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Clinical Variability in 2 Siblings With Late-Onset Pompe Disease.

To the Editor: Pompe disease (glycogen storage disease type II and acid maltase deficiency) is a rare inherited autosomal recessive disorder that results from a deficiency of the lysosomal enzyme acid 1,4 a-glucosidase (GAA).1 The disease manifests with a clinical spectrum of severity that ranges from severe infantile onset to the milder late onset of the disease.2–5 Mutations in GAA occur in homozygous or compound heterozygous and are associated with the absence of GAA activity in the infantile form, and with a residual GAA activity ranging from 3% to 35% of control values in the late-onset forms. These data indicate a clear-cut relationship between enzyme activity levels and the severity of the phenotype in the infantile form, whereas in lateonset patients, there is no definite correlation.4 We report herein 2 brothers, aged 40 (patient 1) and 45 years (patient 2), who presented with myalgia, hyperCKaemia, and exercise-induced fatigue with an age of onset between 10 and 35 years, respectively. Patient 1 had moderate axial and proximal weakness predominately in the lower limbs, with moderate respiratory insufficiency and the need for nightly noninvasive artificial ventilation. His brother (patient 2) had proximal quadriparesis, markedly in the upper limbs with asymmetrical scapular winging, misdiagnosed initially as long thoracic nerve lesions. Both patients had elevated creatine kinase levels. A biceps brachii muscle biopsy showed in both the classic vacuolar myopathy with periodic acid-Schiff-positive vacuoles and increased of lysosomal activity. After the suspicion of Pompe disease, both patients had confirmed decreased GAA activity in dried blood spot testing, with a reduction of at least 30% from the normal value. The sequencing of the coding region of GAA (NM_000152.3) demonstrated the presence of C.-32-13T.G and c.2560C.T (p.Arg854) mutations (compound heterozygosis). The first variant is located in the 59UTR c.-3213T.G (intron 1), and the second in exon 18, and both have been already described as pathogenic. Only the patient 1 has received intravenous Myosyme, and after 6 months, the 6-minute walking test improved from 103 to 180 m. The forced vital capacity changed from 83% (sat position) and 51% (supine position) to 85% (sat position) to 54.6% (supine position). The most common phenotypic pattern in approximately 80% of late-onset Pompe disease is lower limb girdle weakness, in addition to truncal and diaphragmatic muscular weakness with creatine kinase elevation.1,3 Patient 1 had respiratory muscular insufficiency in combination with limb girdle weakness, which is a find that is reported in 55% of patients, but respiratory failure can precede the onset of overt muscular weakness and should be a red flag during clinical evaluation.3 The other patient had an uncommon presentation characterized by an asymmetrical pattern of weakness with a clear predominance in the upper limbs, a find that is not frequently reported and that is quite similar to the facioscapulohumeral muscular dystrophy phenotype with facial sparing.2,5 At present, no definitive mechanism is involved in the variability of the clinical presentation and outcome in the late-onset Pompe disease population, but recognizing this point is crucial to avoid misdiagnosis.