A Natural History Study of Patients With Hereditary Inclusion Body Myopathy

• The functional outcome measures (potential endpoints) to be used to test future therapeutic interventions. [ Time Frame: 0, 6, 12, 18, and possibly 24 months ] [ Designated as safety issue: No ]
• The identification of potential serum biomarkers (sialylated as disease markers and the correlation between muscle magnetic resonance imaging (MRI) findings with progression of the disease [ Time Frame: 0, 6, 12, 18, and possibly 24 months ] [ Designated as safety issue: No ]
• The rates of progression for individual subjects. [ Time Frame: 0, 6, 12, 18, and possibly 24 months ] [ Designated as safety issue: No ]

Background:

- Hereditary inclusion body myopathy (HIBM) is a disease that causes walking difficulties and increasing muscle weakness. It usually develops in young adults (between 20 and 30 years of age), and affects arm and leg muscles. HIBM is caused by mutations in a gene that may affect how the muscles function. Researchers want to learn more about the causes, symptoms, and effects of HIBM.

Objectives:

- To collect genetic and medical information from people with hereditary inclusion body myopathy.

Eligibility:

- Individuals between 18 and 80 years of age who have hereditary inclusion body myopathy and do not use a wheelchair. - Participants must be willing to stop any current treatment of HIBM while enrolled in the study.

Design:

• Participants will be screened with a medical history, physical exam, and neurological exam.
• At the first visit, participants will have the following tests:
• Questionnaires about the impact of HIBM on daily activities, mood, and quality of life
• 24-hour urine collection
• Blood samples
• Heart function tests
• Muscle strength and endurance tests, including walking
• Imaging study of the muscles
• Participants will return for followup visits at 6, 12, and 18 months. They may be asked to return for a final visit at 24 months. Not all tests will be performed at each visit.
• Treatment will not be provided as part of this protocol.

For more information, visit our website: http://hibmstudy.nhgri.nih.gov/

Hereditary Inclusion Body Myopathy (HIBM) is an autosomal recessive neuromuscular disorder with onset in early adulthood characterized by progressive muscle weakness. The causative gene, GNE, codes for the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE/MNK) that catalyzes the first two steps in the biosynthesis of sialic acid (SA). The subsequent paucity of SA production is presumed to cause decreased sialylation of HIBM muscle glycoproteins, resulting in muscle deterioration. To date, the amount of prospectively collected and published natural history data on HIBM has been minimal due to the rare nature of this disease. This natural history study seeks to further characterize the rate of progression of the disease and how it relates to age of onset. Additionally, the study is designed to elucidate functional outcome measures (endpoints) for future therapeutic trials, and correlate serum biomarkers and muscle magnetic resonance imaging (MRI) findings to progression of the disease.

• Malicdan MC, Noguchi S, Nishino I. Recent advances in distal myopathy with rimmed vacuoles (DMRV) or hIBM: treatment perspectives. Curr Opin Neurol. 2008 Oct;21(5):596-600. Review.
• Argov Z, Mitrani-Rosenbaum S. The hereditary inclusion body myopathy enigma and its future therapy. Neurotherapeutics. 2008 Oct;5(4):633-7. Review.
• Huizing M, Krasnewich DM. Hereditary inclusion body myopathy: a decade of progress. Biochim Biophys Acta. 2009 Sep;1792(9):881-7. Epub 2009 Jul 24. Review.

• INCLUSION CRITERIA:

  1. Age 18-80 years, either gender, inclusive.
  2. Diagnosis of HIBM based upon a consistent clinical course and identification of GNE gene mutations. Molecular confirmation of the diagnosis will be obtained for all subjects in the study. Most subjects will be homozygous for the Iranian Jewish GNE mutation (p.M712T) in the kinase domain, but subjects with other mutations in the kinase (MNK) or the epimerase domain (GNE) as well as other ethnic backgrounds will also be eligible.

  3. Subjects may be taking ManNAc at the time of their enrollment, but must be willing to stop treatment with ManNAc, sialic acid (SA), intravenous immunoglobulin (IVIG), and/or other supplements containing SA (e.g., St John's wort, sialyllactose) after the screening

     assessment and must be willing to remain off treatment for the duration of the study. An exception includes receiving a single dose of ManNac that may be given as part of the Phase 1 study of ManNAc for HIBM.

  4. Ability to travel to the NIH Clinical Center repeatedly for admissions.

EXCLUSION CRITERIA:

1. Inability to stand and walk unassisted, with or without a gait aide for 2 minutes.
2. Significant osteoarthritis affecting the ability to perform quantitative and functional studies of muscle strength.
3. Psychiatric illness or neurological disease that would interfere with the subject's ability to comply with the requirements of this protocol. This includes uncontrolled/untreated psychotic depression, bipolar disorder, schizophrenia, substance abuse or dependence, antisocial personality disorder, or panic disorder.
4. Hepatic laboratory parameters (aspartate aminotransferase [AST], alanine aminotransferase [ALT], gamma-GTP) or renal laboratory parameters (creatinine, blood urea nitrogen [BUN]) greater than 3 times the upper limit of normal.
5. Presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematological, metabolic, or gastrointestinal disease not related to the primary disease process.
6. Pregnancy or the possibility of pregnancy.