What causes glycogenoses?

Glycogenoses types la and lb are inherited in an autosomal recessive manner. The gene encoding glucose-6-phosphatase (G6PC) is mapped to chromosome 17q21. More than 100 mutations have been identified. The gene encoding the transport protein (G6PT) is mapped to chromosome llq23. About 70 different mutations have been described.

Glycogenosis type III is an autosomal recessive disorder caused by amylo-1,6-glucosidase (debranching enzyme) deficiency (GDE). The defect of this enzyme results in accumulation of glycogen of abnormal structure. The GDE gene is mapped to chromosome 1p21. About 50 mutations of this gene have been identified. Glycogenosis IIIb is usually caused by mutations in the third exon of the gene, while mutations in other regions usually result in glycogenosis IIIa. No clear genotypical correlations have been found between the severity of the mutation and the clinical manifestations of the disease.

Glycogenosis type IV is inherited in an autosomal recessive manner. The gene encoding the GBE enzyme is mapped to chromosome 3p14. Three point mutations - R515C, F257L and R524X - were found in most patients with the liver form of the disease. In patients with the non-progressive liver form, the Y329S mutation was found. In the adult form of the disease, all mutations found are relatively mild, which may explain the late manifestation of the disease.

Glycogenosis type VI is an autosomal recessive disorder associated with mutations in the gene for the hepatic isoform of glycogen phosphorylase. Three isoforms of phosphorylase are known, which are encoded by different genes. The gene for the hepatic isoform of glycogen phosphorylase PYGL is mapped to chromosome 14q21-q22.

Glycogenosis type IX. Phosphorylase kinase (PK) is a decahexameric protein consisting of four subunits. Two isoforms of the alpha subunit (al - liver and aM - muscle) are encoded by two genes located on the X chromosome (RNA2 and RNA1, respectively); beta subunit (encoded by the RNAV gene), two isoforms of the y subunit (yT - liver/testes and yM - muscle, encoded by the PKHG2 and PKHG1 genes, respectively) and three isoforms of calmodulin (CALM1, CALM2, CALM3) are encoded by autosomal genes. The RNA2 gene is mapped to Xp22.2-p22.1, the RNAV gene to 16ql2-ql3, andthe PKHG2 gene to chromosome 16p12-p11.

The most common liver variant, XLG or GSD IXa (caused by mutations in the RNA2 gene), is divided into two subtypes: XLG 1, the classic, common variant, and XLG 2. In XLG 1, RNA activity in the liver and blood cells is reduced, while in XLG 2, RNA activity in the liver, erythrocytes, and leukocytes is normal. Therefore, even normal activity of this enzyme does not exclude XLG glycogenosis. This is due to the fact that XLG 2 is caused by mutations that have a regulatory effect on the enzyme activity, but do not change its activity in vitro.

Glycogenosis type 0 is an autosomal recessive disorder caused by mutations in the glycogen synthase gene. The glycogen synthase gene (GYS2) is mapped to chromosome 12p12.2.

Glycogenosis type II, or Pompe disease, is inherited in an autosomal recessive manner. The gene encoding a-glycosidase (GAA) is mapped to chromosome 17q25. More than 120 mutations are known. Clear genotypic correlations have been established for some mutations, for example, the IVSI splice site mutation (-13T->G) occurs in more than half of patients with the late form of the disease.

Glycogenosis type V

An autosomal recessive disease associated with mutations in the myophosphorylase gene. The myophosphorylase gene (PYGM) is mapped to chromosome llql3. More than 40 mutations are known. The most common is the R49X mutation - 81% of mutant alleles in European countries. No genotypic correlations have been identified - patients with the same genotype may have a more severe or milder course of the disease.

Glycogenosis type VII

An autosomal recessive disorder caused by mutations in the PFK-M gene. ThePFK-M gene is mapped to chromosome 12 and encodes the muscle subunit of phosphofrutokinase. At least 15 mutations have been described in the PFK-M gene in patients with PFK deficiency.

Glycogenosis type IIb

An X-linked dominant disorder associated with LAMP-2 (lysosome-associated membrane protein 2) deficiency. The LAMP2 gene is mapped to Xq28.

Phosphoglycerate kinase deficiency

Phosphoglycerate kinase (PGK) is a protein encoded by the PGK1 gene. The gene is mapped to Xql3.

Glycogenosis type XI, or lactate dehydrogenase deficiency, is an autosomal recessive disorder. Lactate dehydrogenase is a tetrameric enzyme consisting of two subunits, M (or A) and H (or B), and is represented by 5 isoforms. The gene for the M subunit LDHM is mapped to chromosome 11.

Glycogenosis type X, or phosphoglycerate mutase deficiency (PGAM), is an autosomal recessive disorder. Phosphoglycerate mutase is a dimeric enzyme: different tissues contain different proportions of the muscle (MM) or brain (BB) isoforms and hybrid variants (MB). The MM isoform predominates in muscle tissue, while most other tissues are dominated by BB. The PGAMM gene is mapped to chromosome 7 and encodes the M subunit.

Glycogenosis type XII, or aldolase A deficiency, is an autosomal recessive disorder. Aldolase has three isoforms (A, B, C): skeletal muscles and erythrocytes contain predominantly the A-isoform, which is encoded by the ALDOA gene. The gene is mapped to chromosome 16.

Glycogenosis type XIII, or beta-enolase deficiency, is an autosomal recessive disorder, beta-enolase is a dimeric enzyme that exists in several isoforms formed by combinations of three subunits, a, beta and y, the beta subunit is encoded by the EN03 gene, mapped to chromosome 17.