Infantile Form Of Pompe Disease Research Articles

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Article| April 2023 ACE Question ASA Monitor April 2023, Vol. 87, 12. https://doi.org/10.1097/01.ASM.0000924952.53516.f9 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Search Site Citation ACE Question. ASA Monitor 2023; 87:12 doi: https://doi.org/10.1097/01.ASM.0000924952.53516.f9 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll PublicationsASA Monitor Search Advanced Search Topics: anesthesiology continuing education (ace) The juvenile form of Pompe disease is MOST often associated with which of the following clinical abnormalities? Pompe disease is a disorder of carbohydrate metabolism and one of several glycogen storage diseases. The defective enzyme (acid α-glucosidase) impedes the breakdown of glycogen into glucose, thus impairing gluconeogenesis. The enzyme is located in cellular lysosomes, particularly heart and skeletal muscle. Left untreated, glycogen deposits accumulate in end organs, specifically the heart and skeletal muscles, which can result in cardiomegaly and congestive heart failure, skeletal muscle weakness, and hypotonia. The infantile form of Pompe disease (Figure) presents early in life with congestive heart failure and death before age 2 years. The juvenile form of Pompe disease presents with significant weakness of skeletal and respiratory muscles. Another feature of the juvenile form is cardiac hypertrophy and subaortic stenosis, as well as enlargement and protrusion of the tongue, possibly making intubation difficult.... You do not currently have access to this content.

Pompe disease - What do we currently know about the disease?


 Introduction: Pompe disease (PD) is a rare metabolic disorder caused by a partial or complete deficiency of acid α-glucosidase (GAA) which leads to lysosomal accumulation of glycogen. Excessive amounts of glycogen accumulate mainly in the cells of the heart and skeletal muscles and cause dysfunction of these tissues. It is inherited in an autosomal recessive manner. The most common diagnostic methods include genetic tests and the measurement of enzyme activity in leukocytes or fibroblasts. A screening test is also available that tests the enzyme activity in dried blood spot (DBS). The treatment of PD is mostly based on synthetic GAA enzyme supply to the patients. The therapy reduces glycogen storage and improves muscle function, decreases heart size and prolongs the lives of those with infantile form of PD. In the adult onset of the disease treatment increases physical efficiency and reduces the progression of respiratory failure.
 
 
 Aim of the study: Systematization of current knowledge about Pompe disease with particular emphasis on possible clinical presentations, diagnostics and therapeutic options.
 Material and methods: Literature review based on PubMed data using the following keywords: Pompe disease, Glycogenosis type ii, glucosidase alpha
 Summary : Pompe disease is a rare disease with many problems related to diagnosis and possible therapies. Its symptoms can be very misleading and cause a delay in diagnosis . It is critical to start the therapy as soon as possible to best manage the disease. The prognosis of PD is poor, especially in children under 12 months of age. Gene therapy research is currently underway and early results are very promising. There is still much to learn about dealing with this disease.

Ранняя манифестация младенческой формы болезни Помпе (случай из практики)

Despite the fact that more than 70% of hereditary diseases can be considered rare, their prevalence in the population is 2%. Pompe disease (glycogen storage disease type II, glycogenosis type II) is a rare genetic disease that is accompanied with a damage to muscle cells and nerve fibers due to the accumulation of glycogen in them. The latter is due to a deficiency of the acid alpha-glucosidase enzyme. The relevance of Pompe disease is due to her rarity and the set of nonspecific symptoms, as well as the fact that it can manifest at any age. Depending on the onset, early infantile and late adult forms are distinguished. The early infantile form of Pompe disease manifests itself from the first months of life, the clinic includes generalized muscle weakness, frequent respiratory infections, macroglossia, hepato- and cardiomegaly. The article describes a case of infantile Pompe disease in a child of the first year of life, which shows that without the results of specific tests, including genetic ones, the diagnosis will not be verified, and the way to a reasonable assignment of such tests often turns out to be long. A pediatrician, as well as subspecialist physicians, should be wary of infants with unusual combinations of symptoms, multiple organ lesions, since it is extremely important to transfer such a child for a consultation with a geneticist in a timely manner. Such actions will help not only save lives, but also preserve the quality of life of these patients. Due to the complexity of diagnosis, today it is promising to include Pompe disease in the list of diseases for newborn screening. In this case, the treatment will be preventive and will not allow the symptoms of the disease to develop. Preventive therapy will allow not only reduce the risk of fatal outcome in Pompe disease, but also significantly decrease the percentage of disability.

