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Hereditary inclusion body myopathy | |
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Other names | Hereditary inclusion body myopathy type 2 |
Hereditary inclusion body myopathies (HIBM) are a group of rare 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 individuals, but all share similar structural features in the muscles.
HIBMs are a group of muscle wasting disorders that are uncommon in the general world population. One autosomal recessive form of HIBM is known as IBM2 or GNE myopathy, which is a common genetic disorder amongst people of Iranian Jewish descent. [1] IBM2 has also been identified in other minorities throughout the world, including those of Asian, European, and South American, and Middle Eastern descent. In Japan and other 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. It can progress to marked disability within 10 to 15 years, causing many people with IBM2 to become full-time wheelchair users. The weakness and severity can vary from person to person. In some, weakness in the legs is noticed first. In some others, the hands are weakened more rapidly than the legs. 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 the disease, which is the reason IBM2 is often referred to as quadriceps-sparing myopathy (QSM).
Some early signs of HIBMs include:
The different forms have different mutations and inheritance patterns. See the detailed descriptions for details
The exact mechanisms of these diseases are not well understood. GNE/MNK a key enzyme in the sialic acid biosynthetic pathway, and loss-of-function mutations in GNE/MNK may lead to a lack of sialic acid, which in turn could affect sialoglycoproteins. GNE knockout mice show problems similar to people with IBM and people with IBM dystroglycan have been found to lack sialic acid. However, the part of the dystroglycan that is important in muscle function does not seem to be affected. Another protein, neural cell adhesion molecule is under-sialyated in people with IBM, but as of 2016, it had no known role in muscle function. [2]
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 the 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 person has IBM2:
Types of hereditary inclusion body myopathy:
The condition now called Desmin-related myofibrillar myopathy (also called myofibrillar myopathy-1) was formerly known as inclusion body myopathy 1 (IBM1). [13]
More types of HIMBs, linked to other genes, may be identified in the future.
Treatment is palliative, not curative (as of 2009). [14]
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 the clinical need of the individual. Sometimes tuning of rigid AFOs can enhance knee stability.
A 2009 review noted that muscle weakness usually begins after age 20 and after 20–30 years, the person usually requires a wheelchair for mobility. There was no mention of increased mortality. [14]
Because lack of sialic acid appears to be part of the pathology of IBM caused by GNE mutations, clinical trials with sialic acid supplements, and with a precursor of sialic acid, N-Acetylmannosamine, have been conducted, and as of 2016 further trials were planned. [2]
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. [15] 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.
Alternative names include: Inclusion body myopathy, autosomal recessive; Inclusion body myopathy, quadriceps-sparing; QSM; Hereditary inclusion body myopathy; HIBM; Distal myopathy with rimmed vacuoles; DMRV; Nonaka myopathy; Rimmed vacuole myopathy; Quadriceps Sparing Myopathy; GNE myopathy
Other Names: IBM3; Myopathy with congenital joint contractures, ophthalmoplegia, and rimmed vacuoles; Inclusion body myopathy autosomal dominant; Hereditary inclusion body myopathy - joint contractures - ophthalmoplegia; Hereditary inclusion body myopathy type 3; HIBM3
Myopathy With Congenital Joint Contractures, Ophthalmoplegia, And Rimmed Vacuoles Inclusion Body Myopathy 3, Autosomal Dominant, Formerly; IBM3, Formerly
Other Names: IBMPFD; Inclusion body myopathy with Paget disease of bone and frontotemporal dementia; Limb-girdle muscular dystrophy with Paget disease of bone; Pagetoid amyotrophic lateral sclerosis; Pagetoid neuroskeletal syndrome
Alternative names: Myopathy, Myofibrillar, Desmin-Related. Desminopathy, Primary. Desmin-Related Myopathy; DRM. Myofibrillar Myopathy With Arrhythmogenic Right Ventricular Cardiomyopathy. Desmin-Related Myopathy With Arrhythmogenic Right Ventricular Cardiomyopathy. Arrhythmogenic Right Ventricular Dysplasia, Familial, 7, Formerly. ARVD7, Formerly. Arrhythmogenic Right Ventricular Cardiomyopathy 7, Formerly; ARVC7, Formerly. Inclusion Body Myopathy 1, Autosomal Dominant, Formerly. IBM1, Formerly. Cardiomyopathy, Dilated, 1f And Limb-Girdle Muscular Dystrophy Type 1d, Formerly. CMD1f And LGMD1d, Formerly. Cardiomyopathy, Dilated, with Conduction Defect and Muscular Dystrophy; CDCD3, formerly.