Pompe disease

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Classification according to ICD-10
E74.0 Glycogen storage disease
ICD-10 online (WHO version 2019)

The Pompe disease , also known as Pompe disease or acid maltase- called deficiency, belongs to the group of the glycogen storage diseases , and is classified as Type II (see also lysosomal storage disease ). The rare (incidence: 1: 40,000 to 1: 150,000 births), hereditary metabolic disease is predominantly noticeable as a muscle weakness and is therefore also counted among the myopathies . At least 300 people are currently diagnosed in Germany; how high the number of unreported cases is is unknown; It is estimated that 5,000-10,000 people are affected worldwide.

history

The disease is named after the Dutch pathologist Joannes Cassianus Pompe (1901–1945), who first described the symptoms in 1932. The disease was classified as glycogen storage disease type II by GT Cori in 1954. In 1963, HG Hers discovered the lack of lysosomal α-glucosidase as the cause of the disease. The adult form was first described by AG Engel in 1969. A therapeutic attempt with alpha-glucosidase, which at that time was obtained from the placenta , was carried out as early as 1973 .

Clinic and course

The disease can occur at all ages and is divided into the early (IOPD: infantile onset Pompe Disease) and the late (LOPD: late onset Pompe Disease) form depending on the severity and time at which the first symptoms appear. In infants (infantile Pompe disease) it usually ends fatally in the first year of life due to heart failure in the context of hypertrophic cardiomegaly . In the infantile form, the first symptoms appear at around two months, the diagnosis is made at an average of five months and death occurs at around nine months.

  • Manifestation in early infancy.
  • No or only low (<1%) residual activity of glucosidase.
  • Heart, skeletal and respiratory muscles severely affected.
  • If left untreated, rapid progression: life expectancy usually less than a year (cause of death mostly heart failure as part of hypertrophic cardiomegaly).

Non-classic infantile form (infants)

  • Also occurs in infancy, but there is residual GAA activity (up to 30%)
  • No heart involvement.
  • Symptoms similar to the late juvenile / adult form.

Late juvenile / adult form (children, adolescents and adults)

  • Manifested in childhood, adolescence or adulthood.
  • ATM residual activity available of up to 30%.
  • Also progressive, but slower than the infantile form.

The course in adolescent (juvenile) and adult patients (adult Pompe disease or late-onset ) is inconsistent and unpredictable. Observed symptoms are progressive muscle weakness, especially of the respiratory muscles ( diaphragmatic weakness ) and skeletal muscles near the trunk (upper arm, pelvis / thigh). Both mild and severe courses with the need for ventilation and loss of independent locomotion can occur here. There is a continuous spectrum of diseases; There are no defined stages of the disease. On average, the first symptoms in the adult form appear around the age of 28 (according to other reports around the age of 36) and manifest themselves in difficulties with exercise and running. The average diagnosis is made at 36 years of age, the need for a wheelchair at 46 years of age, and breathing assistance at 49 years of age. There is no connection between respiratory and motor function; they depend on the duration of the illness, not on the age. An early onset of the disease indicates a worse course. Fatigue is frequently reported, and there is conflicting data on pain. Mental performance is not impaired. Death usually occurs from respiratory failure or other lung problems such as pneumonia . Death from rupture of a cerebral aneurysm is frequently described; Other disease complications are described, such as cerebral aneurysms; The cause could be a weak vascular wall due to glycogen deposits.

root cause

The cause is a genetic defect in the enzyme α-1,4-glucosidase (acid maltase, glucosidase alpha acid, for short: GAA), which results in either a complete absence or a reduced activity. This prevents the breakdown of glycogen , a storage form of sugar to form glucose, in the muscles . The glycogen is mainly deposited in the lysosomes of the muscle cells and thus destroys the muscle cells. The residual activity of the enzyme is inversely correlated with the severity of the disease . In the infantile type, enzyme activity is usually only <1%; in the late-onset M. Pompe, which can manifest itself in children, adolescents and adults, it is up to 30%.

The metabolic disease is autosomal - recessive inherited, both sexes are equally affected. The gene is located on chromosome 17, region q25.2-q25.3 and is 28 kbp in length. The genetics of the disease are heterogeneous; To date, over 300 different mutations have been described; those affected are compound heterozygous . In the infantile form, there are usually two severe mutations and thus a complete enzyme defect. In sibling studies, a high degree of correspondence between genotype and disease course was found here. In the adult form, on the other hand, there is no connection between genotype and phenotype .

