Hereditary inclusion body myopathy

Hereditary inclusion body myopathies (HIBM) are a heterogeneous group of genetic disorders which have different symptoms. Generally, they are neuromuscular disorders characterized by muscle weakness developing in young adults. Hereditary inclusion body myopathies comprise both autosomal recessive and autosomal dominant muscle disorders that have a variable expression (phenotype) in individual patients, but all share similar structural features in the muscles.

HIBMs are a group of muscle wasting disorders, which are uncommon in the general world population. One autosomal recessive form of HIBM is known as IBM2, which is a common genetic disorder amongst people of Iranian-Jewish descent. IBM2 has also been identified in other minorities throughout the world, including people of Asian (Japanese and others), European, and South American origin, as well as Muslim patients in the Middle Eastern, Palestinian, and Iranian origin. In Japan and many East Asian countries, this disorder is known as Distal Myopathy with Rimmed Vacuoles (DMRV).

IBM2 causes progressive muscle weakness and wasting. Muscle wasting usually starts around the age of 20 - 30 years, although we have seen young onset at 17 and old onset at 52. As such, it affects the most productive times of our lives. It can progress to marked disability within 10 - 15 years, confining many patients to the wheelchair. The weakness and severity can vary from person to person. In some, weakness in the legs is noticed first. In few others, the hands are weakened more rapidly than the legs. Weakness is progressive, which means the muscle become weaker over time. IBM2 does not seem to affect the brain, internal organs or sensation. The quadriceps are relatively spared, and remain strong until the late stages of disease, which is the reason IBM2 is often referred to as Quadriceps Sparing Myopathy (QSM).

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Signs and symptoms

Some early signs of HIBMs includes:

• Difficulty walking on heels, and difficulty running;
• Weak index finger;
• Frequent loss of balance.
• On muscle biopsy, the typical finding includes inclusion bodies, rimmed vacuoles and accumulation of abberant proteins similar to those found in senile plaques of Alzheimer's Brain disease (amyloid beta, hyperphosphorylated tau, amongst others).

Diagnosis

The most useful information for accurate diagnosis is the symptoms and weakness pattern. If the quadriceps are spared but the hamstrings and iliopsoas are severely affected in a person between ages of 20 - 40, it is very likely HIBM will be at the top of the differential diagnosis. The doctor may order any or all of the following tests to ascertain if a patient has IBM2:

• Blood test for serum Creatine Kinase (CK or CPK);
• Nerve Conduction Study (NCS) / Electomyography (EMG);
• Muscle Biopsy;
• Magnetic Resonance Imaging (MRI) or Computer Tomography (CT) Scan to determine true sparing of quadriceps;
• Blood Test or Buccal Swab for genetic testing;

This disorder is formally classified on Mendelian Inheritance in Man (MIM) as IBM2 or DMRV. You can reach the online description of this disorder at OMIM:600737(IBM2) or OMIM:605820(DMRV).http://hibm.org/hrg/pages/welcome/what-is-hibmibm2.php

Classification

Types of hereditary inclusion body myopathy:

1. An autosomal dominant form (IBM1) where the quadriceps are one of the first muscles to become weak. Needham (2007) lists IBM1 under OMIM 601419: [1]
2. An autosomal recessive form (IBM2), common among people of Middle Eastern and Jewish heritage. This form mainly affects leg muscles, but with an unusual distribution that spares the quadriceps: a so-called quadriceps-sparing myopathy (QSM), the quadriceps are among the last muscles to become weak. See: OMIM # 600737.[2]
3. Nonaka distal myopathy with rimmed vacuoles, essentially a form of IBM2. See: OMIM # 605820: [3]
4. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD), is linked to a slightly different gene on chromosome 9 (located at 9p13-p12). See: OMIM # 167320 [4]
5. Inclusion body myopathy-3 (IBM3) is linked to mutations in a gene encoding myosin heavy chain II proteins on chromosome 17 (located at 17p13.1). See: OMIM # 605637 [5]

More types of HIMBs, linked to other genes, may be identified in the future.

Genetics

The different forms have different mutations and inheritance patterns. See the detailed OMIM descriptions for details (given above).

Mechanisms

The exact mechanisms of these diseases are not well understood.

Hereditary inclusion body myopathy (IBM) constitutes a unique group of neuromuscular disorders characterized by adult-onset slowly progressive distal and proximal weakness, and a typical muscle pathology including rimmed vacuoles and filamentous inclusions. Autosomal dominant (IMB3; OMIM 605637) and autosomal recessive (IBM2; OMIM 600737) forms have been described. The autosomal recessive form, first characterized in Jews of Persian descent, is a myopathy that affects mainly leg muscles, but with an unusual distribution that spares the quadriceps, so-called quadriceps-sparing myopathy (QSM). This disorder was subsequently found in other Middle Eastern families, the gene was mapped to 9p13-p12, and in 104 affected persons from 47 Middle Eastern families the same mutation in homozygous state was found in the GNE gene (Eisenberg et al., 2001). Affected individuals in families of other ethnic origins were found to be compound heterozygotes for other distinct mutations in the GNE gene. From OMIM 603824.

Treatment

Treatment is palliative, not curative.

See also

• Inclusion body myositis, a more common and non-hereditary form.

References

• Eisenberg, I.; Avidan, N.; Potikha, T.; Hochner, H.; Chen, M.; Olender, T.; Barash, M.; Shemesh, M.; Sadeh, M.; Grabov-Nardini, G.; Shmilevich, I.; Friedmann, A.; Karpati, G.; Bradley, W. G.; Baumbach, L.; Lancet, D.; Ben Asher, E.; Beckmann, J. S.; Argov, Z.; Mitrani-Rosenbaum, S. The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy. Nature Genet. 29: 83-87, 2001.
• Needham M, Mastaglia FL, Garlepp MJ. (2007) Genetics of inclusion-body myositis. Muscle Nerve. Mar 15; [Epub ahead of print] May, 2007, pps. 549-561.