SNOMEDCT: 719302009; ORPHA: 98766; DO: 0050882;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11q13.2 | Spinocerebellar ataxia 5 | 600224 | Autosomal dominant | 3 | SPTBN2 | 604985 |
A number sign (#) is used with this entry because of evidence that spinocerebellar ataxia-5 (SCA5) is caused by heterozygous mutation in the SPTBN2 gene (604985) on chromosome 11q13.
Homozygous mutation in the SPTBN2 gene causes autosomal recessive spinocerebellar ataxia-14 (SCAR14; 615386).
For a general discussion of autosomal dominant spinocerebellar ataxia (SCA), see SCA1 (164400).
Ranum et al. (1994) examined a large kindred in which 56 of 170 individuals distributed over 10 generations were affected by a dominant ataxia that was clinically and genetically distinct from those previously mapped. The family had 2 major branches, both of which descended from the paternal grandparents of President Abraham Lincoln. Disease onset varied from 10 to 68 years and anticipation was evident. There were several 3-generation examples of grandmothers having onset 10 to 20 years later in life than their daughters, who in turn had onset 10 to 20 years later in life than their children. Furthermore, all 4 cases of juvenile onset (10 to 18 years) were instances of maternal inheritance.
Stevanin et al. (1999) reported a French family with SCA5. The overall clinical phenotype was a slowly progressive cerebellar syndrome beginning in the third decade (range, 14 to 40 years).
Burk et al. (2004) reported a large German family in which 15 members spanning 4 generations were affected with SCA in an autosomal dominant pattern of inheritance. Mean age at onset was 32.8 years (range, 15 to 50 years), with a tendency toward earlier onset in later generations. The most consistent clinical feature was downbeat nystagmus; 3 affected patients had downbeat nystagmus as an isolated feature. Other common features included gait, stance, and limb ataxia, dysarthria, intention tremor, resting tremor, impaired smooth pursuit, and gaze-evoked nystagmus. Symptom progression was slow, and all patients were ambulatory despite disease duration of up to 31 years. MRI showed atrophy of the cerebellar vermis and hemispheres.
Clinical Variability
Jacob et al. (2012) reported a 12-year-old girl with congenital SCA5. She presented in early infancy with hypotonia and global developmental delay, and began walking with a wide-based gait at age 3 to 4 years. Other features included intention tremor, mild dysarthria, nystagmus, facial myokymia, dysmetria, dysdiadochokinesis, hyperreflexia, and ankle clonus. Brain imaging showed mildly progressive cerebellar atrophy. She was in a normal school with a modified program and was very social. There was no family history of a neurologic disorder.
Parolin Schnekenberg et al. (2015) reported a 5-year-old girl of Mediterranean descent with infantile onset of SCA5. She presented with head nodding and unsteady arm movements in infancy, and MRI showed cerebellar hypoplasia. She thereafter had delayed development with intellectual disability, convergent squint, poor expressive language, and ataxic gait, although she could take a few steps with help. She was initially diagnosed clinically with ataxic cerebral palsy and had been delivered by emergency caesarean section for fetal distress, but exome sequencing identified a de novo heterozygous missense mutation in the SPTBN2 gene (R480W; 604985.0005). This was the same mutation identified in the patient reported by Jacob et al. (2012), who had similar unusually early onset of the disorder.
By linkage analysis in a large American family with SCA, Ranum et al. (1994) mapped the disease locus, designated SCA5, to the centromeric region of chromosome 11.
In a large German family with autosomal dominant SCA, Burk et al. (2004) found linkage to a 6.5-cM (6.35-Mb) interval on chromosome 11q13 (maximum multipoint lod score of 5.76 between markers D11S1883 and D11S4136). In combination with previous linkage data (Koob et al., 1995), Burk et al. (2004) narrowed the SCA5 locus to a 5.15-Mb interval between PYGM (608455) and D11S4136.
In affected individuals from an 11-generation American kindred descended from President Lincoln's grandparents whose spinocerebellar ataxia mapped to chromosome 11q13, as well as in 2 additional families, Ikeda et al. (2006) found mutations in the SPTBN2 gene (604985.0001-604985.0003). Beta-3 spectrin is highly expressed in Purkinje cells and stabilizes the glutamate transporter EAAT4 (600637) at the surface of the plasma membrane. Ikeda et al. (2006) found marked differences in EAAT4 and the glutamate receptor GluR-delta-2 (602368) by protein blot and cell fractionation in SCA5 autopsy tissue. Cell culture studies demonstrated that mutant beta-III spectrin failed to stabilize EAAT4 at the plasma membrane. Ikeda et al. (2006) concluded that spectrin mutations, which had theretofore been unknown as a cause of ataxia and neurodegenerative disease, affect membrane proteins involved in glutamate signaling.
In a 12-year-old girl with infantile-onset SCA5, Jacob et al. (2012) identified a heterozygous missense mutation in the SPTBN2 gene (R480W; 604985.0005). The report expanded the phenotype associated with heterozygous SPTBN2 mutations.
Parolin Schnekenberg et al. (2015) identified a de novo heterozygous R480W mutation in the SPTBN2 gene in a 5-year-old girl of Mediterranean descent with infantile-onset SCA5. The mutation was found by exome sequencing. In vitro functional expression studies in cultured hippocampal neurons showed that the mutation resulted in decreased sodium currents compared to wildtype. The patient was originally diagnosed with ataxic cerebral palsy.
