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Inclusion body myopathy with early-onset paget disease and frontotemporal dementia(IBMPFD1)

MedGen UID:
322251
Concept ID:
C1833662
Disease or Syndrome
Synonyms: IBMPFD1; INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA 1; Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia; MULTISYSTEM PROTEINOPATHY 1
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Lower motor neuron degeneration with Paget-like bone disease (703544004); Pagetoid amyotrophic lateral sclerosis (703544004); Muscular dystrophy limb-girdle with Paget disease of bone (703544004); Pagetoid neuroskeletal syndrome (703544004); Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (703544004); IBMPFD - Inclusion body myopathy with early onset Paget disease and frontotemporal dementia (703544004)
 
Gene (location): VCP (9p13.3)
OMIM®: 167320
Orphanet: ORPHA52430

Disease characteristics

Inclusion body myopathy associated with Paget disease of bone (PDB) and/or frontotemporal dementia (IBMPFD) is characterized by adult-onset proximal and distal muscle weakness (clinically resembling a limb-girdle muscular dystrophy syndrome), early-onset PDB, and premature frontotemporal dementia (FTD). Muscle weakness progresses to involve other limb and respiratory muscles. Cardiac failure and cardiomyopathy have been observed in later stages. PDB involves focal areas of increased bone turnover that typically lead to spine and/or hip pain and localized enlargement and deformity of the long bones; pathologic fractures occur on occasion. Early stages of FTD are characterized by dysnomia, dyscalculia, comprehension deficits, paraphasic errors, and relative preservation of memory, and later stages by inability to speak, auditory comprehension deficits for even one-step commands, alexia, and agraphia. Mean age at diagnosis for muscle disease and PDB is 42 years; for FTD, 55 years. [from GeneReviews]
Authors:
Virginia Kimonis  |  Sandra Donkervoort  |  Giles Watts   view full author information

Additional descriptions

From OMIM
IBMPFD is an autosomal dominant disorder characterized by incomplete penetrance of 3 main features: disabling muscle weakness (in 90%), osteolytic bone lesions consistent with Paget disease (in 51%), and frontotemporal dementia (in 32%). Muscle weakness is an isolated symptom in about 30% of patients and the presenting symptom in greater than half of patients, suggesting that IBMPFD may commonly be seen in a neuromuscular clinic without its other syndromic features (review by Weihl et al., 2009). Genetic Heterogeneity of IBMPFD/MSP IBMPFD2 (MSP2; 615422) is caused by mutation in the HNRNPA2B1 gene (600124) on chromosome 7p15. IBMPFD3 (MSP3; 615424) is caused by mutation in the HNRNPA1 gene (164017) on chromosome 12q13. Bucelli et al. (2015) suggested use of the designation MSP4 to include disparate phenotypes in muscle, brain, spinal cord, and bone caused by mutation in the SQSTM1 gene (601530); see 617158.  http://www.omim.org/entry/167320
From GHR
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 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. 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, a 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.People with IBMPFD usually live into their fifties or sixties.  https://ghr.nlm.nih.gov/condition/inclusion-body-myopathy-with-early-onset-paget-disease-and-frontotemporal-dementia

