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Types of Limb Girdle Muscular Dystrophy

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TYPES OF LIMB GIRDLE MUSCULAR DYSTROPHY

Background

(LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD classification has been made based on clinical and molecular characteristics. It divides cases into autosomal dominant ((LIMB GIRDLE MUSCULAR DYSTROPHY-LGMD1) and autosomal recessive ((LIMB GIRDLE MUSCULAR DYSTROPHY-LGMD2) syndromes. Dominant means inherited from one parent and recessive means inherited from both the parents.  This list continues to expand, and, as of this writing, specific mutations are known for 3 autosomal dominant (LIMB GIRDLE MUSCULAR DYSTROPHY-LGMDs and 14 autosomal recessive (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMDs.

Age

The age of onset varies among the different mutations.  Age of onset can vary among families with the same mutation. Reported age of onset of (LIMB GIRDLE MUSCULAR DYSTROPHY) LGMDs is between 1 and 50 years,

Types of (LIMB GIRDLE MUSCULAR DYSTROPHY) LGMD

Autosomal recessive limb-girdle muscular dystrophy ((LIMB GIRDLE MUSCULAR DYSTROPHY) LGMD:
All patients have a history of progressive, proximal muscle weakness. Described below are the major distinguishing characteristics.

(LIMB GIRDLE MUSCULAR DYSTROPHY-LGMD2A (calpainopathy)

  • (LIMB GIRDLE MUSCULAR DYSTROPHY-LGMD2A is likely the most common autosomal recessive LIMB GIRDLE MUSCULAR DYSTROPHY (LGMD), accounting for up to 30% of all cases..
  • The most typical presentation is of weakness due to scapular-humeral-pelvic weakness that may be similar to the presentation of facioscapulohumeral dystrophy, but without facial weakness.
  • Hip-girdle weakness is most prominent in the gluteus maximus and hip adductors. Along with abdominal weakness, this leads to a wide-based, lordotic gait.
  • The combination of scapular winging, severe weakness of hip adductors and elbow flexors, normal respiratory function, and contractures has specificity for (LIMB GIRDLE MUSCULAR DYSTROPHY) LGMD2A.7
  • Atrophy is often prominent.
  • Progression tends to be slow, and wheelchair use begins 11-28 years after the onset of symptoms.
  • The clinical course varies widely among and within families.
  • Facial and cardiac involvements have not been reported.

LIMB GIRDLE MUSCULAR DYSTROPHY (LGMD2B) (dysferlinopathy)

  • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD2B is also a common cause of autosomal recessive (LIMB GIRDLE MUSCULAR DYSTROPHY) LGMD.
  • In the limb-girdle presentation, pelvic and femoral muscles are affected first, with the proximal portions of the arms becoming weak later. With Miyoshi myopathy, the presentation includes gastrocnemius weakness and difficulty with toe walking. The forearm muscles are weak and atrophic, with sparing of intrinsic hand muscles. As the disease progresses, the 2 modes of presentation usually become indistinguishable.
  • The most common phenotype (25-35% of patients) have a mixed picture with both proximal and distal weakness. The patient's gait is unique, with a waddling component combined with inability to raise his or her heels off the ground.
  • The disease slowly progresses, and patients are usually confined to a wheelchair 10-30 years after the onset of weakness.
  • Rare cases present with distal leg pain or swelling with or without weakness or with asymptomatic hyperCKemia.
  • Misdiagnosis as polymyositis can occur since inflammation can be present on muscle biopsy.

LIMB GIRDLE MUSCULAR DYSTROPHY (LGMD2C-2F) (Sarcoglycanopathies)

  • Onset is usually at ages 6-8 years, but onset at or before 2 years and as late as the teens (or even adulthood) have been reported.
  • Some delay in motor milestones is not uncommon.
  • Weakness affects the hip and abdominal and shoulder musculature. Scapular winging is more common in (LIMB GIRDLE MUSCULAR DYSTROPHY) LGMD2C-2F than in Duchenne muscular dystrophy.
  • Hypertrophy of the calf is common, and the tongue muscles may become enlarged.
  • Progression tends to be more rapid than that of other (LIMB GIRDLE MUSCULAR DYSTROPHY) LGMDs, with loss of ambulation usually at 12-16 years but can be as early as 10 years. Patients with a late onset tend to have a more slowly progressive course.
  • Intelligence is normal.
  • Cardiomyopathy is reported in about 30% of cases and is most common with (LIMB GIRDLE MUSCULAR DYSTROPHY) LGMD2E or 2F.
  • Progressive weakness leads to restrictive lung disease and hypoventilation and the need for ventilatory assistance.

