DISORDERS OF CARBOHYDRATE METABOLISM
Dietary glucose, consumed as disaccharides, i.e. sucrose, lactose and maltose or polysaccharides, e.g. starch, is the principle substrate for energy (ATP) generation via the processes of glycolysis (glucose gt; pyruvate) or mitochondrial oxidation (pyruvate gt; CO2 and water).
Unutilized glucose is stored as glycogen in liver and muscles, which may be reconverted into glucose by glycogenolysis during high requirements, e.g. exercise. Thus, maintenance of euglycemic state is principally a function of balance between free glucose and stored glycogen. Galactose and Fructose, other energyproducing monosaccharides, are of limited significance. Galactose, derived from milk products as Lactase (glucose + galactose), is an important component of many glycolipids, glycoproteins and glycosaminoglycans. Neoglucogenesis, i.e. de novo glucose synthesis from other sources, e.g. fats, also contribute to euglycemic state.Disorders of carbohydrate metabolism may be broadly divided into: (a) defects in glycogen degradation, i.e. glycogen storage disorders, (b) disorders of galactose or fructose metabolism, e.g. galactosemia, (c) disorders of glucose utilization, e.g. pyruvate metabolic defects, mitochondrial oxidation defects, etc., and (d) disorders of neoglucogenesis. The last two groups predominantly presents with lactic acidosis.
Glycogen storage disorders (GSD) include heterogeneous group of inborn errors in carbohydrate metabolism, all characterized by abnormal accumulation of normal or altered glycogen in various tissues, due to various enzymatic defects in synthesis or degradation of glycogen.
More than 14 forms of GSDs are known so far, classified numerically in order of identification or the principle organs of involvement, e.g. liver (Ia, Ib, III, VI, VI, VII, IX, XI, 0), muscles (V, VII), or both (II, III). All GSDs are autosomal recessive, except IXb, which is X-linked recessive.
Some important forms are as follows:Type I (von Gierke disease) is the commonest GSD with two variants (a and b) which usually present in early infancy with: (a) gross hepatomegaly and renal enlargement, (b) doll-like facies with short stature, (c) normal mental development, and (d) recurrent hypoglycemia or lactic acidosis, specially on fasting. Bleeding tendencies are common due to platelet function defects. Type Ib variant is also associated with recurrent infections due to neutropenia or neutrophil function defects.
Diagnosis rests on clinical suspicion, abnormal plasma glucose, lactate and lipid values and no rise of glucose
levels after glucagon administration. Diagnosis rests on next generation sequencing. Liver biopsy for enzyme assay is avoided, being an invasive procedure.
Treatment aims to maintain normoglycemia by frequent feedings or continuous gavage and introduction of uncooked corn starch in diet as a source of slow- release glucose (1.5-2.5 gm/kg every 4-6 hours), along with supportive and symptomatic measures. Supporting measures include control of acidosis, infections and bleeding tendencies, allopurinol therapy for hyperuricemia and regular vitamin/mineral supplementation. Untreated cases may die in infancy during hypoglycemia/acidotic episodes, survivors may improve with age, though some develop gout, uric acid nephropathy and hepatic adenomas in adulthood. Patients of GSD1b with neutropenia may require G CSF injections.
Type II (Pompe disease) is a lysosomal disorder with lysosomal storage of glycogen in muscles due to acid alpha-glucosidase deficiency.
Clinically, it presents with two phenotypes of generalized myopathy, with different age of onset and severity:
a. Infantile form presents in neonatal period with: (a) generalized hypotonia or 'floppy baby' with feeding difficulties, and (b) cardiomegaly and CCF due to progressive hypertrophic cardiomyopathy. Most cases die in infancy due to aspiration or respiratory failure.
b. Juvenileform presents with delayed motor development or difficult walking in late childhood, followed by gradual progressive proximal muscle weakness, swallowing difficulties and respiratory failure. Most cases die in second decade.
c. Adult form is a very slowly progressive proximal myopathy, manifesting beyond 2-3rd decade of life, without cardiac involvement.
