Instituto Valenciano de Microbiología

Masía El Romeral
Ctra. de Bétera a San Antonio Km. 0.3
46117 Bétera (Valencia)
Phone. 96 169 17 02
Fax 96 169 16 37
CIF B-96337217


Glycogenosis Type IX (Glycogen storage disease type IX) - Genes PHKA1, PHKA2, PHKB and PHKG2

Type IX glycogen storage disease (GSD IX) is a disorder caused by an inability to break down glycogen. The different forms of the disease can affect the degradation of glycogen in liver cells, in muscle cells , or both. The lack of glycogen breakdown interferes with the normal function of the affected tissue.

When the disease affects the liver, signs and symptoms usually begin in early childhood. In general, baseline characteristics include hepatomegaly and slow growth. Affected children tend to be lower than normal. Fasting, affected individuals may have hypoglycemia or ketosis. In addition, affected children may have delayed development of motor skills and some individuals have mild muscle weakness. Puberty is delayed in some adolescents with GSD IX. In the form of the disease that affects the liver, signs and symptoms usually improve with age. Usually these individuals reach their development and normal height as adults. However, some individuals have liver fibrosis, which rarely progresses to cirrhosis.

Glycogenosis type IX can affect muscle tissue, although this form of the disease is very rare and not well understood. The characteristics of this form may appear at any time from childhood to adulthood. People affected may show fatigue, muscle pain and cramps, especially during exercise. In addition, most affected individuals have muscle weakness that worsens over time. The disease can also cause myoglobinuria, which occurs when muscle tissue breaks down and releases abnormally myoglobin excreted in the urine. Myoglobinuria can make the urine red or brown.

In a small number of people with GSD IX, the disease affects both the liver and muscles. These individuals show a combination of the features described above, although muscle problems usually mild.

This process is due to mutations in the PHKA1 (phosphorylase kinase regulatory subunit alpha 1), PHKA2 (phosphorylase kinase regulatory subunit alpha 2), PHKB (phosphorylase kinase regulatory subunit beta) or PHKG2 (phosphorylase kinase catalytic subunit gamma 2) genes. These genes encoding subunits of an enzyme called phosphorylase kinase b. The enzyme consists of 16 subunits, four subunits each types alpha, beta, gamma and delta. Constitute at least two different versions of phosphorylase kinase b from subunits: one is most abundant in liver cells and other muscle cells.

The PHKA1 genes located on the long arm of chromosome X (Xq12-q13) and PHKA2, located on the short arm of the X chromosome (Xp22.2-p22.1), encode alpha subunits of phosphorylase kinase b. The protein encoded from PHKA1 gene is a subunit of the muscle enzyme, while the protein encoded from PHKA2 gene is part of liver enzyme. The PHKB gene, located on the long arm of chromosome 16 (16q12-q13), encoding the beta subunit, which is found in both muscle and liver. The PHKG2 gene, located on the short arm of chromosome 16 (16p11.2), encoding the gamma subunit of the liver enzyme. Either in the liver or muscles, phosphorylase b kinase plays an important role in providing energy for cells. The main cellular energy source is glucose. Glucose is stored in liver and muscle cells as glycogen. Glycogen can be broken down quickly when glucose is needed, for example, to maintain normal levels of blood glucose between meals or for obtaining energy during exercise. Phosphorylase b active kinase another enzyme called glycogen phosphorylase b by conversion to the more active form, glycogen phosphorylase. When active, this enzyme breaks down glycogen.

Mutations in any of the PHKA1, PHKA2, PHKG2 PHKB genes and reduce the activity of phosphorylase kinase b in liver cells or muscle and blood cells. This reduction in enzyme function alters glycogen breakdown. Consequently, glycogen accumulates in the cells, and glucose is not available for energy. Glycogen accumulation in the liver leads to liver enlargement and liver 's inability to break down glycogen into glucose contributes to hypoglycemia and ketosis. Reducing energy production in muscle cells leads to muscle weakness, pain and cramps.

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IX glycogenosis type may have different patterns of inheritance depending on the genetic cause of the disease. When the disease is due to mutations in the PHKA1 or PHKA2 gene is inherited in an X - linked recessive pattern in males, an altered copy of the gene in each cell is sufficient to express the disease. In women, a mutation would have to happen in both copies of the gene to express the disease. However, some women with an altered copy of the gene PHKA2 have signs and symptoms of GSD IX, as mild hepatomegaly or short stature in childhood. These features are usually mild, but can be more severe in rare cases. Because it is unlikely that women have two altered copies of this gene, males are affected by X - linked recessive disorders much more frequently than women. A feature of the X - linked inheritance is that fathers can not pass X - linked traits to their sons chromosome. On the other hand, when the disease is due to mutations in the PHKB or PHKG2 gene is inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.

Tests performed in IVAMI: in IVAMI perform detection of mutations associated with glycogen storage disease type IX, by complete PCR amplification of the exons of PHKA1, PHKA2, PHKG2 PHKB and genes, respectively, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).