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disease severity and is responsive to therapy. In addition to its role as a biomarker,
the discovery of increased serpin-serine protease complex formation provides a
valuable insight into possible pathophysiological mechanisms of MPS.
Gaucher’s disease is the most common LSD. Gene defect leads to defi ciency or
decreased activity of glucocerebrosidase followed by the accumulation of glucosyl-
ceramide. Frequent manifestations are hepatosplenomegaly, anemia, skeletal and
hematological abnormalities. Recently used enzyme replacement therapy (ini-
fucerase) seems to eliminate the need for bone marrow transplantation and has
favorable effects on symptoms and outcome. Development of gene therapy (reintro-
duction of missing DNA sequence) offers the possibility of cure of the disease. The
biochemical markers secreted by Gaucher’s cells are numerous, but none of those
identifi ed to date has offered all the expected qualities of a biomarker. Chitotriosidase
and chemokine CCL18 are the most useful biomarkers to monitor enzyme replace-
ment therapy. The identifi cation of new biomarkers in the near future should enable
a clearer understanding of the pathophysiology of this complex disease, which
involves numerous cell processes.
Fucosidosis, another LSD, is an autosomal recessive disorder resulting from a
defi ciency of α-L-fucosidase, encoded by the FUCA1 gene, which leads to failure
in the catabolism of glycoproteins and glycosphingolipids resulting in the accumu-
lation of a range of fuco-oligosaccharides and sphingolipids in all tissues including
brain and liver. Severely affected patients present within the fi rst year of life with
mental retardation, growth retardation, and abnormalities in various other organs.
Most of the diagnostic procedures are either invasive or impractical. PCR can be
useful only once the mutation is known. The most practical test is detection by mass
spectrometry of the elevated oligosaccharides as a biomarker in urine.
Prenatal diagnosis is available for many LSDs using chorionic villus samples or
amniocytes. Such diagnoses can be problematical if sample transport and culture
are required prior to analysis. It is possible to identify useful biomarkers for the
diagnosis of LSDs from amniotic fl uid. Each disorder produces a unique signature
metabolic profi le of protein, oligosaccharide, and glycolipid biomarkers. Some
metabolite elevations directly related to the disorder whilst others appeared unre-
lated to the primary defect. Many LSDs are clearly distinguishable from control
populations by the second trimester and in one case in the fi rst trimester. Samples
from GM1 gangliosidosis and mucopolysaccharidosis type VII display a correlation
between gestational age and amount of stored metabolite. These results provide
proof of principal for the use of biomarkers contained in amniotic fl uid as clinical
tests for some of the more frequent LSDs.
Sequencing in Genetic Disorders
An introduction to DNA sequencing and its relation to personalized medicine were
discussed in Chap. 2. Details of sequencing technologies are described in a special
report on this subject (Jain 2015c ). Applications of sequencing in genetic disorders
are given in this chapter.
16 Personalized Management of Genetic Disorders