Хвороба Помпе: діагностика та сучасні підходи до терапії

The article presents a clinical case of a child with an infantile form of Pompe disease. At the age of 5 months, the girl became ill with acute bronchitis and the gentle systolic murmur over the surface of the heart detected by the district pediatrician during auscultation was the reason for referral to a cardiologist. Echocardiography diagnosed hypertrophic cardiomyopathy and the child was hospitalized for further examination. The mother did not complain. Given the slightly reduced muscle tone, elevated levels of transaminases and hypertrophic cardiomyopathy, and after consultation with a neurologist and geneticist, it was decided to conduct a genetic examination. A pathogenic variant of p.1447G> A (p.Gly483Arg) was detected in the GAA gene in a homozygous state and a clinical diagnosis was made: Pompe disease, infantile classical form. One month after diagnosis, pre-existing human recombinant α-glucosidase replacement therapy was initiated. During 18 months of treatment, the child's condition was satisfactory, no adverse side effects from enzyme replacement therapy were recorded, but lysosomal glycogenic load in the heart tissue was significantly reduced (according to echocardiography). Pompe disease is a rare genetic disease that is important to diagnose in a timely manner. Today, it is extremely important for doctors to understand the timeliness of referral to specialized centers for the necessary genetic scanning of children with suspected CP. Diagnosis of CP involves the detection of characteristic symptoms, confirmation of the diagnosis based on the detected low level of α-glucosidase in the patient's blood. The appointment of specific therapy for CP can stop the progression of the disease and significantly improve the quality and life expectancy of such patients. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of these Institutes. The informed consent of the patient was obtained for conducting the studies. No conflict of interest was declared by the authors. Key words: Pompe disease, diagnosis, treatment.

PO-0043 Classic Infantile-onset Pompe Disease: A Study Of 8 Cases

Introduction Classic infantile pompe disease is an autosomal recessive inherited disorder caused by a deficiency of alpha 1–4 glucosidase, resulting in accumulation of glycogen in skeletal muscle and heart. It’s characterised by hypotonia, cardiomegaly and hypertrophic cardiomyopathy, feeding difficulties and respiratory distress, all patients died in the first year of life. Patients and methods A retrospective study of cases of classic infantile pompe disease collected in the Department of Paediatrics, Hospital Hedi Chaker, Sfax over a period of 7 years (2008–2013). Results During the study period we collected 8 cases of the disease. The average age at diagnosis was 3 months and 6 days. All patients were eutrophic. Hypotonia was noted in all cases, Respiratory distress in seven cases, cyanosis in 4 cases and a systolic murmur in 5 cases. Hepatomegaly was constant, macroglossia was noted in one patient. Chest radiography showed cardiomegaly in all cases. Electrocardiogram, showed electrical signs of left ventricular hypertrophy, wide QRS complex, a shortening of the PR interval was seen in 4 cases. Echocardiography confirmed diagnosis of hypertrophic cardiomyopathy. The dosage of acid maltase activity practiced in 5 patients, showed no enzyme activity. The genetic study of 4 patients showed a mutation in the homozygous state of the GAA gene. Treatment was purely symptomatic involving propranolol, oxygen and antibiotics. All patients died. Conclusion The fatal evolution of the classic infantile form of Pompe disease is being changed by the advent of enzyme replacement therapy wich significantly increased the survival of these patients.

