Glycogen storage disease

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Glycogen storage disease I

Glycogen storage disease I (GSD1) has defects in the G6PC gene at 17q21 for glucose-6-phosphatase. It is manifest by recurrent hypoglycaemia often on exercise and survival into adulthood is now possible. Hyperlipidaemia leading to xanthoma is common and hyperuricemia leading to gout is possible. Liver adenomas may be present with the potential for malignant transformation. Treatment success has included frequent meals high in cornstarch.

Glycogen storage disease Ib

Due to defects in glucose-6-phosphate transporter gene SLC37A4 at 11q23 . Recurrent infections and neutropenia with hepatomegaly, hyperlipidaemia and xanthoma or liver adenomas are possible.

Glycogen storage disease Ic

The criteria is increased latency in hepatic microsomal inorganic pyrophosphatase activity and most is due to defects in glucose-6-phosphate transporter gene SLC37A4 at 11q23-q24.2. Most have recurrent infections and neutropenia with hepatomegaly. Some do not have hypoglycaemia.

Glycogen storage disease II

Pompe disease (best termed this as multiple other names are very confusing - glycogen storage disease type II, acid maltase deficiency, glycogenosis type II, acid α-glucosidase deficiency, GSD-II, AMD, GAA deficiency) is due to a deficiency of lysosomal alpha-glucosidase (which also has multiple names - acid α-glucosidase, lysosomal hydrolase, EC, acid maltase, GAA) caused by mutations of GAA gene at 17q25.2-q25.3. It is a progressive lysosomal storage disorder manifest as a metabolic myopathy and hypertrophic cardiomyopathy as glycogen can not be broken down to glucose, so glycogen accumulates.

There is a fair spectrum from a rapidly progressive infantile onset form fatal in first year of life to a less rapidly-progressing late-onset form manifest by:

  • Generalised proximal myopathy
    • Leads to respiratory embarrassment (ventilation) and physical dependence
  • Cardiomyopathy (will not develop if sufficient acid α-glucosidase activity)
  • Hypotonia.

Treatment with alglucosidase alfa to delay disease progression appears promising in the milder forms.

Glycogen storage disease III

Glycogen storage disease III (GSD3) is a autosomal recessive condition caused by mutation in the gene AGL at 1p21 coding the glycogen debrancher enzyme. Patients present in infancy or early childhood with hepatomegaly, hypoglycaemia, and growth retardation. There are four phenotypes:

  1. Enzyme-deficient in both liver and muscle (IIIa). Muscle weakness is minimal in childhood but can become more severe in adults with some cardiomyopathy
  2. 15% are enzyme-deficient in liver only (IIIb)
  3. Selective loss of only glucosidase debranching activity (IIIc)
  4. Selective loss of only transferase debranching activity (IIId)

Glycogen storage disease IV

Glycogen storage disease IV (GSD4) has defects in the gene GBE1 at 3p12 coding the glycogen branching enzyme. It can overlap with adult polyglucosan body disease caused by mutations of the same gene. The enzyme product catalyzes the transfer of alpha-1,4-linked glucosyl units from the outer end of a glycogen chain to an alpha-1,6 position on the same or a neighboring glycogen chain. Liver disease of childhood, progressing to lethal cirrhosis is characteristic. There are 4 neuromuscular phenotypes:

  1. Perinatal, with fetal akinesia deformation sequence (FADS) and perinatal death
  2. Hypotonia, neuronal involvement, and death in early infancy
  3. Childhood myopathy or cardiomyopathy
  4. Adult isolated myopathy or adult

Glycogen storage disease V

McArdle disease (glycogen storage disease V, GSD5) is caused by defects of the PYGM gene at 11q13 coding for muscle glycogen phosphorylase. The classic presentation is benign exercise intolerance and muscle cramps. Transient myoglobinuria after exercise is possible but it is rarely rare leading to acute renal failure.

Glycogen storage disease VI

Glycogen storage disease VI (GSD6) has autosomal recessive inheritance with defects in the PYGL gene at 14q21-q22 causing hepatic phosphorylase deficiency. It has an excellent prognosis despite mild to moderate hypoglycaemia, mild ketosis, growth retardation, and prominent hepatomegaly.

Glycogen storage disease VII

Glycogen storage disease VII (GSD7) has a defect in the PFKM gene at 12q13.3 that codes for coding muscle phosphofructokinase. It is autosomal recessive with, sometimes mild exercise intolerance, muscle cramping, exertional myopathy, and compensated haemolysis. Myoglobinuria can occur.

Glycogen storage disease VIII

Now GSD9a below.

Glycogen storage disease IX

Glycogen storage disease IXa

Glycogen storage disease IXa (GSD9a) is X-linked recessive and has defects in the PHKA2 gene at Xp22.2-p22.1 coding for the alpha-2 subunit of hepatic phosphorylase kinase. Phenotype is mild hepatomegaly, growth retardation, elevation of glutamate-pyruvate transaminase and glutamate-oxaloacetate transaminase, hypercholesterolaemia, hypertriglyceridaemia, and fasting hyperketosis dissapearoing in adult life.

Glycogen storage disease IXa1

GSD9A1 has no phosphorylase kinase activity in liver or erythrocytes

Glycogen storage disease IXa2

GSD9A2 has no phosphorylase kinase activity in liver but normal in erythrocytes

Glycogen storage disease IXb

Glycogen storage disease IXb (GSD9b) has defects in the PHKB gene at 16q12-q13 coding for the beta subunit of phosphorylase kinase. Phenotype can vary from massive hepatomegaly to GSD2 type.

Glycogen storage disease IXc

Glycogen storage disease IXc (GSD9c) has defects in the PHKG2 gene at 16p12.1-p11.2 coding for the gamma subunit of phosphorylase kinase. There is childhood onset of hepatomegaly, hypotonia, growth retardation and liver dysfunction which rarely develop to hepatic fibrosis or cirrhosis. In adult life symptoms usually resolve.

Glycogen storage disease IXd

Glycogen storage disease IXd (GSD9d) has defects in the PHKA1 gene at Xq13 coding for the alpha subunit of muscle phosphorylase kinase. Phenotype includes severe exercise intolerance and muscle cramps and muscle weakness.

Glycogen storage disease X

Glycogen storage disease X (GSD10) has defects in the PGAM2 gene at 7p13-p12.3 coding for muscle phosphoglycerate mutase. Exercise-induced cramps, occasional myoglobinuria, intolerance strenuous exercise, hyperlipidaemia and hyperuricaemia have been described.

Glycogen storage disease XI

Glycogen storage disease XI (GSD11) has defects in the LDHA gene at 11p15.4 causes lactate dehydrogenase A deficiency. It has exertional myoglobinuria and easy fatigue. Sometimes is associated with desquamating erythematosquamous lesions mostly on the extensor surfaces.

Glycogen storage disease XII

Glycogen storage disease XII (GSD12) has defects in the ALDOA gene at 16p11.2 causing aldolase A deficiency. This is an autosomal recessive disorder with hereditary haemolytic anaemia.

Glycogen storage disease XIII

Glycogen storage disease XIII (GSD13) has defects in the ENO3 gene at 17pter-p12 coding for beta-enolase. This is manifest as exercise intolerance, myalgias, and increased serum creatine kinase.

Glycogen storage disease XIV

Glycogen storage disease XIV (GSD14) has defects in the PGM1 gene at 1p31 coding for phosphoglucomutase-1 manifest by exercise intolerance and episodic rhabdomyolysis.