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
The most important are the mucopolysaccharidoses and sphingolipidoses. Type 2 glycogenosis is a lysosomal storage disorder, but most glycogenoses are not. For a more complete listing of lysosomal storage disorders, see Table Lysosomal Storage Disorders.
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Because reticuloendothelial cells (eg, in the spleen) are rich in lysosomes, reticuloendothelial 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.
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 (except for MPS type II).
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 (caused by 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, echocardiography 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.
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 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 (nonneuronopathic) 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 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. 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 (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 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.
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.
Tay-Sachs Disease and Sandhoff's Disease
Tay-Sachs disease and Sandhoff's disease are sphingolipidoses caused by hexosaminidase deficiency that causes severe neurologic symptoms and early death.
Gangliosides are complex sphingolipids present in the brain. There are 2 major forms, GM1 and GM2, both of which may be involved in lysosomal storage disorders; there are 2 main types of GM2 gangliosidosis, each of which can be caused by numerous different mutations.
Deficiency of hexosaminidase A results in accumulation of GM2 in the brain. Inheritance is autosomal recessive; the most common mutations are carried by 1/27 normal adults of Eastern European (Ashkenazi) Jewish origin, although other mutations cluster in some French-Canadian and Cajun populations.
Children with Tay-Sachs disease start missing developmental milestones after age 6 mo and develop progressive cognitive and motor deterioration resulting in seizures, intellectual disability, paralysis, and death by age 5 yr. A cherry-red macular spot is common.
Diagnosis is clinical and can be confirmed by enzyme assay.
In the absence of effective treatment, management is focused on screening adults of childbearing age in high-risk populations to identify carriers (by way of enzyme activity and mutation testing) combined with genetic counseling.
There is a combined hexosaminidase A and B deficiency. Clinical manifestations include progressive cerebral degeneration beginning at 6 mo, accompanied by blindness, cherry-red macular spot, and hyperacusis. It is almost indistinguishable from Tay-Sachs disease in course, diagnosis, and management, except that there is visceral involvement (hepatomegaly and bone change) and no ethnic association.
Krabbe's disease is a sphingolipidosis that causes intellectual disability, paralysis, blindness, deafness, and pseudobulbar palsy, progressing to death.
Krabbe's disease (galactosylceramide lipidosis, globoid cell leukodystrophy) is caused by an autosomal recessive galactocerebroside β-galactosidase deficiency.
It affects infants and is characterized by intellectual disability, paralysis, blindness, deafness, and pseudobulbar palsy, progressing to death.
Diagnosis is by detecting enzyme deficiency in WBCs or cultured skin fibroblasts.
Because bone marrow transplantation effectively delays onset of symptoms, prenatal testing or neonatal screening (routine in New York) is sometimes done.
Metachromatic leukodystrophy is a sphingolipidosis caused by arylsulfatase A deficiency, which causes progressive paralysis and dementia resulting in death by age 10 yr.
In metachromatic leukodystrophy (sulfatide lipidosis), arylsulfatase A deficiency causes metachromatic lipids to accumulate in the white matter of the CNS, peripheral nerves, kidney, spleen, and other visceral organs; accumulation in the nervous system causes central and peripheral demyelination. Numerous mutations exist; patients vary in age at onset and speed of progression.
The infantile form is characterized by progressive paralysis and dementia usually beginning before age 4 yr and resulting in death about 5 yr after onset of symptoms. The juvenile form manifests between 4 yr and 16 yr of age with gait disturbance, intellectual impairment, and findings of peripheral neuropathy. Contrary to the infantile form, deep tendon reflexes are usually brisk. There is also a milder adult form.
Diagnosis is suggested clinically and by findings of decreased nerve conduction velocity; it is confirmed by detecting enzyme deficiency in WBCs or cultured skin fibroblasts.
There is no effective treatment.
Fabry's disease is a sphingolipidosis caused by deficiency of α-galactosidase A, which causes angiokeratomas, acroparesthesias, corneal opacities, recurrent febrile episodes, and renal or heart failure.
Fabry's disease (angiokeratoma corporis diffusum) is an X-linked deficiency of the lysosomal enzyme α-galactosidase A, which is needed for normal trihexosylceramide catabolism. Glycolipid (globotriaosylceramide) accumulates in many tissues (eg, vascular endothelium, lymph vessels, heart, kidney).
Diagnosis in males is clinical, based on appearance of typical skin lesions (angiokeratomas) over the lower trunk and by characteristic features of peripheral neuropathy (causing recurrent burning pain in the extremities), corneal opacities, and recurrent febrile episodes. Death results from renal failure or cardiac or cerebral complications of hypertension or other vascular disease. Heterozygous females are usually asymptomatic but may have an attenuated form of disease often characterized by corneal opacities.
Diagnosis is by assay of galactosidase activity—prenatally in amniocytes or chorionic villi and postnatally in serum or WBCs.
Treatment is enzyme replacement with recombinant α-galactosidase A (agalsidase beta) combined with supportive measures for fever and pain. Kidney transplantation is effective for treating renal failure.
Cholesteryl Ester Storage Disease and Wolman's Disease
Cholesteryl ester storage disease and Wolman's disease are sphingolipidoses caused by lysosomal acid lipase deficiency resulting in hyperlipidemia and hepatomegaly.
These diseases are rare, autosomal recessive disorders that result in accumulation of cholesteryl esters and triglycerides, mainly in lysosomes of histiocytes, resulting in foam cells in the liver, spleen, lymph nodes, and other tissues. Serum low-density lipoprotein (LDL) is usually elevated.
Wolman's disease is the more severe form, manifesting in the first weeks of life with poor feeding, vomiting, and abdominal distention secondary to hepatosplenomegaly; infants usually die within 6 mo.
Cholesteryl ester storage disease is less severe and may not manifest until later in life, even adulthood, at which time hepatomegaly may be detected; premature atherosclerosis, often severe, may develop.
Diagnosis is based on clinical features and detection of acid lipase deficiency in liver biopsy specimens or cultured skin fibroblasts, lymphocytes, or other tissues. Prenatal diagnosis is based on the absence of acid lipase activity in cultured chorionic villi.
There is no proven treatment, but statins reduce plasma LDL levels, and cholestyramine combined with a low-cholesterol diet has reportedly alleviated other signs.
Last full review/revision February 2010 by Chin-To Fong, MD