Clinical features

Amyotrophic lateral sclerosis
MedGen UID:
274
Concept ID:
C0002736
Disease or Syndrome
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving both upper motor neurons (UMN) and lower motor neurons (LMN). UMN signs include hyperreflexia, extensor plantar response, increased muscle tone, and weakness in a topographic representation. LMN signs include weakness, muscle wasting, hyporeflexia, muscle cramps, and fasciculations. Initial presentation varies. Affected individuals typically present with either asymmetric focal weakness of the extremities (stumbling or poor handgrip) or bulbar findings (dysarthria, dysphagia). Other findings may include muscle fasciculations, muscle cramps, and labile affect, but not necessarily mood. Regardless of initial symptoms, atrophy and weakness eventually affect other muscles. The mean age of onset is 56 years in individuals with no known family history and 46 years in individuals with more than one affected family member (familial ALS or FALS). Average disease duration is about three years, but it can vary significantly. Death usually results from compromise of the respiratory muscles.
Back pain
MedGen UID:
2530
Concept ID:
C0004604
Sign or Symptom
Acute or chronic pain located in the posterior regions of the THORAX; LUMBOSACRAL REGION; or the adjacent regions.
Dystonia
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Hip pain
MedGen UID:
5556
Concept ID:
C0019559
Sign or Symptom
A sensation of discomfort emanating from the pelvis, its supporting structures, or its articulation with the femur (acetabulofemoral or femoroacetabular joint).
Myopathy
MedGen UID:
10135
Concept ID:
C0026848
Disease or Syndrome
A disorder of muscle unrelated to impairment of innervation or neuromuscular junction.
Proximal muscle weakness
MedGen UID:
113169
Concept ID:
C0221629
Finding
A lack of strength of the proximal muscles.
Difficulty climbing stairs
MedGen UID:
68676
Concept ID:
C0239067
Finding
Reduced ability to climb stairs.
Pelvic girdle muscle atrophy
MedGen UID:
66014
Concept ID:
C0240679
Finding
Muscular atrophy affecting the muscles that attach to the pelvic girdle (the gluteal muscles, the lateral rotators, adductor magnus, adductor brevis, adductor longus, pectineus, and gracilis muscles).
Scapular winging
MedGen UID:
66822
Concept ID:
C0240953
Finding
Abnormal protrusion of the scapula away from the surface of the back.
Elevated serum creatine phosphokinase
MedGen UID:
69128
Concept ID:
C0241005
Finding
The caveolinopathies, a group of muscle diseases, can be classified into five phenotypes, which can be seen in different members of the same family: Limb-girdle muscular dystrophy 1C (LGMD1C), characterized by onset usually in the first decade, mild-to-moderate proximal muscle weakness, calf hypertrophy, positive Gower sign, and variable muscle cramps after exercise. Isolated hyperCKemia (i.e., elevated serum concentration of creatine kinase (CK) in the absence of signs of muscle disease) (HCK). Rippling muscle disease (RMD), characterized by signs of increased muscle irritability, such as percussion-induced rapid contraction (PIRC), percussion-induced muscle mounding (PIMM), and/or electrically silent muscle contractions (rippling muscle). Distal myopathy (DM), observed in one individual only Hypertrophic cardiomyopathy (HCM), without skeletal muscle manifestations.
Frontotemporal dementia
MedGen UID:
83266
Concept ID:
C0338451
Disease or Syndrome