Diagnosis is suspected on elevated CPK and LDH levels with EMG showing myopathic features. Muscle biopsy shows presence of glycogen positive vacuoles, though can be avoided by using NGS or demonstration of reduced enzyme activity on DBS. Prenatal diagnosis using amniocytes or chorionic villi is possible by targeted variant testing
Treatment includes enzyme replacement therapy (IV Alglucosidase alfa) every 2 weeks, along with supportive cardiac care and physiotherapy.
Other uncommon GSDs include:
• Type III (Debrancher deficiency) has two variants— type IIIa, involving liver and muscles both, and type IIIb, with only liver involvement. Clinically, it manifests in early childhood with milder features of GSD type I, i.e. hepatomegaly, hypoglycaemic spells and growth failure but without renal enlargement (d/d type I). Liver disease tends to improve with age, while muscular weakness and wasting appears and worsens after puberty. Diagnosis rests on next generation sequencing.
• Type IV (Anderson disease) presents in infancy with failure to thrive, hepatosplenomegaly and progressive cirrhosis with chronic liver failure and portal hypertension that leads to death by 5 years. Diagnosis rests on next generation sequencing.
• Type V (McArdle disease) presents in late childhood/ adults with muscle cramps and myoglobinuria after strenuous exercise due to rhabdomyolysis. Ischemic exercise test, i.e. no rise in blood lactate but elevated ammonia levels after exercise is a useful screening test for muscle glycogenoses.
• Type VII (Tarui disease) has similar presentation as in type V, except—(a) earlier onset with more severe cramps and myoglobinuria, not preventable with high glucose diet, (b) evidence of continued compensated hemolysis with high bilirubin and reticulocyte count,
• Type VI (Hers disease) presents with hepatomegaly and growth retardation in early childhood but runs a benign course and improves by puberty without treatment.
• Type XI (Fanconi-Bickel syndrome) presents like type IA along with hyperlipidemia, hyperuricemia and renal dysfunction.
• Phosphoryl kinase deficiency is clinically heterogeneous group of GSDs, (previously classified as type VIa, VIII-X), where enzyme defects may be limited to liver, muscle or both.
Galactosemia: Galactose, derived from milk and other dairy products, is converted into Glucose-6 phosphate, before utilization as metabolic fuel or in synthesis of other galactosides, enzymatic defects in this galactose metabolism lead to excessive accumulation of galactose and its metabolites in various tissues, galactosuria and hypoglycemia, collectively termed as galactosemia. Three major types, all autosomal recessive, are known. Classical galactosemia denotes deficiency of Galactose- 1-phoshate uridyltransferase (GALT) leading to accumulation of Galactose-1 phosphate and its metabolites, toxic to liver and other organs.
Clinically, baby is normal at birth and manifestations begin after 3-4 days of breast feeding with intractable vomiting, diarrhea and failure to thrive. Unconjugated hyperbilirubinemia is common and untreated cases may develop chronic liver disease, cataracts and renal tubular acidosis.
Diagnosis rests on elevated RBC Galactose-1 Phosphate levels (gt;10 mg/dl) and reduced enzyme activity (lt;1 %) on molecular studies. However, a positive Benedict test in urine but negative urine dipstick test suggesting presence og non-glucose reducing substances is a useful screening test. Universal galactosemia screening in newborns is practiced in many countries.
Treatment involves strict elimination of galactose, i.e. milk/milk products from diet, which may reverse growth failure, cataracts and hepatic dysfunction and prevent further damage. However, mental retardation, if already developed, is irreversible. A soy-based formula may be used for infant feeding
Galactokinase deficiency, a mild variant of galactosemia, is usually asymptomatic except cataracts in older children and biochemical galactosemia/galactosuria. Mental retardation is absent. Diagnosis depends on erythrocyte enzyme assay and rearing on galactose-free diet may prevent/regress cataracts.
Lactic acidosis is a common presentation of many metabolic disorders involving—(a) glucose utilization, e.g. pyruvate metabolic defects, mitochondrial respiratory chain defects, etc., and (b) neoglucogenesis. While serum pyruvate levels are increased in disorders of neoglucogenesis or pyruvate metabolism, they are normal in mitochondrial oxidation defects.
Lactic acidosis is also seen in many fatty acid oxidation defects (with abnormal serum acylcarnitine profile) and organic acidurias (with presence of unusual organic acids in urine), as well as in acquired states, e.g. hypoxemia.
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