関: Pompe disease、Pompe's disease、type II glycogen storage disease

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write by means of a keyboard with types; "type the acceptance letter, please" (同)typewrite
a small metal block bearing a raised character on one end; produces a printed character when inked and pressed on paper; "he dropped a case of type, so they made him pick them up"
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all of the tokens of the same symbol; "the word `element contains five different types of character"
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identify as belonging to a certain type; "Such people can practically be typed" (同)typecast
an impairment of health or a condition of abnormal functioning
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the 9th letter of the Roman alphabet (同)i
caused by or altered by or manifesting disease or pathology; "diseased tonsils"; "a morbid growth"; "pathologic tissue"; "pathological bodily processes" (同)morbid, pathologic, pathological

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〈C〉(…の)『型』,タイプ,類型,種類(kind)《+of+名》 / 〈C〉(その種類の特質を最もよく表している)『典型』,手本,模範《+of+名》 / 〈U〉《集合的に》活字;〈C〉(1個の)活字 / 〈U〉(印刷された)字体,活字 / 〈C〉(貨幣・メダルなどの)模様,図柄 / 〈C〉血液型(blood group) / …‘を'タイプに打つ / (…として)…‘を'分類する《+名+as+名(doing)》 / …‘の'型を決める / タイプライターを打つ
(体の)『病気』,疾患 / (精神・道徳などの)病気,病弊
女性の話術芸人 =diseur
(倉庫などに)貯蔵すること,保管 / 貯蔵所,倉庫 / 保管料
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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/07/03 09:15:15」(JST)

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Glycogen storage disease type II (also called Pompe disease /ˈpɒmpə/ or acid maltase deficiency) is an autosomal recessive metabolic disorder^[1] which damages muscle and nerve cells throughout the body. It is caused by an accumulation of glycogen in the lysosome due to deficiency of the lysosomal acid alpha-glucosidase enzyme. It is the only glycogen storage disease with a defect in lysosomal metabolism, and the first glycogen storage disease to be identified, in 1932 by the Dutch pathologist J. C. Pompe.

The build-up of glycogen causes progressive muscle weakness (myopathy) throughout the body and affects various body tissues, particularly in the heart, skeletal muscles, liver and nervous system.

Classification

There are exceptions, but levels of alpha-glucosidase determines the type of GSD II an individual may have. More alpha glucosidase present in the individuals muscles means symptoms occur later in life and progress more slowly. GSD II is broadly divided into two onset forms based on the age symptoms occur.^[2]

Infantile-onset form is usually diagnosed at 4–8 months; muscles appear normal but are limp and weak preventing them from lifting their head or rolling over. As the disease progresses heart muscles thicken and progressively fail. Without treatment death usually occurs due to heart failure and respiratory weakness.^[2]

Late/later onset form occurs later than one to two years and progresses more slowly than Infantile-onset form. One of the first symptoms is a progressive decrease in muscle strength starting with the legs and moving to smaller muscles in the trunk and arms, such as the diaphragm and other muscles required for breathing. Respiratory failure is the most common cause of death. Enlargement of the heart muscles and rhythm disturbances are not significant features but do occur in some cases.^[2]

Signs and symptoms

Infantile

The infantile form usually comes to medical attention within the first few months of life. The usual presenting features are cardiomegaly (92%), hypotonia (88%), cardiomyopathy (88%), respiratory distress (78%), muscle weakness (63%), feeding difficulties (57%) and failure to thrive (50%).

The main clinical findings include floppy baby appearance, delayed motor milestones and feeding difficulties. Moderate hepatomegaly may be present. Facial features include macroglossia, wide open mouth wide open eyes, nasal flaring (due to respiratory distress), and poor facial muscle tone. Cardiopulmonary involvement is manifest by increased respiratory rate, use of accessory muscles for respiration, recurrent chest infections, decreased air entry in the left lower zone (due to cardiomegaly), arrhythmias and evidence of heart failure.

Median age at death in untreated cases is 8.7 months and is usually due to cardiorespiratory failure.