The clinical manifestations of MAPT-related disorders (MAPT-related tauopathies) are most typically those of frontotemporal dementia (FTDP-17), but also include progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), mild late-onset parkinsonism, and dementia with epilepsy. Clinical presentation of frontotemporal dementia (FTD) is variable: some present with slowly progressive behavioral changes, language disturbances, and/or extrapyramidal signs, whereas others present with rigidity, bradykinesia, supranuclear palsy, and saccadic eye movement disorders. Onset is usually between ages 40 and 60 years, but may be earlier or later. The disease progresses over a few years into profound dementia with mutism. PSP is characterized by progressive vertical gaze palsy in combination with a prominent loss of balance at early stages of the disease. With progression, axial rigidity, dysarthria, and dysphagia become prominent, often in combination with a frontal dysexecutive syndrome. CBD is a progressive neurodegenerative disorder which affects both the frontoparietal cortex and the basal ganglia, resulting in a mild to moderate dementia in combination with asymmetric parkinsonism, ideomotor apraxia, aphasia, and an alien-hand syndrome.
Shoulder girdle muscle weakness
MedGen UID:
96533
Concept ID:
C0427063
Finding
The shoulder, or pectoral, girdle is composed of the clavicles and the scapulae. Shoulder-girdle weakness refers to lack of strength of the muscles attaching to these bones, that is, lack of strength of the muscles around the shoulders.
Pelvic girdle muscle weakness
MedGen UID:
96534
Concept ID:
C0427064
Finding
Weakness of the muscles of the pelvic girdle (also known as the hip girdle), that is, lack of strength of the muscles around the pelvis.
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
A finding referring to walking difficulties.
Limb muscle weakness
MedGen UID:
107956
Concept ID:
C0587246
Finding
Reduced strength and weakness of the muscles of the arms and legs.
Dysphasia
MedGen UID:
242346
Concept ID:
C0973461
Mental or Behavioral Dysfunction
Impairment of verbal communication skills, often resulting from brain damage.
Lumbar hyperlordosis
MedGen UID:
263149
Concept ID:
C1184923
Finding
An abnormal accentuation of the inward curvature of the spine in the lumbar region.
Elevated alkaline phosphatase of bone origin
MedGen UID:
318930
Concept ID:
C1833667
Finding
An abnormally increased level of bone isoforms of alkaline phosphatase, tissue-nonspecific isozyme in the blood.
Shoulder girdle muscle atrophy
MedGen UID:
339837
Concept ID:
C1847766
Finding
Amyotrophy affecting the muscles of the shoulder girdle.
Distal amyotrophy
MedGen UID:
338530
Concept ID:
C1848736
Disease or Syndrome
Muscular atrophy affecting muscles in the distal portions of the extremities.
Rimmed vacuoles
MedGen UID:
340089
Concept ID:
C1853932
Finding
Presence of abnormal vacuoles (membrane-bound organelles) in the sarcolemma. On histological staining with hematoxylin and eosin, rimmed vacuoles are popcorn-like clear vacuoles with a densely blue rim. The vacuoles are often associated with cytoplasmic and occasionally intranuclear eosinophilic inclusions.
Abnormality of pelvic girdle bone morphology
MedGen UID:
866545
Concept ID:
C4020847
Anatomical Abnormality
An abnormality of the bony pelvic girdle, which is a ring of bones connecting the vertebral column to the femurs.
Pelvic girdle amyotrophy
MedGen UID:
867170
Concept ID:
C4021528
Disease or Syndrome
Atrophy of the muscles of the pelvic girdle (also known as hip girdle), i.e., the gluteal muscles, the lateral rotators, the adductors, the psoas major and the iliacus muscle.
Temporal cortical atrophy
MedGen UID:
870489
Concept ID:
C4024936
Disease or Syndrome
Atrophy of the temporal cortex.
Frontal cortical atrophy
MedGen UID:
870517
Concept ID:
C4024965
Anatomical Abnormality
Atrophy of the frontal cortex.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVInclusion body myopathy with early-onset paget disease and frontotemporal dementia

