An integrative correlation of myopathology, phenotype and genotype in late onset Pompe disease

Kulessa, Martin; Weyer-Menkhoff, Iris; Viergutz, Lara; Kornblum, Cornelia; Claeys, Kristl G.; Schneider, Ilka; Plöckinger, Ursula; Young, Peter; Boentert, Matthias; Vielhaber, Stefan; Mawrin, Christian; Bergmann, Markus; Weis, Joachim; Ziagaki, Athanasia; Stenzel, Werner; Deschauer, M.; Nolte, Dagmar; Hahn, Andreas; Schöser, Benedikt; Schänzer, Anne

doi:10.1111/nan.12580

Cited by 14 publications

(10 citation statements)

References 49 publications

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“…Not surprisingly, a detailed analysis of muscle biopsies from a large cohort of LOPD patients before the ERT initiation demonstrated a correlation between the severity of muscle damage and response to therapy. However, no correlation between the duration of the disease and more severe muscle damage was observed, and there was no meaningful genotype-phenotype correlation in this group [48].…”

Section: An Expanded Set Of Clinical Characteristicsmentioning

confidence: 64%

Pompe Disease: New Developments in an Old Lysosomal Storage Disorder

Meena

Raben

2020

Biomolecules

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Pompe disease, also known as glycogen storage disease type II, is caused by the lack or deficiency of a single enzyme, lysosomal acid alpha-glucosidase, leading to severe cardiac and skeletal muscle myopathy due to progressive accumulation of glycogen. The discovery that acid alpha-glucosidase resides in the lysosome gave rise to the concept of lysosomal storage diseases, and Pompe disease became the first among many monogenic diseases caused by loss of lysosomal enzyme activities. The only disease-specific treatment available for Pompe disease patients is enzyme replacement therapy (ERT) which aims to halt the natural course of the illness. Both the success and limitations of ERT provided novel insights in the pathophysiology of the disease and motivated the scientific community to develop the next generation of therapies that have already progressed to the clinic.

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Section: An Expanded Set Of Clinical Characteristicsmentioning

confidence: 64%

Pompe Disease: New Developments in an Old Lysosomal Storage Disorder

Meena

Raben

2020

Biomolecules

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“…Histological analysis of the muscle samplings detected a percentage of vacuolated fibres of 3.09% ± 5.02%, higher in the patients II-9 of family 1 (11.18%) and II-5 of family 2 (15.31%). Although the vacuolated fibres are representative of autophagy impairment in skeletal muscles, they do not seem to correlate with duration of the disease, age at biopsy nor with the residual GAA enzyme activity [18,24]. Finally, response to ERT and adverse reaction to therapy were considered.…”

Section: Clinical Evaluation Of the Lopd Patientsmentioning

confidence: 99%

Rare Variants in Autophagy and Non-Autophagy Genes in Late-Onset Pompe Disease: Suggestions of Their Disease-Modifying Role in Two Italian Families

Napolitano

Bruno

Terracciano

et al. 2021

IJMS

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Pompe disease is an autosomal recessive disorder caused by a deficiency in the enzyme acid alpha-glucosidase. The late-onset form of Pompe disease (LOPD) is characterized by a slowly progressing proximal muscle weakness, often involving respiratory muscles. In LOPD, the levels of GAA enzyme activity and the severity of the clinical pictures may be highly variable among individuals, even in those who harbour the same combination of GAA mutations. The result is an unpredictable genotype–phenotype correlation. The purpose of this study was to identify the genetic factors responsible for the progression, severity and drug response in LOPD. We report here on a detailed clinical, morphological and genetic study, including a whole exome sequencing (WES) analysis of 11 adult LOPD siblings belonging to two Italian families carrying compound heterozygous GAA mutations. We disclosed a heterogeneous pattern of myopathic impairment, associated, among others, with cardiac defects, intracranial vessels abnormality, osteoporosis, vitamin D deficiency, obesity and adverse response to enzyme replacement therapy (ERT). We identified deleterious variants in the genes involved in autophagy, immunity and bone metabolism, which contributed to the severity of the clinical symptoms observed in the LOPD patients. This study emphasizes the multisystem nature of LOPD and highlights the polygenic nature of the complex phenotype disclosed in these patients.

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“…Pompe disease (OMIM 232300) is an autosomal recessive disease due to mutations in the α-1,4-glucosidase gene ( GAA ) and consequent lysosomal α-glucosidase deficiency [ 1 ]. More than 500 variants of GAA genetic mutations have been identified and the clinical phenotypes show a high variability without clear relation to a certain genotype [ 2 – 8 ]. In patients with infantile onset Pompe disease (IOPD) and late onset Pompe disease (LOPD), enzyme replacement treatment (ERT) with recombinant GAA reduces muscle weakness, respiratory insufficiency, and increases life expectancy [ 9 – 12 ].…”

Section: Introductionmentioning

confidence: 99%

Small fiber involvement is independent from clinical pain in late-onset Pompe disease

Enax-Krumova

Dahlhaus

Görlach

et al. 2022

Orphanet J Rare Dis

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Background Pain occurs in the majority of patients with late onset Pompe disease (LOPD) and is associated with a reduced quality of life. The aim of this study was to analyse the pain characteristics and its relation to a small nerve fiber involvement in LOPD patients. Methods In 35 patients with LOPD under enzyme replacement therapy without clinical signs of polyneuropathy (19 females; 51 ± 15 years), pain characteristics as well as depressive and anxiety symptoms were assessed using the PainDetect questionnaire (PDQ) and the hospital anxiety and depression scale (HADS), respectively. Distal skin biopsies were analysed for intraepidermal nerve fiber density (IENFD) and compared to age- and gender-matched reference data. Skin biopsies from 20 healthy subjects served as controls to assure validity of the morphometric analysis. Results Pain was reported in 69% of the patients with an average intensity of 4.1 ± 1.1 on the numeric rating scale (NRS; anchors: 0–10). According to PDQ, neuropathic pain was likely in one patient, possible in 29%, and unlikely in 67%. Relevant depression and anxiety symptoms occurred in 31% and 23%, respectively, and correlated with pain intensity. Distal IENFD (3.98 ± 1.95 fibers/mm) was reduced in 57% of the patients. The degree of IENFD reduction did not correlate with the durations of symptoms to ERT or duration of ERT to biopsy. Conclusions Pain is a frequent symptom in treated LOPD on ERT, though a screening questionnaire seldom indicated neuropathic pain. The high frequency of small nerve fiber pathology in a treated LOPD cohort was found regardless of the presence of pain or comorbid risk factors for SFN and needs further exploration in terms of clinical context, exact mechanisms and when developing novel therapeutic options for LOPD.

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An integrative correlation of myopathology, phenotype and genotype in late onset Pompe disease

Abstract: Muscle morphology in LOPD patients shows a high variability with, in most cases, moderate pathology.Increased pathology is associated with more fibrosis and autophagy.

Cited by 14 publications

References 49 publications

Pompe Disease: New Developments in an Old Lysosomal Storage Disorder

Pompe Disease: New Developments in an Old Lysosomal Storage Disorder

Rare Variants in Autophagy and Non-Autophagy Genes in Late-Onset Pompe Disease: Suggestions of Their Disease-Modifying Role in Two Italian Families

Small fiber involvement is independent from clinical pain in late-onset Pompe disease

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