Distal myopathy, Welander type (ORPHA:603)
A rare distal myopathy characterized by weakness in the distal upper extremities, usually finger and wrist extensors which later progresses to all hand muscles and distal lower extremity, primarily in toe and ankle extensors.
Epidemiology
Distal myopathy, Welander type (WDM) prevalence is unknown. The condition is mainly restricted to a geographical area around the Baltic Sea especially in Finland and Sweden (mid-eastern region), where the estimated prevalence is 1/10,000. However, some patients have been reported in the United Kingdom.
Clinical description
WDM is a late adult-onset disorder (onset between 40 and 60 years) characterized by initial weakness of index finger extensors followed by extension weakness in the other fingers. Weakness slowly progresses to all hand and lower leg muscles. In the lower limb, the anterior tibial muscle and toe extensors are typically affected leading to walking difficulties and steppage gait. Proximal limb muscles are only rarely involved. Muscle stretch reflexes are preserved (except ankle reflexes which may be lost later in the disease). Cardiac muscle involvement has not been observed. Rare homozygotes individuals show an earlier onset and proximal muscle involvement with faster progression.
Etiology
WDM is caused by a missense change (c.1362G>A; p.E384K) in TIA1 gene (2p13) which encodes nucleolysin TIA1 isoform p40, a key component of stress granules (SGs). Under conditions of cellular stress or metabolic changes, nucleolysin TIA1 isoform p40 promotes messenger ribonucleoprotein (mRNP) complexes to assemble in SGs to repress translation. The mutation leads to reduced dynamics of the SGs and abnormal autophagic processing with rimmed vacuolar pathology. In addition, the WDM phenotype has been reported in patients with a digenic combination of a SQSTM1 mutation and TIA1-N357S variant.
Diagnostic methods
Diagnosis relies on molecular genetic testing. Additional examinations include muscle biopsy of distal muscles showing dystrophic features and prominent rimmed vacuoles. Sensory examination is usually normal, although some deficits on quantitative temperature and vibration testing have been described. The serum creatine kinase (CK) level is usually normal or slightly elevated. Needle electromyography (EMG) shows small brief 'myopathic' motor units, although a mixed 'myopathic-neuropathic' pattern may be observed. Fibrillations and complex repetitive discharges are often, but not invariably, present. Muscle magnetic resonance imaging shows considerable involvement of posterior calf muscles besides fatty degenerative changes in the anterior compartment.
Differential diagnosis
Differential diagnosis includes sporadic inclusion body myositis (sIBM), MATR3 distal myopathy, and muscle filaminopathy.
Genetic counseling
WDM is inherited as an autosomal dominant trait. Where one parent is affected, there is a 50% risk of disease transmission to offspring. Penetrance is 100% by age 75 years.
Management and treatment
Management is mainly symptomatic and includes the help of an occupational and a physical therapists and practical tools for finger and hand weakness. Foot drop and wrist weakness may be helped by orthoses.
Prognosis
The progression is benign and life expectancy is normal although the fine motor hand skills are usually lost. Homozygotes exhibit earlier onset, faster progression, and patients become wheelchair-bound by the age of 50 years.

                            Last update: 
                            December 2019


                            - Expert reviewer(s): 
                            Pr Bjarne UDD