Glycogen storage disease type V

Signs and symptoms

In the classic phenotype, symptom onset is usually noticed in childhood, with a median age of 3 years, but diagnosis is often delayed until the third or fourth decade of life; the median diagnostic delay is 29 years. Misdiagnosis occurs in approximately 90% of patients, and about 62% receive multiple misdiagnoses before a correct diagnosis. Prolonged delay, misdiagnosis, or inappropriate exercise advice severely impacts quality of life.

An ultra-rare adult-onset limb–girdle phenotype presents after age 70 due to a recessive homozygous PYGM mutation (p. Lys42Profs*48), causing severe upper and lower limb atrophy, possible ptosis, and camptocormia; as of 2017, two cases have been reported. A fatal infantile-onset phenotype results in profound muscle weakness and respiratory failure within weeks of birth, with two reported cases in 1978 and 1989.

Genetics

McArdle disease is inherited in an autosomal recessive manner. If both parents are carriers, each child has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected. Two autosomal recessive forms occur: childhood-onset and adult-onset. The PYGM gene is located on chromosome 11q13.

Ninety-five different mutations have been reported, with forms varying between ethnic groups; for example, R50X is most common in North America and Western Europe, and Y84X is most common among central Europeans. The R138W mutation disrupts the pyridoxal phosphate binding site. The myophosphorylase structure consists of 842 amino acids with a molecular weight of 97 kDa. Ser-14 is modified by phosphorylase kinase during activation, Lys-680 binds pyridoxal phosphate, and other sites are estimated to bind AMP or be involved in subunit association or allosteric control.

Diagnosis

Laboratory tests that may aid diagnosis include muscle biopsy, which shows absence of myophosphorylase in muscle fibers and sometimes abnormal glycogen accumulation stained by periodic acid-Schiff. Genetic sequencing of the PYGM gene can determine the presence of mutations and is less invasive than biopsy.

An ischemic forearm exercise test, or a nonischemic version, can be performed; findings consistent with McArdle disease include failure of lactate to rise in venous blood and exaggerated ammonia levels, indicating a severe muscle glycolytic block. Serum lactate may fail to rise partly due to increased uptake via the monocarboxylate transporter MCT1, which is upregulated in McArdle disease. Ammonia levels rise as a by-product of AMP deaminase in the purine nucleotide cycle.

Treatment

Supervised exercise programs have been shown in small studies to improve exercise capacity, lowering heart rate and serum creatine kinase, and increasing the intensity threshold before symptoms occur. Oral sucrose treatment taken 30 minutes before exercise improves exercise tolerance, but frequent ingestion is problematic because it increases insulin release, which inhibits fatty acid release and delays second wind, and can lead to obesity and related ill health. Low-dosage creatine treatment showed significant improvement in a small study, while high-dosage creatine worsened myalgia. A ketogenic diet has demonstrated benefit, as ketones readily convert to acetyl CoA for oxidative phosphorylation, acting as a main fuel before fatty acid catabolism takes over during second wind.

Did You Know?

• The ischemic forearm test involves squeezing a hand dynamometer at maximal strength for about a minute with a blood pressure cuff set at 250 mmHg blocking blood flow.
• Naturally occurring myophosphorylase deficiency has been found in Charolais cattle and Merino sheep.
• Artificially induced myophosphorylase deficiency has been created in mice for laboratory experiments.