Alternative titles; symbols
SNOMEDCT: 716107009; ORPHA: 2379; DO: 0111781;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq28 | Waisman syndrome | 311510 | X-linked recessive | 3 | RAB39B | 300774 |
A number sign (#) is used with this entry because of evidence that Waisman syndrome (WSMN) is caused by mutation in the RAB39B gene (300774) on chromosome Xq28.
Mutation in the RAB39B gene has also been found in patients with X-linked mental retardation-72 (MRX72; 300271); Parkinson disease in patients with MRX72 has not been reported.
Waisman syndrome is an X-linked neurologic disorder characterized by delayed psychomotor development, impaired intellectual development, and early-onset Parkinson disease (summary by Wilson et al., 2014).
Laxova et al. (1985) reported a large family of German ancestry living in Wisconsin in which multiple males had an X-linked form of mental retardation associated with megalencephaly and early-onset parkinsonism. The family was first seen by Dr. Harry A. Waisman in 1967. The patients had delayed psychomotor development with speech and language delay and persistent frontal lobe reflexes. In the second decade of life, the patients developed extrapyramidal signs, including cogwheel rigidity, tremor, slurred speech, shuffling gait, and postural changes; some patients had choreoathetoid movements. Three patients had seizures. CT scan of 2 patients showed no evidence of intracranial calcification.
Wilson et al. (2014) reported an Australian family in which 3 brothers presented in childhood with nonprogressive impaired intellectual development, including delayed developmental milestones, cognitive impairment, and impaired speech; they also had macrocephaly. One patient developed a tremor in late childhood, but not frank parkinsonism. The other 2 brothers were both diagnosed with L-DOPA-responsive akinetic-rigid Parkinson disease by their mid-forties. Features of Parkinson disease in the 2 brothers included tremor, shuffling gait, bradykinesia, dyskinesia, cogwheel rigidity, and hypokinetic dysarthria. Brain imaging in 1 patient who had dementia showed evidence of iron and/or calcium deposition in the substantia nigra and globus pallidus. Neuropathologic examination of 1 patient showed loss of pigmented neurons in the substantia nigra, as well as alpha-synuclein (SNCA; 163890)-immunoreactive Lewy bodies and Lewy neurites in surviving neurons. Other findings included cortical Lewy bodies, tau (MAPT; 157140) immunoreactivity, and axonal spheroids, all of which are observed in other neurodegenerative disorders.
The transmission pattern of Waisman syndrome in the families reported by Laxova et al. (1985) and Wilson et al. (2014) was consistent with X-linked recessive inheritance.
In 3 affected brothers from an Australian family segregating Waisman syndrome, Wilson et al. (2014) identified a hemizygous 45-kb deletion of chromosome Xq28, including the entire RAB39B gene and the last 3 coding exons of the CLIC2 gene (300138). Patient fibroblasts showed absence of both the RAB39B and CLIC2 transcripts. Although mutation in the CLIC2 gene had been associated with a syndromic form of intellectual disability (MRXS32; 300886), Wilson et al. (2014) suggested that disruption of RAB39B was responsible for the phenotype in this family.
Gregg et al. (1991) demonstrated linkage of Waisman syndrome with high lod scores and no recombinants to the F8C gene (300841) and to 4 DNA markers located in the region Xq27.3-qter, i.e., Xq28.
In affected members of the Wisconsin kindred with Waisman syndrome reported by Laxova et al. (1985), Wilson et al. (2014) identified a hemizygous missense mutation in the RAB39B gene (T168K; 300774.0003), resulting in destabilization and increased turnover of the mutant protein, consistent with a loss of function. The mutation was found by direct sequencing of the RAB39B gene after a deletion of RAB39B and 3 exons of the CLIC2 gene was identified in an Australian family with a similar phenotype. No CLIC2 sequence variants were identified in the Wisconsin kindred. In vitro cellular studies showed that loss of RAB39B was associated with reduced steady-state levels of alpha-synuclein. Wilson et al. (2014) concluded that dysregulation of SNCA homeostasis and defects in vesicular trafficking resulted in the manifestations of this neurologic disorder. Mutations in the RAB39B gene were not found in 187 individuals with early-onset Parkinson disease or in 48 males with neurodegeneration with brain iron accumulation (see, e.g., NBIA1, 234200). Wilson et al. (2014) concluded that it was unclear whether MRX72 and WSMN represent the same disorder, with parkinsonism being an age-dependent manifestation, or whether each represents a distinct phenotype resulting from RAB39B mutations.
Mata et al. (2015) reported a large US family of European origin in which 7 individuals, 5 males and 2 females, were affected with Parkinson disease, with 2 of the males having mild intellectual disability. The age of onset of Parkinson disease symptoms in the males ranged from 29 to 53, and in the females was 55 and 57. All had classical symptoms of parkinsonism that were levodopa-responsive. All affected individuals carried a missense mutation in the RAB39B gene (G192R; 300774.0004). Three unaffected females aged 40, 55, and 86 years, as well as an unaffected male aged 41 years, also carried the mutation.
Gregg, R. G., Metzenberg, A. B., Hogan, K., Sekhon, G., Laxova, R. Waisman syndrome, a human X-linked recessive basal ganglia disorder with mental retardation: localization to Xq27.3-qter. Genomics 9: 701-706, 1991. [PubMed: 1674730] [Full Text: https://doi.org/10.1016/0888-7543(91)90363-j]
Laxova, R., Brown, E. S., Hogan, K., Hecox, K., Opitz, J. M. An X-linked recessive basal ganglia disorder with mental retardation. Am. J. Med. Genet. 21: 681-689, 1985. [PubMed: 4025396] [Full Text: https://doi.org/10.1002/ajmg.1320210409]
Mata, I. F., Jang, Y., Kim, C.-H., Hanna, D. S., Dorschner, M. O., Samii, A., Agarwal, P., Roberts, J. W., Klepitskaya, O., Shprecher, D. R., Chung, K. A., Factor, S. A., and 14 others. The RAB39B p.G192R mutation causes X-linked dominant Parkinson's disease. Molec. Neurodegener. 10: 50, 2015. Note: Electronic Article. [PubMed: 26399558] [Full Text: https://doi.org/10.1186/s13024-015-0045-4]
Wilson, G. R., Sim, J. C. H., McLean, C., Giannandrea, M., Galea, C. A., Riseley, J. R., Stephenson, S. E. M., Fitzpatrick, E., Haas, S. A., Pope, K., Hogan, K. J., Gregg, R. G., and 21 others. Mutations in RAB39B cause X-linked intellectual disability and early-onset Parkinson disease with alpha-synuclein pathology. Am. J. Hum. Genet. 95: 729-735, 2014. [PubMed: 25434005] [Full Text: https://doi.org/10.1016/j.ajhg.2014.10.015]