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Gaucher disease.
Curr Opin Chem Biol. 2007 Jul 20;
Although Gaucher
disease is a rare disorder, recent developments in novel means for
therapeutic intervention have invigorated both academic research and
pharmaceutical industry discovery programmes. The common mutations
found in the lysosomal enzyme deficient in Gaucher disease, beta-glucocerebrosidase,
earmark these proteins for destruction by the endoplasmic reticulum-localised
protein folding machinery, resulting in enzyme insufficiency,
lysosomal glycolipid storage and subsequent pathology. However, many
of these mutants can be rescued from global misfolding to preserve
glycolipid substrate binding and eventual catalysis in the lysosome,
by the addition of subinhibitory concentrations of pharmacologically
active small molecules. This novel, chaperon-mediated approach has
benefited from insights into the molecular understanding of beta-glucocerebrosidase
structure, drug design and development in cellular models for disease.
Gaucher
disease: progressive mesenteric and mediastinal lymphadenopathy
despite enzyme therapy.J
Pediatr. 2007;150(2):202-6.
A 5-year-old
male with Gaucher's disease type 3 developed progressive mesenteric
and mediastinal lymphadenopathy over 12 months, despite enzyme
replacement therapy, contributing to the development of a
protein-losing enteropathy. These complications are unique, indicating
poorly accessible, differentially responsive compartments in patients
with Gaucher's disease who are receiving enzyme therapy.
The biology of
the Gaucher cell: the cradle of human chitinases.Int
Rev Cytol. 2006;252:71-128.
Gaucher disease (GD)
is the most common lysosomal storage disorder and is caused by
inherited deficiencies of glucocerebrosidase, the enzyme responsible
for the lysosomal breakdown of the lipid glucosylceramide. GD is
characterized by the accumulation of pathological, lipid laden
macrophages, so-called Gaucher cells. Following the development of
enzyme replacement therapy for GD, the search for suitable surrogate
disease markers resulted in the identification of a thousand-fold
increased chitinase activity in plasma from symptomatic Gaucher
patients and that decreases upon successful therapeutic intervention.
Biochemical investigations identified a single enzyme, named
chitotriosidase, to be responsible for this activity. Chitotriosidase
was found to be an excellent marker for lipid laden macrophages in
Gaucher patients and is now widely used to assist clinical management
of patients. In the wake of the identification of chitotriosidase, the
presence of other members of the chitinase family in mammals was
discovered. Amongst these is AMCase, an enzyme recently implicated in
the pathogenesis of asthma. Chitinases are omnipresent throughout
nature and are also produced by vertebrates in which they play
important roles in defence against chitin-containing pathogens and in
food processing.
CCL18: a urinary marker of Gaucher cell burden in Gaucher patients.J
Inherit Metab Dis. 2006 Aug;29(4):564-71.
Glucosylceramide-laden
tissue macrophages in Gaucher patients secrete large quantities of
chitotriosidase and CC chemokine ligand 18 (CCL18), resulting in
markedly increased plasma levels. We have comparatively investigated
the occurrence of both parameters in plasma and urine samples of
Gaucher patients. Chitotriosidase was high in urine samples of some
symptomatic patients, but elevations did not correlate with increased
plasma concentrations. Urinary chitotriosidase was particularly high
in a patient with severe kidney involvement and local storage cell
infiltration. Urinary levels of CCL18 were also highly elevated in
samples from Gaucher patients as compared to controls. The median
value of the CCL18/creatinine ratio in urine samples of 31 Gaucher
patients was 143.3 pg/micromol (range 32-551) and in those of 12
normal subjects was 4.1 pg/micromol (range 1.3-6.8). In sharp contrast
to chitotriosidase, increases in the low-molecular-mass chemokine
CCL18 in urine and plasma specimens of Gaucher patients correlated
well. A correlation was also observed for reductions in urinary and
plasma CCL18 following therapy. It is concluded that assessment of
urinary CCL18 of Gaucher patients gives insight into the total body
burden on Gaucher cells, whereas that of chitotriosidase does not.
Urinary chitotriosidase appears rather to be a reflection of renal
pathology.
Identification and
use of biomarkers in Gaucher disease and other lysosomal storage
diseases.Acta
Paediatr Suppl. 2005 Mar;94(447):43-6;
The value of
biomarkers in the clinical management of lysosomal storage diseases is
best illustrated by the present use of plasma chitotriosidase levels
in the diagnosis and monitoring of Gaucher disease. The enzyme
chitotriosidase is specifically produced and secreted by the
pathological storage macrophages (Gaucher cells). Plasma
chitotriosidase levels are elevated on average 1000-fold in
symptomatic patients with Gaucher disease and reflect the body burden
on storage cells. Changes in plasma chitotriosidase reflect changes in
clinical symptoms. Monitoring of plasma chitotriosidase levels is
nowadays commonly used in decision making regarding initiation and
optimization of costly therapeutic interventions (enzyme replacement
therapy or substrate reduction therapy). A novel substrate has been
developed that further facilitates the measurement of chitotriosidase
in plasma samples. Moreover, an alternative Gaucher-cell marker,
CCL18, has been very recently identified and can also be employed to
monitor the disease, particularly in those patients lacking
chitotriosidase due to a genetic mutation. There is a need for
comparable surrogate markers for other lysosomal storage diseases and
the search for such molecules is an area of intense investigation.
Conclusion: The use of biomarkers can provide valuable insight into
the molecular pathogenesis of LSDs, such as Gaucher disease and Fabry
disease.
Neurological features in Gaucher's disease during enzyme replacement
therapy.Acta
Paediatr. 2001 Feb;90(2):229-31.
This report
describes two patients with Gaucher's disease who had unusual clinical
symptoms during enzyme replacement therapy. One patient was a female
with type 3 Gaucher's disease. She developed a pericardial effusion at
7 y of age, which contained many Gaucher cells despite enzyme
replacement therapy. She died from neurological deterioration during
enzyme replacement therapy, despite an improvement in her visceral
manifestations. The other patient is a male with type 2 Gaucher's
disease, who has achieved long-term survival after being supported by
mechanical ventilation and enzyme replacement therapy. While on enzyme
replacement therapy at the age of 4 y, he suffered a generalized
cutaneous disease which was clinically diagnosed as ichthyosis.
Conclusion: These cases suggest that ordinary enzyme replacement
therapy is insufficient for some of the non-neurological
manifestations of severe types of Gaucher's disease.
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