Lysosomal storage diseases are due to inborn errors of metabolism which are mainly inherited in an autosomal recessive manner. Glucosylceramide lipidoses:
Gaucher’s disease
This is the most prevalent lysosomal storage disease and is due to a deficiency in glucocerebrosidase, a specialized lysosomal acid l3-glucosidase. This results in accumulation of glucosylceramide in the lysosomes of the reticuloendothelial system, particularly the liver, bone marrow and spleen. Several mutations have been characterized in the glucocerebrosidase gene, the commonest being a single base change causing the substitution of arginine to serine; this is seen in 70% of Jewish patients. The typical Gaucher cell, a glucocerebroside-containing reticuloendothelial histiocyte, is found in the bone marrow. There are three clinical types, the commonest presenting in adult life with an insidious onset of hepatosplenomegaly.
There is a high incidence in Ashkenazi
Jews (1 in 3000 births), and patients have a characteristic pigmentation on exposed parts, particularly the forehead and hands. The clinical spectrum is variable with patients developing anaemia, evidence of hypersplenism and pathological fractures due to bone involvement. Nevertheless, many have a normal life-span.
Acute Gaucher’s disease presents in infancy or childhood with rapid onset of hepatosplenomegaly with neurological involvement due to Gaucher cells in the brain. The outlook is poor.
Some patients with non-neuropathic Gaucher’s disease show considerable improvement with infusion of L-glucerase (mannose-terminated placental glucocerebrosidase).
Sphingomyelin cholesterol lipidoses:
Niemann-Pick disease
The disease is due to a deficiency of lysosomal sphingomyelinase which results in the accumulation of sphingo myelin cholesterol and glycosphingolipids in the reticuloendothelial macrophages and many organs, particularly the liver, spleen, bone marrow and lymph nodes. The disease usually presents within the first 6 months of life with mental retardation and hepatosplenomegaly. Typical foam cells are found in the marrow, lymph nodes, liver and spleen.
The mucopolysaccharidoses (MPS)
These are a group of disorders caused by the deficiency of lysosomal enzymes required for the catabolism of glycosaminoglycans (rn ucopolysaccharides). The catabolism of dermatan sulphate, heparan sulphate, keratin sulphate or chondroitin sulphate may be affected either singularly or together. Accumulation of glycosaminoglycans in the lysosomes of various tissues results in the disease. Ten forms ofMPS have been described; all are chronic but progressive and a wide spectrum of clinical severity can be seen within a single enzyme defect. The MPS types show many clinical features though in variable amounts with dysostosis, abnormal facies, poor vision and hearing and joint dysmobility (either stiff or hypermobile) being frequently seen. Mental retardation is present in, for example, Hurler (MPS IH) and San Filippo A (MPS IlIA) types, but normal intelligence and life-span are seen in Scheie (MPS IS).
The GM2 gangliosidoses
In these conditions there is accumulation of GM2 gangliosides in the central nervous system and peripheral nerves. It is particularly common (1 : 2000) in Ashkenazi Jews. Tay-Sachs disease is the severest form where there is a progressive degeneration of all cerebral function, with fits, epilepsy, dementia and blindness and death usually occurs before 2 years of age. The macula has a characteristic cherry spot appearance.
Fabry’s disease
This X-linked recessive condition is due to a deficiency of the lysosomal hydrolase a-galactosidase, causing an accumulation of glycosphingolipids with terminal a-galactosyl moieties in the lysosomes of various tissues including the liver, kidney, blood vessels and the ganglion cells of the nervous system. The patients present with peripheral nerve involvement, but eventually most patients develop renal problems in adult life.
Diagnosis
Many of the sphingolipidoses can be diagnosed by demonstrating the enzyme deficiency in the appropriate tissue.
Prenatal diagnosis is becoming possible in a number of the conditions by obtaining specimens of amniotic cells. Carrier states can also be identified, so that sensible genetic counselling can be given.
