Hematology

Glycogen storage diseases: hematological aspects

Glycogen storage diseases: hematological aspects

What every physician needs to know:

The glycogen storage diseases (GSDs) are a group of inherited inborn errors of metabolism resulting from mutations in the genes responsible for the proteins (enzymes) involved with glycogen synthesis, degradation, and regulation. These diseases can be autosomal recessive (AR) or X-linked (XL). Accumulation of glycogen in the liver, skeletal muscle, or myocardium can impair the function of these sites, and deficiencies of these enzymes in red blood cells can lead to hemolysis.

When impaired hepatic glycogen metabolism is present, patients have fasting hypoglycemia, ketosis and potentially progressive liver damage. Whereas, in muscle, where glycogen is the primary energy source, glycogen accumulates and muscle weakness and cramping occurs, exercise intolerance is present, and myoglobinuria is detectable. When red blood cell (RBC) glycolytic enzymes are deficient, a life-long non-spherocytic hemolytic anemia results and, in addition, platelet function can be impaired. The following discussion will concentrate on the GSDs that have hematological manifestations.

Are you sure your patient has a glycogen storage disease? What should you expect to find?

The GSDs are rare conditions and diagnosis can frequently be delayed as a result. If the symptoms of fasting hypoglycemia, muscle weakness, muscle cramping are noted, especially in a child or young adult, then further testing including tissue sampling, enzyme levels, and molecular analysis may then be appropriate.

Glucose-6-phosphatase deficiency (GSD type I, von Gierke's disease) is an AR disease due to mutations on chromosome 17q21 (type Ia) or chromosome 11q23 (type Ib). In early childhood, patients will present with hepatomegaly, hypoglycemia and ketotosis. In addition, neutropenia and neutrophil dysfunction is found in over 50% of patients and this is associated with increased perioral and perianal infections, which can be ameliorated with granulocyte colony-stimulating factor (G-CSF). The neutropenia can be intermittent but not cyclical. Also, there is a correlation of the neutropenia with the presence inflammatory bowel disease.

Phosphofructokinase deficiency (GSD VII, Tarui's disease) is an AR disease due to mutations in the M isoform of the enzyme on chromosome 12q13. Besides the muscle weakness, fatigue, and exercise intolerance, a moderate hemolytic anemia due to impaired red blood cell glycolysis is also noted. Phosphoglycerate kinase deficiency is an XL disease due to mutations of Xq13. Patients present with seizures, intellectual disability and a non-spherocytic hemolytic anemia. The presence of myopathy is variable. In addition, they can also present with hemolysis without central nervous system involvement.

Lastly, lactate dehydrogenase deficiency, which is an AR disorder, is due to a specific deficiency of either the M or H isoforms of the enzyme. The M form is located on chromosome 11p15 and the H form on chromosome 12p12.2. Hemolysis has been noted only with a deficiency of the H isoform.

Beware of other conditions that can mimic a glycogen storage disease:

Other red cell enzyme deficiencies can impact glutathione oxidation, the glycolytic pathway (Embden-Meyerhof-Parnas), and nucleotide degradation and salvage. Glucose-6-phosphate dehydrogenase (G6PD) can either present as a chronic hemolytic anemia or as sporadic episodes of hemolysis related to oxidant stresses that may occur with certain medications, infections or certain foods such as fava beans.

Pyruvate kinase deficiency is the most common glycolytic enzyme deficiency that leads to life-long hemolytic anemia. Pyrimidine 5' nucleotidase deficiency presents with congenital hemolytic anemia because the residual nucleotides in young red cells (reticulocytes) cannot be metabolized and are presumed toxic. Basophilic stippling is prominent. The latter (basophilic stippling) can be seen with lead intoxication, but is reversible with treatment, whereas the in 5' nucleotidase deficiency it is not. Disorders of platelet function are common and can include Von Willebrand disease, Glanzmann's thrombasthenia, platelet storage pool disorders, and the effect of medications such as aspirin. Neutropenia can be congenital, or from autoimmune causes, medications, or bone marrow disorders.

Which individuals are most at risk for developing a glycogen storage disease:

Phosphofructokinase (PFK) deficiency is seen with greater frequency in Ashkenazi Jewish patients, due to a founder mutation causing an exon skip at a splice site. Along with a single nucleotide deletion, this accounts for 95% of the mutations leading to PFK deficiency.

With glucose-6-phosphatase deficiency (GSD I) a number of mutations have been described and therefore it has been found in various populations including Hispanics, Asians Chinese and Japanese, Ashkenazi Jews, and other Caucasians. Phosphoglycerate kinase (PGK) deficiency has been seen in various populations and therefore, no specific group is at greater risk.

