Lysosomal Storage Disorders

Lysosomal Storage Disorders

Lysosomal enzymes break down macromolecules, either those from the cell itself (eg, when cellular structural components are being recycled) or those acquired outside the cell. Inherited defects or deficiencies of lysosomal enzymes (or other lysosomal components) can result in accumulation of undegraded metabolites. Because there are numerous specific deficiencies, storage diseases are usually grouped biochemically by the accumulated metabolite. Subgroups include mucopolysaccharidoses, sphingolipidoses (lipidoses), and mucolipidoses. The most important are the mucopolysaccharidoses and sphingolipidoses. Type 2 glycogenosis is a lysosomal storage disorder, but most glycogenoses are not.

Because reticuloendothelial cells (eg, in the spleen) are rich in lysosomes, such tissues are involved in a number of lysosomal storage disorders, but generally, tissues richest in the substrate are most affected. Thus the brain, which is rich in gangliosides, is particularly affected by gangliosidoses, whereas mucopolysaccharidoses affect many tissues because mucopolysaccharides are present throughout the body.

Mucopolysaccharidoses: Mucopolysaccharidoses (MPS) are inherited deficiencies of enzymes involved in glycosaminoglycan breakdown. Glycosaminoglycans (previously termed mucopolysaccharides) are polysaccharides abundant on cell surfaces and in extracellular matrix and structures. Enzyme deficiencies that prevent glycosaminoglycan breakdown cause accumulation of glycosaminoglycan fragments in lysosomes and cause extensive bone, soft tissue, and CNS changes. Inheritance is usually autosomal recessive.

Age at presentation, clinical manifestations, and severity vary by type. Common manifestations include coarse facial features, neurodevelopmental delays and regression, joint contractures, organomegaly, stiff hair, progressive respiratory insufficiency (from airway obstruction and sleep apnea), cardiac valvular disease, skeletal changes, and cervical vertebral subluxation.

Diagnosis is suggested by history, physical examination, bone abnormalities (eg, dysostosis multiplex) found during skeletal survey, and elevated total and fractionated urinary glycosaminoglycans. Diagnosis is confirmed by enzyme analysis of cultured fibroblasts (prenatal) or peripheral WBCs (postnatal). Additional testing is required to monitor organ-specific changes (eg, echocardiogram for valvular disease, audiometry for hearing changes).

Treatment of MPS type I (Hurler’s disease) is enzyme replacement with α-l-iduronidase, which effectively halts progression and reverses all non-CNS complications of the disease. Hematopoietic stem cell (HSC) transplantation has also shown promise in early studies but is ineffective for CNS disease. The combination of enzyme replacement and HSC transplantation is under study.

Sphingolipidoses: Sphingolipids are normal lipid components of cell membranes; they accumulate in lysosomes and cause extensive neuronal, bone, and other changes when enzyme deficiencies prevent their breakdown. Although incidence is low, carrier rate of some forms is high. Gaucher’s disease is the most common sphingolipidosis. Others include Niemann-Pick, Tay-Sachs, Sandhoff’s, Fabry’s, Krabbe’s, and cholesteryl ester storage diseases and metachromatic leukodystrophy.

Gaucher’s Disease

Gaucher’s disease is a sphingolipidosis resulting from glucocerebrosidase deficiency, causing deposition of glucocerebroside and related compounds. Symptoms and signs vary by type but are most commonly hepatosplenomegaly or CNS changes. Diagnosis is by enzyme analysis of WBCs.

Glucocerebrosidase normally hydrolyzes glucocerebroside to glucose and ceramide. Genetic defects of the enzyme cause glucocerebroside accumulation in tissue macrophages through phagocytosis, forming Gaucher’s cells. Accumulation of Gaucher’s cells in the perivascular spaces in the brain causes gliosis in the neuronopathic forms. There are 3 types, which vary in epidemiology, enzyme activity, and manifestations.

Type I (non-neuronopathic) is most common (90% of all patients). Residual enzyme activity is highest. Ashkenazi Jews are at greatest risk; 1:12 is a carrier. Onset ranges from age 2 yr to late adulthood. Symptoms and signs include splenohepatomegaly, bone disease (eg, osteopenia, pain crises, osteolytic lesions with fractures), growth failure, delayed puberty, ecchymoses, and pingueculae. Epistaxis and ecchymoses resulting from thrombocytopenia are common. X-rays show flaring of the ends of the long bones (Erlenmeyer flask deformity) and cortical thinning.

Type II (acute neuronopathic) is rarest, and residual enzyme activity in this type is lowest. Onset occurs during infancy. Symptoms and signs are progressive neurologic deterioration (eg, rigidity, seizures) and death by age 2 yr.

Type III (subacute neuronopathic) falls between types I and II in incidence, enzyme activity, and clinical severity. Onset occurs at any time during childhood. Clinical manifestations vary by subtype and include progressive dementia and ataxia (IIIa), bone and visceral involvement (IIIb), and supranuclear palsies with corneal opacities (IIIc). Patients who survive to adolescence may live for many years.

Diagnosis and Treatment

Diagnosis is by enzyme analysis of WBCs. Carriers are detected, and types are distinguished by mutation analysis. Although biopsy is unnecessary, Gaucher’s cells—lipid-laden tissue macrophages in the liver, spleen, lymph nodes, or bone marrow that have a wrinkled tissue-paper appearance—are diagnostic.

Enzyme replacement with placental or recombinant glucocerebrosidase is effective in types I and III; there is no treatment for type II disease. The enzyme is modified for efficient delivery to lysosomes. Patients receiving enzyme replacement require routine Hb and platelet monitoring; routine assessment of spleen and liver volume by CT or MRI; and routine assessment of bone disease by skeletal survey, dual-energy x-ray absorptiometry scanning, or MRI. Miglustat some trade names ZAVESCA (100 mg po tid), a glucosylceramide synthase inhibitor, reduces glucocerebroside concentration (the substrate for glucocerebrosidase) and is an alternative for patients unable to receive enzyme replacement.

Splenectomy may be helpful for patients with anemia, leukopenia, or thrombocytopenia or when spleen size causes discomfort. Patients with anemia may also need blood transfusions.

Bone marrow or stem cell transplantation provides a definitive cure but is considered a last resort because of substantial morbidity and mortality.

Niemann-Pick Disease

Niemann-Pick disease is a sphingolipidosis caused by deficient sphingomyelinase activity, resulting in accumulation of sphingomyelin (ceramide phosphorylcholine) in reticuloendothelial cells.

Niemann-Pick disease inheritance is autosomal recessive and appears most often in Ashkenazi Jews; 2 types, A and B, exist. Type C Niemann-Pick disease is an unrelated enzymatic defect involving abnormal cholesterol storage.

Type A patients have < 5% of normal sphingomyelinase activity. The disease is characterized by hepatosplenomegaly, failure to thrive, and rapidly progressive neurodegeneration. Death occurs by age 2 or 3 yr.

Type B patients have sphingomyelinase activity within 5 to 10% of normal. Type B is more variable clinically than type A. Hepatosplenomegaly and lymphadenopathy may occur. Pancytopenia is common. Most patients with type B have little or no neurologic involvement and survive into adulthood; they may be clinically indistinguishable from those with type I Gaucher’s disease. In severe cases of type B, progressive pulmonary infiltrates cause major complications.

Diagnosis and Treatment

Both types are usually suspected by history and examination, most notably hepatosplenomegaly. Diagnosis can be confirmed by sphingomyelinase assay on WBCs and can be made prenatally by using amniocentesis or chorionic villus sampling. Bone marrow or stem cell transplantation is under investigation as a potential treatment option.