ORPHA: 228169; DO: 4751;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q13.3 | Striatal degeneration, autosomal dominant | 609161 | Autosomal dominant | 3 | PDE8B | 603390 |
A number sign (#) is used with this entry because of evidence that autosomal dominant striatal degeneration-1 (ADSD1) is caused by heterozygous mutation in the PDE8B gene (603390) on chromosome 5q13.
See also infantile striatonigral degeneration (SNDI; 271930), a more severe disorder caused by mutation in the NUP62 gene (605815).
Autosomal dominant striatal degeneration is a neurologic disorder characterized by variable movement abnormalities due to dysfunction in the striatal part of the basal ganglia (summary by Kuhlenbaumer et al., 2004).
Genetic Heterogeneity of Autosomal Dominant Striatal Degeneration
See also ADSD2 (616922), caused by mutation in the PDE10A gene (610652) on chromosome 6q27.
Kuhlenbaumer et al. (2004) reported a large German family in which 8 members spanning 3 generations had basal ganglia disease inherited in an autosomal dominant pattern. Family history suggested 5 affected members in previous generations. The proband presented at age 38 years with mild slurring of speech and 'stiffness' in her tongue. The dysarthria progressed, and the patient later developed gait disturbance, mild bradykinesia, dysdiadochokinesia, and brisk lower extremity reflexes. Tremor was not present and the symptoms did not respond to levodopa treatment, thus clearly distinguishing the disorder from Parkinson disease (168600). Other affected family members had similar symptoms with onset in the fourth or fifth decade, but the exact age at onset could not be determined because of the insidious onset and slow progression of the disorder. Cranial MRI studies showed characteristic symmetric abnormalities of the basal ganglia, primarily a signal increase on T2-weighted images and a corresponding signal decrease on T1-weighted images. Lesions appeared to start in the dorsal putamen and later involved the caudate. Large lesions showed a slight mass effect. Kuhlenbaumer et al. (2004) noted that the disorder in this family, which they termed 'autosomal dominant striatal degeneration (ADSD),' showed some similarities to adult-onset basal ganglia disease (606159), which is caused by mutation in the ferritin light chain gene (FTL; 134790) on chromosome 19q13. However, that disease is characterized by hyperkinesia, whereas ADSD shows hypokinesia.
Barsottini et al. (2015) reported a 60-year-old Portuguese woman who presented with a 2-year history of progressive slowness of movements and slurred speech. Physical examination showed mild bradykinesia, dysarthria, and brisk deep tendon reflexes. The symptoms did not respond to dopamine treatment. Brain imaging showed symmetric lesions of the striatum, with a putaminal lesion showing an anteroposterior gradient with relative sparing of the anterior region. The nucleus accumbens and medial portion of the caudate head were also affected. There was also symmetric restricted diffusion in the dorsal portion of the putamen, nucleus accumbens, and tail of the caudate nucleus. The patient's deceased mother and brother reportedly had parkinsonism, but samples were not available for study.
Azuma et al. (2015) reported a Japanese mother and son with ADSD1. Although the mother had mild dysarthria at age 17 years, both presented with gait difficulties associated with parkinsonism and more severe dysarthria in their thirties. Head CT of the mother at age 39 showed low-density areas in the basal ganglia. At age 69, she had parkinsonism that was not responsive to dopaminergic treatment. Brain MRI showed atrophic changes in the putamen and increased T2-weighted signals in the caudate and putamen. Her son had similar clinical and radiographic features in this thirties. In addition, PET imaging performed in the son demonstrated markedly decreased pre- and postsynaptic dopaminergic function in the striatum.
The transmission pattern of ADSD1 in the family reported by Azuma et al. (2015) was consistent with autosomal dominant inheritance.
By genomewide linkage analysis, Kuhlenbaumer et al. (2004) mapped a candidate ADSD disease locus to a 3.25-Mb region on chromosome 5q13.3-q14.1 (maximum lod score of 4.10 at marker D5S1962). All affected family members shared a disease-associated haplotype.
In affected members of the family with adult-onset autosomal dominant striatal degeneration reported by Kuhlenbaumer et al. (2004), Appenzeller et al. (2010) identified a heterozygous mutation in the PDE8B gene (603390.0002), resulting in a loss of protein function.
In a 60-year-old Portuguese woman with ADSD1, Barsottini et al. (2015) identified a heterozygous truncating mutation in the PDE8B gene (603390.0003). Functional studies of the variant and studies of patient cells were not performed.
In a Japanese mother and son with ADSD1, Azuma et al. (2015) identified a heterozygous truncating mutation in the PDE8B gene (603390.0004). Functional studies of the variant and studies of patient cells were not performed. Azuma et al. (2015) postulated that the mutation would disrupt proper regulation of cAMP, which is a second messenger of dopamine signaling downstream of the dopamine receptor.
Appenzeller, S., Schirmacher, A., Halfter, H., Baumer, S., Pendziwiat, M., Timmerman, V., De Jonghe, P., Fekete, K., Stogbauer, F., Ludemann, P., Hund, M., Quabius, E. S., Ringelstein, E. B., Kuhlenbaumer, G. Autosomal-dominant striatal degeneration is caused by a mutation in the phosphodiesterase 8B gene. Am. J. Hum. Genet. 86: 83-87, 2010. [PubMed: 20085714] [Full Text: https://doi.org/10.1016/j.ajhg.2009.12.003]
Azuma, R., Ishikawa, K., Hirata, K., Hashimoto, Y., Takahashi, M., Ishii, K., Inaba, A., Yokota, T., Orimo, S. A novel mutation of PDE8B gene in a Japanese family with autosomal-dominant striatal degeneration. Mov. Disord. 30: 1964-1967, 2015. [PubMed: 26769607] [Full Text: https://doi.org/10.1002/mds.26345]
Barsottini, O. G. P., Martins, P. M., Chien, H. F., Raskin, S., Nunes, R. H., da Rocha, A. J, . Pedroso, J. L. Familial striatal degeneration: new mutation and neuroimaging clues. Neurology 85: 1816-1818, 2015. [PubMed: 26475694] [Full Text: https://doi.org/10.1212/WNL.0000000000002128]
Kuhlenbaumer, G., Ludemann, P., Schirmacher, A., De Vriendt, E., Hunermund, G., Young, P., Hund-Georgiadis, M., Schuierer, G., Moller, H., Ringelstein, E. B., Van Broeckhoven, C., Timmerman, V., Stogbauer, F. Autosomal dominant striatal degeneration (ADSD): clinical description and mapping to 5q13-5q14. Neurology 62: 2203-2208, 2004. [PubMed: 15210883] [Full Text: https://doi.org/10.1212/01.wnl.0000130485.89814.10]