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Myopathy, distal, 6, adult-onset, autosomal dominant(MPD6)

MedGen UID:
1684760
Concept ID:
C5203349
Disease or Syndrome
Synonyms: MPD6; MYOPATHY, DISTAL, 6, ADULT-ONSET, AUTOSOMAL DOMINANT
 
Gene (location): ACTN2 (1q43)
 
Monarch Initiative: MONDO:0032853
OMIM®: 618655

Definition

Autosomal dominant adult-onset distal myopathy-6 (MPD6) is a muscle disorder characterized by slowly progressive distal muscle weakness, primarily affecting the lower limbs and resulting in gait difficulties. Some patients develop involvement of proximal and upper limb muscles (summary by Savarese et al., 2019) [from OMIM]

Clinical features

From HPO
Foot dorsiflexor weakness
MedGen UID:
356163
Concept ID:
C1866141
Finding
Weakness of the muscles responsible for dorsiflexion of the foot, that is, of the movement of the toes towards the shin. The foot dorsiflexors include the tibialis anterior, the extensor hallucis longus, the extensor digitorum longus, and the peroneus tertius muscles.
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
The term gait disturbance can refer to any disruption of the ability to walk.
Proximal muscle weakness
MedGen UID:
113169
Concept ID:
C0221629
Finding
A lack of strength of the proximal muscles.
Distal muscle weakness
MedGen UID:
140883
Concept ID:
C0427065
Finding
Reduced strength of the musculature of the distal extremities.
Autophagic vacuoles
MedGen UID:
107466
Concept ID:
C0544966
Finding
The lysosomal-vacuolar pathway has a role in the controlled intracellular digestion of macromolecules such as protein complexes and organelles. This feature refers to the presence of an abnormally increased number of autophagic vacuoles in muscle tissue.
Increased variability in muscle fiber diameter
MedGen UID:
336019
Concept ID:
C1843700
Finding
An abnormally high degree of muscle fiber size variation. This phenotypic feature can be observed upon muscle biopsy.
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.
Type 1 muscle fiber predominance
MedGen UID:
344274
Concept ID:
C1854387
Finding
An abnormal predominance of type I muscle fibers (in general, this feature can only be observed on muscle biopsy).
Z-band streaming
MedGen UID:
480908
Concept ID:
C3279278
Finding
Streaming or smearing of the Z band, which is then no longer confined to a narrow zone which bisects the I band. The Z disk may extend across the I band or the entire sarcomere in a zigzag manner. Focal thickening, smudging, and blurring of the Z band takes place concurrently. Myofibrillar disorganization is a frequent but not invariable accompanying change.
Internally nucleated skeletal muscle fibers
MedGen UID:
1623054
Concept ID:
C4531255
Anatomical Abnormality
An abnormally increased proportion of nuclei of sarcomeres with an internal localization. Individual muscle fibers are syncytia, formed by embryonic fusion of many myoblasts or later, myosatellite cells. Each muscle fiber contains many nuclei, peripherally positioned immediately adjacent to the sarcolemmal membrane. In healthy muscle only 3-5% of fibers contain nuclei that are located internally, within the cell, but many disease processes lead to internal nuclei.
Elevated circulating creatine kinase concentration
MedGen UID:
69128
Concept ID:
C0241005
Finding
An elevation of the level of the enzyme creatine kinase (also known as creatine phosphokinase (CK; EC 2.7.3.2) in the blood. CK levels can be elevated in a number of clinical disorders such as myocardial infarction, rhabdomyolysis, and muscular dystrophy.

Recent clinical studies

Etiology

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
Am J Med Genet A 2008 Mar 15;146A(6):745-57. doi: 10.1002/ajmg.a.31862. PMID: 18260132Free PMC Article
Udd B, Partanen J, Halonen P, Falck B, Hakamies L, Heikkilä H, Ingo S, Kalimo H, Kääriäinen H, Laulumaa V
Arch Neurol 1993 Jun;50(6):604-8. doi: 10.1001/archneur.1993.00540060044015. PMID: 8503797

Diagnosis

Savarese M, Palmio J, Poza JJ, Weinberg J, Olive M, Cobo AM, Vihola A, Jonson PH, Sarparanta J, García-Bragado F, Urtizberea JA, Hackman P, Udd B
Ann Neurol 2019 Jun;85(6):899-906. Epub 2019 Apr 3 doi: 10.1002/ana.25470. PMID: 30900782
Al-Tahan S, Al-Obeidi E, Yoshioka H, Lakatos A, Weiss L, Grafe M, Palmio J, Wicklund M, Harati Y, Omizo M, Udd B, Kimonis V
Neuromuscul Disord 2018 Jun;28(6):491-501. Epub 2018 Apr 17 doi: 10.1016/j.nmd.2018.04.007. PMID: 29754758
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
Am J Med Genet A 2008 Mar 15;146A(6):745-57. doi: 10.1002/ajmg.a.31862. PMID: 18260132Free PMC Article
Udd B, Partanen J, Halonen P, Falck B, Hakamies L, Heikkilä H, Ingo S, Kalimo H, Kääriäinen H, Laulumaa V
Arch Neurol 1993 Jun;50(6):604-8. doi: 10.1001/archneur.1993.00540060044015. PMID: 8503797

Prognosis

Ryan MM, Schnell C, Strickland CD, Shield LK, Morgan G, Iannaccone ST, Laing NG, Beggs AH, North KN
Ann Neurol 2001 Sep;50(3):312-20. doi: 10.1002/ana.1080. PMID: 11558787

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