LIMB GIRDLE MUSCULAR DYSTROPHY (LGMD2G) (telethoninopathy)

    • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD2G has been reported in only a few patients, with significant phenotypic variability between and within families.
    • The age of onset is 2-15 years.
    • Weakness is predominantly proximal, but one half of patients may present with foot drop and anterior compartment atrophy, and nearly all eventually develop distal leg weakness. Gluteal and thigh atrophy may be prominent.9
    • Calf hypertrophy occurs in about 50%.
    • Wheelchair confinement occurs in the third to fourth decade.
    • Cardiomyopathy occurs in about 50%.

LIMB GIRDLE MUSCULAR DYSTROPHY (LGMD2H) (tripartite motif–containing gene 32 [TRIM32]–related dystrophy)

    • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD2H has been observed mostly in the Hutterite people of Manitoba. A few non-Hutterites also have been shown to have (LIMB GIRDLE MUSCULAR DYSTROPHY) LGMD2H and have a more variable phenotype.10
    • This disease is allelic with sarcotubular myopathy (see Congenital Myopathies).
    • Most Hutterite patients have a mild phenotype, with limb-girdle weakness and a waddling gait at presentation. The proximal arm muscles and the distal leg muscles are involved late. The age of onset is 8-27 years, but some patients are asymptomatic in their third decade. Back pain and fatigue are common. Progression is slow, with continued ambulation until around 50 years of age or later.
    • In non-Hutterites, scapular winging is common. Other features can include facial weakness, respiratory insufficiency, ankle contractures, and cramps. Presentation can be in the late first decade into young adulthood, and one patient had asymptomatic hyperCKemia noted at age 64.

LIMB GIRDLE MUSCULAR DYSTROPHY (LGMD2I) (fukutin-related proteinopathy)

    • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD2I may be a fairly common cause of autosomal recessive (LIMB GIRDLE MUSCULAR DYSTROPHY) LGMD, causing 11% of all cases in Brazil and 38% of cases in Denmark.
    • The disease is allelic with congenital muscular dystrophy 1C (MDC 1C). (See Congenital Muscular Dystrophy.)
    • The presentation of patients with a mutation in fukutin-related protein (FKRP) gene can vary from severe congenital muscular dystrophy to mild, late-onset (LIMB GIRDLE MUSCULAR DYSTROPHY) LGMD.
    • The (LIMB GIRDLE MUSCULAR DYSTROPHY) LGMD phenotype is variable. Patients can have a severe Duchenne-like presentation with delay in motor milestones, hypotonia, and severe proximal weakness. Progression to wheelchair by the teenage years and restrictive respiratory failure (even when patients are ambulant) is common. Like in Duchenne muscular dystrophy, treatment with corticosteroids may improve strength. The most common presentation is with a Becker-like onset with normal early motor milestones. An adult-onset form occurs at 11-40 years of age and is slowly progressive.
    • In a large study in Denmark, 2 groups of patients could be delineated based on genotype-phenotype correlations. Of the 38 patients studied, 27 (71%) had a homozygous mutation (826A>C) while 11 (29%) had a compound heterozygous mutation.11
      • The patients with a homozygous mutation had a later onset (mean of 18 y) and slower progression than patients with a compound heterozygous mutation. Only 15% lost the ability to ambulate by their mid 40s. Presentation with exertional myoglobinuria, calf hypertrophy and cardiomyopathy were all more common than in patients with a compound heterozygous mutation.
      • The patients with a compound heterozygous mutation had an earlier onset (mean of 5 y) and more rapid progression. All lost the ability to ambulate by their mid 20s. Tongue hypertrophy, more severe respiratory failure, contractures, and spine abnormalities were more common than in patients with a homozygous mutation.
    • Cardiac involvement can occur in up to 60% of patients with (LIMB GIRDLE MUSCULAR DYSTROPHY) LGMD2I as measured by reduced left ventricular ejection fraction.12. There is no clear correlation between severity of cardiac disease and severity of muscle disease. Severely abnormal ejection fraction can occur in about 10% of patients and may cause symptomatic congestive heart failure. Rhythm abnormalities are not present. 

