Variable clinical features and genotype-phenotype correlations in 18 patients with late-onset Pompe disease

Abstract

Background: Pompe disease is a lysosomal storage disorder caused by the deficiency of enzyme acid alphaglucosidase (GAA) which results in accumulation of glycogen, particularly in the skeletal, cardiac, and smooth muscles. The late-onset form with symptoms presenting in childhood through adulthood, is characterized by proximal muscle weakness, respiratory insufficiency, and unlike the infantile-onset form often with no cardiac involvement. Methods: We report our experience with 18 adult patients (14 males/4 females) with Pompe disease, several of whom had unique findings and novel pathogenic variants. Patients ranged in ages from 22-74 years (mean 53.7 years) and were diagnosed at an age range of 11-65 years (mean 43.6 years), often after a history of progressive muscle disease of several years' duration. All 18 patients were treated with alglucosidase alfa (Lumizyme) and their response to treatment was monitored by measurements of their pulmonary function and muscle weakness, six-minute walk test (6MWT), and other functional studies. Results: Genetic sequencing revealed that 16 out of 18 individuals had the common c.-32-13T>G splicing variant, and six patients, including two sibships had four novel pathogenic variants: c.1594G>A, c.2655_2656delCG, c.1951-1952delGGinsT, and c.1134C>G. A male with the c.1594G>A variant developed an intracerebral aneurysm at the age of 43 years treated with surgery. Two siblings with the c.2655_2656delCG developed very high antibody titers, one of whom developed a severe infusion reaction. Other clinical features included BiPAP requirement in twelve, tinnitus in seven, scoliosis in five, cardiomyopathy in three, one individual was diagnosed with a cerebral aneurysm who underwent successful Penumbra coil placement, and another individual was diagnosed with both Graves' disease and testicular cancer. Conclusions: Our study illustrates significant variability in the range of clinical features, and the variable clinical response to enzyme replacement therapy. It also alerts us to the importance of careful monitoring and early management of complications. Possible genotype-phenotype associations with the novel mutations identified may emerge with larger studies.

Pompe Disease: New Developments in an Old Lysosomal Storage Disorder

“…The emerging new features of the disease include vascular and cerebrovascular defects, for example, intracranial aneurysm or dilative arteriopathy, hearing loss, central and peripheral nervous system abnormalities, scoliosis, progressive loss of bone mass, as well as gastrointestinal and urinary tract symptoms [40] (reviewed in [41]). A small subset of LOPD patients develop cardiomyopathy which improves on ERT [42].…”

Cardiovascular disease in non-classic Pompe disease: A systematic review

“…Eight cohort studies performed cardiac imaging and/or function tests using TTE, one study did not report what type of diagnostic modality was used [31]. Most commonly reported findings were various valvular abnormalities/dysfunction (VA/VD), LVH and decreased ejection fraction (dEF).…”

“…One study reported two children with a hypertrophic cardiomyopathy (HCM), both patients did not carry the common IVS1 mutation and had a very early onset of Pompe disease symptoms (before the age of 1) [25]. One study reported three adults (aged 22, 40 and 42 years) with cardiomyopathy (unspecified) which improved with ERT, of whom one had a childhood onset of Pompe disease and did not carry the common IVS1 mutation [31].…”

Clinical examination of patients with late-onset Pompe disease: typical and not typical symptoms and signs

“…Сколиоз чаще развивается у детей с БП, реже у взрослых [34]. По данным Регистра Помпе, он выявляется у 24,8 % больных [35] и вносит отрицательный вклад в дыхательную функцию грудной клетки.…”

“…Снижение слуха у больных с БППН, по одним данным, не превышает число случаев в общей популяции [45], близкие данные приводят и другие исследователи [46]. Из 20 пациентов в 57 % случаев выявлена нейросенсорная и в 33 % -кондуктивная тугоухость [47].…”