POMPE DISEASE AND METABOLIC DISORDERS

Polyglucosan body myopathy-2, the pure skeletal myopathy form of glycogen storage disease type XV, is caused by glycogenin-1 deficiency, the priming enzyme of glycogen synthesis. To detail the clinical and morphological features in patients with polyglucosan body myopathy 2, we retrospectively analysed muscle symptoms and muscle biopsies from 17 patients from 12 families with pathogenic GYG1 gene mutations. Seven patients were male and ten patients were female. Age at onset varied from 15 to 79 years. Initial symptom was lower limb girdle weakness (4 patients), distal lower limb weakness (3 patients), upper limb girdle weakness (2 patients), muscle fatigability during running (2 patients), scapulo-peroneal weakness (1 patient), asymmetric hand and lower proximal limb weakness (1 patient), exercise intolerance with myalgia followed by limb girdle weakness (1 patient), and sports difficulties (1 patient). Clinical course was slowly progressive, with extension of weakness to proximal segments in distal patients. Associated mild axial weakness was found in 3 patients. Only 1 patient developed facial weakness. Strikingly, asymmetric weakness was noted in 6 patients. Proximal patients developed marked waddling gait necessitating the use of a cane/rollator, or intermittent wheelchair. Distal patients developed stepping gait. Serum CK were normal or slightly elevated in 8 patients, and highly elevated in 9 patients. None of the patients developed cardiac or respiratory involvement. Muscle biopsy showed vacuoles filled with hyperintense PAS-positive material partially resistant to α-amylase in 5-50% of fibers (14 patients). All patients presented one homozygous or two compound heterozygous GYG1 mutations. Nine patients were homozygous for the common c.143+3G>C mutation and three were heterozygous. Polyglucosan body myopathy 2 shows an extremely variable clinical phenotype including slowly progressive limb girdle, scapulo-peroneal or distal, often-asymmetric weakness. Muscle fatigability, effort intolerance and myalgia are rare manifesting symptoms. On the other hand, the histopathologic phenotype is homogenous and easily recognisable. A multicentre international natural history study will be useful in view of a possible therapeutic approach.