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Autosomal dominant limb-girdle muscular dystrophy type 1F(LGMDD2)

MedGen UID:: 333983
•Concept ID:: C1842062
•: Disease or Syndrome

Synonyms:	LGMDD2; Limb-girdle muscular dystrophy, type 1F; MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL DOMINANT 2
SNOMED CT:	Autosomal dominant limb girdle muscular dystrophy type 1F (719989007)
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. Autosomal dominant inheritance (Orphanet)

Gene (location): Gene(s) directly associated with this condition or phenotype.	TNPO3 (7q32.1)

Monarch Initiative:	MONDO:0012034
OMIM®:	608423
Orphanet:	ORPHA55595

Definition

Autosomal dominant limb-girdle muscular dystrophy-2 (LGMDD2) is a myopathy characterized by proximal muscle weakness primarily affecting the lower limbs, but also affecting the upper limbs in most patients. Affected individuals also have distal muscle weakness of the hands and lower leg muscles. There is variability in presentation and progression. Some patients present in early childhood with mildly delayed walking and difficulty running and jumping, whereas others present as adults with mainly pelvic-girdle weakness. Patients with early onset tend to have a more severe disorder, and may develop contractures, loss of independent ambulation, and respiratory insufficiency. Muscle biopsy shows dystrophic changes with abnormal nuclei, rimmed vacuoles, and filamentous inclusions (summary by Melia et al., 2013). For a phenotypic description and a discussion of genetic heterogeneity of autosomal dominant limb-girdle muscular dystrophy, see LGMDD1 (603511). [from OMIM]

Clinical features

From HPO

Scapular winging

MedGen UID:: 66822
•Concept ID:: C0240953
•: Anatomical Abnormality

Abnormal protrusion of the scapula away from the surface of the back.

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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.

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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.

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Dysphagia

MedGen UID:: 41440
•Concept ID:: C0011168
•: Disease or Syndrome

Difficulty in swallowing.

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Delayed ability to walk

MedGen UID:: 66034
•Concept ID:: C0241726
•: Finding

A failure to achieve the ability to walk at an appropriate developmental stage. Most children learn to walk in a series of stages, and learn to walk short distances independently between 12 and 15 months.

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Motor delay

MedGen UID:: 381392
•Concept ID:: C1854301
•: Finding

A type of Developmental delay characterized by a delay in acquiring motor skills.

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Joint contracture

MedGen UID:: 3228
•Concept ID:: C0009918
•: Anatomical Abnormality

A limitation in the passive range of motion of a joint resulting from loss of elasticity in the periarticular tissues owing to structural changes of non-bony tissues, such as muscles, tendons, ligaments, joint capsules or skin. A contracture prevents movement of the associated body part.

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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.

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Difficulty climbing stairs

MedGen UID:: 68676
•Concept ID:: C0239067
•: Finding

Reduced ability to climb stairs.

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Distal muscle weakness

MedGen UID:: 140883
•Concept ID:: C0427065
•: Finding

Reduced strength of the musculature of the distal extremities.

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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.

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Difficulty running

MedGen UID:: 108251
•Concept ID:: C0560346
•: Finding

Reduced ability to run.

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Centrally nucleated skeletal muscle fibers

MedGen UID:: 330782
•Concept ID:: C1842170
•: Finding

An abnormality in which the nuclei of sarcomeres take on an abnormally central localization (or in which this feature is found in an increased proportion of muscle cells).

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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.

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Spinal rigidity

MedGen UID:: 346721
•Concept ID:: C1858025
•: Finding

Reduced ability to move the vertebral column with a resulting limitation of neck and trunk flexion.

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EMG: myopathic abnormalities

MedGen UID:: 867362
•Concept ID:: C4021726
•: Pathologic Function

The presence of abnormal electromyographic patterns indicative of myopathy, such as small-short polyphasic motor unit potentials.

