Inherited Metabolic Disorders

Question 1

Glycogen Storage Diseases

Answer 1

Glycogen storage disease:

Von Gierke’s disease (type I):
Deficienct Enzyme = Glucose-6-phosphatase
- Hepatic glycogen accumulation.
- Key features include hypoglycaemia, lactic acidosis, hepatomegaly

Pompe’s disease (type II)
Deficient Enzyme = Lysosomal alpha-1,4-glucosidase
- Cardiac, hepatic and muscle glycogen accumulation.
- Key features include cardiomegaly

Cori disease (type III)
Deficient Enzyme = Alpha-1,6-glucosidase (debranching enzyme)
- Hepatic, cardiac glycogen accumulation
- Key features include muscle hypotonia

McArdle’s disease (type V)
Deficient Enzyme = Glycogen phosphorylase - Skeletal muscle glycogen accumulation.
- Key features include myalgia, myoglobulinaemia with exercise

Question 2

Lysosomal Storage Diseases

Answer 2

Lysosomal Storage Diseases

Gaucher’s disease
Defect = Beta-glucocerebrosidase
- Most common lipid storage disorder resulting in accumulation of glucocerebrosidase in the brain, liver and spleen.
- Key features include hepatosplenomegaly, aseptic necrosis of the femur

Tay-Sachs disease
Defect = Hexosaminidase A
- Accumulation of GM2 ganglioside within lysosomes.
- Key features include developmental delay, cherry red spot on the macula, liver and spleen normal size (cf. Riemann-Pick)

Niemann-Pick disease
Defect = Sphingomyelinase
- Key features include hepatosplenomegaly, cherry red spot on the macula

Fabry disease
Defect= Alpha-galactosidase-A
- Accumulation of ceramide trihexoside.
- Key features include angiokeratomas, peripheral neuropathy of extemeties, renal failure

Krabbe’s Disease
Defect = Galactocerebrosidase
- Key features include peripheral neuropathy, optic atrophy, globoid cells

Metachromatic leukodystrophy
Defect = Arylsulfatase A
- Demyelination of the central and peripheral nervous system

Question 3

Fabry’s Disease - Example Question

Answer 3

An 18-year-old migrant from Syria presents to you after recent successful application for asylum. He has no family with him in the country. Since he can remember he gets severe burning pain and tingling in the hands and feet, particularly after exertion or when weather temperatures are extremely hot or cold. He remembers once having a transient episode of slurred speech and right facial droop that lasted less than 24 hours. He has never had the opportunity to consult about his problems. Physical examination reveals a rash of blue-black telangiectasia across his trunk and a mid-systolic murmur heard loudest in the apex and radiating into the axilla. The examination is otherwise unremarkable. He recalls that his younger brother, who died some years ago, had similar problems and his sister, who he is no longer in touch with, seems to have not had any problems. Which of the following findings is consistent with the underlying diagnosis?

Positive anticentromere antibodies
> Deficiency in plasma levels of alpha-galactosidase
Aortic coarctation visualised by aortic angiography
Raised HBA1C
Excessive excretion of mucopolysaccharides in urine

The diagnosis is Fabry disease.

This is an X-linked recessive lipid storage disorder in which there a deficiency in the fat enzyme alpha-galactosidase. This results in the accumulation of alpha-galactosyl-lactosyl-ceramide in various tissues, including kidney, liver, blood vessels and nerve ganglion cells. It often presents with severe features in childhood/adolescence but can also less typically present in the 5th or 6th decade with milder features. The clinical features of Fabry disease include:

acroparaesthesia: tingling, burning pain in the hands and feet triggered by stress such as emotion, extreme temperatures, or exercise
Angiokeratoma corporis diffusum: lightly verrucous, deep-red to blue-black papules on the trunk (in the bathing trunk distribution)
Cardiac: mitral valve prolapse or regurgitation usually, but any valvular heart defect can occur
Strokes: including young strokes/TIAs
Chronic Kidney Disease: proteinuria usually, can present late in fulminant renal failure

Classically death occurred in the 4th decade but this has improved since the availability of dialysis. It would be important to organise urgent renal investigations in this young man amongst your workup.

Another lipid storage disorders that may come up:

Gaucher’s disease: autosomal recessive disorder characterised by a deficiency of glucocerebrosidase, resulting in glucocerebroside accumulating in the phagocytic cells of the body and hence you get massive (painless) splenomegaly (can be a typical otherwise well, young PACES patient and the condition is found principally in Jews of European stock). You expect the pancytopenia picture on blood tests; typical of hypersplenism. Life span is shortened but not markedly.

Question 4

Mucopolysaccharidoses

Answer 4

Mucopolysaccharidoses

Hurler syndrome (type I)
Defect = Alpha-1-iduronidase
- Accumulation of glycosaminoglycans (heparan and dermatan sulfate).
- Key features include gargoylism, hepatosplenomegaly, corneal clouding

Hunter syndrome (type II)	
Defect = Iduronate sulfatase	
- Accumulation of glycosaminoglycans (heparan and dermatan sulfate). 
- Key features include coarse facial features, behavioural problems/learning difficulties short stature, no corneal clouding