Paediatrics chapters
Glycogen storage diseases
Inherited enzyme defects that stop glycogen being made or broken down normally: the liver types that cause fasting hypoglycaemia and a big liver, the muscle types that cause cramps, and Pompe disease of the heart.
- Glycogen storage diseases are mostly autosomal recessive enzyme defects; liver types (I, III, VI, VIII) cause fasting hypoglycaemia and hepatomegaly, muscle types (V, VII) cause exercise cramps and fatigue.
- Type I (von Gierke, glucose-6-phosphatase) is the classic: infant with doll-like face, protuberant abdomen, big liver and kidneys, hypoglycaemia, lactic acidosis, high uric acid and triglycerides, bleeding and poor growth.
- Type II (Pompe, lysosomal acid alpha-glucosidase) is a heart and muscle disease: floppy infant with huge heart, heart failure, short PR; treat type I with frequent feeds, night glucose and uncooked cornstarch, Pompe with enzyme replacement.
On this page
Overview
Glycogen is the branched storage form of glucose, kept mainly in the liver (to keep blood glucose up during fasting) and muscle (fuel for anaerobic work). In glycogen storage diseases (GSD), an enzyme needed to make or break down glycogen is missing, so glycogen of normal or abnormal structure piles up in the tissue.
- Liver forms present with hypoglycaemia and hepatomegaly.
- Muscle forms present with weakness, cramps and fatigue on exercise.
- Pompe disease affects the heart and all muscles.
The hepatic glycogen storage diseases are the commonest inborn errors that cause hypoglycaemia (Akbar).
Glycogen metabolism in brief
- Synthesis: from UDP-glucose by glycogen synthetase and brancher enzyme; stimulated by insulin.
- Breakdown: triggered by glucagon and adrenaline. Phosphorylase releases glucose-1-phosphate from the straight chains; debrancher enzyme handles the branch points.
- Glucose-1-phosphate becomes glucose-6-phosphate (phosphoglucomutase).
- Glucose-6-phosphatase removes the phosphate so that glucose can enter the blood. It works in liver and kidney but is absent in muscle, so muscle glycogen fuels only the muscle itself.
Inheritance
- Almost all are autosomal recessive.
- Nelson notes that one form of liver phosphorylase kinase deficiency is X-linked.
- Consanguinity raises the risk, as with other recessive metabolic disorders.
Classification by organ
| Group | Types | Main effect |
|---|---|---|
| Liver, with direct effect on blood glucose | I, VI, VIII | Fasting hypoglycaemia, big liver |
| Muscle, with poor anaerobic exercise | V, VII | Cramps, fatigue, myoglobinuria |
| Liver and muscle | III | Hypoglycaemia plus myopathy |
| Other tissues, no direct effect on glucose or exercise | II, IV | Heart and muscle (II); cirrhosis (IV) |
The individual types
| Type and name | Enzyme missing | Key features | Outlook |
|---|---|---|---|
| Ia: von Gierke | Glucose-6-phosphatase | Hypoglycaemia, lactic acidosis, ketosis, big liver, hypotonia, poor growth, diarrhoea, bleeding, gout, high triglycerides, xanthomas | Good with early diagnosis and strict diet; hepatomas may appear in late childhood |
| Ib | Glucose-6-phosphate translocase | As Ia plus neutropenia and infections, bowel problems | Infections were the main cause of death |
| II: Pompe | Lysosomal acid alpha-glucosidase (acid maltase) | Profound symmetrical weakness, hypotonia, cardiomegaly, heart failure, short PR interval | Infantile form usually fatal in the first year; enzyme replacement helps |
| III: Cori (Forbes) | Debranching enzyme | Early hypoglycaemia, ketonuria, hepatomegaly that shrinks with age, may have muscle weakness | Very good for the liver disease |
| IV: Andersen | Branching enzyme | Cirrhosis from a few months of age, early liver failure | Poor; death in the first decade |
| V: McArdle | Muscle phosphorylase | Exercise cramps and fatigue from adolescence, myoglobinuria | Good with limited exertion |
| VI: Hers | Liver phosphorylase | Mild hypoglycaemia, hepatomegaly, ketonuria | Good |
| VII: Tarui | Muscle phosphofructokinase | Like type V | Like type V |
| VIII | Phosphorylase kinase | Like type III but no myopathy | Good |
"Very Poor Carbohydrate Metabolism": Von Gierke (I), Pompe (II), Cori (III), McArdle (V).
Pompe Pumps poorly: the heart is the organ of type II.
Type I: von Gierke disease
Why the features occur
Without glucose-6-phosphatase the liver cannot release glucose either from glycogen breakdown or from gluconeogenesis. Glucose-6-phosphate is pushed into other pathways, producing lactate, uric acid and triglycerides.
Clinical features
- Symptoms may start at birth or in early infancy: hypoglycaemia with sweating, irritability, fast breathing, seizures or coma.
- Protuberant abdomen with marked hepatomegaly and enlarged kidneys.
- Doll-like face, short stature, growth failure.
- Bleeding tendency (platelet dysfunction), hypotonia, diarrhoea.
- Later: gout, xanthomas, and liver tumours in adolescence and adult life (sometimes malignant).
- In the newborn the liver may not yet be large.
A typical scenario (Akbar): a 9-month-old with sweating and fast breathing, a liver 5 cm below the costal margin and a random glucose of about 40 mg/dL; liver biopsy confirms glycogen storage.
In von Gierke disease the liver is large but not cirrhotic. A big liver with early cirrhosis suggests type IV; floppiness with a big heart suggests Pompe.
