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 young onset at 17 and old onset at 52 has been recorded. 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).

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)^[1] lists IBM1 under OMIM 601419:
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. Also see OMIM:605820(DMRV).
3. Nonaka distal myopathy with rimmed vacuoles, essentially a form of IBM2. See: OMIM # 605820:
4. IBM is a frequent component of multisystem proteinopathy, which may also include FTD, ALS and sometimes bone involvement. MSP is frequently caused by mutations in valosin-containing protein (VCP) on chromosome 9 (located at 9p13-p12), but has also been linked to mutations in certain RNA-binding proteins and factors that regulate ubiquitin-dependent autophagy. See: multisystem proteinopathy.

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

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 aberrant proteins similar to those found in senile plaques of Alzheimer's disease (amyloid beta, hyperphosphorylated tau, amongst others)Reference

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.^[2] 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.

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;

Treatment

Treatment is palliative, not curative.

Treatment options for lower limb weakness such as foot drop can be through the use of Ankle Foot Orthoses (AFOs) which can be designed or selected by an Orthotist based upon clinical need for that patient. Sometimes tuning of rigid AFOs can enhance knee stability.

There was an initial study done at the National Human Genome Research Institute in Bethesda, MD testing the efficacy of administering sialic acid to patients with HIBM. Because the study cohort was so small, no significant results were determined. Anecdotal reports by patients suggested limb muscle strength was improved. Further, patients with HIBM have reported taking sialic acid on their own. A number of labs are studying sialic acid and its derivatives as a potential therapeutic for HIBM.

External links

• GeneReviews/NCBI/NIH/UW entry on Inclusion Body Myopathy 2
• GeneReviews/NCBI/NIH/UW entry on Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia
• Inclusion body myositis, a more common and non-hereditary form.

References