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Assessing metabolic profiles in human myoblasts from patients with late-onset Pompe disease.

ABSTRACT: Background:Pompe disease is a neuromuscular disease caused by a deficiency of lysosomal acid alpha-glucosidase (GAA) which degrades glycogen, resulting in progressive accumulation of lysosomal glycogen, lysosomal swelling and rupture. In addition, mitochondrial abnormalities have been frequently observed in muscle biopsy specimens of Pompe patients. Enzyme replacement therapy (ERT) using alglucosidase alfa, a recombinant human GAA, is so far the only available therapy. We evaluated glycolysis and basal respiration in primary human myoblasts from patients with Pompe disease and in mouse myoblasts from GAA knockout mice before and after alglucosidase alfa treatment. Methods:We tested patient-derived primary human myoblasts and immortalized GAA-/- mouse myoblasts for GAA activity, glycolytic activity, and mitochondrial respiration before and after alglucosidase alfa treatment using enzyme activity assays and SeaHorse measurements. Results:A significant reduction in glycolysis (30%) and in mitochondrial respiration (50%) was observed in both, human and mouse GAA-deficient myoblasts. Treatment with alglucosidase alfa resulted in partial recovery of both metabolic pathways with some variability in human myoblasts. Conclusions:Future assessments of treatment efficacy should include screening for the metabolic effects on both glycolysis and mitochondrial respiration in order to obtain a better read-out of the cellular energy metabolism.

SUBMITTER: Meinke P

PROVIDER: S-EPMC6642930 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Assessing metabolic profiles in human myoblasts from patients with late-onset Pompe disease.

Meinke Peter P Limmer Sarah S Hintze Stefan S Schoser Benedikt B

Annals of translational medicine 20190701 13

<h4>Background</h4>Pompe disease is a neuromuscular disease caused by a deficiency of lysosomal acid alpha-glucosidase (GAA) which degrades glycogen, resulting in progressive accumulation of lysosomal glycogen, lysosomal swelling and rupture. In addition, mitochondrial abnormalities have been frequently observed in muscle biopsy specimens of Pompe patients. Enzyme replacement therapy (ERT) using alglucosidase alfa, a recombinant human GAA, is so far the only available therapy. We evaluated glyco ...[more]

PMID: 31392189

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Project description:Our objective was to investigate brain structure, cerebral vasculature, and cognitive function in a cohort of patients with late-onset Pompe disease, with particular reference to the differences from those with the classic infantile phenotype, where extensive white-matter abnormalities (WMA) and impaired cognition on long-term enzyme treatment are reported in a subset of patients. Brain imaging (T1, T2, T2 fluid-attenuated inversion recovery, susceptibility-weighted images, and magnetic resonance angiography-time of flight) was combined with extensive cognitive testing of general intelligence (Wechsler IQ Test, Montreal Cognitive Assessment [MoCA]) and specific neuropsychological domains (verbal fluency, cognitive flexibility, attention, memory, and visuospatial abilities). We included 19 patients with late-onset Pompe disease (age range 11-56 years). Two patients showed mild punctate WMA within normal range for age, with a Fazekas score (FS) of 1 to 2. Magnetic resonance angiography revealed a slight vertebrobasilar dolichoectasia in two patients yet did not show any aneurysms or vascular dissections. Most patients had age-adjusted scores within the normal range for the Wechsler index scores (verbal comprehension, perceptual reasoning, working memory, and processing speed) and combined total intelligence (IQ) score (median 101, interquartile range 91-111; one patient had a below-average score for total IQ) as well as for the specific domains verbal fluency, attention, and memory. A subset of patients performed suboptimally on the Rey Complex Figure Test (9/14 patients) or cube-copying/clock-drawing test of the MoCA (8/10 patients). We therefore concluded that our study showed no brain abnormalities, other than minor microvascular lesions considered within normal range for age, nor general cognitive impairment in late-onset Pompe patients. These findings are in sharp contrast with the widespread WMA and cognitive problems found in some classic infantile patients.

Project description:BackgroundPompe disease is a lysosomal storage disorder caused by the deficiency of enzyme acid alpha-glucosidase (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.MethodsWe 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.ResultsGenetic 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.ConclusionsOur 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.

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Assessing metabolic profiles in human myoblasts from patients with late-onset Pompe disease.

Publications

Assessing metabolic profiles in human myoblasts from patients with late-onset Pompe disease.

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