Glycogen Storage Disease Type 9

Phosphorylase kinase deficiency (PKD) is a genetic disorder and also a type of glycogen storage disease (GSD) that is inherited in either an X-linked or autosomal recessive pattern. There are several types of PKD, stemming from the deficiency of either liver phosphorylase kinase, muscle phosphorylase kinase, or both. PKD has been referred to by several different names in the past, however, it is now commonly known as GSD IX. Furthermore, the enzyme phosphorylase kinase (PK) has alpha, beta, gamma, and delta subunits, in which specific mutations can occur. These characteristics of PK lead to a wide range of clinical manifestations of PKD. The liver subtypes present similarly and thus have no clinical distinction. The muscle PKD subtype is extremely rare.

The features of liver PKD are usually mild, although severe cases have been reported [1] [2]. The illness often presents in early childhood, with hepatomegaly, hyperketotic hypoglycemia, ketosis, weakness and poor development of muscles, impaired growth, and delay in motor and other developmental domains. [2] [3]. The growth restriction is self-limiting and is typically corrected until adulthood, although puberty may be delayed [4] [5].

Organs that can be involved in PKD include the liver, kidneys, ovaries, and spleen. Conditions such as renal tubular acidosis, splenomegaly, liver fibrosis and cirrhosis, and polycystic ovary syndrome have been described [2] [6]. Symptoms and positive biochemical markers diminish with age, thus most adults are asymptomatic [5] [7].

The onset of muscle PKD may be in childhood or adulthood. Most of the manifestations exhibited relate to the musculoskeletal system, exemplified by myalgia, cramps, weakness, exercise intolerance, and myoglobinuria. Similar to liver PKD, presentation varies greatly, but the disease course is mild [8].

The diagnosis of PKD relies on physical findings and genetic testing. Biochemical assessments of phosphorylase kinase in various body tissues are also routine. Serum studies of patients with liver PKD may reveal high aspartate aminotransferase (AST) and alanine aminotransferase (ALT), hyperlipidemia, hypoglycemia, and increased ketones [1] [2]. Glucagon response may be deranged [9]. Moreover, on microscopic examination, the liver histology may appear altered, as abnormal hepatocytes, fibrosis, and inflammation are sometimes observed.

Muscle PKD may cause high serum creatine kinase and dysfunction in glycogen metabolism in response to submaximal exercise [10] [11]. The electrical activity of muscle tissue, measured via electromyography, is often negative for signs of disease. Muscle biopsy and histology may reveal the accumulation of glycogen, supported by biochemical findings of elevated muscle glycogen. Muscle PKD does not affect the liver, thus no signs of the disorder are found in the latter.

Certain laboratory tests are used to determine the severity of disease, and these include serial blood glucose and ketone measurements, as well as a basic metabolic panel and creatine kinase. Clotting and lipid studies may also be performed. Radiological evaluation of the liver via computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound is recommended.

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