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Autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6)(LGMDD1)

MedGen UID:
1648441
Concept ID:
C4721885
Disease or Syndrome
Synonyms: Autosomal dominant limb-girdle muscular dystrophy type 1D; LGMDD1; MUSCULAR DYSTROPHY, AUTOSOMAL DOMINANT, WITH RIMMED VACUOLES; Muscular dystrophy, limb-girdle, autosomal dominant 1; MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1D
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: 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.
 
Gene (location): DNAJB6 (7q36.3)
 
Monarch Initiative: MONDO:0021018
OMIM®: 603511
Orphanet: ORPHA34516

Definition

Autosomal dominant limb-girdle muscular dystrophy is characterized by proximal and/or distal muscle weakness and atrophy. The age at onset is variable and can range from the first to the sixth decade, although later onset is less common. Most patients present with proximal muscle weakness that progresses to distal involvement, but some can present with distal impairment. The severity is variable: patients with a more severe phenotype can lose ambulation after several decades and have facial weakness with bulbar and respiratory involvement. Muscle biopsy shows dystrophic changes with protein aggregates, myofibrillar degeneration, and rimmed vacuoles (summary by Ruggieri et al., 2015). Genetic Heterogeneity of Autosomal Dominant Limb-Girdle Muscular Dystrophy Other forms of autosomal dominant LGMD include LGMDD2 (608423), previously LGMD1F, caused by mutation in the TNPO3 gene (610032) on chromosome 7q32; LGMDD3 (609115), previously LGMD1G, caused by mutation in the HNRNPDL gene (607137) on chromosome 4q21; and LGMDD4 (618129), previously LGMD1I, caused by mutation in the CAPN3 gene (114240) on chromosome 15q15. For a discussion of autosomal recessive LGMD, see 253600. [from OMIM]

Clinical features

From HPO
Myalgia
MedGen UID:
68541
Concept ID:
C0231528
Sign or Symptom
Pain in muscle.
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.
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
Difficulty in swallowing.
Waddling gait
MedGen UID:
66667
Concept ID:
C0231712
Finding
Weakness of the hip girdle and upper thigh muscles, for instance in myopathies, leads to an instability of the pelvis on standing and walking. If the muscles extending the hip joint are affected, the posture in that joint becomes flexed and lumbar lordosis increases. The patients usually have difficulties standing up from a sitting position. Due to weakness in the gluteus medius muscle, the hip on the side of the swinging leg drops with each step (referred to as Trendelenburg sign). The gait appears waddling. The patients frequently attempt to counteract the dropping of the hip on the swinging side by bending the trunk towards the side which is in the stance phase (in the German language literature this is referred to as Duchenne sign). Similar gait patterns can be caused by orthopedic conditions when the origin and the insertion site of the gluteus medius muscle are closer to each other than normal, for instance due to a posttraumatic elevation of the trochanter or pseudarthrosis of the femoral neck.
Loss of ambulation
MedGen UID:
332305
Concept ID:
C1836843
Finding
Inability to walk in a person who previous had the ability to walk.
Bulbar palsy
MedGen UID:
898626
Concept ID:
C4082299
Disease or Syndrome
Bulbar weakness (or bulbar palsy) refers to bilateral impairment of function of the lower cranial nerves IX, X, XI and XII, which occurs due to lower motor neuron lesion either at nuclear or fascicular level in the medulla or from bilateral lesions of the lower cranial nerves outside the brain-stem. Bulbar weakness is often associated with difficulty in chewing, weakness of the facial muscles, dysarthria, palatal weakness and regurgitation of fluids, dysphagia, and dysphonia.
Decreased compound muscle action potential amplitude
MedGen UID:
908357
Concept ID:
C4230625
Finding
Reduced level of the compound muscle action potential (CMAP), which is recorded following electrical stimulation of a nerve from surface electrodes overlying a muscle supplied by that nerve.
Muscular dystrophy
MedGen UID:
44527
Concept ID:
C0026850
Disease or Syndrome
The term dystrophy means abnormal growth. However, muscular dystrophy is used to describe primary myopathies with a genetic basis and a progressive course characterized by progressive skeletal muscle weakness and wasting, defects in muscle proteins, and histological features of muscle fiber degeneration (necrosis) and regeneration. If possible, it is preferred to use other HPO terms to describe the precise phenotypic abnormalities.
Gowers sign
MedGen UID:
65865
Concept ID:
C0234182
Finding
A phenomenon whereby patients are not able to stand up without the use of the hands owing to weakness of the proximal muscles of the lower limbs.
Difficulty climbing stairs
MedGen UID:
68676
Concept ID:
C0239067
Finding
Reduced ability to climb stairs.
Flexion contracture
MedGen UID:
83069
Concept ID:
C0333068
Anatomical Abnormality
A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.
Facial palsy
MedGen UID:
87660
Concept ID:
C0376175
Disease or Syndrome
Facial nerve palsy is a dysfunction of cranial nerve VII (the facial nerve) that results in inability to control facial muscles on the affected side with weakness of the muscles of facial expression and eye closure. This can either be present in unilateral or bilateral form.
Difficulty running
MedGen UID:
108251
Concept ID:
C0560346
Finding
Reduced ability to run.
Muscle fiber splitting
MedGen UID:
322813
Concept ID:
C1836057
Finding
Fiber splitting or branching is a common finding in human and rat skeletal muscle pathology. Fiber splitting refers to longitudinal halving of the complete fiber, while branching originates from a regenerating end of a necrotic fiber as invaginations of the sarcolemma. In fiber branching, one end of the fiber remains intact as a single entity, while the other end has several branches.
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.
Dyspnea
MedGen UID:
3938
Concept ID:
C0013404
Sign or Symptom
Difficult or labored breathing. Dyspnea is a subjective feeling only the patient can rate, e.g., on a Borg scale.
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.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  

Recent clinical studies

Etiology

Sandell SM, Mahjneh I, Palmio J, Tasca G, Ricci E, Udd BA
Eur J Neurol 2013 Dec;20(12):1553-9. Epub 2013 Jul 19 doi: 10.1111/ene.12239. PMID: 23865856

Diagnosis

Zima J, Eaton A, Pál E, Till Á, Ito YA, Warman-Chardon J, Hartley T, Cagnone G, Melegh BI; Care4Rare Canada, Boycott KM, Melegh B, Hadzsiev K
Eur J Med Genet 2020 Feb;63(2):103655. Epub 2019 Apr 27 doi: 10.1016/j.ejmg.2019.04.012. PMID: 31034989
Sandell SM, Mahjneh I, Palmio J, Tasca G, Ricci E, Udd BA
Eur J Neurol 2013 Dec;20(12):1553-9. Epub 2013 Jul 19 doi: 10.1111/ene.12239. PMID: 23865856

Clinical prediction guides

Zima J, Eaton A, Pál E, Till Á, Ito YA, Warman-Chardon J, Hartley T, Cagnone G, Melegh BI; Care4Rare Canada, Boycott KM, Melegh B, Hadzsiev K
Eur J Med Genet 2020 Feb;63(2):103655. Epub 2019 Apr 27 doi: 10.1016/j.ejmg.2019.04.012. PMID: 31034989
Sandell SM, Mahjneh I, Palmio J, Tasca G, Ricci E, Udd BA
Eur J Neurol 2013 Dec;20(12):1553-9. Epub 2013 Jul 19 doi: 10.1111/ene.12239. PMID: 23865856

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