SNP Shot: Genomic Insights

Glycogen storage disease type IX (GSD IX) is a disorder resulting from the body's inability to properly break down glycogen, a complex sugar. The condition manifests in different forms, impacting glycogen breakdown in either liver cells, muscle cells, or both. This impaired glycogen breakdown disrupts the normal function of the affected tissue.

When GSD IX affects the liver, symptoms commonly appear in early childhood. These usually include an enlarged liver (hepatomegaly) and slowed growth, resulting in shorter stature. During fasting periods, affected individuals may experience low blood sugar (hypoglycemia) or elevated ketone levels in the blood (ketosis). Ketones are produced when fats are broken down due to the lack of available sugars. Children may also exhibit delayed motor skill development, such as delays in sitting, standing, or walking, and some may have mild muscle weakness. Puberty may also be delayed in some adolescents. In the liver-affecting form of GSD IX, symptoms generally improve with age. Developmental delays typically resolve, and adults reach normal height. However, some individuals may develop liver fibrosis (scar tissue buildup), which can, in rare cases, progress to irreversible liver disease (cirrhosis).

GSD IX can also affect muscle tissue, although this form is rare and less understood. Symptoms can emerge from childhood to adulthood. Individuals may experience fatigue, muscle pain, and cramps, particularly during exercise (exercise intolerance). Many experience progressive muscle weakness. This form of GSD IX can also lead to myoglobinuria, a condition where abnormal muscle breakdown releases the protein myoglobin into the urine. Myoglobinuria can cause the urine to turn red or brown.

A small percentage of individuals with GSD IX experience effects in both the liver and muscles. These individuals exhibit a combination of the symptoms described above, although the muscle-related problems are usually mild.

Inheritance:

The inheritance pattern of GSD IX varies depending on the causative gene. When caused by mutations in the PHKA1 or PHKA2 genes, GSD IX follows an X-linked recessive inheritance pattern. These genes are located on the X chromosome, one of the sex chromosomes. Males (with one X chromosome) are affected if they have one altered copy of the gene in each cell. Females (with two X chromosomes) must have mutations in both copies of the gene to develop the disorder. However, some women with one altered copy of the PHKA2 gene may exhibit mild symptoms of GSD IX, such 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 females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. When GSD IX is caused by mutations in the PHKB or PHKG2 genes, it is inherited in an autosomal recessive pattern. This means that both copies of the gene in each cell must have mutations for the condition to manifest. Individuals with an autosomal recessive condition inherit one copy of the mutated gene from each parent, who are typically carriers without symptoms themselves.