Type II: Pompe disease
- A lysosomal storage disease, so it does not cause hypoglycaemia.
- Glycogen fills cardiac and skeletal muscle and nerve cells.
- Infantile form: floppy baby, large tongue, massive cardiomegaly on chest X-ray, heart failure, cyanosis or shock.
- ECG: short PR interval.
- Enzyme replacement with recombinant human alpha-glucosidase, started early, is effective.
Hypotonia + macroglossia + huge heart + short PR in an infant = Pompe disease (type II). Blood glucose is normal.
Muscle types: V (McArdle) and VII
- Exercise intolerance, cramps, muscle pain and easy fatigue, usually noticed in adolescence; occasionally dark urine from myoglobinuria.
- Ischaemic exercise test: blood lactate normally rises briskly after exercise; in type V there is little or no rise.
- CK may be raised.
- No specific treatment; avoid strenuous exercise. Prognosis is good.
Investigations
| Test | Finding |
|---|---|
| Blood glucose (fasting) | Low in liver types |
| Blood lactate, uric acid, triglycerides | Raised in types I and III |
| Blood gases | Low pH (lactic acidosis) in type I |
| Urine and blood ketones | Present in fasting |
| Glucagon test | Normally raises glucose by about 40-60% above fasting; flat curve in type I |
| Oral glucose tolerance (Akbar: load 1.5 g/kg) | In type I, a diabetic-type curve with a high rise and slow fall |
| CK, EMG, ischaemic exercise test | For muscle types |
| DNA mutation testing (white cells) | Confirms most types and avoids biopsy |
| Enzyme assay | In leucocytes, liver or muscle when DNA testing is not possible |
| Liver biopsy | Glycogen over 5% of liver weight, ballooned hepatocytes, low or absent glucose-6-phosphatase in type I |
| Muscle biopsy | In muscle types |
| Chest X-ray, ECG, echo | Cardiomegaly and short PR in Pompe |
Fasting glucose 60 mg/dL; a normal 40-60% rise gives
60 × 1.4 = 84 mg/dL and 60 × 1.6 = 96 mg/dL
Normal child: about 84-96 mg/dL after glucagon
Type I: glucose stays near 60 (flat curve), because glucose-6-phosphatase cannot release glucose
In type I the glucagon test is flat because the defect is in the last step of glucose release, not in the hormonal signal.
GSD belongs in the differential diagnosis of hypoglycaemia and of hepatomegaly in any infant.
Management
Hepatic GSD (especially type I)
- Aim: keep blood glucose normal and prevent lactic acidosis.
- Frequent daytime feeds and snacks; avoid long fasts.
- In infancy, nocturnal intragastric glucose feeds for the first 1-2 years.
- Later, uncooked cornstarch (slowly digested) or night feeds keep glucose steady.
- Watch for complications: gout, infections with neutropenia in type Ib, and liver tumours in later life.
- Severe liver disease may need a liver transplant.
Muscle GSD
- No specific treatment; adjust activity to avoid cramps and myoglobinuria.
Pompe disease
- Enzyme replacement therapy early in life; supportive cardiac and respiratory care.
Type I treatment = "no fasting": frequent feeds, night-time glucose, then uncooked cornstarch.
Expect: the enzyme for each named type (von Gierke glucose-6-phosphatase, Pompe acid maltase, Cori debrancher, Andersen brancher, McArdle muscle phosphorylase); type I triad of hypoglycaemia, lactic acidosis and big liver with high uric acid and triglycerides; doll face and big kidneys; type Ib neutropenia; Pompe as a heart disease with short PR, large tongue and hypotonia and normal glucose; McArdle with no lactate rise on ischaemic exercise; flat glucagon response in type I; treatment with frequent feeds and uncooked cornstarch; liver tumours as a late complication; autosomal recessive inheritance.
Quick revision
- Glycogen stored in liver (glucose) and muscle (exercise); glucose-6-phosphatase absent in muscle.
- Mostly autosomal recessive.
- Liver types I, VI, VIII; muscle V, VII; both III; others II, IV.
- Type I: glucose-6-phosphatase; hypoglycaemia, lactic acidosis, high urate and triglycerides, doll face, big liver and kidneys.
- Type Ib: neutropenia and infections.
- Type II Pompe: acid maltase; cardiomegaly, short PR, hypotonia, big tongue; enzyme replacement.
- Type III: debrancher; liver enlargement improves with age.
- Type IV: brancher; early cirrhosis.
- Type V McArdle: cramps on exercise; no lactate rise.
- Type I care: frequent feeds, night glucose, uncooked cornstarch; watch for liver tumours.
Written by The House Job from standard references (Basis of Paediatrics by Pervez Akbar; Nelson Essentials of Paediatrics).
FAQ
Why does von Gierke disease cause lactic acidosis and high uric acid?
The liver cannot convert glucose-6-phosphate to glucose, so the excess is diverted into lactate, uric acid and fat production. Fasting makes this worse.
Why does Pompe disease not cause hypoglycaemia?
The missing enzyme works in lysosomes, not in the pathway that releases glucose into the blood. Glycogen collects in heart and muscle, but liver glucose output is normal.
What is uncooked cornstarch used for?
It is digested slowly and releases glucose over several hours. Children with type I disease take it to avoid hypoglycaemia between meals and overnight.
How is McArdle disease different from the liver types?
It affects only muscle, so blood glucose is normal. The child gets cramps and fatigue on exercise, and blood lactate fails to rise after ischaemic exercise.