Ikeda et al. (2006) pointed out that the history of ataxia in the Lincoln family raised the question of whether President Abraham Lincoln carried the SCA5 mutation. Historical descriptions suggested that the President had an uneven gait, an early sign of ataxia. William Russell, a reporter for the London Times, wrote of Lincoln in 1861, 'Soon afterwards there entered, with a shambling, loose, irregular, almost unsteady gait, a tall, lank, lean man....' The identification of the SCA5 mutation makes it possible to unequivocally determine if President Lincoln carried the mutation using preserved artifacts containing his DNA. In 1991, the identification of a gene underlying Marfan syndrome sparked debate on the testing of President Lincoln's DNA to determine whether his tall stature could have resulted from that disease (McKusick, 1991). Unlike the case for Marfan syndrome, the Lincoln family history indicates that President Lincoln was at risk of developing SCA5. Ikeda et al. (2006) concluded that determining President Lincoln's status relative to SCA5 would be of historical interest and would increase public awareness of ataxia and neurodegenerative disease.
By reviewing primary historical literature to characterize the phenotype, Sotos (2009) concluded that neither Abraham Lincoln's father nor President Lincoln himself had SCA5. There remains controversy about this topic (see Ranum et al., 2010; Janus, 2010, and Sotos, 2010).
Burk, K., Zuhlke, C., Konig, I. R., Ziegler, A., Schwinger, E., Globas, C., Dichgans, J., Hellenbroich, Y. Spinocerebellar ataxia type 5: clinical and molecular genetic features of a German kindred. Neurology 62: 327-329, 2004. [PubMed: 14745083] [Full Text: https://doi.org/10.1212/01.wnl.0000103293.63340.c1]
Ikeda, Y., Dick, K. A., Weatherspoon, M. R., Gincel, D., Armbrust, K. R., Dalton, J. C., Stevanin, G., Durr, A., Zuhlke, C., Burk, K., Clark, H. B., Brice, A., Rothstein, J. D., Schut, L. J., Day, J. W., Ranum, L. P. W. Spectrin mutations cause spinocerebellar ataxia type 5. Nature Genet. 38: 184-190, 2006. [PubMed: 16429157] [Full Text: https://doi.org/10.1038/ng1728]
Jacob, F.-D., Ho, E. S., Martinez-Ojeda, M., Darras, B. T., Khwaja, O. S. Case of infantile onset spinocerebellar ataxia type 5. J. Child Neurol. 28: 1292-1295, 2012. [PubMed: 22914369] [Full Text: https://doi.org/10.1177/0883073812454331]
Janus, T. J. Abraham Lincoln did not have type 5 spinocerebellar ataxia. (Letter) Neurology 74: 1837 only, 2010. [PubMed: 20513824] [Full Text: https://doi.org/10.1212/01.wnl.0000380856.69503.5c]
Koob, M. D., Lundgren, J. K., Nowak, N. J., Shows, T. B., Perlin, M. W., Schut, L. J., Ranum, L. P. W. High-resolution genetic and physical mapping of spinocerebellar ataxia type 5 (SCA5) on 11q13. (Abstract) Am. J. Hum. Genet. 57 (Suppl.): A196 only, 1995.
McKusick, V. A. The defect in Marfan syndrome. Nature 352: 279-281, 1991. [PubMed: 1852198] [Full Text: https://doi.org/10.1038/352279a0]
Parolin Schnekenberg, R., Perkins, E. M., Miller, J. W., Davies, W. I. L., D'Adamo, M. C., Pessia, M., Fawcett, K. A., Sims, D., Gillard, E., Hudspith, K., Skehel, P., Williams, J., and 9 others. De novo point mutations in patients diagnosed with ataxic cerebral palsy. Brain 138: 1817-1832, 2015. Note: Erratum: Brain 139: e14, 2016. [PubMed: 25981959] [Full Text: https://doi.org/10.1093/brain/awv117]
Ranum, L. P. W., Krueger, K. A. D., Schut, L. J. Abraham Lincoln may have had SCA type 5. (Letter) Neurology 74: 1836-1837, 2010. [PubMed: 20513822] [Full Text: https://doi.org/10.1212/01.wnl.0000380855.61880.4f]
Ranum, L. P. W., Schut, L. J., Lundgren, J. K., Orr, H. T., Livingston, D. M. Spinocerebellar ataxia type 5 in a family descended from the grandparents of President Lincoln maps to chromosome 11. Nature Genet. 8: 280-284, 1994. [PubMed: 7874171] [Full Text: https://doi.org/10.1038/ng1194-280]
Sotos, J. G. Abraham Lincoln did not have type 5 spinocerebellar ataxia. Neurology 73: 1328-1332, 2009. [PubMed: 19841386] [Full Text: https://doi.org/10.1212/WNL.0b013e3181bd13c7]
Sotos, J. G. Reply from the author. (Letter) Neurology 74: 1837-1838, 2010. [PubMed: 20513824] [Full Text: https://doi.org/10.1212/01.wnl.0000380856.69503.5c]
Stevanin, G., Herman, A., Brice, A., Durr, A. Clinical and MRI findings in spinocerebellar ataxia type 5. Neurology 53: 1355-1357, 1999. [PubMed: 10522902] [Full Text: https://doi.org/10.1212/wnl.53.6.1355]