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The value of muscle biopsies in Pompe disease: identifying lipofuscin inclusions in juvenile- and adult-onset patients.

Abstract

BACKGROUND

Pompe disease, an inherited deficiency of lysosomal acid alpha-glucosidase (GAA), is a metabolic myopathy with heterogeneous clinical presentations. Late-onset Pompe disease (LOPD) is a debilitating progressive muscle disorder that can occur anytime from early childhood to late adulthood. Enzyme replacement therapy (ERT) with recombinant human GAA is currently available for Pompe patients. Although ERT shows some benefits, the reversal of skeletal muscle pathology - lysosomal glycogen accumulation and autophagic buildup - remains a challenge. In this study, we examined the clinical status and muscle pathology of 22 LOPD patients and one atypical infantile patient on ERT to understand the reasons for muscle resistance to ERT.

RESULTS

The patients were divided into three groups for analysis, based on the age of onset and diagnosis: adult-onset patients, juvenile-onset patients, and those identified through newborn screening (NBS). The areas of autophagic buildup found in patients' biopsies of all three groups, contained large autofluorescent inclusions which we show are made of lipofuscin, an indigestible intralysosomal material typically associated with ageing. These inclusions, analysed by staining, spectral analysis, time-resolved Fluorescence Lifetime Imaging (FLIM), and Second Harmonic Generation (SHG) imaging, were the major pathology remaining in many fibers after ERT. The best outcome of ERT both clinically and morphologically was observed in the NBS patients.

CONCLUSIONS

The muscle biopsy, in spite of its shortcomings, allowed us to recognize an underreported, ERT-resistant pathology in LOPD; numerous lysosomes and autolysosomes loaded with lipofuscin appear to be a hallmark of LOPD skeletal muscle. Lipofuscin accumulation - a result of inefficient lysosomal degradation - may in turn exacerbate both lysosomal and autophagic abnormalities.

Authors+Show Affiliations

No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableLaboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA. kishn001@mc.duke.edu.No affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Intramural
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

24383498

Citation

Feeney, Erin J., et al. "The Value of Muscle Biopsies in Pompe Disease: Identifying Lipofuscin Inclusions in Juvenile- and Adult-onset Patients." Acta Neuropathologica Communications, vol. 2, 2014, p. 2.
Feeney EJ, Austin S, Chien YH, et al. The value of muscle biopsies in Pompe disease: identifying lipofuscin inclusions in juvenile- and adult-onset patients. Acta Neuropathol Commun. 2014;2:2.
Feeney, E. J., Austin, S., Chien, Y. H., Mandel, H., Schoser, B., Prater, S., ... Raben, N. (2014). The value of muscle biopsies in Pompe disease: identifying lipofuscin inclusions in juvenile- and adult-onset patients. Acta Neuropathologica Communications, 2, p. 2. doi:10.1186/2051-5960-2-2.
Feeney EJ, et al. The Value of Muscle Biopsies in Pompe Disease: Identifying Lipofuscin Inclusions in Juvenile- and Adult-onset Patients. Acta Neuropathol Commun. 2014 Jan 2;2:2. PubMed PMID: 24383498.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The value of muscle biopsies in Pompe disease: identifying lipofuscin inclusions in juvenile- and adult-onset patients. AU - Feeney,Erin J, AU - Austin,Stephanie, AU - Chien,Yin-Hsiu, AU - Mandel,Hanna, AU - Schoser,Benedikt, AU - Prater,Sean, AU - Hwu,Wuh-Liang, AU - Ralston,Evelyn, AU - Kishnani,Priya S, AU - Raben,Nina, Y1 - 2014/01/02/ PY - 2013/10/29/received PY - 2013/12/18/accepted PY - 2014/1/4/entrez PY - 2014/1/5/pubmed PY - 2014/1/5/medline SP - 2 EP - 2 JF - Acta neuropathologica communications JO - Acta Neuropathol Commun VL - 2 N2 - BACKGROUND: Pompe disease, an inherited deficiency of lysosomal acid alpha-glucosidase (GAA), is a metabolic myopathy with heterogeneous clinical presentations. Late-onset Pompe disease (LOPD) is a debilitating progressive muscle disorder that can occur anytime from early childhood to late adulthood. Enzyme replacement therapy (ERT) with recombinant human GAA is currently available for Pompe patients. Although ERT shows some benefits, the reversal of skeletal muscle pathology - lysosomal glycogen accumulation and autophagic buildup - remains a challenge. In this study, we examined the clinical status and muscle pathology of 22 LOPD patients and one atypical infantile patient on ERT to understand the reasons for muscle resistance to ERT. RESULTS: The patients were divided into three groups for analysis, based on the age of onset and diagnosis: adult-onset patients, juvenile-onset patients, and those identified through newborn screening (NBS). The areas of autophagic buildup found in patients' biopsies of all three groups, contained large autofluorescent inclusions which we show are made of lipofuscin, an indigestible intralysosomal material typically associated with ageing. These inclusions, analysed by staining, spectral analysis, time-resolved Fluorescence Lifetime Imaging (FLIM), and Second Harmonic Generation (SHG) imaging, were the major pathology remaining in many fibers after ERT. The best outcome of ERT both clinically and morphologically was observed in the NBS patients. CONCLUSIONS: The muscle biopsy, in spite of its shortcomings, allowed us to recognize an underreported, ERT-resistant pathology in LOPD; numerous lysosomes and autolysosomes loaded with lipofuscin appear to be a hallmark of LOPD skeletal muscle. Lipofuscin accumulation - a result of inefficient lysosomal degradation - may in turn exacerbate both lysosomal and autophagic abnormalities. SN - 2051-5960 UR - https://www.unboundmedicine.com/medline/citation/24383498/The_value_of_muscle_biopsies_in_Pompe_disease:_identifying_lipofuscin_inclusions_in_juvenile__and_adult_onset_patients_ L2 - https://actaneurocomms.biomedcentral.com/articles/10.1186/2051-5960-2-2 DB - PRIME DP - Unbound Medicine ER -