Diagnosis

The reliable diagnosis of M. Pompe is based on the enzyme determination (GAA enzyme activity) with subsequent genetic confirmation. The diagnosis is e.g. B. possible by means of a simple dry blood test.

For this dry blood test, a few drops of blood are placed on a dry blood card. After they have dried, the card is mailed to a specialized laboratory. There the blood is removed from the filter card and processed for the following tests.

To determine the enzyme activity, a defined amount of substrate is added to a defined amount of blood. After a certain time z. B. analyzed by mass spectroscopy how much product was created by the enzyme reaction. This shows how active the enzyme is. It is important that a certified assay is used to ensure the reliability of the readings.

The gene for the acidic alpha- glucosidase is sequenced for the genetic analysis . Both tests - the measurement of the enzyme activity and the genetic analysis - can - depending on the laboratory - be carried out from the material of a dry blood card.

Since not all muscles are equally affected in Pompe disease, a muscle biopsy can also provide normal or unspecific findings and is therefore not a reliable method for confirming the diagnosis. Histologically, massive glycogen storage in the muscle fibers can be detected in the PAS staining .

Creatine kinase ( CK ), lactate dehydrogenase ( LDH ), aspartate aminotransferase (AST, GOT ) and alanine aminotransferase (ALT, GPT ) are often increased (over 90%), while Glc4 is increased in urine.

The determination of the GAA enzyme activity by means of dry blood testing should be considered in children, adolescents and adults with elevated creatine kinase (CK) and muscular complaints as well as findings that indicate a muscle disorder of the limb-belt type.

Pompe disease is a rare muscle disease, the symptoms of which are similar to numerous other muscle diseases that can be considered as differential diagnoses .

treatment

Enzyme replacement therapy has been available for the specific treatment of Pompe disease since 2006 . The enzyme (alglucosidase alfa, trade name Myozyme ), which is recombinantly produced in CHO cells, is administered as an infusion every 14 days. In patients with a classically infantile course, enzyme replacement therapy can considerably extend both ventilation-free and overall survival. At 3.5 years of age, more than half of the patients are still alive, and around a third do not require ventilation. Some of the children learn to sit or walk. The disease can be stabilized in patients with a late course. The therapy costs between 50,000 EUR (infants) and 500,000 EUR (adults) annually.

Recommended accompanying therapies range from diet recommendations to breathing and physiotherapy and ultimately also ventilation and artificial nutrition. There is evidence of a benefit from combining exercise and diet high protein.

Further therapeutic approaches such as gene therapy are only in the early stages of animal experiments. In mice who had gene transfer with adenovirus - vector successful. The bone marrow transplant has so far been unsuccessful. A new, but not yet practical approach is treatment with pharmacological chaperones , i.e. substances that increase the residual activity of acid maltase.

Affected families should seek genetic counseling. In healthy parents who are both carriers of the gene defect , the risk of a child developing Pompe disease is 25%.

Trivia

In the US - Drama exceptional situation (2010) with Brendan Fraser and Harrison Ford have a family history is told, are affected in the two children. The father counters the threat by entering into a shaky alliance with a researcher - who in turn has theoretically successfully dealt with a solution to the problem - in order to bring a drug against Pompe disease to market.

In 2012, episode 551 of the German television series In allerfreund (In all friendship ) depicts the case of a patient with Pompe disease. Bernd Herzsprung embodies the affected patient .

