Homozygotic intronic GAA mutation in three siblings with late-onset Pompe's disease

Abstract

Pompe's disease (PD) is a metabolic myopathy caused by the accumulation of lysosomal glycogen, secondary to acid α-glucosidase (GAA) enzyme deficiency. Childhood and lateonset forms are described, differing by the age of onset and symptoms. In this study were analyzed affected siblings with Pompe's disease (PD) and their distinct clinical and pathological presentations. Method: Diagnosis was performed by the clinical presentation of limb-girdle dystrophies and respiratory compromise. Confirmatory diagnoses were conducted by muscle biopsy, GAA activity measurement and by GAA gene genotyping. results: The findings suggested muscular involvement due to GAA deficiency. GAA genotyping showed they are homozygous for the c.-32-3C>A mutation. conclusion: Herein we reported a family where three out of five siblings were diagnosed with late-onset PD, although it is a rare metabolic disease inherited in an autossomal recessive manner. We emphasize the importance of including this presentation within the differential diagnoses of the limb-girdle dystrophies once enzyme replacement therapy is available.

Homozygosity for the common GAA gene splice site mutation c.-32-13T>G in Pompe disease is associated with the classical adult phenotypical spectrum

“…The phenotype severity spectrum found in our six patients is in line with the reported four singles and three siblings of Pompe patients with a homozygous c.-32-13T>G mutation [16][17][18][19]. All patients had an adulthood disease onset with mild to moderate proximal leg weakness, moderate CK elevations, and reduced GAA activity in leucocytes or in muscle homogenates [16][17][18][19]. In a few patients, additional elevation of glycogen content in muscle tissue was reported [17,18].…”

“…All three siblings had difficulties in climbing stairs, standing-up, and frequent drops. Ten years later ventilatory failure evolved and a mild to moderate limb-girdle muscular weakness was noticed [19]. The c.-32-13T>G mutation is never reported in the classic infantile Pompe disease form.…”

“…Homozygosity for this most common Caucasian GAA gene splice site mutation is an unexpected rare event compared to the appraised frequency in the population with regard to the predicted incidence of the disease ranging between 1:40,000 and 1:250,000 [ [12], www.pompecenter.nl, [15]]. In the fast growing cluster of publications related to Pompe disease over the past 20 years, four singles and three siblings of Pompe patients with a homozygous c.-32-13T>G mutation are reported so far [16][17][18][19].…”

Highlighting intrafamilial clinical heterogeneity in late-onset Pompe disease

“…The late onset form of the disease has a variable age of onset and is characterized by a spectrum of symptoms and phenotypes that largely comprise a slowly progressive myopathy and respiratory muscle involvement [1], [2]. Intrafamilial phenotypic variability has been reported in Pompe disease, as well as in other glycogen storage diseases even in siblings sharing a similar genetic background [3], [4], [5].…”

Pompe disease: further challenges to pursue

“…Genotype-phenotype correlation has been one of the adopted strategy to this end. Reuser' s group has built up the Pompe Disease Mutation Database enumerating all GAA variations and describing their effect to facilitate diagnosis and counseling for patients and families with Pompe disease 12,13 . This database available at http://www.pompecenter.nl provides a continuously enlarging list of 372 sequence variants in the GAA gene (MIM#606800; RefSeq NT_024871.11; NM_000152.3; NP000143.2).…”