Novel valosin containing protein mutation in a Swiss family with hereditary inclusion body myopathy and dementia.

Inclusion body myopathy associated with Paget's disease of the bone and frontotemporal dementia is a rare but highly penetrant autosomal dominant progressive disorder linked to mutations in valosin containing protein (VCP). Here, we characterize a novel mutation in the linker 1 domain of VCP leading to inclusion body myopathy and/or frontotemporal dementia in 3 generations of a Swiss family. A detailed history of several years of clinical follow-up and electrophysiological, radiological and pathological findings are presented. Five out of 6 individuals suffered from progressive myopathy and 2 out of 6 from frontotemporal dementia, respectively. A radiologically suspected Paget's disease of the bone could not been confirmed at autopsy. This case study illustrates that only a subset of individuals shows the full triad of the disease complex and that clinicopathological findings are - when interpreted apart from familial history - hard to distinguish from sporadic inclusion body myositis.

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia linked to VCP p.Arg155Cys in a Korean family.

BACKGROUND: Missense mutations in the valosin-containing protein (VCP) gene on chromosome 9p13.3-p12 cause inclusion body myopathy with Paget disease of bone and frontotemporal dementia (hereafter referred to as IBMPFD; OMIM 167320). OBJECTIVE: To describe detailed clinical, electrophysiological, biochemical, and neuroimaging findings in IBMPFD linked to VCP p.Arg155Cys in a Korean family. DESIGN: Case series. Clinical, electrophysiological, biochemical, and neuroimaging findings were obtained by direct evaluation and from previous medical records. SETTING: Tertiary referral hospital. PARTICIPANTS: Three affected family members in a Korean family. RESULTS: The clinical features of myopathy, Paget disease of bone, and semantic dementia (a clinical subtype of frontotemporal dementia) in our patients were similar to those of previously reported cases. However, the brain magnetic resonance imaging features in our patients, including asymmetric anterior and lateral temporal and inferior parietal atrophy with ventricular dilatation on the affected side, differed from those of previously published features in patients with IBMPFD and in patients with typical semantic dementia who show anterior temporal and frontal atrophy. CONCLUSION: To our knowledge, this report provides the first documented IBMPFD family in Asia and broadens the phenotypic spectrum of VCP mutation-associated frontotemporal dementia.

Sporadic inclusion body myositis in Japanese is associated with the MHC ancestral haplotype 52.1.

In Caucasians, sporadic inclusion body myositis has been associated with the MHC ancestral haplotypes; HLA-A1, B8, DR3 (8.1AH) and HLA-B35, DR1 (35.2AH). It is not known whether these haplotypes carry susceptibility for the disease in other ethnic groups. We report here the results of HLA-B and -DRB1 typing using a high-resolution sequence-based technique in a cohort of 31 Japanese patients with definite sIBM. Patient allele frequencies were 40.3% for HLA-B*5201 (10.7% in controls: p<0.001) and 37.1% for HLA-DRB1*1502 (10% in controls: p<0.001). Both alleles were found together as part of a conserved haplotype (52.1AH) at a frequency of 37.1% in patients (8.4% in controls: p<0.001). This is the first description of a haplotypic MHC association with sporadic inclusion body myositis in Japanese patients. These findings indicate that different MHC ancestral haplotypes are associated with sIBM in different ethnic groups and further emphasize the importance of genetic factors in this condition.

Hereditary inclusion body myopathy: the Middle Eastern genetic cluster.

BACKGROUND: Recessively inherited hereditary inclusion body myopathy (HIBM) with quadriceps sparing was initially described only in Jews originating from the region of Persia. The recent identification of the gene responsible for this myopathy and the common "Persian Jewish mutation" (M712T) enabled the re-evaluation of atypical phenotypes and the epidemiology of HIBM in various communities in the Middle East. OBJECTIVE: To test for the M712T mutation in the DNA from HIBM patients in the Middle East. METHODS: DNA from all suspected HIBM patients was tested for the M712T mutation. Unaffected members of families with genetically proven HIBM were studied too. In the majority of families, haplotype construction with markers spanning the 700-kb region of the HIBM gene was performed. RESULTS: One hundred twenty-nine HIBM patients of 55 families (Middle Eastern Jews, Karaites, and Arab Muslims of Palestinian and Bedouin origin) were homozygous for the M712T mutation, and all carried the same haplotype. Five clinically unaffected subjects were also homozygous for the common mutation and haplotype, including two older adults (ages 50 and 68 years). Atypical features with this same mutation were marked quadriceps weakness in five patients, proximal weakness only in two patients, facial weakness in three patients, and a muscle biopsy showing perivascular inflammation in one patient. CONCLUSIONS: The phenotypic spectrum of recessive HIBM is wider than previously described, and the diagnostic criteria for this myopathy must be changed. The Middle Eastern cluster is the result of a founder mutation, with incomplete penetrance, that is approximately 1,300 years old and is not limited to Jews.

