Distal anoctaminopathy (ORPHA:399096)
Distal anoctaminopathy is a rare, autosomal recessive distal myopathy characterized by early adult-onset, slowly progressive, often asymmetrical, lower limb muscle weakness initially affecting the calves (with relative anterior muscle sparing) and later proximal muscle involvement, as well as highly elevated creatine kinase (CK) serum levels.
Epidemiology
Worldwide prevalence of distal anoctaminopathy is unknown, but it may represent up to 10% of anoctamin-5 related muscle disease. To date, more than 20 cases have been described in the literature with males being predominantly affected.
Clinical description
Age at onset ranges from 20 to 50 years (with first symptoms as early as late teens) with patients typically presenting hypertrophy of distal lower leg muscles (predominantly the calf muscles (gastrocnemius medialis and soleus muscles)) which evolves into muscle atrophy with disease progression. Muscle weakness and wasting are usually asymmetrical and early symptoms include calf muscle tightness during running, reduced sports performance and difficulty to walk on tiptoes. Uncomfortable burning muscle sensation preceding muscle weakness may also be observed. In advanced stages of the disease, muscle weakness and wasting in the proximal lower and upper limbs (especially in the biceps brachii) appears. Clinical manifestations can be mild, or subjectively nonexistent, in spite of presenting clear changes on muscle imaging. Bulbar or respiratory symptoms have not been reported, however rhabdomyolysis has been observed in some patients. Intrafamilial clinical variability has been observed.
Etiology
Distal anoctaminopathy is caused by loss of function mutations in the gene ANO5 (11p14.3) which encodes a protein highly expressed in skeletal and cardiac muscle, as well as bone. ANO5 functions are largely unknown. It has been proposed that ANO5 may participate in membrane repair pathway, possibly at levels different from that of dysferlin.
Diagnostic methods
Diagnosis is based on clinical, muscle histology and laboratory examinations. Muscle biopsy shows non-specific myopathic changes, whereas blood biochemistry reveals markedly increased CK levels (typically >10 times the normal). Diagnosis is confirmed by genetic screening of ANO5.
Differential diagnosis
Differential diagnosis includes other distal myopathies, in particular Miyoshi myopathy (which is differentiated by absence of dysferlin on biopsy).
Genetic counseling
Transmission is autosomal recessive and genetic counseling is recommended for at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child.
Management and treatment
Currently no specific treatment exists and management is mainly supportive. To prolong survival and improve quality of life, weight control to avoid obesity, physical therapy and stretching exercises to promote mobility, and use of mechanical aids to help ambulation and mobility are recommended.
Prognosis
The progression of the disease is slow and patients generally maintain the ability to walk, although use of ambulatory aids are usually needed in the later stages of the disease.

                            Last update: 
                            September 2018


                            - Expert reviewer(s): 
                            Dr Johanna PALMIO  - Pr Bjarne UDD