Late onset form

This form differs from the infantile principally in the relative lack of cardiac involvement. The onset is more insidious and has a slower progression. Cardiac involvement may occur but is milder than in the infantile form. Skeletal involvement is more prominent with a predilection for the lower limbs.

Late onset features include impaired cough, recurrent chest infections, hypotonia, progressive muscle weakness, delayed motor milestones, difficulty swallowing or chewing and reduced vital capacity.

Prognosis depends on the age of onset on symptoms with a better prognosis being associated with later onset disease.

Diagnosis

Muscle biopsy showing large vacuoles in a case of Pompe disease (HE stain, frozen section).

The usual initial investigations include chest X ray, electrocardiogram and echocardiography. Typical findings are those of an enlarged heart with non specific conduction defects. Biochemical investigations include serum creatine kinase (typically increased 10 fold) with lesser elevations of the serum aldolase, aspartate transaminase, alanine transaminase and lactic dehydrogenase. Diagnosis is made by estimating the acid alpha glucosidase activity in either skin biopsy (fibroblasts), muscle biopsy (muscle cells) or in white blood cells. The choice of sample depends on the facilities available at the diagnostic laboratory.

In the late onset form, the findings on investigation are similar to those of the infantile form with the caveat that the creatinine kinases may be normal in some cases. The diagnosis is by estimation of the enzyme activity in a suitable sample.

On May 17, 2013 the Secretary's Discretionary Advisory Committee on Heritable Diseases in Newborns and Children (DACHDNC) approved a recommendation to the Secretary of Health and Human Services to add Pompe to the Recommended Uniform Screening Panel (RUSP).^[3] The HHS secretary must first approve the recommendation before the disease is formally added to the panel.

Cause

The disease is caused by a mutation in a gene (acid alpha-glucosidase: also known as acid maltase) on long arm of chromosome 17 at 17q25.2-q25.3 (base pair 75,689,876 to 75,708,272). The number of mutations described is currently (in 2010) 289 with 67 being non-pathogenic mutations and 197 pathogenic mutations. The remainder are still being evaluated for their association with disease.

The gene spans approximately 20 kb and contains 20 exons with the first exon being noncoding. The coding sequence of the putative catalytic site domain is interrupted in the middle by an intron of 101 bp. The promoter has features characteristic of a 'housekeeping' gene. The GC content is high (80%) and distinct TATA and CCAAT motifs are lacking.

Most cases appear to be due to three mutations. A transversion (T → G) mutation is the most common among adults with this disorder. This mutation interrupts a site of RNA splicing.

The gene encodes a protein — acid alpha-glucosidase (EC 3.2.1.20) — which is a lysosomal hydrolase. The protein is an enzyme that normally degrades the alpha -1,4 and alpha -1,6 linkages in glycogen, maltose and isomaltose and is required for the degradation of 1–3% of cellular glycogen. The deficiency of this enzyme results in the accumulation of structurally normal glycogen in lysosomes and cytoplasm in affected individuals. Excessive glycogen storage within lysosomes may interrupt normal functioning of other organelles and lead to cellular injury.

A putative homologue — acid alpha-glucosidase-related gene 1 — has been identified in the nematode Caenorhabditis elegans.

Treatment

Cardiac and respiratory complications are treated symptomatically. Physical and occupational therapy may be beneficial for some patients. Alterations in diet may provide temporary improvement but will not alter the course of the disease. Genetic counseling can provide families with information regarding risk in future pregnancies.

On April 28, 2006 the US Food and Drug Administration approved a Biologic License Application (BLA) for Myozyme (alglucosidase alfa, rhGAA),^[4] the first treatment for patients with Pompe disease, developed by a team of Duke University researchers. This was based on enzyme replacement therapy using biologically active recombinant human alglucosidase alfa produced in Chinese Hamster Ovary cells. Myozyme falls under the FDA Orphan Drug designation and was approved under a priority review.

