Info

a-Galactosidase A Anderson-Fabry

PHOSPHORYLCHOLINE-Cer

Gal-GalNAc-Gal-Glc-Cer

GM1 ganglioside ß-galactosidase GM1 gangliosidosis

GalNAc-Gal-Glc-Cer

NANA

ß-D-Hexosaminidase A

Tay-Sachs ß-D-Hexosaminidase A and B Sandhoff d

Gal-Glc-Cer NANA

Gal-GalNAc-Gal-Glc-Cer o

GM1 ganglioside ß-galactosidase GM1 gangliosidosis g

- GalNAc-Gal-Glc-Cer

ß-D-Hexosaminidase A and B Sandhoff

Gal-Glc-Cer

Gal-Glc-Cer

Ceramide-lactoside- a-Galactosidase A ß-galactosidase Anderson-Fabry

Lactosylceramidosis

Glc-Cer fi-Glucocerebrosidase Gaucher

Sphingomyelinase Niemann-Pick

Ceraminidase Farber fi-Glucocerebrosidase Gaucher

Galactocerebroside ß-galactosidase Krabbe

Arylsulphatases A, B and C Gal-Cer ^—0— Gal-Cer SO4 Metachromatic leucodystrophy Multiple sulphatase deficiency

Galactocerebroside ß-galactosidase Krabbe

Clinical features

Clinical manifestations are due to cellular and tissue damage consequent upon accumulation of abnormal RE cells in various tissues. Three main clinical phenotypes are observed (Table 19.4), determined in large part by the residual activity of the mutant enzyme. All three types are progressive disorders. The residual enzyme activity in type II is so low that abnormal cells accumulate in the central nervous system (CNS). This is the acute neuronopathic form of the disease, which presents with neurological complications in early infancy and usually leads to death before the age of 2 years. Type III GD is the subacute neurono-pathic form that leads to a slowly progressive neurodegenerative disorder. Type I is the commonest form of GD and typically does not cause neurological disease. It is particularly common among

Table 19.4 Clinical manifestations of Gaucher's disease.

Manifestation

Type 1

Type 2

Type 3

Onset

1 year

< 1 year

2-20 years

Hepatosplenomegaly

++

+/-

+

Bone disease

++

-

+/-

Cardiac valve disease

-

-

+

CNS disease

-

+++

+/-

Oculomotor apraxia

-

+

+/-

Corneal opacities

-

+/-

+/-

Age at death

60-90 years

< 5 years

< 30 years

subjects of Ashkenazi Jewish origin; within this community, as many as 1 in 15-20 subjects are carriers, and approximately 1 in 800-1000 subjects are homozygous. Type I GD is a heterogeneous disorder that may present in childhood or in late adult life (> 60 years old). It is likely that many subjects are asymptomatic. Symptomatic individuals have hepatosplenomegaly, skeletal disease and bone marrow infiltration, leading to pancytopenia. Rarer manifestations of type I GD include renal involvement, pulmonary disease and skin involvement. Patients with type I GD have an increased incidence of malignancy generally and an increased incidence of haematological malignancies, especially B-lymphocyte disorders (myeloma, monoclonal gammopathy of undetermined significance) and myelodysplasia.

Laboratory features

Affected individuals have mutations within the GC gene; more than 300 different mutations have been described. The commonest mutation causing type I disease is a single basepair substitution in codon 370 (N370S), which accounts for approximately 70% of mutant alleles in affected Ashkenazi Jewish subjects. A basepair substitution in codon 444 (L444P) is the commonest mutation underlying neuronopathic GD. Diagnosis is confirmed by enzymatic assay of GC activity in leucocytes, fibroblasts and urine. However, enzymatic assay does not always identify heterozygote subjects and measured enzyme activity correlates poorly with clinical severity.

Splenic enlargement and marrow infiltration frequently lead to anaemia, leucopenia and thrombocytopenia.

Changes in serum immunoglobulins are frequent. Polyclonal hypergammaglobulinaemia is found in more than one-third of patients, and monoclonal gammopathy of undetermined significance (MGUS) is seen in up to 20%. Liver function tests are often abnormal, reflecting infiltration of the liver by Gaucher's cells leading to necrosis, fibrosis and, occasionally, even frank cirrhosis. There is an increased incidence of gallstones. The serum cholesterol level is typically lowered. GD is associated with a bleeding diathesis, attributable to abnormal platelet function and thrombocytopenia. Factor XI deficiency is commonly observed and is largely due to co-inheritance of other genetic abnormalities that are also common among Ashkenazi Jews.