Web links

Individual evidence

  1. ↑ B. Schoser et al. a .: 208th ENMC International Workshop: Formation of a European Network to develop a European data sharing model and treatment guidelines for Pompe disease. Ed .: Neuromuscular Disord. No. 25 , 2015, p. 674-678 .
  2. ↑ JC Pompe: Over idiopathic hypertrophy van het hart. In: Ned Tijdschr Geneeskd. 1932; 76, pp. 304-311.
  3. ↑ GT Cori: Enzymes and glycogen structure in glycogen storage disease. In: Austrian magazine for paediatrics and child care. Volume 10, Numbers 1-2, 1954, pp. 38-42, PMID 13236242 .
  4. ↑ H G. Hers: alpha-glucosidase deficiency in generalized glycogen storage disease (Pompe's disease). In: Biochemical Journal . Volume 86, January 1963, pp. 11-16, PMID 13954110 . PMC 1201703 (free full text).
  5. ↑ AG Engel: Acid maltase deficiency of adult life. In: Transactions of the American Neurological Association. Volume 94, 1969, pp. 250-252, PMID 4244774 .
  6. ↑ T. de Barsy, P. Jacquemin, F. Van Hoof, HG Hers: Enzyme replacement in Pompe disease: an attempt with purified human acid alpha-glucosidase. In: Birth defects original article series. Volume 9, Number 2, March 1973, pp. 184-190, PMID 4611528 .
  7. ↑ PS Kishnani et al. a .: Pompe disease diagnosis and management guideline . Ed .: Genet Med. 8th edition. 2006, p. 267-288 .
  8. ^ Van der Ploeg Ans & Reuser A .: Pompe's Disease . tape 372 . Lancet, 2008, p. 1342-53 .
  9. ^ List of genetic mutations from the Pompe Center
  10. ↑ JH Wokke et al: Genotype-phenotype correlation in adult-onset acid maltase deficiency. In: Annals of neurology. Volume 38, Number 3, September 1995, pp. 450-454, doi: 10.1002 / ana.410380316 . PMID 7668832 .
  11. ↑ WE Smith et al.: Sibling phenotype concordance in classical infantile Pompe disease. In: American journal of medical genetics. Part A. Volume 143A, Number 21, November 2007, pp. 2493-2501. doi: 10.1002 / ajmg.a.31936 . PMID 17853454 .
  12. ^ NA van der Beek, JM de Vries, ML Hagemans, WC Hop, MA Kroos, JH Wokke, M. de Visser, BG van Engelen, JB Kuks, AJ van der Kooi, NC Notermans, KG Faber, JJ Verschuuren, AJ Reuser , AT van der Ploeg. PA van Doorn: Clinical features and predictors for disease natural progression in adults with Pompe disease: a nationwide prospective observational study. In: Orphanet J Rare Dis. 2012 Nov 12; 7, p. 88. doi: 10.1186 / 1750-1172-7-88 .
  13. ^ Regina Kröll: European Medicines Agency . In: The European pharmaceutical law . Springer Fachmedien Wiesbaden, Wiesbaden 2017, ISBN 978-3-658-17202-2 , p. 68–137 ( europa.eu [PDF; accessed January 30, 2019]). European Medicines Agency ( Memento of the original from August 20, 2007 in the Internet Archive ) Info: The archive link has been inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice.  @1@ 2Template: Webachiv / IABot / www.emea.europa.eu
  14. ↑ PS Kishnani et al.: Early treatment with alglucosidase alfa prolongs long-term survival of infants with Pompe disease . tape 66 , no. 3 . Pediatric Research, September 2009, pp. 329-335 .
  15. ↑ A. Chakrapani et al. a .: Treatment of infantile Pompe disease with alglucosidase alpha: the UK experience . tape 33 . J Inherit Metab Dis, 2010, p. 747-750 .
  16. ↑ CM van Gelder u. a .: Enzyme therapy and immune response in relation to CRIM status: the Dutch experience in classic infantile Pompe disease . tape 38 . J Inherit Metab Dis, 2015, p. 305-314 .
  17. ↑ A. Hahn A and a .: Outcome of patients with classical infantile pompe disease receiving enzyme replacement therapy in Germany . Ed .: JIMD Rep. 2015, p. 65-75 .
  18. ↑ A. Broomfield et al. a .: Response of 33 UK patients with infantile-onset Pompe disease to enzyme replacement therapy . Ed .: Orphanet J Rara Dis. tape 13 , 2018, p. 32 .
  19. ^ R. Parini et al.: Survival and long-term outcomes in late-onset Pompe disease following alglucosidase alfa treatment: a systematic review and meta-analysis . Ed .: J Neurol. 2017, p. 264 .
  20. ^ AE Slonim et al: Modification of the natural history of adult-onset acid maltase deficiency by nutrition and exercise therapy . tape 35 , no. 1 . Muscle & Nerve, January 2007, p. 70-77 .
  21. ^ AE Slonim et al: Modification of the natural history of adult-onset acid maltase deficiency by nutrition and exercise therapy. In: Muscle & Nerve. Volume 35, Number 1, January 2007, pp. 70-77. doi: 10.1002 / mus.20665 . PMID 17022069 .
  22. ↑ G. Parenti et al .: Pharmacological enhancement of mutated alpha-glucosidase activity in fibroblasts from patients with Pompe disease. In: Molecular Therapy: the Journal of the American Society of Gene Therapy. Volume 15, Number 3, March 2007, pp. 508-514, doi: 10.1038 / sj.mt.6300074 . PMID 17213836 .