Mutations spectrum of GNE in hereditary inclusion body myopathy sparing the quadriceps.

Hereditary Inclusion Body Myopathy (HIBM) is a unique group of neuromuscular disorders characterized by adult onset and a typical muscle pathology. We have recently identified the gene encoding for a bifunctional enzyme, UDP-N-acetylglucosamine 2 epimerase/N-acetylmannosamine kinase (GNE), as the mutated gene in the prototype form of the disease presenting quadriceps sparing, particularly common in Middle Eastern Jews. Interestingly, we have identified the homozygous M712T Middle Eastern Jewish mutation also in two unrelated Middle Eastern Moslem families. We have also evaluated the involvement of GNE in several families from worldwide non-Jewish ethnic origins presenting symptoms similar to the Middle Eastern HIBM prototype. A total of 14 GNE mutations were identified (one nonsense and 13 missense), of which six are novel: an homozygous missense mutation in a consanguineous family from Italy and in a non consanguineous family from USA, and distinct compound heterozygotes in families from Germany, Italy, Ireland, Bahamas, USA and East India. This study brings to 17 the number of reported GNE mutations in quadriceps sparing myopathy, occurring either in the epimerase or the kinase domain of the enzyme. The mechanism leading to this unique phenotype still remains to be elucidated.

Fine-structure mapping of the hereditary inclusion body myopathy locus.

The gene responsible for a recessive form of hereditary inclusion body myopathy (HIBM) has previously been mapped to a 10-cM interval on chromosome 9p1-q1. We report the results of further mapping studies using two-point linkage analyses and linkage disequilibrium analyses with 20 HIBM families. We demonstrate that the HIBM gene (HGMW-approved symbol IBM2) lies between loci D9S1791 and D9S50, which are about 1 Mb apart. Genetic analyses in 56 affected individuals of Persian, Afghani, and Iraqi Jewish descent demonstrated a common haplotype at these loci, indicating that a founding mutation accounts for disease in these related ethnic groups. beta-Tropomyosin, an abundant skeletal muscle protein that maps within 1 cM of D9S1791, was excluded as the disease gene because an intragenic polymorphism did not exhibit linkage disequilibrium in HIBM probands. We conclude that the disease gene resides in a 1-Mb interval on chromosome 9 and speculate that a novel muscle protein encoded there is mutated in HIBM.

Genetics of inclusion body myopathies.

We review the current knowledge about the genetic susceptibility to develop inflammatory inclusion body myositis, especially in relation to the increased presence of the HLA DR3 allele in patients with familial and sporadic forms, indicating an autoimmune predisposition. The main focus of the review is the clinical and genetic presentations of the various hereditary inclusion body myopathies. Criteria for diagnosis and classification of these myopathies are presented. The spectrum of the recessive forms of hereditary inclusion body myopathies currently linked to chromosome 9p1-q1 is described, with emphasis on the up-to-date status of the gene search for these forms.

Various types of hereditary inclusion body myopathies map to chromosome 9p1-q1.

Hereditary inclusion body myopathies are a clinically heterogeneous group of disorders characterized by adult-onset, slowly progressive muscle weakness and typical histopathology: rimmed vacuoles and filamentous inclusions. The disorders are usually inherited as an autosomal recessive trait. The gene responsible for the disease found in Iranian Jews, who present with quadriceps-sparing myopathy, maps to chromosome 9p1-q1. We address the question of whether hereditary inclusion myopathies are genetically as well as clinically heterogeneous disorders. We mapped the disease gene segregating in two families of Afghani-Jewish and one family of Iraqi-Jewish descent to the chromosome 9 locus. Similarly, the disease gene segregating in a non-Jewish family from India mapped to the same locus. By contrast, the disease gene segregating in a French-Canadian family in which affected individuals had central nervous system involvement as well as hereditary inclusion body myopathy, did not map to this locus. We conclude that many but not all forms of autosomal recessive hereditary inclusion body myopathy are caused by a gene defect that maps to chromosome 9p1-q1.