The FDA has approved Myozyme for administration by intravenous infusion of the solution. The safety and efficacy of Myozyme were assessed in two separate clinical trials in 39 infantile-onset patients with Pompe disease ranging in age from 1 month to 3.5 years at the time of the first infusion. Myozyme treatment clearly prolongs ventilator-free survival and overall survival. Early diagnosis and early treatment leads to much better outcomes. The treatment is not without side effects which include fever, flushing, skin rash, increased heart rate and even shock; these conditions, however, are usually manageable.

Myozyme costs an average of US$300,000 a year and must be taken for the patients' entire life, so some American insurers have refused to pay for it.^[5] On August 14, 2006, Health Canada approved Myozyme for the treatment of Pompe disease. On June 14, 2007 the Canadian Common Drug Review issued their recommendations regarding public funding for Myozyme therapy. Their recommendation was to provide funding to treat a very small subset of Pompe patients (Infants less one year of age with cardiomyopathy).^[6] Genzyme received broad approval in the European Union. On May 26, 2010 FDA approved Lumizyme, a similar version of Myozyme, for the treament of late-onset Pompe disease.

A new treatment option for this disease is called Lumizyme. Lumizyme and Myozyme have the same generic ingredient (Alglucosidase Alfa) and manufacturer (Genzyme Corporation). The difference between these two products is in the manufacturing process. Today, the Myozyme is made using a 160-L bioreactor, while the Lumizyme uses a 4000-L bioreactor. Because of the difference in the manufacturing process, the FDA claims that the two products are biologically different. Moreover, Lumizyme is FDA approved as replacement therapy for late-onset (noninfantile) Pompe disease without evidence of cardiac hypertrophy in patients 8 years and older. Myozyme is FDA approved for replacement therapy for infantile-onset Pompe disease.

Recent studies on chaperone molecules to be used with myozyme are starting to show promising results on animal models.

Prognosis

The prognosis for individuals with Pompe disease varies according to the onset and severity of symptoms. Without treatment the disease is particularly lethal in infants and young children.

Myozyme (alglucosidase alfa) is a recombinant form of the human enzyme acid alpha-glucosidase, and is also currently being used to replace the missing enzyme. In a study^[7] which included the largest cohort of patients with Pompe disease treated with enzyme replacement therapy (ERT) to date findings showed that Myozyme treatment clearly prolongs ventilator-free survival and overall survival in patients with infantile-onset Pompe disease as compared to an untreated historical control population. Furthermore, the study demonstrated that initiation of ERT prior to 6 months of age, which could be facilitated by newborn screening, shows great promise to reduce the mortality and disability associated with this devastating disorder. Taiwan and several states in the United States have started the newborn screening and results of such regimen in early diagnosis and early initiation of the therapy have dramatically improved the outcome of the disease; many of these babies have reached the normal motor developmental milestones.^[8]

Another factor affecting the treatment response is generation of antibodies against the infused enzyme, which is particularly severe in Pompe infants who have complete deficiency of the acid alpha-glucosidase.^[9] Immune tolerance therapy to eliminate these antibodies has improved the treatment outcome.^[10]

A Late Onset Treatment Study (LOTS) was published in 2010.^[11] The study was undertaken to evaluate the safety and efficacy of aglucosidase alfa in juvenile and adult patients with Pompe disease. LOTS was a randomized, double-blind, placebo-controlled study that enrolled 90 patients at eight primary sites in the United States and Europe. Participants received either aglucosidase alfa or a placebo every other week for 18 months. The average age of study participants was 44 years. The primary efficacy endpoints of the study sought to determine the effect of Myozyme on functional endurance as measured by the six-minute walk test and to determine the effect of aglucosidase alfa on pulmonary function as measured by percent predicted forced vital capacity.

The results showed that, at 78 weeks, patients treated with aglucosidase alfa increased their distance walked in six minutes by an average of approximately 25 meters as compared with the placebo group which declined by 3 meters (P=0.03). The placebo group did not show any improvement from baseline. The average baseline distance walked in six minutes in both groups was approximately 325 meters. Percent predicted forced vital capacity in the group of patients treated with aglucosidase alfa increased by 1.2 percent at 78 weeks. In contrast, it declined by approximately 2.2 percent in the placebo group (P=0.006).

