Late onset Pompe disease: Clinical and neurophysiological spectrum of 38 patients including long-term follow-up in 18 patients
Introduction
Pompe disease, also known as glycogenosis type II, glycogen storage disease type II, or acid maltase deficiency is an autosomal recessive inherited disorder, which is progressively debilitating. In a considerable number of children, death occurs by cardiac and respiratory failure. A significant number of adult patients suffer from respiratory failure, too. This rare disorder has an estimated prevalence of 1 in 40,000 [1], [2]. It is a lysosomal storage disorder caused by a deficiency of the enzyme acid alpha-glucosidase (GAA), which converts glycogen to glucose in the acid environment of lysosomes (pH 4–5). GAA deficiency leads to an accumulation of glycogen within lysosomes, and rupture of lysosomes results in cellular dysfunction, abnormal autophagy and structural disorganization in different tissues [3]. Glycogen depositions are mainly localized in cardiac, skeletal and smooth muscle, whereas other tissues may be affected less frequently [4].
Initially, Pompe disease was described as rapidly progressive infantile disorder, which led to death by respiratory and cardiac failure within the first two years of life. The children presented with hypertrophic cardiomyopathy and severe generalized muscle weakness. This rare form is termed now the classical infantile form of Pompe disease. In the last 30 years, a growing number of patients with a late onset type of this disease have been described [5]. As in patients with infantile onset, there is a progressive deterioration of proximal and truncal muscles with predominant involvement of the lower limbs. Respiratory function may be affected early, but the heart was reported spared in most adult patients [6], [7]. Initial symptoms may be subtle with some difficulties climbing stairs or rising from a chair or an elevation of creatine kinase levels. Initial symptoms are non-specific and may mimic other neuromuscular disorders. Therefore, there is a substantial risk to miss accurate diagnosis. Nevertheless, most patients progress to a severe generalized weakness. A considerable number becomes wheelchair bound and/or may require assisted ventilation [5], [8].
Until recently, no effective therapy for Pompe’s disease was known. However, in 2006 enzyme replacement therapy with recombinant human acid alpha-glucosidase has been approved for clinical use in patients with Pompe disease in Europe and US. Clinical studies in infants have shown that enzyme replacement led to improvement in skeletal and cardiac muscle function and to increased survival in many patients [9], [10], [11], [12], [13], [14]. Moreover, there is some evidence that this treatment may also be applicable in late onset patients [4]. Single late onset patients have already been successfully treated [15].
For that reason, clinical suspicion and correct diagnosis of adult Pompe patients has received additional attention. The purpose of this paper is to describe clinical, neurophysiological and radiological findings of late onset Pompe disease in a group of 38 patients diagnosed in our neuromuscular department between 1985 and 2006.
Section snippets
Patients and methods
We included 38 patients in whom Pompe disease was diagnosed at the neuromuscular department of the University of Munich (Friedrich-Baur-Institute) between 1985 and 2006. All patients were caucasians, 13 patients were male, 25 patients female. The mean age at time of diagnosis was 40.9 years (7–61). There was a family history of Pompe disease in 4 patients (11%).
Diagnosis of Pompe disease was based on muscle biopsy findings with a severely reduced acid maltase activity and an increase of total
Age at onset and time delay for making the correct diagnose
Thirty-eight patients (32 adult, 6 juvenile) have been examined. The mean age of the patients at time of diagnosis was 40.9 years (range 7.3–7 years). First symptoms were evident at age 30.7 years (range 1–52.6 years). Onset of the disease was uncertain in eight patients who reported minor symptoms such as poor performance at school sport. The mean time lag between onset of first symptoms and diagnosis was 10.4 years (range between 0.1 years in a presymptomatic boy with elevated liver enzymes
Discussion
This report describes clinical and diagnostic findings in a cohort of 38 patients with late onset Pompe disease who were diagnosed at our neuromuscular department during a period of 21 years.
Acknowledgments
We thank Priya Kishnani for critical review of the manuscript. We thank Mrs. Kaus, Schäfer, Schmuck, and Wiens for excellent technical assistance. B.G.H.S., D.P., H.L., M.C.W. and W.M.-F. are members of the German network on muscular dystrophies (MD-NET, 01GM0601) funded by the German ministry of education and research (BMBF, Bonn, Germany).
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