Terapia de reemplazo enzimático en la forma infantil de la enfermedad de Pompe: experiencia de un caso con 7 años de seguimiento en Argentina

The infantile form of Pompe disease drives children to death before the first year of life due to cardiomyopathy and respiratory insufficiency. We present the seven-year follow-up experience with enzyme replacement therapy on a child with Pompe disease, being the longest follow-up in the country. The treatment was well tolerated without adverse reactions. The echocardiographic and electrocardiographic parameters clearly improved during the first year and remain stable. Motor milestones (like rolling over or sitting down without support) were initially achieved, but, after the third year were getting lost. The average age of ventilator dependence was also delayed (16 months). The 7-year old patient remains alive with severe generalized muscle weakness. The child notably overcame the average age of survival and onset of ventilator dependence. Although the cardiovascular improvement was clear, enzyme replacement therapy efficacy on skeletal muscle was limited in this patient.

The cost-effectiveness of enzyme replacement therapy (ERT) for the infantile form of Pompe disease: comparing a high-income country's approach (England) to that of a middle-income one (Colombia)

Determining the cost-effectiveness of enzyme replacement therapy (ERT) for the classical infantile form of Pompe disease (complete acid a-glucosidase deficiency-related) in two different settings: England and Colombia. Pompe disease is very rare (1:40,000 births incidence). A literature review was made and historic databases searched for National Health Service (NHS) reimbursed costs in England and by health insurers in Colombia; expert opinion was elicited. Two Markov models were constructed for comparing both countries; alive with symptoms and dead were the transition states used. Patients aged < 6 months receiving ERT were assumed to have 75 % survival rate and better health-related quality of life (HR-QoL) compared to those without treatment (0.700 HR- QoL using the EQ-5D scale). The incremental cost-effectiveness ratio (ICER) per quality-adjusted life year (QALY) gained was £234,307.7 for England and £109,991 for Colombia. Uncertainty about Anal HR-QoL with ERT, disease progression and cost from palliative care had the biggest impact on the ICER in both models. If ERT costs were reduced to 10,000 times per dose and HR-QoL was 0.750-0.820 ICER, then £165,000 could be attainable for England and £65,000 for Colombia. Transaction costs per case in Colombia were high. ERT was more effective than no ERT in treating infantile Pompe disease, but high levels of uncertainty still remain about survival and progression rates and QoL in the long-run. ICERs were high compared to CE thresholds. Manufacturers' ERT costs and monopoly had a major impact on Anal CEA results.

Gingival Overgrowth in Pompe Disease: A Case Report

Pompe disease, or glycogen storage disease type 2, is a rare inheritable metabolic disease caused by a deficiency of the lysosomal enzyme acid α-glucosidase. Patients with the classic infantile form of Pompe disease present with symptoms during the first 3 months after birth, and most will die within their first year. Recently, enzyme replacement therapy (ERT) with recombinant human α-glucosidase became commercially available for Pompe disease. This is a case report of an 8-year-old girl with the infantile form of Pompe disease who is one of the longest survivors through ERT. The patient was tetraplegic when she started ERT. At age 3 years, she developed massive gingival overgrowth and could not close her mouth, prompting a reduction of the gingival overgrowth surgically. We expected that massive accumulation of glycogen would explain the gingival overgrowth. However, histopathology of the gingiva tissue showed marked glycogen accumulation in smooth muscle cells of the arteries, but the glycogen content in fibroblasts did not exceed that of control individuals. Further, there was an increase of immature collagen in the connective tissue, and signs of a mild chronic inflammation. We concluded that glycogen storage is not a direct causative factor of gingival overgrowth in our patient. Chronic inflammation, dryness of the gingiva, or even the minimal glycogen accumulation in the fibroblasts may have played a role.

Early administration of enzyme replacement therapy for Pompe disease: Short‐term follow‐up results

