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Hereditary inclusion body myopathy: the Middle Eastern genetic cluster
Z Argov1, I Eisenberg, G Grabov-Nardini
1Department of Neurology and Agnes Ginges Center for Human Neurogenetics, Hadassah University Hospital and Hebrew University-Hadassah Medical School, Jerusalem. zargov@md2.huji.ac.il
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.
Insights
The common M712T mutation causes hereditary inclusion body myopathy (HIBM) in Middle Eastern populations, not just Persian Jews. This founder mutation, approximately 1,300 years old, shows incomplete penetrance and a wider spectrum of symptoms than previously recognized.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Hereditary inclusion body myopathy (HIBM) with quadriceps sparing was initially identified in Persian Jews.
- The M712T mutation in the HIBM gene was recently discovered, prompting re-evaluation of HIBM epidemiology and phenotypes.
Observation:
- The M712T mutation was investigated in HIBM patients across diverse Middle Eastern communities.
- DNA analysis and haplotype construction were performed on affected individuals and unaffected family members.
Findings:
- 129 HIBM patients from 55 families (Middle Eastern Jews, Karaites, Arab Muslims) were homozygous for the M712T mutation and shared a common haplotype.
- Five unaffected individuals were also homozygous, indicating incomplete penetrance of the mutation.
- Atypical HIBM presentations included quadriceps weakness, proximal weakness, facial weakness, and perivascular inflammation on muscle biopsy.
Implications:
- The phenotypic spectrum of recessive HIBM is broader than previously understood.
- Diagnostic criteria for HIBM require revision to encompass atypical presentations.
- The M712T mutation represents a founder mutation in the Middle East, approximately 1,300 years old, affecting multiple ethnic groups.