Limb-girdle muscular dystrophies (LGMD) were initially defined on the basis of dystrophic features at muscle biopsy and predominant progressive proximal muscle involvement. Despite the definition of limb-girdle involvement, LGMD are characterized by considerable clinical heterogeneity and present clinical overlap with other muscle diseases. Onset varies between birth and late adult age.

Overall frequency of LGMD is low, with a prevalence of 2.27/100,000 in northern England, and single entities are quite rare [11]. LGMD2A due to mutations in calpain 3 gene (CAPN3) is the most frequent limb-girdle dystrophy in many populations, while LGMD2I, determined by mutations in fukutin-related protein gene (FKRP), is the most common form in northern Europe [12].

LGMD diagnosis requires clinical data, muscle biopsy, and finally, genetic testing. LGMD phenotype is generally characterized by predominant limb-girlde muscle involvement, with sparing of facial and extraocular muscles, while distal weakness may be detected later in the disease course or in severe cases.

There are no established specific drug treatments for LGMD.

Rehabilitation, periodic cardiac and respiratory evaluation, and appropriate management of cardiac and respiratory complications are strongly recommended to improve LGMD quality of life and longevity.

LGMD prognosis has been poorly investigated due to the lack of studies on large cohorts of patients. In addition, most of the studies were retrospective; hence, only partial data on LGMD natural history are available. However, correct characterization of LGMD is important, because different subtypes may have different severity (see Table 38.1).

To summarize, LGMD prognosis could be generally assessed by skeletal muscular progression to severe motor function disability, heart involvement, and respiratory problems. Bulbar involvement and its complications, such as the need for nasogastric feeding or gastrostomy, are uncommon.

Severe progression of skeletal muscle weakness, presenting in early life, and sometimes leading to loss of ambulation, has been mainly reported in sarcoglycanopathies (LGMD2C-F), LGMD2I, and LGMD2J. However, patients affected by other LGMD subtypes may lose walking ability, though less frequently and later in the disease course.

Patients with mutations in caveolin 3 gene (CAV3) seem to have a relatively better prognosis compared to patients with other mutated genes. Among these patients, only 60 % usually develop muscle weakness, while the remaining patients present myalgia, myoglobinuria, or muscle rippling. A similar behavior has been reported for LGMD2L, due to anoctamin 5 gene (ANO5) mutations.

Respiratory involvement has been mainly reported in sarcoglycanopathies and in LGMD2I, sometimes with respiratory failure, while the patient is still ambulant.

Heart involvement, most frequently cardiomyopathy, has been observed in particular in LGMD1B, LGMD1E, sarcoglycanopathies, and LGMD2I. However, in addition to dilated cardiomyopathy sometimes requiring heart transplant, LGMD1B shows a high incidence of arrhythmias preceding skeletal muscle involvement in some patients and often needing a pacemaker or implantable cardioverter defibrillator. A high intrafamilial phenotype heterogeneity in LGMD1B has been described, with asymptomatic members affected only by heart disease [13].

Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant myopathy, which involves facial, shoulder girdle, and distal lower limb muscles.

FSHD is a relatively common myophathy (the third common muscular dystrophy after Duchenne muscular dystrophy and myotonic dystrophy), with an estimated prevalence ranging from 1:14,000 to 1:20,000 [14].

The disease is characterized by wasting and weakness of facial muscles (particularly of orbicularis oculi with difficulty in closing eyes and orbicularis oris with inability to protrude lips, to use a straw, and to whistle), shoulder girdle (scapulae winging with inability to fully abduct and/or flex arms above 45–90°), and distal lower limb muscles (weakness of foot dorsiflexors, with foot drop during walking). Clinical phenotype is very broad, ranging from isolated facial weakness to severe shoulder girdle and distal weakness. Moreover, phenotype may be extremely variable in the same family also, suggesting that other factors, such as epigenetic modifiers, may modulate genetic abnormality and phenotype.