Epidemiology

Glycogen storage disease type II has an autosomal recessive pattern of inheritance.

The incidence of the disease is approximately 1 in 140,000 for infantile GSD II and 1 in 60,000 for adult GSD II.^[12] It has been reported in almost all ethnic populations. It has an autosomal recessive inheritance pattern. This means the defective gene is located on an autosome, and two copies of the gene—one from each parent—are required to be born with the disorder. As with all cases of autosomal recessive inheritance, children have a 1 in 4 chance of inheriting the disorder when both parents carry the defective gene, and although both parents carry one copy of the defective gene, they are usually not affected by the disorder.

History

The disease is named after Joannes Cassianus Pompe, who characterized it in 1932.^[13]^[14] Pompe described accumulation of glycogen in muscle tissue in some cases of a previously unknown disorder. This accumulation was difficult to explain as the enzymes involved in the usual metabolism of glucose and glycogen were all present and functioning.

The basis for the disease remained a puzzle until Christian de Duve's discovery of lysosomes in 1955 for which he won the Nobel Prize in 1974. His co-worker Henri G. Hers realised in 1965 that the deficiency of a lysosomal enzyme (alpha glucosidase) for the breakdown of glycogen could explain the symptoms of Pompe disease. This discovery led to establishing the concept of lysosomal storage diseases, of which 49 have been described (to date).

Despite recognizing the basis for the disease treatment proved difficult. Administration of the enzyme lead to its uptake by the liver and not the muscle cells where it is needed. In the early 1990s two Dutch scientists, Arnold Reuser and Ans van der Ploeg a PhD student using alpha-glucosidase containing phosphorylated mannose residues purified from bovine testes, they were able to show that an increase in the enzyme's activity in the normal mouse muscles.^[15]

Later in 1998, Dr. Yuan-Tsong Chen and colleagues at Duke University (陳垣崇,Dr. Chen is currently the director of the Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.), using the enzyme produced in Chinese Hamster Ovary cells demonstrated for the first time that the enzyme can clear the glycogen and improved the muscle function in Pompe disease quail. The results of the work at Duke were impressive with one treated bird recovering to the point of being able to fly again.^[16]

This was followed by production of clinical grade alpha-glucosidase in Chinese hamster ovary (CHO) cells and in the milk of transgenic rabbits.^[17] This work eventually culminated in the start of clinical trials with the first clinical trial including 4 babies receiving enzyme from rabbit milk at Erasmus MC Sophia Children’s Hospital and 3 babies receiving enzyme grown in CHO cells^[9] at Duke University in 1999.

The currently approved Myozyme is manufactured by Genzyme Corp. in Cambridge, Massachusetts, USA. Its development was a complex process. Genzyme first partnered with Pharming Group NV who had managed to produce acid alpha-glucosidase from the milk of transgentic rabbits. They also partnered with a second group based at Duke University using Chinese hamster ovary cells. In 2001, it acquired Novazyme which was also working on this enzyme. Genzyme also had its own product (Myozyme) grown in CHO cells under development. In November 2001, Genzyme chief executive Henri Termeer organised a systematic comparison of the various potential drugs in a mouse model of Pompe disease. It was found that Duke enzyme was the most efficacious, followed by Myozyme. However, due to easier manufacture of Myozyme, work on the other products was then discontinued.

Funding for research in this field was in part provided by Muscular Dystrophy Association and Acid Maltase Deficiency Association in USA and the Association of Glycogen Storage Disorders in UK and the International Pompe Association.

John Crowley became involved in the fund-raising efforts in 1998 after two of his children were diagnosed with Pompe's. He joined the company Novazyme in 1999, which was working on enzyme replacement treatment for Pompe's. Novazyme was sold to Genzyme in 2001 for over US$100 million. The 2010 film Extraordinary Measures is based on Crowley's search for a cure.