LIMB GIRDLE MUSCULAR DYSTROPHY (LGMD2J) (titinopathy)

    • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD2J has been described only in Finnish patients. Some family members have a typical limb girdle phenotype with severe proximal weakness ((LIMB GIRDLE MUSCULAR DYSTROPHY) LGMD2J) while other family members have distal dominant weakness (Finnish [tibial] muscular dystrophy).
    • The onset of the (LIMB GIRDLE MUSCULAR DYSTROPHY) LGMD syndrome is at ~10-30 years, with proximal weakness. Some patients later develop distal weakness.
    • The disease slowly progresses, and wheelchair confinement usually occurs within 20 years, but some patients are ambulant past 60 years.
    • No facial weakness or cardiac involvement is noted.

LIMB GIRDLE MUSCULAR DYSTROPHY (LGMD2K)

    • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD2K has been described in Turkish and Italian families.
    • The disease is allelic with Walker-Warburg syndrome. (See Congenital Muscular Dystrophy.)
    • The age of onset is 1-6 years.
    • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD2K is characterized by severe proximal muscle weakness with slow progression. Contractures may be present.
    • Results of ophthalmologic and funduscopic examinations, including electroretinography, are normal.
    • Facial dysmorphic features and mental retardation may occur, though brains MRIs are normal.

LIMB GIRDLE MUSCULAR DYSTROPHY (LGMD2L)

    • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD2L has been described in French-Canadian families.13 
    • Age of onset is between 11 and 50 years (mean 33 y). While there is intra-familial variability, all patients had quadriceps weakness and atrophy that could be asymmetric. Muscle pain is common. Facial weakness, calf hypertrophy, and contractures are uncommon. Progression is slow, but wheelchair confinement can occur after 10 years.

LIMB GIRDLE MUSCULAR DYSTROPHY (LGMD2M)

    • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD2M has been described in 3 patients in 2 families with a mutation in the fukutin gene.14
    • The disease is allelic with Fukuyama congenital muscular dystrophy.
    • Patients presented with hypotonia before age 1 year. Progression was moderate with proximal greater than distal weakness affecting the legs more than the arms. The affected children, now aged 7-9 years can still walk.
    • Interestingly, these children have worsening weakness during febrile illnesses, and like boys with Duchenne muscular dystrophy, their weakness improves with steroids.
    • All children had normal intelligence and normal brain MRIs.

Autosomal-dominant (LIMB GIRDLE MUSCULAR DYSTROPHY -LGMD:

Autosomal dominant (LIMB GIRDLE MUSCULAR DYSTROPHY) LGMD is less common than autosomal recessive (LIMB GIRDLE MUSCULAR DYSTROPHY) LGMD, accounting for about 10% of all cases. In general, patients with autosomal dominant (LIMB GIRDLE MUSCULAR DYSTROPHY) LGMD have a later onset and slower course than those of autosomal recessive (LIMB GIRDLE MUSCULAR DYSTROPHY) LGMD. Creatine kinase (CK) elevations are also not as great in autosomal dominant (LIMB GIRDLE MUSCULAR DYSTROPHY) LGMD as in autosomal recessive (LIMB GIRDLE MUSCULAR DYSTROPHY) LGMD.

  • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD1A (myotilinopathy, also Myofibrillar myopathies)
    • Onset varies from young adulthood to the mid 70s.
    • Presentation is often with distal weakness causing foot drop, but can also be distal and proximal or just proximal, but progresses to clinically significant proximal and distal weakness in all patients.
    • The progression is slow, with late loss of ambulation or, rarely, respiratory insufficiency.
    • Dysarthria may be prominent.
    • Cardiomyopathy or arrhythmia is noted in 50%.
    • Neuropathy noted in more than 50% may account for distal weakness.
  • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD1B (laminopathy, allelic with autosomal dominant Emery-Dreifuss muscular dystrophy).
    • Onset can be from childhood
    • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD1B results in proximal weakness with slow progression.
    • Distal limb and facial weakness may be late manifestations.
    • Cardiac disease begins by the 30s-50s and affects two thirds of patients. Atrioventricular (AV) block progresses from first degree to complete. Dilated cardiomyopathy and ventricular arrhythmias may also be present.
  • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD1C (caveolinopathy)
    • Onset is usually in the first or second decade, but it may manifest into early adulthood. Presentation is usually with proximal weakness but can also be with distal weakness. Progression is slow to moderate and may be variable within families.
    • Patients may present without weakness, but with myalgia, exercise-induced cramps, or rippling muscles and rhabdomyolysis has been reported.15
    • Calf hypertrophy affects some patients.
    • Adults usually remain ambulant.
    • Patients may also present with elevation of CK levels without weakness but with myalgia and cramps, distal weakness, hypertrophic cardiomyopathy, or rippling-muscle disease. The last condition is mechanical or activity-induced, electrically silent muscle contraction that moves laterally in wavelike fashion across the muscle. Myoedema, or mounding of the muscle after percussion, may be observed. Patients may also have proximal weakness, muscle hypertrophy, or myalgias.
  • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD1D (Online Mendelian Inheritance in Man [OMIM] %603511)
    • Two families have been described.
    • Onset is in adulthood, with proximal weakness.
    • Progression is slow.
    • Dysarthria may be present.
  • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD1E (Dilated cardiomyopathy with conduction defect and muscular dystrophy, OMIM %602067)
    • One large family has been described.
    • Onset is in early adulthood, with proximal weakness.
    • Progression is slow.
    • Cardiac arrhythmia and cardiomyopathy are noted in all patients beginning 1-2 decades after weakness and may lead to sudden death.
  • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD1F
    • One large family has been described.
    • Onset is from the first year of life to the mid 50s.
    • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD1F causes early proximal weakness with progression to distal weakness in most patients.
    • Patients with a young onset may have rapid progression and require use of a wheelchair by their 20s-30s. They may also have facial and respiratory weakness and/or spinal deformity.
  • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD1G
    • One family has been described.
    • Onset is in the 30s-40s.
    • Presentation is with proximal weakness and progression is slow.

Clinical features to distinguish the main (LIMB GIRDLE MUSCULAR DYSTROPHY) LGMDs are often most helpful early in the disease.

  • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD1A: Dysarthria and swallowing difficulty are common. Distal weakness may be present.
  • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD1B: Frequent cardiac complications include cardiomyopathy and arrhythmia and there may be a family history of sudden cardiac death. Respiratory complications and contractures are common.
  • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD1C: Onset is usually in childhood. Patients may present with myalgias, rippling muscles, or asymptomatic elevations of CK levels. Calf hypertrophy may be prominent.
  • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD2A: Patients have prominent atrophy of the periscapular muscles, biceps, gluteus maximus, thigh adductors, and hamstring muscles, with sparing of the hip abductors, sartorius, and gracilis. Presentation may be with toe walking. Contractures are common, in which case the disease needs to be differentiated from (LIMB GIRDLE MUSCULAR DYSTROPHY) LGMD1B, Emery-Dreifuss muscular dystrophy, Bethlem myopathy, and laminin-α2 deficiency. This is a common cause of asymptomatic hyperCKemia.
  • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD2B: Patients may have early weakness and/or atrophy of the gastrocnemius (might be detected only on MRI), inability to walk on toes, waddling gait, atrophic distal biceps, and spared periscapular and deltoid muscles. Childhood onset is rare, with often sudden onset in the late teens or early 20s most common. Misdiagnosis as polymyositis is not uncommon.
  • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD2C-2F: Patients may have Duchenne- and/or Becker-like weakness but with additional involvement of the periscapular muscles causing scapular winging. Muscle hypertrophy is common, especially of the calf and tongue muscles. Mental development is normal. Cardiomyopathy may be present in some. Respiratory complications are common.
  • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD2G: Patients may have initial anterior tibial weakness causing foot drop or a typical (LIMB GIRDLE MUSCULAR DYSTROPHY) LGMD phenotype.
  • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD2H: Patients may have a late onset, slow progression, no cardiac symptoms, but mild ECG changes. This form is reported almost exclusively in the Hutterite population.
  • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD2I: This form has a widely variable spectrum with prominent muscle hypertrophy and cardiomyopathy (Duchenne-like). Respiratory complications are common. Patients may have prominent tongue hypertrophy and severe weakness and wasting of upper arms, neck flexors, and axial muscles; these features can help in distinguishing this disease from Duchenne muscular dystrophy.
  • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD2J: This is a severe (LIMB GIRDLE MUSCULAR DYSTROPHY) LGMD described in the Finnish population. Distal muscles are affected as the disease progresses. No facial weakness is noted.
  • (LIMB GIRDLE MUSCULAR DYSTROPHY)LGMD2K: May present with global delay. Mental retardation and microcephaly may be present.

Courtesy: Muscular Dystrophy Campaign