#615043
Table of Contents
A number sign (#) is used with this entry because of evidence that autosomal recessive spastic paraplegia-43 (SPG43) is caused by homozygous mutation in the C19ORF12 gene (614297) on chromosome 19q12. One such family has been reported.
Mutation in the C19ORF12 gene can also cause neurodegeneration with brain iron accumulation-4 (NBIA4; 614298), which shows overlapping but additional neurologic features.
Spastic paraplegia-43 (SPG43) is an autosomal recessive neurodegenerative disorder characterized by childhood onset of progressive spasticity affecting the lower and upper limbs (summary by Meilleur et al., 2010).
For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see 270800.
Meilleur et al. (2010) reported 2 sisters from Mali with childhood-onset spastic paraplegia. The girls had onset at ages 7 and 12 years, respectively, of difficulty walking due to progressive spasticity of the lower limbs. Physical examination of the older girl at age 19 years showed mild weakness of the proximal lower limb muscles, contractures of the knees and ankles, and pes cavus. Plantar responses were extensor, and there was marked bilateral spasticity in the legs. The upper limbs were also affected, with distal muscle atrophy, particularly of the intrinsic hand muscles, flexion contractures of the fingers, and decreased fine motor skills in the hands. There was also decreased vibration sense in the lower limbs. The younger sister was similarly, but more mildly, affected. Brain imaging was not feasible due to the family's remote location. Cognition in both sisters was normal. On reexamination of the older sister 5 years after the original report by Meilleur et al. (2010), Landoure et al. (2013) noted that she had severe atrophy and decreased sensation in the arms and legs with decreased reflexes, but no cognitive decline, facial or bulbar weakness, or vision loss. Brain MRI showed no abnormalities and no iron deposition.
The transmission pattern of SPG43 in the family reported by Meilleur et al. (2010) was consistent with autosomal recessive inheritance.
By homozygosity mapping of 2 sisters from Mali with SPG, Meilleur et al. (2010) found a common 17.7-Mb region on chromosome 19p13.11-q12 between SNPs rs36692 and rs12460915. Sequencing of several candidate genes in the region did not identify any mutations.
In 2 sisters, born of consanguineous Malian parents, originally reported by Meilleur et al. (2010) as having autosomal recessive SPG43, Landoure et al. (2013) identified a homozygous missense mutation in the C19ORF12 gene (A63P; 614297.0006). The mutation was found by exome sequencing of 1 of the sisters. The homozygous mutation was not found in 298 Malian controls or in 951 samples in the ClinSeq cohort. The A63P variant was present in 3 of 3,836 African American alleles in the NHLBI Exome Sequencing Project database, but not in 8,222 European American alleles from this database. Sequencing the coding region of C19ORF12 in 16 Australians, 46 French, 195 Americans, and 170 Japanese presenting with hereditary spastic paraplegia did not identify any other variants, suggesting that C19ORF12 mutation is likely a rare cause of this phenotype. Landoure et al. (2013) identified the same homozygous A63P mutation in 2 sibs from a consanguineous Brazilian family with NBIA4, and haplotype analysis indicated a founder effect between the Malian and Brazilian families. Landoure et al. (2013) suggested that the phenotypic differences between the 2 families may be due to other genetic or environmental factors or stochastic effects, and concluded that C19ORF12 mutations cause a neurologic disease spectrum that may or may not include brain iron deposition.
Landoure, G., Zhu, P.-P., Lourenco, C. M., Johnson, J. O., Toro, C., Bricceno, K. V., Rinaldi, C., Melleur, K. G., Sangare, M., Diallo, O., Pierson, T. M., Ishiura, H., and 19 others. Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12. Hum. Mutat. 34: 1357-1360, 2013. [PubMed: 23857908, images, related citations] [Full Text]
Meilleur, K. G., Traore, M., Sangare, M., Britton, A., Landoure, G., Coulibaly, S., Niare, B., Mochel, F., La Pean, A., Rafferty, I., Watts, C., Shriner, D., Littleton-Kearney, M. T., Blackstone, C., Singleton, A., Fischbeck, K. H. Hereditary spastic paraplegia and amyotrophy associated with a novel locus on chromosome 19. Neurogenetics 11: 313-318, 2010. [PubMed: 20039086, images, related citations] [Full Text]
SNOMEDCT: 764736001; ORPHA: 320370; DO: 0110795;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19q12 | ?Spastic paraplegia 43, autosomal recessive | 615043 | Autosomal recessive | 3 | C19orf12 | 614297 |
A number sign (#) is used with this entry because of evidence that autosomal recessive spastic paraplegia-43 (SPG43) is caused by homozygous mutation in the C19ORF12 gene (614297) on chromosome 19q12. One such family has been reported.
