Biology of Disease

Lysosomal storage diseases are congenital disorders that seriously reduce

the quality of life and life expectancy. For example, Tay-Sachs disease leads

to blindness, paralysis, dementia and death, usually by two years of age. In

most cases LSDs are caused by the deficiency of a single enzyme. The diseases

can be subdivided according to which pathway is affected. For example,

enzyme deficiencies in the pathway for degrading glycosaminoglycans

cause mucopolysaccharidoses, deficiencies affecting glycopeptides cause

glycoproteinosis and glycolipid storage diseases result from deficiencies in

enzymes involved in the degradation of sphingolipids.

The commonest lysosomal storage disease is Gaucher’s disease with an inci-

dence of one in 30 000 to one in 50 000 although it is about 30 times more

common in Ashkenazi Jews. The disease is characterized by the presence of

histiocytes, cells belonging either to the macrophage or Langerhans cell line-

age (Chapter 4), enlarged with accumulated lipid. These cells are known as

Gaucher’s cells (Figure 16.14) and are found in the bone marrow, reticuloen-

dothelial system, parts of the circulation and other organs. The disease is an

autosomal inherited recessive condition leading to a deficiency of lysosomal

A-glucocerebrosidase and the accumulation of glucosylceramide within lyso-

somes. The pathogenic mechanisms are poorly understood but three forms

are recognized: type 1 or adult, type 2 or infantile and type 3 or juvenile; the

differences presumably arise from different mutations in the gene encoding

the enzyme.

Adult, type 1, Gaucher’s disease may present from infancy to adulthood.

Although some sufferers may die at a young age due to pulmonary

infections, most survive to late adult life. Type 1 disease is characterized by

hepatosplenomegaly, the enlargement of the liver typically occurring after

that of the spleen. The abdomen can also enlarge due to distention of the

colon. Most of these visceral features arise from macrophage dysfunction.

The skin bruises very easily and becomes pale yellow in color. Febrile

episodes with generalized pain in the body and limbs occur. Painful bones,

joints, degeneration of vertebral bodies and arthritic hip joints are common.

Pathological fractures may also occur. Mild anemia and recurrent pulmonary

infections are characteristic. Some patients show neurological abnormalities,

decreased intelligence, with ataxia and fits.

Infantile, type 2, Gaucher’s disease is much more severe with death occur-

ring by the age of two years following progressive psychomotor regression.

The earliest symptoms include a protuberant abdomen usually due to hepat-

osplenomegaly and a general failure to thrive. Indeed, after six months devel-

opmental arrest and neurological regression are obvious characteristics. Fits

may occur. The patient becomes spastic, with laryngeal spasms causing dif-

ficulties in swallowing, and strabismus (a squint or abnormal alignment of

the eyes). Deterioration is rapid, leading to recurrent pulmonary infections

and death.

Juvenile, type 3, Gaucher’s disease is the rarest of the three. Although it presents

later than type 2 and has a slower progression it also has a characteristic

neurological deterioration. The major features are hepatosplenomegaly,

convulsions and psychomotor retardation. Ataxia, spasticity and strabismus

may also occur.

Inclusion cell (I-cell) disease or mucolipidosis II is rare, with an incidence of

about one in 640 000. All lysosomal hydrolases are actually produced but a lack

ofN-acetylglucosylaminyl-1-phosphotransferase activity means they fail to be

tagged with mannose 6-phosphate residues, with the result that they are not

delivered to lysosomes but are secreted from the cell. The disease is named

from the densely staining intracytoplasmic regions present in the fibroblasts

of sufferers (Figure 16.15). Overt symptoms are present at birth or appear

within the first few years of life. There is psychomotor developmental delay

X]VeiZg&+/ MEMBRANE, ORGANELLE AND CYTOSKELETAL DISORDERS

W^dad\nd[Y^hZVhZ

Nucleus

Cytoplasm with

stored material

Figure 16.14 Schematic of a Gaucher’s cell

based on several light micrographs. Note how

the stored material (glucosylceramide, see

Table 16.4) gives the cytoplasm a characteristic

‘wrinkled’ appearance.

X]VeiZg&+/ MEMBRANE, ORGANELLE AND CYTOSKELETAL DISORDERS

)+) W^dad\nd[Y^hZVhZ