Late onset Pompe disease: Clinical and neurophysiological spectrum of 38 patients including long-term follow-up in 18 patients

Abstract

To describe the clinical and neurophysiological spectrum and prognosis in a large cohort of biochemically and genetically proven late onset Pompe patients. Thirty-eight diagnosed with late onset Pompe disease at our neuromuscular department during 1985 and 2006 are described in detail.

The mean delay from onset of symptoms or first medical consultation until diagnosis was 10.4 and 7.1 years, respectively. A different diagnosis was suggested in 11 of 38 patients. Ten patients underwent repeated muscle biopsies before diagnosis of Pompe disease was established. Limb girdle weakness was the most frequent presenting sign. Six patients complained of myalgia. Wolf–Parkinson–White syndrome was found in 3 of 38 patients. Respiratory failure preceded the onset of overt limb muscle weakness in three patients. The course of the patients was progressive in all, but there was a wide variety of progression, which did not correlate with the age of disease onset. In 71% of the patients, neurophysiological investigations revealed a myopathic EMG pattern, half of the patients had spontaneous activity including complex repetitive discharges. A normal EMG was found in 9% of the patients. Nerve conduction studies were normal in all.

Pompe disease should be taken into consideration in patients with unexplained limb girdle muscular weakness with respiratory failure. Cardiac manifestations may not be restricted to infantile Pompe disease.

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.