Lysosomal Storage Disorders — Sphingolipidoses, Mucopolysaccharidoses (Hurler vs Hunter) and I-Cell Disease

Lysosomes are acidic organelles full of hydrolases that break down lipids, glycosaminoglycans and other macromolecules. In a lysosomal storage disorder (LSD) one of these enzymes — or a protein needed to deliver it — is missing, so the undigested substrate builds up inside lysosomes and the cells swell and fail. Individually each is rare, but together LSDs affect about 1 in 5,000 to 1 in 8,000 births.

• Sphingolipidoses — defects in sphingolipid breakdown: Gaucher, Niemann-Pick, Tay-Sachs, Fabry, Krabbe, metachromatic leukodystrophy.
• Mucopolysaccharidoses (MPS) — defects in glycosaminoglycan breakdown: Hurler (MPS I), Hunter (MPS II) and others.
• Targeting defects — the enzyme is made but never reaches the lysosome: I-cell disease (mucolipidosis II).

Gaucher disease is the most prevalent lysosomal storage disorder. Deficient glucocerebrosidase lets glucocerebroside accumulate in macrophages of the liver, spleen and bone marrow. Without treatment the liver can enlarge two- to three-fold and the spleen up to 15-fold. Marrow infiltration causes thrombocytopenia, anaemia and leukopenia, bone pain, avascular necrosis, osteoporosis, pathological fractures and the Erlenmeyer flask deformity.

The hallmark Gaucher cell is a lipid-laden macrophage, mostly in bone marrow, with a wrinkled-paper (crumpled tissue paper) cytoplasm that is PAS-positive. Diagnosis rests on enzyme assay and genetics, not biopsy. Raised chitotriosidase, ACE, acid phosphatase and ferritin help in monitoring.

Niemann-Pick type B is a milder visceral form — hepatosplenomegaly, interstitial lung disease with recurrent infections, thrombocytopenia and slow bone growth — with neurological signs and a cherry-red spot in about one-third. Type C is different: it results from NPC1 or NPC2 mutations that block cholesterol trafficking out of lysosomes, and it presents at any age with ataxia, dystonia, supranuclear gaze palsy, dysphagia and liver disease.

In Tay-Sachs, GM2 accumulates in retinal ganglion cells around the macula, turning it grey-white, while the fovea — which has no ganglion cells — stays red: that is the cherry-red spot. Sandhoff disease (both hexosaminidase A and B deficient) resembles Tay-Sachs but adds hepatosplenomegaly, cardiomegaly and skeletal changes.

Fabry disease is the X-linked sphingolipidosis. Deficient α-galactosidase A lets globotriaosylceramide build up in cells throughout the body. Boys present in childhood with burning acroparesthesia of the hands and feet, angiokeratomas, reduced sweating, corneal and lens opacities (cornea verticillata; spoke-like cataract), then proteinuria progressing to end-stage renal disease, cardiac involvement with arrhythmias, and stroke in adulthood. Heterozygous women are usually milder. Enzyme replacement therapy slows progression.

Krabbe disease (globoid cell leukodystrophy) is caused by galactocerebrosidase deficiency (gene on chromosome 14). Galactosylceramide and the toxic metabolite psychosine accumulate in the central and peripheral nervous systems, where galactolipids are abundant in oligodendrocytes and Schwann cells. The classic infantile form starts at 4–6 months with irritability, feeding difficulty and hypersensitivity to touch, noise or light, then optic atrophy, opisthotonus and severe spasticity. Brain biopsy shows multinucleated globoid cells.

Metachromatic leukodystrophy (MLD) is caused by arylsulfatase A deficiency (rarely by saposin B deficiency), so sulfatides accumulate and destroy central and peripheral myelin; they also deposit in kidney, testes and gallbladder. Tissue shows metachromatic granules. Forms are late infantile (6 months to 4 years), juvenile (4–16 years) and adult (over 16 years).

The mucopolysaccharidoses are failures to degrade glycosaminoglycans (GAGs). Both Hurler and Hunter store dermatan sulfate and heparan sulfate, so they share coarse facies, hepatosplenomegaly, hernias, joint stiffness and skeletal dysostosis multiplex. The exam separates them by inheritance and the eye.

ERT improves the blood picture, organ size, bone, heart and lung function and quality of life, but because it cannot enter the brain it does not treat central nervous system disease — the reason Gaucher ERT is used for types 1 and 3 and miglustat is valued in neuropathic disease. Newborn screening programmes for the commoner LSDs are finding more cases, many with late-onset phenotypes.

Newly made lysosomal hydrolases are tagged in the cis-Golgi by N-acetylglucosamine-1-phosphotransferase (GlcNAc-1-phosphotransferase, gene GNPTAB), which adds the mannose-6-phosphate (M6P) signal to more than 70 lysosomal enzymes. M6P receptors in the trans-Golgi network then route them to lysosomes. In I-cell disease (mucolipidosis II), an autosomal recessive loss of this phosphotransferase means the enzymes are made normally but are missorted — they leave the cell instead of reaching the lysosome.

• Biochemistry: many lysosomal enzymes are high in plasma, while urinary GAGs are normal or only mildly raised. Cells are packed with inclusions — hence 'inclusion cell'.
• Clinical picture: evident at birth; coarse facies, thickened skin, gingival hypertrophy, joint contractures, growth failure, dysostosis multiplex, mitral valve thickening; death within the first decade (average about 5 years).
• Hurler look-alike: I-cell disease resembles Hurler, but the corneas are often clear (19 of 21 patients in one series) and urine GAG excretion is not heavy.