References

^ Pompe disease at NLM Genetics Home Reference
^ ^a ^b ^c "Type II Glycogen Storage Disease". The Association for Glycogen Storage Disease. Retrieved 22 May 2012.
^ Genetic, Alliance. "Federal Advisory Committee Recommends Pompe Disease for Newborn Screening". Genetic Alliance. Retrieved 2013-05-17.
^ "FDA Approval News for Myozyme". Retrieved 2009-12-16.
^ Burden of Proof: As Costs Rise, New Medicines Face Pushback; Insurers Limit Coverage To FDA-Approved Uses; $300,000 Drug Denied By Geeta Anand, The Wall Street Journal, September 18, 2007.
^ Canadian Common Drug Review Recommendations on Public Funding for Myozyme
^ Wagner KR (2007). "Enzyme replacement for infantile Pompe disease: the first step toward a cure". Neurology 68 (2): 88–9. doi:10.1212/01.wnl.0000253226.13795.40. PMID 17210887.
^ Chien YH; Lee, NC; Thurberg, BL; Chiang, SC; Zhang, XK; Keutzer, J; Huang, AC; Wu, MH et al. (2009). "Pompe disease in infants: improving the prognosis by newborn screening and early treatment". Pediatrics 124 (6): e1116–25. doi:10.1542/peds.2008-3667. PMID 19948615.
^ ^a ^b Amalfitano A, Bengur AR, Morse RP, Majure JM, Case LE, Veerling DL, Mackey J, Kishnani P, Smith W, McVie-Wylie A, Sullivan JA, Hoganson GE, Phillips JA 3rd, Schaefer GB, Charrow J, Ware RE, Bossen EH, Chen YT (2001). "Recombinant human acid alpha-glucosidase enzyme therapy for infantile glycogen storage disease type II: results of a phase I/II clinical trial.". Genetics in Medicine 3 (2): 132–8. doi:10.1097/00125817-200103000-00008. PMID 11286229.
^ Mendelsohn NJ; Messinger, YH; Rosenberg, AS; Kishnani, PS (2009). "Elimination of antibodies to recombinant enzyme in Pompe disease". N Engl J Med 360 (2): 194–5. doi:10.1056/NEJMc0806809. PMID 19129538.
^ Van der Ploeg AT (2010). "A randomized study of alucosidase alfa in late-onset Pompe disease". N Engl J Med 362 (15): 1396–1406. doi:10.1056/NEJMoa0909859. PMID 20393176.
^ Ausems MG, Verbiest J, Hermans MP et al. (September 1999). "Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling". Eur. J. Hum. Genet. 7 (6): 713–6. doi:10.1038/sj.ejhg.5200367. PMID 10482961.
^ Pompe, J.C. (1932). "Over idiopathische hypertrophie van het hart". Ned. Tijdschr. Geneeskd. 76: 304–312.
^ Genetics of Glycogen-Storage Disease Type II (Pompe Disease) at eMedicine
^ Van der Ploeg AT, Kroos MA, Willemsen R, Brons NH, Reuser AJ (February 1991). "Intravenous administration of phosphorylated acid alpha-glucosidase leads to uptake of enzyme in heart and skeletal muscle of mice". J. Clin. Invest. 87 (2): 513–8. doi:10.1172/JCI115025. PMC 296338. PMID 1991835.
^ Kikuchi T, Yang HW, Pennybacker M et al. (February 1998). "Clinical and metabolic correction of pompe disease by enzyme therapy in acid maltase-deficient quail". J. Clin. Invest. 101 (4): 827–33. doi:10.1172/JCI1722. PMC 508631. PMID 9466978.
^ Van den Hout H, Reuser AJ, Vulto AG, Loonen MC, Cromme-Dijkhuis A, Van der Ploeg AT (July 2000). "Recombinant human alpha-glucosidase from rabbit milk in Pompe patients". Lancet 356 (9227): 397–8. doi:10.1016/S0140-6736(00)02533-2. PMID 10972374.