Similarly, Lactate dehydrogenase (LDH) deficiency is not increased in any particular sub-population group.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

As with all hemolytic anemias, the serum indirect bilirubin is elevated, as are LDH levels (except in LDH deficiency), haptoglobin levels are depressed, and reticulocytes are elevated. In GSD, many laboratory abnormalities are present including anemia, neutropenia, hyperuricemia, hypercholesterolemia, and hypertriglyceridemia. Although platelet counts are normal in these patients, platelet dysfunction can lead to epistaxis. Neutropenia is also frequently reported, as well as neutrophil dysfunction (delayed chemotaxis).

Patients with PFK deficiency can have anemia, myoglobinuria, and hyperuriecemia. Those with PGK deficiency can be anemic, and will have myoglobinuria, and elevated creatine kinase (CPK) levels. Lastly, those with LDH deficiency can be anemic and have reduced or absent red blood cell LDH levels.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of a glycogen storage disease?

There are no specific imaging studies that are helpful in these diseases. Hepatomegaly and sometimes splenomegaly can be seen, but are not diagnostically helpful signs per se.

If you decide the patient has a glycogen storage disease, what therapies should you initiate immediately?

There are no specific emergency measures that need to be taken in any of these diseases. All therapeutic interventions are on a chronic basis and depend, to some degree, upon the specific disease being treated.

More definitive therapies?

With GSD I, treatment on a chronic basis with uncooked cornstarch, maltodextrin, and diazoxide can help the metabolic aspects of the disease. G-CSF (filgrastrim) has been beneficial for the neutropenia. Liver transplantation has improved the metabolic defects, but not the anemia. Desmopressin has improved platelet function in some of these patients.

In PFK deficiency, with respect to the muscle disease, avoiding strenuous exercise is advised. For those with more severe hemolytic anemia, splenectomy has been utilized successfully, although the red blood cell defect persists, but the anemia is better compensated.

In those with PGK deficiency, there is no specific treatment available, although splenectomy has been tried in those patients with more severe anemia with some benefit.

Again, in LDH deficient patients, there is no specific therapy. There is a greater risk of dystocia during pregnancy, so Ceserean section is usually advised.

One report showed that bone marrow transplantation can improve thrombocytopenia, neutropenia, inflammatory bowel disease symptoms, and the metabolism in type1b GSD.

What other therapies are helpful for reducing complications?

No additional therapies are available for the four subtypes of GSD with hematological findings. However, for GSD II (Pompe disease), enzyme replacement therapy is available and has improved muscular function in all age groups.

What should you tell the patient and the family about prognosis?

In GSD I, complications of the disease are noted in over 70% of adults including: hepatomegaly, short stature, hyperuricemia, anemia, hypercholesterolemia, hypertriglyceridemia, hepatic adenomas (10% become malignant), proteinuria, and renal calcifications. More rarely: osteopenia, fractures, and pulmonary hypertension has been noted.

In patients with PFK deficiency, the disease is usually mild, but more severe infantile forms have been reported. Once diagnosed, strenuous exercise must be avoided.

For those with PGK deficiency, some patients develop seizures and impaired cognitive abilities, whereas others may only have the hemolytic anemia. The myopathy is slowly progressive when present.

LDH deficiency tends to be a milder disease, even in adulthood.

"What if" scenarios.

Probably the most problematic concern for these patients is delay in diagnosis. Predominantly, these diseases present in childhood, so early recognition of the signs and symptoms of an inherited metabolic disease becomes of critical importance. For the glycogen storage diseases where dietary changes and muscle function are an issue, early intervention can minimize the morbidity.

Pathophysiology

The liver and muscles are most affected by disorders of glycogen metabolism. In the liver, glycogen is the storage form of glucose that can be made available to the tissues which are unable to synthesize enough glucose, especially during fasting. When liver glycogen/glucose metabolism is impaired due to an enzyme deficiency, patients have fasting hypoglycemia, ketosis, and possibly hepatomegaly, which improve with eating or glucose administration.

With respect to the hematological manifestations, in GSD I, decreased plasma levels of von Willebrand factor antigen (VWF:Ag) has been identified in over half the patients studied, which can lead to platelet dysfunction. Platelet glucose-6-phosphatase levels seem to be normal in the platelets. Similar to patients with von Willebrand disease, this defect appears to be improved with desmopressin administration. In addition, a naturally occurring inhibitor of ristocetin-induced aggregation may also play a role in causing platelet dysfunction. The cause of the neutropenia seen in GSD I patients is not known, although the neutrophil dysfunction may be related to impaired glycogenolysis.