Pompe disease (glycogen storage disease II, OMIM # 232300), is a hereditary lysosomal disorder. It is characterized by deficiency of acid alpha-glucosidase enzyme (acid maltase, GAA, OMIM *606800, EC 3.1.26.2), secondary to mutations in the GAA gene (HGNC:4065) on chromosome 17q25.2-q25.3. Absent enzyme activity in the infantile form of Pompe disease results in abnormal glycogen deposition in the skeletal, cardiac, and smooth muscles, leading to hypertrophic cardiomyopathy, feeding abnormalities, hypotonia, weakness, respiratory insufficiency, and ultimately death. Prenatal diagnosis is accomplished by enzyme assay, mutation analysis or electron microscopy of amniotic fluid cells or chorionic villus sample. However, these techniques may not always be available, and can result in perinatal morbidity and fetal loss. Early diagnosis of Pompe disease results in early institution of enzyme replacement therapy (ERT), which minimizes morbidity and prolongs survival. We report the case of a 35-week part-of-twin neonate, whose older sibling died earlier because of infantile Pompe disease. At 32 weeks of gestation, fetal echocardiography showed hypertrophic cardiomyopathy in twin 1, which persisted until birth at 35 weeks of gestation. Diagnosis was confirmed after birth by enzyme assay, and mutation analysis showing homozygosity for the sequence change 1327-2A>G (GAA intr 8). Administration of ERT at 18 h of age, resulted in normalization of cardiac abnormalities within 21 weeks of therapy, and normal neurodevelopmental assessment at 46 weeks, using Griffiths Mental Development Scales. To our knowledge, this is the youngest patient reported to receive ERT for Pompe disease, and the first report of prenatal diagnosis of Pompe disease by fetal echocardiography.

Broad spectrum of Pompe disease in patients with the same c.-32-13T→G haplotype

Pompe disease (acid maltase deficiency, glycogen storage disease type II; OMIM 232300) is an autosomal recessive lysosomal storage disorder characterized by acid alpha-glucosidase deficiency due to mutations in the GAA gene. Progressive skeletal muscle weakness affects motor and respiratory functions and is typical for all forms of Pompe disease. Cardiac hypertrophy is an additional fatal symptom in the classic infantile subtype. c.-32-13T-->G is the most common mutation in adults. To delineate the disease variation among patients with this mutation and to define the c.-32-13T-->G haplotypes in search for genotype-phenotype correlations. We studied 98 compound heterozygotes with a fully deleterious mutation (11 novel mutations are described) and the common c.-32-13T-->G mutation. All patients were Caucasian. None had the classic infantile form of Pompe disease. The clinical course varied far more than anticipated (age at diagnosis <1 to 78 years; age at onset: <1 to 52 years). The acid alpha-glucosidase activities in a subset of patients ranged from 4 to 19.9 nmol/mg/h. Twelve different c.-32-13T-->G haplotypes were identified based on 17 single-nucleotide polymorphisms located in the GAA gene. In 76% of the cases, c.-32-13T-->G was encountered in the second most common GAA core haplotype (DHRGEVVT). In only one case was c.-32-13T-->G encountered in the major GAA core haplotype (DRHGEIVT). Patients with the same c.-32-13T-->G haplotype (c.q. GAA genotype) may manifest first symptoms at different ages, indicating that secondary factors may substantially influence the clinical course of patients with this mutation.

Molecular study on the infantile form of Pompe disease in Chinese in Taiwan.

Glycogen-storage disease type II, Pompe disease, is caused by the deficiency of acid alpha-D-glucosidase in lysosome. Previously we found that acid alpha-D-glucosidase did exist in the skin fibroblasts and there was also no difference of mRNA in quantity and size of Chinese infantile type Pompe disease patients in Taiwan. However, functional assay of the acid alpha-D-glucosidase of these patients showed its enzyme function to be defective. In the present study, first we identified a substitution site in four Chinese infantile patients with Pompe disease which is a cytidine to adenosine (C1935-->A) transversion at 5' end of exon 14 causing substitution of glutamic acid for aspartic acid at position 645 of the acid alpha-D-glucosidase. This substitution was introduced in wild-type cDNA and expressed in COS-1 cells. The Asp-645-->Glu substitution resulted in significant reduction of acid alpha-D-glucosidase activity. Second, according to the screening data in 25 Chinese Pompe disease patients using digestion of RT-PCR amplified specific fragment with Aat II, the restriction fragment length analysis showed that patients presented the 861 bp band and the normal individuals presented the 728 bp and 133 bp polymorphic bands. We found that the frequency of mutant allele is 0.8 in infantile patients with Chinese Pompe disease and 0 in normal individuals. These results therefore indicate that Asp-645-->Glu mutation results in infantile form of Pompe disease as the major cause in Chinese patients in Taiwan.