External links

The website of the Pompe's Group of the Association for Glycogen Storage Disease (UK)
Acid Maltase Deficiency Association, Inc.—A US patient support group founded in 1995.
United Pompe Foundation
International Pompe Association—A federation of Pompe disease patient's groups worldwide.
Genzyme's Pompe Information site
FDA Approval News for Myozyme
Canadian Association of Pompe
Hide & Seek Foundation for Lysosomal Disease Research
GeneReview/NIH/UW entry on Glycogen Storage Disease Type II (Pompe Disease)
Australian Pompe's Association
Asociación Española de Enfermos de Glucogenosis
Fact files on Pompe Disease
Understanding Pompe Disease - US National Institute of Arthritis and Musculoskeletal and Skin Diseases

UpToDate Contents

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1. リソソーム酸マルターゼ欠損症（糖原病II型、ポンペ病） lysosomal acid maltase deficiency glycogen storage disease ii pompe disease
2. 先天性代謝異常：疫学、病因、および臨床的特徴 inborn errors of metabolism epidemiology pathogenesis and clinical features
3. グルコースおよびグリコーゲン代謝の遺伝性疾患の概要 overview of inherited disorders of glucose and glycogen metabolism
4. 先天性代謝異常：個々の障害の発見 inborn errors of metabolism identifying the specific disorder
5. 筋緊張低下および脱力を呈する幼児に対するアプローチ approach to the infant with hypotonia and weakness

English Journal

The generation of induced pluripotent stem cells (iPSCs) from patients with infantile and late-onset types of Pompe disease and the effects of treatment with acid-α-glucosidase in Pompe's iPSCs.

Higuchi T1, Kawagoe S2, Otsu M3, Shimada Y4, Kobayashi H5, Hirayama R6, Eto K7, Ida H5, Ohashi T5, Nakauchi H3, Eto Y8.Author information 1Department of Genetic Diseases and Genomic Science, The Jikei University School of Medicine, Tokyo, Japan; Department of Gene Therapy, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan.2Department of Genetic Diseases and Genomic Science, The Jikei University School of Medicine, Tokyo, Japan; Department of Dermatology, The Jikei University School of Medicine, Tokyo, Japan.3Stem Cell Bank, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.4Department of Gene Therapy, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan.5Department of Genetic Diseases and Genomic Science, The Jikei University School of Medicine, Tokyo, Japan; Department of Gene Therapy, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan; Department of Pediatrics, The Jikei University School of Medicine, Tokyo, Japan.6Department of Genetic Diseases and Genomic Science, The Jikei University School of Medicine, Tokyo, Japan; Advanced Clinical Research Center, Institute of Neurological Diseases, Kanagawa, Japan.7Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.8Department of Genetic Diseases and Genomic Science, The Jikei University School of Medicine, Tokyo, Japan; Advanced Clinical Research Center, Institute of Neurological Diseases, Kanagawa, Japan. Electronic address: yosh@sepia.ocn.ne.jp.AbstractPompe disease (PD), which is also called glycogen storage disease type II (GSDII), is one of the lysosomal storage diseases (LSDs) caused by a deficiency in acid-α-glucosidase (GAA) in the lysosome and is characterized by the accumulation of glycogen in various cells. PD has been treated by enzyme replacement therapy (ERT). We generated induced pluripotent stem cells (iPSCs) from the cells of patients with infantile-type and late-onset-type PD using a retrovirus vector to deliver transgenes encoding four reprogramming factors, namely, OCT4, SOX2, c-MYC, and KLF4. We confirmed that the two types of PD-iPSCs exhibited an undifferentiated state, alkaline phosphatase staining, and the presence of SSEA-4, TRA-1-60, and TRA-1-81. The PD-iPSCs exhibited strong positive staining with Periodic acid-Schiff (PAS). Moreover, ultrastructural features of these iPSCs exhibited massive glycogen granules in the cytoplasm, particularly in the infantile-type but to a lesser degree in the late-onset type. Glycogen granules of the infantile-type iPSCs treated with rhGAA were markedly decreased in a dose-dependent manner. Human induced pluripotent stem cell provides an opportunity to build up glycogen storage of Pompe disease in vitro. It represents a promising resource to study disease mechanisms, screen new drug compounds and develop new therapies for Pompe disease.
Molecular genetics and metabolism.Mol Genet Metab.2014 Mar 4. pii: S1096-7192(14)00084-5. doi: 10.1016/j.ymgme.2014.02.012. [Epub ahead of print]
Pompe disease (PD), which is also called glycogen storage disease type II (GSDII), is one of the lysosomal storage diseases (LSDs) caused by a deficiency in acid-α-glucosidase (GAA) in the lysosome and is characterized by the accumulation of glycogen in various cells. PD has been treated by enzyme
PMID 24642446

