Moyamoya Disease 2

A number sign (#) is used with this entry because evidence suggests that susceptibility to moyamoya disease-2 (MYMY2) may be conferred by variation in the RNF213 gene (613768) on chromosome 17q25.

Description

Moyamoya disease is a progressive cerebral angiopathy characterized by bilateral internal carotid artery stenosis and abnormal collateral vessels. The abnormal vessels resemble a 'puff of smoke' (moyamoya) on cerebral angiogram. Affected individuals can develop transient ischemic attacks and/or cerebral infarction, and rupture of the collateral vessels can cause intracranial hemorrhage (summary by Kamada et al., 2011).

For a general phenotypic description and a discussion of genetic heterogeneity of moyamoya disease, see MYMY1 (252350).

Clinical Features

Liu et al. (2011) reported a Caucasian father of Czech descent and his 3 affected children with moyamoya disease. The father had a mild ischemic stroke at age 30 years, and his mother had died of ischemic stroke at age 35. The 3 children developed moyamoya disease at ages 5, 9, and 3 years, respectively. One had involuntary movements and another had signs of ischemic stroke. Diagnosis of the disorder was confirmed by brain MRI.

Miyatake et al. (2012) reported 2 Japanese sibs with MYMY2 confirmed by genetic analysis. One sib was homozygous for the 14576G-A RNF213 variant (613768.0001) and the other was heterozygous for the same variant. The homozygous 21-year-old brother had a transient ischemic attack (TIA) at age 2 years and was found to have moyamoya disease. Brain imaging showed a low-density area around the right middle cerebral artery and atrophy of the right cerebral hemisphere; this was associated with left hemiparesis. Cerebral angiograms showed multiple bilateral vascular abnormalities. He had progression of the disorder, with recurrent strokes despite multiple surgeries, and slow intellectual deterioration. Residual features included headache, paresis, and visual defects. His 18-year-old sister, who was heterozygous for the mutation, had her fist transient ischemic attack at age 17 years. Brain MRI was normal, but cerebral angiograms showed unilateral changes consistent with moyamoya disease. The occlusive changes were not as severe as in her affected brother. Vascular surgery resulted in complete remission of TIAs. Family genetic analysis showed that both unaffected parents and an unaffected third sib also carried a heterozygous 14576G-A mutation. The report suggested a dosage effect for the 14576G-A variant.

Other Features

Nishimura et al. (2003) described a 4-year-old boy with microcephalic osteodysplastic primordial dwarfism II (MOPD2; 210720) and cafe-au-lait spots who developed left hemiparesis and seizures and was found to have moyamoya disease on MRI, with infarction of the right cerebral hemisphere. FISH analysis of the neurofibromatosis locus (NF1; 162200) did not show any deletions, and the boy had no neurofibromas or Lisch nodules.

Young et al. (2004) reported a second patient with MOPD2, cafe-au-lait spots, and moyamoya disease. She began having episodes of weakness and seizures at age 2.5 years; cerebral angiography revealed typical moyamoya vessels and MRI showed multiple areas of cerebral infarction. Standard karyotyping, specific sister chromatid exchange and diepoxy chromosome breakage analysis, and mitochondrial mutation testing were normal. Young et al. (2004) suggested that the list of moyamoya disease associations should be extended to include the unusual combination of MOPD2 with multiple cafe-au-lait spots.

Mapping

Yamauchi et al. (2000) stated that moyamoya disease and neurofibromatosis (NF1; 162200), which maps to chromosome 17q11, had been associated in over 50 reported cases. They therefore undertook a linkage study in 24 multiplex families with moyamoya disease, using markers on chromosome 17. Two-point linkage analysis gave a maximum lod score of 3.11 at a recombination fraction of 0.00 for marker D17S939. Multipoint linkage analysis yielded a maximum lod score of 4.59 for a 9-cM region between D17S785 and D17S836.

By genomewide parametric linkage analysis of 15 extended Japanese families with autosomal dominant moyamoya disease, Mineharu et al. (2008) found significant linkage to chromosome 17q25.3, with a maximum multipoint lod score of 6.57 at D17S704 under a narrow diagnostic classification and 8.07 under a broad diagnostic classification. The results suggested that the diagnostic criteria in the broad classification could be applied to the diagnosis of patients with familial occurrence. The study indicated that middle cerebral artery stenosis or occlusion of uncertain causes, as well as unilateral disease may also be considered to be in the spectrum of moyamoya disease. Haplotype analysis revealed segregation of a disease haplotype in all families but 1, and informative crossovers mapped the locus to a 3.5-Mb region between D17S1806 and 17qtel, encompassing 94 annotated genes. Direct sequencing excluded mutations in the BAIAP2 (605475), TIMP2 (188825), RAC3 (602050), and RAB40B genes. Mineharu et al. (2008) noted that the locus did not overlap with that reported by Yamauchi et al. (2000), suggesting that there may be 2 loci in this region.