Recent clinical studies

Etiology

Broccolini A, Mirabella M
Biochim Biophys Acta 2015 Apr;1852(4):644-50. Epub 2014 Aug 19 doi: 10.1016/j.bbadis.2014.08.007. PMID: 25149037
Benatar M, Wuu J, Fernandez C, Weihl CC, Katzen H, Steele J, Oskarsson B, Taylor JP
Neurology 2013 May 14;80(20):1874-80. Epub 2013 May 1 doi: 10.1212/WNL.0b013e3182929fc3. PMID: 23635965Free PMC Article
Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, MacLea KS, Freibaum B, Li S, Molliex A, Kanagaraj AP, Carter R, Boylan KB, Wojtas AM, Rademakers R, Pinkus JL, Greenberg SA, Trojanowski JQ, Traynor BJ, Smith BN, Topp S, Gkazi AS, Miller J, Shaw CE, Kottlors M, Kirschner J, Pestronk A, Li YR, Ford AF, Gitler AD, Benatar M, King OD, Kimonis VE, Ross ED, Weihl CC, Shorter J, Taylor JP
Nature 2013 Mar 28;495(7442):467-73. Epub 2013 Mar 3 doi: 10.1038/nature11922. PMID: 23455423Free PMC Article

Diagnosis

Evangelista T, Weihl CC, Kimonis V, Lochmüller H; VCP related diseases Consortium.
Neuromuscul Disord 2016 Aug;26(8):535-47. Epub 2016 May 30 doi: 10.1016/j.nmd.2016.05.017. PMID: 27312024
St John L, Larner AJ
Br J Hosp Med (Lond) 2015 Oct;76(10):602-3. doi: 10.12968/hmed.2015.76.10.602. PMID: 26457944
Gu JM, Ke YH, Yue H, Liu YJ, Zhang Z, Zhang H, Hu WW, Wang C, He JW, Hu YQ, Li M, Fu WZ, Zhang ZL
Bone 2013 Jan;52(1):9-16. Epub 2012 Sep 19 doi: 10.1016/j.bone.2012.09.012. PMID: 23000505
Spina S, Van Laar AD, Murrell JR, Hamilton RL, Kofler JK, Epperson F, Farlow MR, Lopez OL, Quinlan J, DeKosky ST, Ghetti B
Eur J Neurol 2013 Feb;20(2):251-8. Epub 2012 Aug 20 doi: 10.1111/j.1468-1331.2012.03831.x. PMID: 22900631Free PMC Article
Takata T, Kimura Y, Ohnuma Y, Kawawaki J, Kakiyama Y, Tanaka K, Kakizuka A
J Struct Biol 2012 Aug;179(2):93-103. Epub 2012 Jun 19 doi: 10.1016/j.jsb.2012.06.005. PMID: 22728077

Therapy

Zhang T, Mishra P, Hay BA, Chan D, Guo M
Elife 2017 Mar 21;6 doi: 10.7554/eLife.17834. PMID: 28322724Free PMC Article
Evangelista T, Weihl CC, Kimonis V, Lochmüller H; VCP related diseases Consortium.
Neuromuscul Disord 2016 Aug;26(8):535-47. Epub 2016 May 30 doi: 10.1016/j.nmd.2016.05.017. PMID: 27312024

Prognosis

Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, MacLea KS, Freibaum B, Li S, Molliex A, Kanagaraj AP, Carter R, Boylan KB, Wojtas AM, Rademakers R, Pinkus JL, Greenberg SA, Trojanowski JQ, Traynor BJ, Smith BN, Topp S, Gkazi AS, Miller J, Shaw CE, Kottlors M, Kirschner J, Pestronk A, Li YR, Ford AF, Gitler AD, Benatar M, King OD, Kimonis VE, Ross ED, Weihl CC, Shorter J, Taylor JP
Nature 2013 Mar 28;495(7442):467-73. Epub 2013 Mar 3 doi: 10.1038/nature11922. PMID: 23455423Free PMC Article

Clinical prediction guides

Itoh N, Nagai T, Watanabe T, Taki K, Nabeshima T, Kaibuchi K, Yamada K
Biochem Biophys Res Commun 2017 Dec 2;493(4):1384-1389. Epub 2017 Sep 29 doi: 10.1016/j.bbrc.2017.09.159. PMID: 28970065
Blythe EE, Olson KC, Chau V, Deshaies RJ
Proc Natl Acad Sci U S A 2017 May 30;114(22):E4380-E4388. Epub 2017 May 16 doi: 10.1073/pnas.1706205114. PMID: 28512218Free PMC Article
Bayraktar O, Oral O, Kocaturk NM, Akkoc Y, Eberhart K, Kosar A, Gozuacik D
PLoS One 2016;11(10):e0164864. Epub 2016 Oct 21 doi: 10.1371/journal.pone.0164864. PMID: 27768726Free PMC Article
Rodriguez-Ortiz CJ, Flores JC, Valenzuela JA, Rodriguez GJ, Zumkehr J, Tran DN, Kimonis VE, Kitazawa M
Am J Pathol 2016 Jun;186(6):1623-34. Epub 2016 Apr 20 doi: 10.1016/j.ajpath.2016.02.007. PMID: 27106764Free PMC Article
Dec E, Rana P, Katheria V, Dec R, Khare M, Nalbandian A, Leu SY, Radom-Aizik S, Llewellyn K, BenMohamed L, Zaldivar F, Kimonis V
Clin Transl Sci 2014 Feb;7(1):29-32. Epub 2013 Oct 3 doi: 10.1111/cts.12117. PMID: 24119107Free PMC Article

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