Pearls & Oy-sters: Clues to the diagnosis of adult-onset acid maltase deficiency.

Beltran Papsdorf TB1, Howard JF Jr, Chahin N.Author information 1From the Neuromuscular Disorders Section, Department of Neurology, The University of North Carolina at Chapel Hill.AbstractAdult-onset Pompe disease (acid maltase deficiency, glycogen storage disease type II) should be considered in the differential diagnosis in the adult patient presenting with slowly progressive selective lower extremity weakness, specifically of the hip flexors. Hip flexion weakness may be the only finding in the earliest stages of this disease. EMG findings of myotonic discharges occurring predominately in the lower extremities or paraspinal muscles, in combination with the clinical presentation, is a clue to the diagnosis of late-onset Pompe disease. Testing of all 3 paraspinal muscle levels may be useful in an otherwise normal EMG when Pompe disease is suspected.
Neurology.Neurology.2014 Mar 4;82(9):e73-5. doi: 10.1212/WNL.0000000000000163.
Adult-onset Pompe disease (acid maltase deficiency, glycogen storage disease type II) should be considered in the differential diagnosis in the adult patient presenting with slowly progressive selective lower extremity weakness, specifically of the hip flexors. Hip flexion weakness may be the only f
PMID 24590251

Novel GAA sequence variant c.1211 A>G reduces enzyme activity but not protein expression in infantile and adult onset Pompe disease.

Nilsson MI1, Kroos MA2, Reuser AJ3, Hatcher E1, Akhtar M1, McCready ME4, Tarnopolsky MA5.Author information 1Department of Pediatrics, McMaster University Medical Centre, 1200 Main Street West, Hamilton, Ontario, Canada L8 3Z5.2Department of Clinical Genetics and Pediatrics, Erasmus MC University Medical Center, Rotterdam, Netherlands.3Department of Clinical Genetics and Pediatrics, Erasmus MC University Medical Center, Rotterdam, Netherlands; Center for Lysosomal and Metabolic Disease, Erasmus MC University Medical Center, Rotterdam, Netherlands.4Department of Pathology and Molecular Medicine, McMaster University Medical Centre, 1200 Main Street West, Hamilton, Ontario, Canada L8 3Z5.5Department of Pediatrics, McMaster University Medical Centre, 1200 Main Street West, Hamilton, Ontario, Canada L8 3Z5. Electronic address: tarnopol@mcmaster.ca.AbstractPompe disease is a clinically and genetically heterogeneous autosomal recessive disorder caused by lysosomal acid α-glucosidase (GAA) deficiency. We report on two affected members of a non-consanguineous Caucasian family, including a classical infantile-onset patient with severe cardiomyopathy (IO) and his paternal grandmother with the adult-onset (AO) form. Two compound heterozygous sequence variants of the GAA gene were identified in each patient by mutation analyses (IO=c.1211A>G and c.1798C>T; AO=c.1211A>G and c.692+5G>T). For this study, the biochemical phenotype resulting from the missense mutation c.1211A>G in exon 8, which converts a highly conserved aspartate to glycine (p.Asp404Gly), was of specific interest because it had not been reported previously. Western blotting revealed a robust expression of all GAA isoforms in quadriceps muscle of both patients (fully CRIM positive), while enzymatic activity was 3.6% (IO) and 6.6% (AO) of normal controls. To further validate these findings, the c.1211A>G sequence variant was introduced in wild type GAA cDNA and over-expressed in HEK293T cells. Site-directed mutagenesis analyses confirmed that the mutation does not affect processing or expression of GAA protein, but rather impairs enzyme function. Similar results were reported for c.1798C>T (p.Arg600Cys), which further supports the biochemical phenotype observed in IO. The third mutation (c.692+5G>T, in intron 3) was predicted to affect normal splicing of the GAA mRNA, and qPCR indeed verified a 4-fold lower mRNA expression in AO. It is concluded that the novel sequence variant c.1211A>G results in full CRIM but significantly lower GAA activity, which in combination with c.1798C>T leads to infantile-onset Pompe disease. We surmise that the difference in disease severity between the two family members in this study is due to a milder effect of the intronic mutation c.692+5G>T (vs. c.1798C>T) on phenotype, partially preserving GAA activity and delaying onset in the proband (paternal grandmother).
Gene.Gene.2014 Mar 1;537(1):41-5. doi: 10.1016/j.gene.2013.12.033. Epub 2013 Dec 30.
Pompe disease is a clinically and genetically heterogeneous autosomal recessive disorder caused by lysosomal acid α-glucosidase (GAA) deficiency. We report on two affected members of a non-consanguineous Caucasian family, including a classical infantile-onset patient with severe cardiomyopathy (IO)
PMID 24384324