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Increased endomysial connective tissue

MedGen UID:: 867771
•Concept ID:: C4022161
•: Finding

An increased volume of the endomysium, which is a connective tissue sheath that surrounds each muscule fiber. Together, bundles of muscle fibers form a fasciculus, surrounded by another layer of connective tissue called the perimysium.

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Respiratory insufficiency due to muscle weakness

MedGen UID:: 812797
•Concept ID:: C3806467
•: Finding

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Elevated circulating creatine concentration

MedGen UID:: 1815053
•Concept ID:: C5706147
•: Finding

An elevation above the normal range of creatine in the blood circulation.

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Ptosis

MedGen UID:: 2287
•Concept ID:: C0005745
•: Disease or Syndrome

The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).

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Show all Hide all

Abnormality of limbs
Abnormality of metabolism/homeostasis
- Elevated circulating creatine concentration
Abnormality of the digestive system
- Dysphagia
Abnormality of the eye
- Ptosis
Abnormality of the musculoskeletal system
Abnormality of the nervous system
- Delayed ability to walk
- Motor delay
Abnormality of the respiratory system
- Respiratory insufficiency due to muscle weakness

Term Hierarchy

GTR
MeSH
Orphanet

CClinical test, RResearch test, OOMIM, GGeneReviews, VClinVar

CROGVLimb-girdle muscular dystrophy
- CROGVAutosomal recessive limb-girdle muscular dystrophy
- CROGVMuscular dystrophy, limb-girdle, autosomal dominant
  - CROGVAutosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6)
  - CROGVAutosomal dominant limb-girdle muscular dystrophy type 1F
  - CROGVAutosomal dominant limb-girdle muscular dystrophy type 1G
  - CROGVAutosomal dominant limb-girdle muscular dystrophy type 1H
  - CROGVCaveolinopathy
  - CROGVDesmin-related myofibrillar myopathy
  - CROGVEmery-Dreifuss muscular dystrophy 2, autosomal dominant
  - CROGVMyofibrillar myopathy 3

Phenotypic abnormality
- Abnormality of limbs
  - Abnormality of the musculature of the limbs
    - Limb-girdle muscle atrophy
      - Limb-girdle muscular dystrophy
        Muscular dystrophy, limb-girdle, autosomal dominant
        Autosomal dominant limb-girdle muscular dystrophy type 1F

Follow this link to review classifications for Autosomal dominant limb-girdle muscular dystrophy type 1F in Orphanet.

Recent clinical studies

Etiology

A novel pathogenic variant in TNPO3 in a Hungarian family with limb-girdle muscular dystrophy 1F.

Pál E, Zima J, Hadzsiev K, Ito YA, Hartley T; Care4Rare Canada Consortium, Boycott KM, Melegh B
Eur J Med Genet 2019 Jul;62(7):103662. Epub 2019 May 6 doi: 10.1016/j.ejmg.2019.05.001. PMID: 31071488

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Diagnosis

Limb-girdle muscular dystrophy 1F is caused by a microdeletion in the transportin 3 gene.

Melià MJ, Kubota A, Ortolano S, Vílchez JJ, Gámez J, Tanji K, Bonilla E, Palenzuela L, Fernández-Cadenas I, Pristoupilová A, García-Arumí E, Andreu AL, Navarro C, Hirano M, Martí R
Brain 2013 May;136(Pt 5):1508-17. Epub 2013 Mar 29 doi: 10.1093/brain/awt074. PMID: 23543484 Free PMC Article

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Prognosis

Clinical phenotype, muscle MRI and muscle pathology of LGMD1F.

Peterle E, Fanin M, Semplicini C, Padilla JJ, Nigro V, Angelini C
J Neurol 2013 Aug;260(8):2033-41. Epub 2013 Apr 30 doi: 10.1007/s00415-013-6931-1. PMID: 23632945

Limb-girdle muscular dystrophy 1F is caused by a microdeletion in the transportin 3 gene.

See all (2)