The abnormal lipid-laden macrophages are readily detected on tissue biopsy (e.g. bone marrow aspirate, Figure 19.3), although biopsy is no longer considered necessary to make the diagnosis. The serum levels of ferritin, angiotensin-converting enzyme (ACE) and acid phosphatase are typically elevated. The enzyme chitotriosidase is derived from macrophages and is typically grossly elevated in untreated GD, and declines progressively with treatment. Levels may be as high as 30 000 units/L (normal range < 150 units/L); values below 1000 units/L generally indicate stable disease, and with prolonged (> 7 years) enzyme replacement therapy, values may even come down into the normal range (Figure 19.4). However, up to 6% of the population are deficient in this enzyme owing to a 24-basepair

Figure 19.3 Gaucher's cells in the bone marrow.

"O

400 -, 300200 1000

12 10 8620 15 10 5 0

Platelets

Leucocytes

Ferritin

Ferritin

Baseline

Years

Figure 19.4 Clinical course in Gaucher's disease.

duplication in the chitotriosidase gene. These individuals cannot be monitored by measurement of plasma chitotriosidase activity. A new surrogate marker, pulmonary activation-regulated cytokine (Parc) (CCL18), is also elevated in plasma of patients with GD and may be useful for monitoring those patients with chitotriosidase deficiency. Parc is a member of the C-C chemokine family and its overexpression may be relevant to some of the pathophysiological features of GD such as abnormalities in neutrophil chemotaxis.

Treatment

All patients with GD should be evaluated by experienced physicians. Recombinant enzyme is made in Chinese hamster ovary (CHO) cells and additional mannose residues are added to the surface of the enzyme to facilitate uptake of the enzyme via the macrophage mannose receptor. This process allows treatment to be targeted to the RE system. GD is the first lysosomal storage disorder to be treated by enzyme replacement therapy (ERT), which has become the 'gold standard' of therapy for type I GD. Indications for ERT include significant pancytopenia (e.g. Hb < 10 g/dL, platelets < 100 X 109/L), skeletal disease and significant hepatosplenomegaly. High-dose ERT (> 100 units/kg every 2 weeks) is under evaluation at present for type II GD. The recombinant enzyme does not cross the blood-brain barrier and, although hepatosplenomegaly improves, ERT has little discernible impact on CNS disease.

However, ERT has recently (2003) been licensed for patients with type III GD, who typically have milder CNS abnormalities (e.g. ophthalmoplegia) in association with advanced systemic changes. ERT is administered by intravenous infusion (typically in the patient's home) every 1-2 weeks. The dose of therapy is titrated against the severity of clinical and laboratory changes. Type I patients with extensive bony disease and hepatosple-nomegaly require 30+ units/kg every 2 weeks (60+ units/kg for type III), and these high doses should be continued for 23 years or more. Patients are monitored regularly with blood tests (the chitotriosidase assay is particularly helpful) and an annual skeletal MRI. Some patients with advanced type I and III disease may benefit from more frequent infusions (e.g. weekly) for the first year or more. The dose of ERT is gradually lowered as the disease burden declines. Patients with less advanced disease may require lower doses (e.g. 5-10 units/kg every 2 weeks), and some patients may only require monthly infusions. ERT is well tolerated and has been available for over 10 years. A small proportion of patients (< 10%) develop antibodies, but these are not usually neutralizing and do not affect treatment efficacy. Infusion reactions are rare and easily managed.

An oral form of therapy (Miglustat, Zavesca®) has recently been developed, and is licensed for mild to moderate type I disease. It is a form of SRT (see above). It is a small molecule that reduces the amount of substrate (glucosylceramide) being produced within lysosomes, such that patients with reduced residual enzyme activity will benefit. It is being evaluated at present in

Figure 19.5 MRI scan showing skeletal changes in Gaucher's disease.

other lysosomal storage disorders (LSDs) (e.g. Tay-Sachs disease, Niemann-Pick type C) as its administration leads to reduction of a range of substrates in addition to glucosylceramide. SRT does cross the blood-brain barrier and is being evaluated in type III GD and in other LSDs affecting the CNS (e.g. Tay-Sachs).

Supportive therapy is frequently required. The skeletal disease in GD (Figure 19.5) is painful and patients may require analgesia. Prior to the use of ERT, patients frequently developed acute 'bone crisis' - episodic, severe pain, typically in the limbs and often precipitated by dehydration. Bisphosphonate therapy is under evaluation for its potential to reduce pain and rate of progression of skeletal disease. Blood component therapy may be required for pancytopenic patients. Splenectomy should be avoided if possible as splenectomized subjects are more likely to develop tissue infiltration in other organs (e.g. liver, lungs, skeleton). Allogeneic stem cell transplantation is a curative modality of therapy, and has a definite role in carefully selected children with neuronopathic GD.

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