Hers disease

ALSO KNOWN AS: Hers’ disease; glycogen storage disease type VI; liver glycogen phosphorylase deficiency

DEFINITION Hers disease, one of a dozen glycogen storage diseases, is a rare genetic defect that prevents the breakdown of glycogen in the liver. Subsequently, glycogen builds up in this organ, leading to its enlargement. Because this glycogen is unavailable to the body, low blood glucose is sometimes observed after overnight fasts. Childhood growth may be impaired. The disease is relatively benign and most patients outgrow the symptoms around puberty.

Risk Factors

The disease exhibits a familial association and is caused by a deleterious mutation in the gene for liver glycogen phosphorylase. The condition is rare, much less frequent than von Gierke disease (1 in 40,000 live births), although one Mennonite community has a high frequency of the disorder (1 in 1,000). Otherwise, it is widely distributed geographically and ethnically; it affects boys and girls equally.

Etiology and Genetics

Hers disease is named for Henri G. Hers, who first described it in 1959. It is an autosomal recessive condition involving a mutation in the gene for liver glycogen phosphorylase, which is located on chromosome 14 in the region 14q21-q22. At least five separate mutations leading to a defective are known.

Glycogen, the storage form of carbohydrate in the body, is a highly branched polymer of glucose molecules. Glycogen phosphorylase is the enzyme that breaks down glycogen by removing glucose molecules one at a time from the end of a glycogen strand. Debranching enzyme is necessary to remove the branch points so that phosphorylase can fully metabolize glycogen (see Forbes disease). A separate gene codes for phosphorylase in muscle, which breaks down glycogen in skeletal and cardiac muscle (as in McArdle’s disease). In the liver, in the absence of phosphorylase, glycogen is unavailable to replenish blood glucose levels between meals and especially overnight. Furthermore, when dietary glucose is available, more will be deposited as glycogen, progressively leading to an enlargement of the liver.

Hers disease is a largely benign condition, and children generally outgrow it at puberty, much like Forbes disease Type IIIb. It is not clear why this should be the case, but it does suggest that the patients may have some residual activity that permits them to metabolize glycogen at a slow rate and especially so around puberty.

Hers disease is sometimes confused with a related disorder, glycogen storage disease (GSD) IX, which is much more common. It is attributed to a deficiency of phosphorylase kinase, an enzyme that activates phosphorylase, so that it can break down glycogen. It generally presents in a similar fashion to Hers disease and its outcome is equally benign. Because phosphorylase consists of four different protein subunits, coded by separate genes and one is found on the X chromosome, this disorder may be X-linked (affecting boys preferentially) or autosomal depending on which gene is deleteriously mutated. Because some forms of phosphorylase kinase are expressed in heart and muscle, these tissues can also be involved in some, but very rare, cases of GSD IX; the cardiac form is fatal in infancy.

Symptoms

Patients present early in childhood with an enlarged liver and perhaps growth retardation. Some exhibit low blood glucose after an overnight fast. The liver enlargement usually disappears around puberty. While growth may be impaired in childhood, adult height is usually reached. Nevertheless, any child with a distended belly or growth impairment should be brought for medical attention.

Screening and Diagnosis

Definitive diagnosis of Hers disease requires a liver biopsy and demonstration of elevated glycogen with a normal structure and deficiency of phosphorylase activity. In GSD IX, phosphorylase activity will be normal, but phosphorylase kinase activity will be low. Deficient activity can also be measured in white blood cells. DNA tests are also available for known deleterious mutations.

Treatment and Therapy

Because Hers disease and GSD IX are usually benign, treatment and therapy are not generally necessary. However, frequent high protein meals may be beneficial to minimize glycogen deposition in the liver and to provide substrates for synthesis of glucose in the body via gluconeogenesis. No treatments are known for the serious but rare heart and muscle forms of GSD IX.

Prevention and Outcomes

Prenatal diagnosis is possible but not warranted in view of the benign nature of the condition. Although each involves a defect in the breakdown of glycogen in the liver, the outcome for Hers disease (and GSD IX) is more favorable than for Forbes disease, which can also involve muscle and heart, and much more favorable than for von Gierke disease, in which gluconeogenesis is also blocked.

Bibliography

Badash, Michelle. "Glycogen Storage Diseases." Health Library. EBSCO Information Services, 5 May 2014. Web. 25 July 2014.

Devlin, Thomas M. Textbook of Biochemistry with Clinical Correlations.7th ed. New York: Wiley, 2011. Print.

Fernandes, John, et al. Inborn Metabolic Diseases: Diagnosis and Treatment.5th ed. Berlin: Springer, 2012. Print.

Hannah, William B., et al. "Glycogen Storage Disease." Nature Reviews Disease Primers, vol. 46, 7 Sept. 2023, doi.org/10.1038/s41572-023-00456-z. Accessed 9 Sept. 2024.

Shannon, Joyce B. Endocrine and Metabolic Disorders Sourcebook. 2nd ed. Detroit: Omnigraphics, 2007. Print.