In patients with PFK deficiency, PGK deficiency and LDH deficiency, hemolysis can occur because of impaired (decreased) adenosine-5'-triphospate (ATP) generation and increased 2,3-bisphosphoglycerate generation from the abnormal glycolysis, leading to problems with red blood cell membrane maintenance. Also, there is membrane calcium leakage that may contribute to the membrane's instability. The abnormal membranes are detected in the spleen predominantly, and therefore the majority of the hemolysis occurs there. As noted above, splenectomy can ameliorate the anemia, but does not correct the metabolic defect. In those with LDH deficiency, the hemolysis tends to be mild.

What other clinical manifestations may help me to diagnose a glycogen storage disease?

Other than hepatomegaly or muscle weakness, there are a paucity of other physical findings except perhaps for short stature.

What other additional laboratory studies may be ordered?

For these patients, genotyping and/or enzyme level measurements can be done. Skin, muscle, or liver biopsies can be utilized for these assays. Red blood cell enzyme levels can be measured directly and can serve as a diagnostic tool in those conditions, where hemolysis is noted.

What’s the evidence?

Rake, JP, Visser, G, Labrune, P. "Glycogen storage disease type I: diagnosis, management, clinical course and outcome.Results of the European study on glycogen storage disease type I". Eur J Ped.. vol. 161. 2002. pp. S 112-19.

[This paper is one of the definitive references for the management of type 1 GSD.]

Visser, G, Rake, JP, Fernandes, J. "Neutropenia, neutrophil dysfunction, and inflammatory bowel disease in glycogen storage disease type Ib: results of the European study on glycogen storage disease type I". J Pediatr.. vol. 137. 2000. pp. 187-191.

[Of interest is the associated hematological abnormalities presumably related to impaired glucose metabolism.]

Muhlhausen, C, Schneppenheim, R, Budde, U. "Decreased plasma concentration of von Willebrand factor antigen (VWF:Ag) in patients with glycogen storage disease type Ia". J Inherit MetabDis.. vol. 28. 2005. pp. 945-50.

[Type 1a GSD patients can have a mild bleeding disorder.]

Marti, GE, Rick, ME, Sidbury, J, Gralnick, HR. "DDAVP infusion in five patients with type Ia glycogen storage disease type Ib. Results of the European study on glycogen storage disease type I". Blood. . vol. 68. 1986. pp. 180-4.

[Indirectly, this study shows that there is a mild bleeding disorder in these patients that is improved with stimulation of Factor VIII production.]

Layzer, RB, Rowland, LP, Ranney, HM. "Muscle phosphofructokinas deficiency". Arch Neurol.. vol. 17. 1967. pp. 512-523.

[One of the definitive papers on this disease.]

Vorgerd, M, Karitzky, J, Ristow, M. "Muscle phosphofructokinase deficiency in two generations". J Neurol Sci.. vol. 141. 1996. pp. 95-99.

[This study shows some of the phenotypic variations of this disease.]

Ronquist, G, Rudolphi, O, Engstrom, I, Waldenstrom, A. "Familial phosphofructokinase deficiency is associated with a disturbed calcium homeostasis in erythrocytes". J Intern Med. . vol. 249. 2001. pp. 85-95.

[Disturbed calcium metabolism can lead to hemolysis.]

Valentine, WN, Hsieh, HS, Paglia, DE. "Hereditary hemolytic anemia associated with phosphoglycerate kinase deficiency in erythrocytes and leukocytes. A probable x-linked syndrome". N Engl J Med.. vol. 280. 1969. pp. 528-34.

[Article by one of the foremost groups studying RBC enzymes.]

Flanagan, JM, Rhodes, M, Wilson, M, Beutler, E. "The identification of a recurrent phosphoglycerate kinase mutation associated with chronic haemolytic anemia and neurological dysfunction in a family from USA". Br J Haematol.. vol. 134. 2006. pp. 233-237.

[Further phenotypic variation in these patients.]

Wakabayashi, H, Tsuchiya, M, Yoshino, K. "Hereditary deficiency of lactate dehydrogenase H-subunit". Intern Med.. vol. 35. 1996. pp. 550-4.

[Good report on this rare entity.]

Pierre, G, Chakupurakal, G, McKiernan, P. "Bone marrow transplantation in glycogen storage disease type 1b". J Pediatr. vol. 152. 2008. pp. 286-8.

[This case report is exceptional and may represent an entire new approach to the GSD's.]
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