A Novel Mutation of the &lt;i&gt;GAA&lt;/i&gt; Gene in a Patient with Adult-onset Pompe Disease Lacking a Disease-specific Pathology

Fujimoto, Shunichiro; Manabe, Yasuhiro; Fujii, Daiji; Kozai, Yuko; Matsuzono, Kosuke; Takahashi, Yoshiaki; Narai, Hisashi; Omori, Nobuhiko; Adachi, Kaori; Nanba, Eiji; Nishino, Ichizo; Abe, Kōji

doi:10.2169/internalmedicine.52.0311

Cited by 7 publications

(4 citation statements)

References 14 publications

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“…Interestingly, lipofuscin inclusions are often seen in otherwise normal looking fibers. It was suggested that these acid phosphatase-positive/periodic acid Schiff (PAS)-negative inclusions may be a hallmark of the disease and a diagnostic marker, particularly in adult form, which every so often represent the diagnostic challenge (Tsuburaya et al, 2012; Fujimoto et al, 2013). …”

Section: Pathogenesismentioning

confidence: 99%

Pompe disease: from pathophysiology to therapy and back again

Lim¹,

Li²,

Raben³

2014

Front. Aging Neurosci.

160

182

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Pompe disease is a lysosomal storage disorder in which acid alpha-glucosidase (GAA) is deficient or absent. Deficiency of this lysosomal enzyme results in progressive expansion of glycogen-filled lysosomes in multiple tissues, with cardiac and skeletal muscle being the most severely affected. The clinical spectrum ranges from fatal hypertrophic cardiomyopathy and skeletal muscle myopathy in infants to relatively attenuated forms, which manifest as a progressive myopathy without cardiac involvement. The currently available enzyme replacement therapy (ERT) proved to be successful in reversing cardiac but not skeletal muscle abnormalities. Although the overall understanding of the disease has progressed, the pathophysiology of muscle damage remains poorly understood. Lysosomal enlargement/rupture has long been considered a mechanism of relentless muscle damage in Pompe disease. In past years, it became clear that this simple view of the pathology is inadequate; the pathological cascade involves dysfunctional autophagy, a major lysosome-dependent intracellular degradative pathway. The autophagic process in Pompe skeletal muscle is affected at the termination stage—impaired autophagosomal-lysosomal fusion. Yet another abnormality in the diseased muscle is the accelerated production of large, unrelated to ageing, lipofuscin deposits—a marker of cellular oxidative damage and a sign of mitochondrial dysfunction. The massive autophagic buildup and lipofuscin inclusions appear to cause a greater effect on muscle architecture than the enlarged lysosomes outside the autophagic regions. Furthermore, the dysfunctional autophagy affects the trafficking of the replacement enzyme and interferes with its delivery to the lysosomes. Several new therapeutic approaches have been tested in Pompe mouse models: substrate reduction therapy, lysosomal exocytosis following the overexpression of transcription factor EB and a closely related but distinct factor E3, and genetic manipulation of autophagy.

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Section: Pathogenesismentioning

confidence: 99%

Pompe disease: from pathophysiology to therapy and back again

Lim¹,

Li²,

Raben³

2014

Front. Aging Neurosci.

160

182

View full text Add to dashboard Cite

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“…The GAA gene on chromosome 17q25.2–25.3 is a long gene with 20 exons encoding a protein with 952 amino acids. More than 450 different mutations, including missense, nonsense, small or large deletions/insertions, and frameshift mutations, have been reported along the length of this gene . There is a good correlation between the type of mutation, the degree of residual enzyme activity, and the severity of clinical presentations …”

mentioning

confidence: 99%

Late‐onset pompe disease in Iran: A clinical and genetic report

et al. 2017

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“…GAA variants classified as variants of uncertain significance (VUS) because of insufficient pathogenic evidence (c.1669A>T (p.Ile557Phe) and c.2132C>G (p.Thr711Arg) reported by Kim EH et al [ 27 ]) or GAA variants described in an incorrect nomenclature were excluded in this study. A total of 17 studies on Japanese patients with Pompe disease were reviewed [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ], and 29 different GAA PLPVs (total of 130 PLPV alleles) were reported in 76 Japanese patients with Pompe disease. Of the GAA variants reported in 17 Japanese studies, 11 were classified as VUS and one was classified as benign, which were excluded from this analysis.…”

Section: Resultsmentioning

confidence: 99%

Two Approaches for a Genetic Analysis of Pompe Disease: A Literature Review of Patients with Pompe Disease and Analysis Based on Genomic Data from the General Population

Park¹

2021

Children

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In this study, two different approaches were applied in the analysis of the GAA gene. One was analyzed based on patients with Pompe disease, and the other was analyzed based on GAA genomic data from unaffected carriers in a general population genetic database. For this, GAA variants in Korean and Japanese patients reported in previous studies and in patients reported in the Pompe disease GAA variant database were analyzed as a model. In addition, GAA variants in the Korean Reference Genome Database (KRGDB), the Japanese Multi Omics Reference Panel (jMorp), and the Genome Aggregation Database (gnomAD) were analyzed. Overall, approximately 50% of the pathogenic or likely pathogenic variants (PLPVs) found in unaffected carriers were also found in real patients with Pompe disease (Koreans, 57.1%; Japanese, 46.2%). In addition, there was a moderate positive correlation (Spearman’s correlation coefficient of 0.45–0.69) between the proportion of certain PLPVs in patients and the minor allele frequency of their variants in a general population database. Based on the analysis of general population databases, the total carrier frequency for Pompe disease in Koreans and Japanese was estimated to be 1.7% and 0.7%, respectively, and the predicted genetic prevalence was 1:13,657 and 1:78,013, respectively.

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A Novel Mutation of the <i>GAA</i> Gene in a Patient with Adult-onset Pompe Disease Lacking a Disease-specific Pathology

Cited by 7 publications

References 14 publications

Pompe disease: from pathophysiology to therapy and back again

Pompe disease: from pathophysiology to therapy and back again

Late‐onset pompe disease in Iran: A clinical and genetic report

Two Approaches for a Genetic Analysis of Pompe Disease: A Literature Review of Patients with Pompe Disease and Analysis Based on Genomic Data from the General Population

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