Environmental Engineering Reference
In-Depth Information
Ashkenazi Jews, gangliosidosis are predominantly on Japanese, while Pompe is
characteristic for Chinese and African), (2) the opportunity to interfere before the
development of significant neurological sequels on cases diagnosed early and
potentially treatable (i.e. bone marrow transplant for the juvenile form of Krabbe
disease); (3) the possibility of prevention in subsequent pregnancies in families
at risk.
Early diagnosis before serious physical and/or mental deterioration is becoming
more critical as efficient therapy becomes a reality for some disorders. Due to the
wide clinical spectrum of symptoms, the diagnosis of LSDs merely by the clinical
manifestation is difficult; sophisticated laboratory biochemical and molecular
genetic testing being required for establishing a definitive diagnosis of lysosomal
storage diseases. In the first approach, various clinical samples can be used for
measuring the accumulated primary substrate or the lysosomal enzyme activities,
such as urine, blood, amniotic fluid, skin fibroblasts and tissue biopsies. The most
commonly screening tests emphasize the presence of certain oligosaccharides,
glycosphingolipids and glycosaminoglycans in urine and/or blood. This is possible
due to the development of tandem mass spectrometry technique for the identifica-
tion and quantification of lysosomal substrates and metabolites [
47
,
48
] (see
Sect.
8.4
for diagnosis of LSD by mass spectrometry). Extremely accurate prenatal
diagnosis of LSDs is also possible by performing enzymatic assays on chorionic
villus samples, cultured trophoblasts, and cultured amniotic fluid cells. Moreover,
in cases of newborn infants who have no family history of LSDs, early diagnosis
tests are based on measuring the activity of certain proteins and/or lysosomal
enzymes, including lysosome-associated membrane proteins (LAMP-1 and -2)
and saposins in blood samples obtained from heal sticks [
49
].
Although so far are no complete cures for storage disorders, scientists worldwide
are working to develop ways to make the lysosome function normally again.
Presently, patients often undergo a variety of therapies and palliative cares, as
dialysis, surgery or physical therapy that can helpful in managing the symptoms,
have a positive impact on the patient
s quality of life, by they do not change the
biochemical cause of the disease and usually do not prevent disease progression.
However, over the past decades there has been a remarkable development in the
number of disease-specific therapies that can address to principal enzyme and/or
storage problem. These therapies include: (1)
enzyme replacement therapy (ERT)
,
based on intravenous administration of a fully functional wild-type lysosomal
enzyme, and become standard of care for Gaucher, Fabry, Pompe, mucopolysac-
charidosis (MPS) type I and VI diseases; (2)
enzyme enhancement therapy (EET)
,
where low molecular-weight pharmacological chaperons are used to prevent pro-
teins misfolding or mistracking by stabilizing the conformation and restoring the
function of a protein. The major advantage of this therapy against ERT rises from
the possibility of treating LSDs that affect the brain since, unlike therapeutic
enzymes, low molecular-weight chaperones might cross the blood-brain barrier;
(3)
hematopoietic stem cell transplantation (HSCT)
involves the production and
secretion of deficient enzyme by the engrafted donor leukocytes in the host tissue,
which later is taken up by residual enzyme-deficient host cells. This therapy is used
'
