FKRP-related limb-girdle muscular dystrophy R9 (ORPHA:34515)
A form of autosomal recessive limb-girdle muscular dystrophy that presents a highly variable age of onset and phenotypic spectrum typically characterized by slowly progressive proximal weakness of the pelvic and shoulder girdle musculature (predominantly affecting the lower limbs), frequently associated with waddling gait, scapular winging, calf and tongue hypertrophy, exercise-induced myalgia, abdominal muscle weakness, cardiomyopathy, respiratory muscle involvement, and myoglobinuria and/or elevated creatine kinase serum levels.
Epidemiology
Due to a founder mutation in Scandinavia (excluding Finland) the prevalence figures for FKRP-related limb-girdle muscular dystrophy R9 (LGMDR9) is much higher than the rest of the world (about 1/50,000). In countries with Scandinavian immigration (Northern Europe and northern states of America) the prevalence is also relatively high.
Clinical description
The age of onset is correlated to the genotype and residual expression of fukutin-related protein. Thus, patients homozygous for the common, mild mutation (c.826C>A) usually have an onset in the third decade, while patients compound heterozygous for this mutation have onset before age 10, and loose ambulation around age 20 and need assisted ventilation 5-10 years after that. The manifesting symptoms start in the lower extremities with difficulties raising from a chair, climbing stairs and running. Later proximal weakness starts in the arms with visible scapular winging. Of note, a third of patients may present with myoglobinuria on physical exertion, before weakness is noticed. Patients may develop a cardiomyopathy that requires medical treatment. In rare cases, a cardiac transplant is required. Left ventricular ejection fraction drops on average 0.4% per year. Patients homozygous for the c.826C>A mutation in FKRP loose ambulation around age 60 and may need assisted ventilation at night, but the timing of these losses is highly variable.
Etiology
The loss of glycosylation of alpha-dystroglycan due to pathogenic variants in FKRP (19q13.32) leads to poor linkage of the myocyte to the extracellular matrix, which produces muscle damage.
Diagnostic methods
The diagnosis is directed towards a limb girdle muscular dystrophy based on clinical presentation with proximal wasting and weakness, most pronounced in legs. The primary diagnosis is based on finding of two pathogenic variants in FKRP. Creatine kinase is usually elevated above 1,000 and can reach undetectable levels after strenuous exercise that can also result in myoglobinuria. A muscle biopsy shows dystrophic changes, and staining for glycosylation of alpha-dystroglycan with VIA4 and IIH6 antibodies shows loss of glycosylation.
Differential diagnosis
The list of other muscle disease which present with proximal weakness is long. First and foremost, the other, numerous, limb girdle dystrophies should be considered. Other differential diagnoses include Becker muscular dystrophy, Bethlem myopathy, mitochondrial myopathy, poly-/dermatomyositis, and muscle glycogenosis (especially Pompe disease and debrancher deficiency). Spinal muscular dystrophy in mild forms and congenital myasthenia patients are also valid differential diagnoses.
Genetic counseling
For parents of an affected child, the risk of having another affected child is 25% at each pregnancy. As this is a recessive rare disease, genetic counselling for affected individuals is rarely needed due to the low carrier frequency in the background population. However, carrier testing of an unaffected spouse is relevant in Scandinavia (excluding Finland) as the carrier frequency is 1/150-200 people.
Management and treatment
Currently, there are no approved specific drugs for the disease. Supportive therapies with assisted ventilation, medical treatment for heart failure, early retirement if weakness becomes too severe, and assisted devices for ambulation and general mobility (e.g. handles in the toilet) are recommended. Different gene therapies and substrate (ribitol) therapies are being researched and clinical trials are imminent.
Prognosis
Quality of life is highly influenced by the loss of motor function and respiratory limitations. Life expectancy is unknown, but usually normal in patients homozygous for the c.826C>A mutation. Patients compound heterozygous for the mutation likely have reduced life expectancy because of invasive ventilation from early age and the subsequent complications.

                            Last update: 
                            March 2021


                            - Expert reviewer(s): 
                            Pr John VISSING