Mutation in the C19ORF12 gene can also cause neurodegeneration with brain iron accumulation-4 (NBIA4; 614298), which shows overlapping but additional neurologic features.
Spastic paraplegia-43 (SPG43) is an autosomal recessive neurodegenerative disorder characterized by childhood onset of progressive spasticity affecting the lower and upper limbs (summary by Meilleur et al., 2010).
For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see 270800.
Meilleur et al. (2010) reported 2 sisters from Mali with childhood-onset spastic paraplegia. The girls had onset at ages 7 and 12 years, respectively, of difficulty walking due to progressive spasticity of the lower limbs. Physical examination of the older girl at age 19 years showed mild weakness of the proximal lower limb muscles, contractures of the knees and ankles, and pes cavus. Plantar responses were extensor, and there was marked bilateral spasticity in the legs. The upper limbs were also affected, with distal muscle atrophy, particularly of the intrinsic hand muscles, flexion contractures of the fingers, and decreased fine motor skills in the hands. There was also decreased vibration sense in the lower limbs. The younger sister was similarly, but more mildly, affected. Brain imaging was not feasible due to the family's remote location. Cognition in both sisters was normal. On reexamination of the older sister 5 years after the original report by Meilleur et al. (2010), Landoure et al. (2013) noted that she had severe atrophy and decreased sensation in the arms and legs with decreased reflexes, but no cognitive decline, facial or bulbar weakness, or vision loss. Brain MRI showed no abnormalities and no iron deposition.
The transmission pattern of SPG43 in the family reported by Meilleur et al. (2010) was consistent with autosomal recessive inheritance.
By homozygosity mapping of 2 sisters from Mali with SPG, Meilleur et al. (2010) found a common 17.7-Mb region on chromosome 19p13.11-q12 between SNPs rs36692 and rs12460915. Sequencing of several candidate genes in the region did not identify any mutations.
In 2 sisters, born of consanguineous Malian parents, originally reported by Meilleur et al. (2010) as having autosomal recessive SPG43, Landoure et al. (2013) identified a homozygous missense mutation in the C19ORF12 gene (A63P; 614297.0006). The mutation was found by exome sequencing of 1 of the sisters. The homozygous mutation was not found in 298 Malian controls or in 951 samples in the ClinSeq cohort. The A63P variant was present in 3 of 3,836 African American alleles in the NHLBI Exome Sequencing Project database, but not in 8,222 European American alleles from this database. Sequencing the coding region of C19ORF12 in 16 Australians, 46 French, 195 Americans, and 170 Japanese presenting with hereditary spastic paraplegia did not identify any other variants, suggesting that C19ORF12 mutation is likely a rare cause of this phenotype. Landoure et al. (2013) identified the same homozygous A63P mutation in 2 sibs from a consanguineous Brazilian family with NBIA4, and haplotype analysis indicated a founder effect between the Malian and Brazilian families. Landoure et al. (2013) suggested that the phenotypic differences between the 2 families may be due to other genetic or environmental factors or stochastic effects, and concluded that C19ORF12 mutations cause a neurologic disease spectrum that may or may not include brain iron deposition.
Landoure, G., Zhu, P.-P., Lourenco, C. M., Johnson, J. O., Toro, C., Bricceno, K. V., Rinaldi, C., Melleur, K. G., Sangare, M., Diallo, O., Pierson, T. M., Ishiura, H., and 19 others. Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12. Hum. Mutat. 34: 1357-1360, 2013. [PubMed: 23857908] [Full Text: https://doi.org/10.1002/humu.22378]
Meilleur, K. G., Traore, M., Sangare, M., Britton, A., Landoure, G., Coulibaly, S., Niare, B., Mochel, F., La Pean, A., Rafferty, I., Watts, C., Shriner, D., Littleton-Kearney, M. T., Blackstone, C., Singleton, A., Fischbeck, K. H. Hereditary spastic paraplegia and amyotrophy associated with a novel locus on chromosome 19. Neurogenetics 11: 313-318, 2010. [PubMed: 20039086] [Full Text: https://doi.org/10.1007/s10048-009-0230-0]
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