohort of 347 patients with a similar disorder who underwent exome sequencing.
The transmission pattern of SPG30 in the families reported by Citterio et al. (2015), Roda et al. (2017), and Pennings et al. (2020) was consistent with autosomal dominant inheritance.
The heterozygous mutations in the KIF1A gene that were identified in some patients with SPG30 by Pennings et al. (2020) occurred de novo.
In a father and son of Finnish descent with pure autosomal dominant SPG30, Ylikallio et al. (2015) identified a heterozygous S69L mutation (601255.0014) in the KIF1A gene; the substitution affected a moderately conserved residue in the motor domain. The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, was found in both patients and was demonstrated to have occurred de novo in the father. The variant was not present in the 1000 Genomes Project or Exome Variant Server databases. Functional studies of the variant and studies of patient cells were not performed.
In 4 affected members of a multigenerational Sicilian family with autosomal dominant SPG30, Citterio et al. (2015) identified a heterozygous S69L mutation in the KIF1A gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed.
In 3 members of a 3-generation family with SPG30, Roda et al. (2017) identified a heterozygous S69L mutation in the KIF1A gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the ExAC database. Functional studies of the variant and studies of patient cells were not performed.
In 4 patients (patients 6, 8A, 8B, and 9), including 2 sibs, with SPG30, Nemani et al. (2020) identified heterozygous mutations in the KIF1A gene. Three patients carried the S69L mutation, whereas 1 had an R11Q mutation. Functional studies of the variants were not performed.
Citterio, A., Arnoldi, A., Panzeri, E., Merlini, L., D'Angelo, M. G., Musumeci, O., Toscano, A., Bondi, A., Martinuzzi, A., Bresolin, N., Bassi, M. T. Variants in KIF1A gene in dominant and sporadic forms of hereditary spastic paraparesis. J. Neurol. 262: 2684-2690, 2015. [PubMed: 26410750] [Full Text: https://doi.org/10.1007/s00415-015-7899-9]
Nemani, T., Steel, D., Kaliakatsos, M., DeVile, C., Ververi, A., Scott, R., Getov, S., Sudhakar, W., Male, A., Mankad, K., Genomics England Research Consortium, Muntoni, F., Reilly, M. M., Kurian, M. A., Carr, L., Munot, P. KIF1A-related disorders in children: a wide spectrum of central and peripheral nervous system involvement. J. Peripher. Nerv. Syst. 25: 117-124, 2020. [PubMed: 32096284] [Full Text: https://doi.org/10.1111/jns.12368]
Pennings, M., Schouten, M. I., van Gaalen, J., Meijer, R. P. P., de Bot, S. T., Kriek, M., Saris, C. G. J., van den Berg, L. H., van Es, M. A., Zuidgeest, D. M. H., Elting, M. W., van de Kamp, J. M., and 12 others. KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia. Europ. J. Hum. Genet. 28: 40-49, 2020. [PubMed: 31488895] [Full Text: https://doi.org/10.1038/s41431-019-0497-z]
Roda, R. H., Schindler, A. B., Blackstone, C. Multigeneration family with dominant SPG30 hereditary spastic paraplegia. Ann. Clin. Transl. Neurol. 4: 821-824, 2017. [PubMed: 29159194] [Full Text: https://doi.org/10.1002/acn3.452]
Ylikallio, E., Kim, D., Isohanni, P., Auranen, M., Kim, E., Lonnqvist, T., Tyynismaa, H. Dominant transmission of de novo KIF1A motor domain variant underlying pure spastic paraplegia. Europ. J. Hum. Genet. 23: 1427-1430, 2015. [PubMed: 25585697] [Full Text: https://doi.org/10.1038/ejhg.2014.297]
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