Pompe disease

Glycogen storage disease type II (also called Pompe disease or acid maltase deficiency) is an autosomal recessive metabolic disorder 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 The incidence of the disease is approximately 1 in 140,000 for infantile GSD II and 1 in 60,000 for adult GSD II.  It has been reported in almost all ethnic populations. It has an autosomal recessive inheritance pattern.

Symptoms

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.

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.

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.

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.

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 in 2010 was  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.

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

Although the cause of the various manifestations is a mutation in the gene, this is not in fact the actual cause, as we need to know what caused the mutation.

As the problem here is a generic one for all inherited diseases caused by mutation it is discussed in the section Inherited illness, please follow the link.

References

• "Type II Glycogen Storage Disease". The Association for Glycogen Storage Disease. Retrieved 22 May 2012.
• 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.
• 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

Observations

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• Visual hallucinations in a patient with adult onset acid maltase deficiency disorder