Carbohydrate Metabolism Disorders

Carbohydrate Metabolism Disorders 

1.Glycogen Storage Diseases

Glycogen storage diseases are caused by deficiencies of enzymes involved in glycogen synthesis or breakdown; the deficiencies may occur in the liver or muscles and cause hypoglycemia or deposition of abnormal amounts or types of glycogen (or its intermediate metabolites) in tissues.

Inheritance for glycogen storage diseases (GSDs) is autosomal recessive except for GSD type VIII/IX, which is X-linked. Incidence is estimated at about 1/25,000 births, which may be an underestimate because milder subclinical forms may be undiagnosed.

2.Glycogen Storage Diseases and Disorders of Gluconeogenesis.

Age of onset, clinical manifestations, and severity vary by type, but symptoms and signs are most commonly those of hypoglycemia and myopathy. Diagnosis is suspected by history, examination, and detection of glycogen and intermediate metabolites in tissues by MRI or biopsy.

Diagnosis is confirmed by significant decrease of enzyme activity in liver (types I, III, VI, and VIII/IX), muscle (types IIb, III, VII, and VIII/IX), skin fibroblasts (types IIa and IV), or RBCs (type VII) or by lack of an increase in venous lactate with forearm activity/ischemia (types V and VII). Prognosis and treatment vary by type, but treatment typically includes dietary supplementation with cornstarch to provide a sustained source of glucose for the hepatic forms of GSD and exercise avoidance for the muscle forms.

Defects in glycolysis (rare) may cause syndromes similar to GSDs. Deficiencies of phosphoglycerate kinase, phosphoglycerate mutase, and lactate dehydrogenase mimic the myopathies of GSD types V and VII; deficiencies of glucose transport protein 2 (Fanconi-Bickel syndrome) mimic the hepatopathy of other GSD types (eg, I, III, IV, VI).

3.Galactosemia

Galactosemia is caused by inherited deficiencies in enzymes that convert galactose to glucose. Symptoms and signs include hepatic and renal dysfunction, cognitive deficits, cataracts, and premature ovarian failure. Diagnosis is by enzyme analysis of RBCs. Treatment is dietary elimination of galactose. Physical prognosis is good with treatment, but cognitive and performance parameters are often subnormal.

Galactose is found in dairy products, fruits, and vegetables; autosomal recessive enzyme deficiencies cause 3 clinical syndromes.

3.1 Galactose-1-phosphate uridyl transferase deficiency: 

Activity of galactose-1-phosphate uridyltransferase (GALT) enzyme (EC 2.7.712). The GALT enzyme has a bimolecular function. It first converts UDP-glucose to glucose-1-P. The intermediate UMPGALT is formed and the second reaction binds galactose-1-P (gal-1P) and releases UDP-galactose. The overall reaction is rate-limiting in producing uryldylated hexoses for post-translational modification of glycoproteins and glycolipids. When GALT enzyme activity is deficient, gal-1P and galactose accumulate. Gal-1P competes with the UTP-dependent glucose-1-P pyrophosphorylase to reduce UDP-glucose production. Galactose is converted to galactitol in cells and produces osmotic effects such as swelling of lens fibers that may result in cataracts. and swelling of neurons that may produce pseudotumor cerebri. Other analytical methods are under study [Jeong et al 2007].

 

This deficiency causes classic galactosemia. Incidence is 1/62,000 births; carrier frequency is 1/125. Infants become anorectic and jaundiced within a few days or weeks of consuming breast milk or lactose-containing formula. Vomiting, hepatomegaly, poor growth, lethargy, diarrhea, and septicemia (usually Escherichia coli) develop, as does renal dysfunction (eg, proteinuria, aminoaciduria, Fanconi syndrome), leading to metabolic acidosis and edema. Hemolytic anemia may also occur. Without treatment, children remain short and develop cognitive, speech, gait, and balance deficits in their teenage years; many also have cataracts, osteomalacia (caused by hypercalciuria), and premature ovarian failure. Patients with the Duarte variant have a much milder phenotype.

3.2 Galactokinase deficiency: Patients develop cataracts from production of galactitol, which osmotically damages lens fibers; idiopathic intracranial hypertension (pseudotumor cerebri) is rare. Incidence is 1/40,000 births.

3.3 Uridine diphosphate galactose 4-epimerase deficiency: There are benign and severe phenotypes. Incidence of the benign form is 1/23,000 births in Japan; no incidence data are available for the more severe form. The benign form is restricted to RBCs and WBCs and causes no clinical abnormalities. The severe form causes a syndrome indistinguishable from classic galactosemia, although sometimes with hearing loss.

Diagnosis and Treatment

Diagnosis is suggested clinically and supported by elevated galactose levels and the presence of reducing substances other than glucose (eg, galactose, galactose 1-phosphate) in the urine; it is confirmed by enzyme analysis of RBCs, hepatic tissue, or both. Most states require that neonates be screened for galactose-1-phosphate uridyl transferase deficiency.

Treatment is elimination of all sources of galactose in the diet, most notably lactose, which is a source of galactose present in all dairy products, including milk-based infant formulas and a sweetener used in many foods. A lactose-free diet prevents acute toxicity and reverses some manifestations (eg, cataracts) but may not prevent neurocognitive deficits. Many patients require supplemental Ca and vitamins. For patients with epimerase deficiency, some galactose intake is critical to ensure a supply of uridine-5-diphosphate-galactose (UDP-galactose) for various metabolic processes.