In a genomewide association study of 72 Japanese patients with moyamoya disease, Kamada et al. (2011) found a significant association with chromosome 17q25-qter (p = 10 x 10(-8)). A follow-up locus-specific association study showed significant association with a 161-kb region entirely within the RNF213 gene.

Molecular Genetics

In Japanese patients with moyamoya disease, Kamada et al. (2011) identified a significant association between disease and a variant in the RNF213 gene (R4859K; 613768.0001). In 19 of 20 families, heterozygosity for the variant was found in 39 (92.9%) of 41 patients with the disorder and in 13 (46.4%) of 28 family members without the disorder. Three (7.1%) patients had the variant in the homozygous state. The overall p value among familial cases was 4.2 x 10(-7). None of 15 family members without the variant developed the disease. The variant was also present in heterozygosity and homozygosity in 45 (71.4%) and 1 (1.6%) of 63 Japanese patients with sporadic disease, respectively, and in 6 (1.4%) of 429 controls. There was no phenotypic difference between homozygous and heterozygous carriers. Overall, carrying the variant conferred an odds ratio of 190.8 for development of the disorder (p = 1.2 x 10(-43)). The R4859K variant was not found in 400 Caucasian controls. Three additional patients with sporadic disease carried 3 different missense variants in the RNF213 gene that were not found in 388 controls.

In affected members of 41 Japanese families and 1 Korean family with moyamoya disease, Liu et al. (2011) identified an R4810K substitution (ss179362673) in the RNF213 gene (613768.0002). The variant segregated with the disorder, although some carriers of the variant did not have moyamoya disease, indicating incomplete penetrance. The mutation was initially found by linkage analysis followed by exome sequencing in eight 3-generation families. Haplotype analysis indicated a founder effect. A case-control study of 251 East Asian patients and 707 controls showed a significant association between R4810K and the disorder (odds ratio of 111.8, p = 10 x 10(-119)). In vitro functional expression studies in HEK293 cells showed that the R4810K protein was expressed and localized normally within the cell, and had normal ubiquitin activity. Direct sequencing identified 5 additional RNF213 variants in 7 of 64 East Asian cases, and 4 variants in 4 (8%) of 50 Caucasian cases (see, e.g., 613768.0003). Although these variants were not found in controls, pathogenicity was difficult to prove. Liu et al. (2011) postulated that variation in the RNF213 gene acts with environmental factors to result in moyamoya disease.

Miyatake et al. (2012) found the 14576G-A transition in the RNF213 gene (613768.0001) in 39 (95.1%) of 41 Japanese patients with familial moyamoya disease, in 129 (79.2%) of 163 Japanese patients with sporadic moyamoya disease, and in 5 (1.8%) of 283 Japanese control individuals. Fifteen of the 168 patients with the variant carried it in the homozygous state, whereas all 5 controls carried it in the heterozygous state. Most patients inherited the allele from either or both unaffected parents; all unaffected parents were heterozygous for the variant. Miyatake et al. (2012) concluded that heterozygosity for the 14576G-A variant confers an odds ratio of 236 for development of the disorder. Patients with the 14576G-A variant had an earlier age at onset (as early as age 4 years in homozygotes) and tended to have a higher frequency of infarcts, posterior cerebral artery involvement, bilateral disease, seizures, and intellectual impairment compared to patients without the variant. However, heterozygosity for the variant was also found in adult patients. Comparisons of clinical features between 5 parent-offspring pairs who were heterozygous for the variant showed anticipation. Other rare variants in the RNF213 gene were not associated with clinical phenotypes.

Population Genetics

Miyatake et al. (2012) found a heterozygous 14576G-A transition in the RNF213 gene (613768.0001) in 1.8% of Japanese control individuals. Since the annual incidence of moyamoya disease in Japan is 0.35-0.94 per 100,000 person-years, Miyatake et al. (2012) estimated that the lifetime incidence risk of moyamoya disease in heterozygous carriers is 1.44 to 3.77%.