#617770
Table of Contents
Alternative titles; symbols
A number sign (#) is used with this entry because of evidence that spinocerebellar ataxia-46 (SCA46) is caused by heterozygous mutation in the PLD3 gene (615698) on chromosome 19q13. One such family has been reported.
For a discussion of genetic heterogeneity of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).
Van Dijk et al. (1995) reported a large Dutch kindred in which 4 sibs and their father had adult-onset sensory ataxic neuropathy with cerebellar signs. The patients presented between 41 and 65 years with swaying during walking in the dark. Additional more variable features included oculomotor abnormalities and distal sensory impairment in a stocking and glove pattern, but predominantly affecting the lower limbs. Several patients had a positive Romberg sign. Brain imaging in all 5 patients did not show cerebellar atrophy. Neurophysiologic studies showed decreased or unobtainable amplitudes of sensory potentials. Sural nerve biopsy showed decreased density of myelinated fibers and some areas of segmental remyelination. The findings were consistent with a sensory ataxia due to a sensory axonal polyneuropathy. The disorder was slowly progressive.
Nibbeling et al. (2017) reported follow-up of the family reported by van Dijk et al. (1995) and referred to the family as RF28. Affected individuals had a variable combination of sensory neuropathy and cerebellar ataxia. In a small minority of them, the cerebellar phenotype was more prominent than the sensory neuropathy. Cerebellar dysarthria was present in most, but not all, and all patients except one had abnormal oculomotor function, manifest as nystagmus, jerky pursuit, square-wave jerks, slow saccades, and saccadic dysmetria. Only some patients had cerebellar atrophy, which was mild. The average age of onset was 53.5 years (range 35 to 70).
The transmission pattern of SCA46 in the family reported by van Dijk et al. (1995) and Nibbeling et al. (2017) was consistent with autosomal dominant inheritance.
In 8 affected members of a family (RF28) with SCA46, Nibbeling et al. (2017) identified a heterozygous missense mutation in the PLD3 gene (L308P; 615698.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that the L308P protein was normally expressed, had normal cellular localization, and was stable. However, phospholipase D activity of the mutant protein was significantly decreased compared to wildtype. The family was 1 of 20 unrelated families with autosomal dominant SCA who underwent whole-exome sequencing.
Nibbeling, E. A. R., Duarri, A., Verschuuren-Bemelmans, C. C., Fokkens, M. R., Karjalainen, J. M., Smeets, C. J. L. M., de Boer-Bergsma, J. J., van der Vries, G., Dooijes, D., Bampi, G. B., van Diemen, C., Brunt, E., and 9 others. Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia. Brain 140: 2860-2878, 2017. [PubMed: 29053796, related citations] [Full Text]
van Dijk, G. W., Wokke, J. H. J., Oey, P. L., Franssen, H., Ippel, P. F., Veldman, H. A new variant of sensory ataxic neuropathy with autosomal dominant inheritance. Brain 118: 1557-1563, 1995. [PubMed: 8595484, related citations] [Full Text]
Alternative titles; symbols
SNOMEDCT: 1279839002; ORPHA: 589522; DO: 0080288;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19q13.2 | ?Spinocerebellar ataxia 46 | 617770 | Autosomal dominant | 3 | PLD3 | 615698 |
A number sign (#) is used with this entry because of evidence that spinocerebellar ataxia-46 (SCA46) is caused by heterozygous mutation in the PLD3 gene (615698) on chromosome 19q13. One such family has been reported.
For a discussion of genetic heterogeneity of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).
Van Dijk et al. (1995) reported a large Dutch kindred in which 4 sibs and their father had adult-onset sensory ataxic neuropathy with cerebellar signs. The patients presented between 41 and 65 years with swaying during walking in the dark. Additional more variable features included oculomotor abnormalities and distal sensory impairment in a stocking and glove pattern, but predominantly affecting the lower limbs. Several patients had a positive Romberg sign. Brain imaging in all 5 patients did not show cerebellar atrophy. Neurophysiologic studies showed decreased or unobtainable amplitudes of sensory potentials. Sural nerve biopsy showed decreased density of myelinated fibers and some areas of segmental remyelination. The findings were consistent with a sensory ataxia due to a sensory axonal polyneuropathy. The disorder was slowly progressive.
Nibbeling et al. (2017) reported follow-up of the family reported by van Dijk et al. (1995) and referred to the family as RF28. Affected individuals had a variable combination of sensory neuropathy and cerebellar ataxia. In a small minority of them, the cerebellar phenotype was more prominent than the sensory neuropathy. Cerebellar dysarthria was present in most, but not all, and all patients except one had abnormal oculomotor function, manifest as nystagmus, jerky pursuit, square-wave jerks, slow saccades, and saccadic dysmetria. Only some patients had cerebellar atrophy, which was mild. The average age of onset was 53.5 years (range 35 to 70).
The transmission pattern of SCA46 in the family reported by van Dijk et al. (1995) and Nibbeling et al. (2017) was consistent with autosomal dominant inheritance.
In 8 affected members of a family (RF28) with SCA46, Nibbeling et al. (2017) identified a heterozygous missense mutation in the PLD3 gene (L308P; 615698.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that the L308P protein was normally expressed, had normal cellular localization, and was stable. However, phospholipase D activity of the mutant protein was significantly decreased compared to wildtype. The family was 1 of 20 unrelated families with autosomal dominant SCA who underwent whole-exome sequencing.
Nibbeling, E. A. R., Duarri, A., Verschuuren-Bemelmans, C. C., Fokkens, M. R., Karjalainen, J. M., Smeets, C. J. L. M., de Boer-Bergsma, J. J., van der Vries, G., Dooijes, D., Bampi, G. B., van Diemen, C., Brunt, E., and 9 others. Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia. Brain 140: 2860-2878, 2017. [PubMed: 29053796] [Full Text: https://doi.org/10.1093/brain/awx251]
van Dijk, G. W., Wokke, J. H. J., Oey, P. L., Franssen, H., Ippel, P. F., Veldman, H. A new variant of sensory ataxic neuropathy with autosomal dominant inheritance. Brain 118: 1557-1563, 1995. [PubMed: 8595484] [Full Text: https://doi.org/10.1093/brain/118.6.1557]
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