Biology of Disease

Treatment largely involves supportive care and symptomatic therapy. Patients
with ALD may be given Lorenzo’s oil (glyceroyl trioleate and trierucate oils)
and a strict dietary regimen that returns VLCFAs to normal concentrations
but does not prevent neurological degeneration. A bone marrow transplant
usually has a successful outcome but only if diagnosis is early and the donor
is a perfect HLA match (Chapter 6). The treatment of Zellweger syndrome is
limited. The most beneficial is the administration of the essential long chain
fatty acid, docosahexaenoic acid (Chapter 10). Sufferers of Refsum’s disease
are given a dietary regimen free of phytanic acid.

16.6 Lysosomal Disorders

Lysosomes are organelles bounded by a single, impermeable membrane. They
contain about 60 different hydrolytic enzymes (hydrolases) that are active at
acid pH and are able to degrade all biological materials (Figure 16.12). Other
membrane-bound vesicles, endosomes and phagosomes, fuse with lysosomes
and deliver materials taken up by the cell by endocytosis or phagocytosis for
degradation by these enzymes.

Lysosomal enzymes are synthesized by the ribosomes of the rough endoplasmic
reticulum and enzymes within the Golgi apparatus. In the Golgi apparatus,
synthetic enzymes recognize sites on the surface of the prolysosomal enzymes
and tag them with mannose 6-phosphate residues that act as molecular
addresses, ensuring that they are integrated into vesicles that eventually
become lysosomes.

Lysosomal storage diseases (LSDs) are caused by mutations in genes encoding
lysosomal hydrolases leading to an accumulation of the substrate for the
inactive enzyme within the lysosome (Figure 16.13). Eventually the cell dies,
impairing the functions of major organs such as the brain and liver. More
than 40 lysosomal storage diseases are known (Table 16.4). All are relatively
uncommon in the general population although several are more prevalent
among Ashkenazi Jews.

LYSOSOMAL DISORDERS

CZhhVg6]bZY!BVjgZZc9Vlhdc!8]g^hHb^i]:YLddY )+(

0.6 μm

Figure 16.12 Electron micrograph of lysosomes

in a synovial cell identified by aryl sulfatase

activity. Courtesy of Dr C.J.P. Jones, Department of

Pathology, University of Manchester, UK.

2.5 μm

Figure 16.13 Electron micrograph of enlarged lysosomes containing a zebra body of
accumulated lipid (GM 2 ganglioside, see Table 16.4) from the cerebral cortex of a 19-
week-old fetus. A diagnosis of Tay-Sachs disease was made by showing a deficiency of
hexoseaminidase A activity in cultured amniotic fluid cells obtained by amniocentesis,
following which the fetus was aborted. Courtesy of Dr A. Cooper, Willink Biochemical Genetics
Unit, Royal Manchester Children’s Hospital, UK.

Disease Enzyme deficiency Material (substrate)

accumulated

Sphingolipidosis GM 1

gangliosidosis

B-galactosidase GM 1 gangliosides

Tay-Sachs disease

(GM 2 )

hexoseaminidase A GM 2 gangliosides

Gaucher’s disease B-glucocerebrosidase glucosylceramide

Niemann-Pick disease sphingomyelinase sphingomyelin

Metachromatic leukodystrophy arylsulfatase A sulfatides

Inclusion cell disease (I-cell disease

or mucolipidosis II)

numerous lysosomal

enzymes absent

glycolipids, glycoproteins,

sialyloligosaccharides

Table 16.4Examples of lysosomal storage diseases