Japanese Journal

乾燥濾紙血液を用いた糖原病II型の酵素学的スクリーニング法の研究 : 免疫捕捉酵素活性測定法と競合酵素阻害法の比較

藤川研人,鈴木健,穴澤昭,田中あけみ,大橋十也,衛藤義勝,大和田操,北川照男
日本マス・スクリーニング学会誌 = Journal of Japanese Society for Mass-screening 21(3), 233-241, 2011-12-01
NAID 10030204872

Novel Mutations in the Gene Encoding Acid .ALPHA.-1,4-glucosidase in a Patient with Late-onset Glycogen Storage Disease Type II (Pompe Disease) with Impaired Intelligence

Muraoka Tomie,Murao Koji,Imachi Hitomi,Kikuchi Fumi,Yoshimoto Takuo,Iwama Hisakazu,Hosokawa Hitoshi,Nishino Ichizo,Fukuda Tokiko,Sugie Hideo,Adachi Kaori,Nanba Eiji,Ishida Toshihiko
Internal Medicine 50(24), 2987-2991, 2011
A 17-year-old Japanese man was referred to our hospital because of highly elevated serum levels of creatine kinase (CK) and transaminases. On admission, the proximal muscles of the lower extremities w …
NAID 130002062715

Silent exonic mutation in the acid-α-glycosidase gene that causes glycogen storage disease type II by affecting mRNA splicing

Maimaiti Mireguli,Takahashi Satoru,Okajima Kazuki [他],SUZUKI Nao,OHINATA Junko,ARAKI Akiko,TANAKA Hajime,MUKAI Tokuo,FUJIEDA Kenji
Journal of human genetics 54(8), 493-496, 2009-08-01
NAID 10030731506

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★リンクテーブル★

リンク元	「ポンペ病」「type II glycogen storage disease」「2型糖原貯蔵障害」
拡張検索	「glycogen storage disease type III」「glycogen storage disease type IIb」
関連記事	「disease」「type」「II」「I」「storage」

「ポンペ病」

Glycogen storage disease type II
Classification and external resources
ICD-10	E74.0
ICD-9	271.0
OMIM	232300
DiseasesDB	5296
eMedicine	med/908 ped/1866
Patient UK	Glycogen storage disease type II
MeSH	D006009
GeneReviews	Glycogen Storage Disease Type II (Pompe Disease);