Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia

Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD) is a condition that can affect the muscles, bones, and brain.

The first symptom of IBMPFD is often muscle weakness (myopathy), which typically appears in mid-adulthood. Weakness first occurs in muscles of the hips and shoulders, making it difficult to climb stairs and raise the arms above the shoulders. As the disorder progresses, weakness develops in other muscles in the arms and legs.  Muscle weakness can also affect respiratory and heart (cardiac) muscles, leading to life-threatening breathing difficulties and heart failure.

About half of all adults with IBMPFD develop a disorder called Paget disease of bone. This disorder causes bones to grow larger and weaker than normal. Paget disease of bone most often affects bones of the hips, spine, and skull, and the long bones of the arms and legs. Bone pain, particularly in the hips and spine, is usually the major symptom of Paget disease. Other complications of Paget disease of bone depend on which bones are affected. Rarely, this condition can weaken bones so much that they break (fracture).

In about one-third of people with IBMPFD, the disorder also affects the brain. IBMPFD is associated with a brain condition called frontotemporal dementia, which becomes noticeable in a person's forties or fifties. People with frontotemporal dementia initially may have trouble speaking, remembering words and names (dysnomia), and using numbers (dyscalculia). Over time, the condition damages parts of the brain that control reasoning, personality, social skills, speech, and language. Personality changes, loss of judgment, and inappropriate social behavior are also hallmarks of the disease. As the dementia worsens, affected people ultimately become unable to speak, read, or care for themselves.

Additional features that rarely occur in IBMPFD include a severe and progressive muscular disease called amyotrophic lateral sclerosis and progressive problems with movement and balance (Parkinson's disease).

People with IBMPFD usually live into their fifties or sixties.

Although the prevalence of IBMPFD is unknown, this condition is rare. It has been diagnosed in several hundred people worldwide.

Variants (also known as mutations) in the VCP gene are the main cause of IBMPFD. The VCP gene provides instructions for making an enzyme called valosin-containing protein, which has a wide variety of functions within cells. One of its most critical jobs is to help break down (degrade) proteins that are abnormal or no longer needed.

Variants in the VCP gene alter the structure of valosin-containing protein, impairing its ability to break down other proteins.  As a result, excess and abnormal proteins build up in muscle, bone, and brain cells. The proteins form clumps that interfere with the normal functions of these cells. It remains unclear how damage to muscle, bone, and brain cells leads to the specific features of IBMPFD.

In individuals with IBMPFD who do not have identified VCP variants, the condition may be caused by rare variants in specific genes or remain unknown. IBMPFD is sometimes known as mutlisystem proteinopathy, often distinguished by its genetic cause. For example, when the condition is caused by VCP gene variants, it is called VCP-associated multisystem proteinopathy (VCP MSP).

Genetic Testing Information

• Genetic Testing Registry: Inclusion body myopathy with Paget disease of bone and frontotemporal dementia

Genetic and Rare Diseases Information Center

• Inclusion body myopathy with Paget disease of bone and frontotemporal dementia

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Clinical Trials

• ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

• INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA 1; IBMPFD1
• INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA 2; IBMPFD2
• INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA 3; IBMPFD3

Scientific Articles on PubMed

• PubMed

• Forman MS, Mackenzie IR, Cairns NJ, Swanson E, Boyer PJ, Drachman DA, Jhaveri BS, Karlawish JH, Pestronk A, Smith TW, Tu PH, Watts GD, Markesbery WR, Smith CD, Kimonis VE. Novel ubiquitin neuropathology in frontotemporal dementia with valosin-containing protein gene mutations. J Neuropathol Exp Neurol. 2006 Jun;65(6):571-81. doi: 10.1097/00005072-200606000-00005. Citation on PubMed
• Guinto JB, Ritson GP, Taylor JP, Forman MS. Valosin-containing protein and the pathogenesis of frontotemporal dementia associated with inclusion body myopathy. Acta Neuropathol. 2007 Jul;114(1):55-61. doi: 10.1007/s00401-007-0224-7. Epub 2007 Apr 25. Citation on PubMed
• Kimonis V. Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia. 2007 May 25 [updated 2019 Sep 12]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from http://www.ncbi.nlm.nih.gov/books/NBK1476/ Citation on PubMed
• Kimonis VE, Mehta SG, Fulchiero EC, Thomasova D, Pasquali M, Boycott K, Neilan EG, Kartashov A, Forman MS, Tucker S, Kimonis K, Mumm S, Whyte MP, Smith CD, Watts GD. Clinical studies in familial VCP myopathy associated with Paget disease of bone and frontotemporal dementia. Am J Med Genet A. 2008 Mar 15;146A(6):745-57. doi: 10.1002/ajmg.a.31862. Citation on PubMed or Free article on PubMed Central
• Kimonis VE, Watts GD. Autosomal dominant inclusion body myopathy, Paget disease of bone, and frontotemporal dementia. Alzheimer Dis Assoc Disord. 2005 Oct-Dec;19 Suppl 1:S44-7. doi: 10.1097/01.wad.0000183081.76820.5a. Citation on PubMed
• Korb M, Peck A, Alfano LN, Berger KI, James MK, Ghoshal N, Healzer E, Henchcliffe C, Khan S, Mammen PPA, Patel S, Pfeffer G, Ralston SH, Roy B, Seeley WW, Swenson A, Mozaffar T, Weihl C, Kimonis V; VCP Standards of Care Working Group. Development of a standard of care for patients with valosin-containing protein associated multisystem proteinopathy. Orphanet J Rare Dis. 2022 Jan 29;17(1):23. doi: 10.1186/s13023-022-02172-5. Citation on PubMed
• Kovach MJ, Waggoner B, Leal SM, Gelber D, Khardori R, Levenstien MA, Shanks CA, Gregg G, Al-Lozi MT, Miller T, Rakowicz W, Lopate G, Florence J, Glosser G, Simmons Z, Morris JC, Whyte MP, Pestronk A, Kimonis VE. Clinical delineation and localization to chromosome 9p13.3-p12 of a unique dominant disorder in four families: hereditary inclusion body myopathy, Paget disease of bone, and frontotemporal dementia. Mol Genet Metab. 2001 Dec;74(4):458-75. doi: 10.1006/mgme.2001.3256. Citation on PubMed
• Nalbandian A, Donkervoort S, Dec E, Badadani M, Katheria V, Rana P, Nguyen C, Mukherjee J, Caiozzo V, Martin B, Watts GD, Vesa J, Smith C, Kimonis VE. The multiple faces of valosin-containing protein-associated diseases: inclusion body myopathy with Paget's disease of bone, frontotemporal dementia, and amyotrophic lateral sclerosis. J Mol Neurosci. 2011 Nov;45(3):522-31. doi: 10.1007/s12031-011-9627-y. Epub 2011 Sep 3. Citation on PubMed
• Nalbandian A, Ghimbovschi S, Radom-Aizik S, Dec E, Vesa J, Martin B, Knoblach S, Smith C, Hoffman E, Kimonis VE. Global gene profiling of VCP-associated inclusion body myopathy. Clin Transl Sci. 2012 Jun;5(3):226-34. doi: 10.1111/j.1752-8062.2012.00407.x. Epub 2012 Apr 4. Citation on PubMed or Free article on PubMed Central