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MD Consult: Books: Goldman: Cecil Medicine: Chapter 223 – LYSOSOMAL STORAGE DISEASES

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier


Margaret M. McGovern   Robert J. Desnick

The lysosomal storage diseases are a family of more than 40 disorders resulting from different defects in lysosomal function. Although most of these disorders are caused by deficiency of a specific hydrolytic enzyme, others are due to impaired receptors or deficiencies of crucial cofactors or protective proteins. Prevalent among these disorders are Fabry’s disease, Gaucher’s disease, and Niemann-Pick disease (NPD)—lipid storage diseases that result from mutations in specific genes encoding lipid-degrading enzymes. The respective enzymatic defects lead to the storage of specific lipids and their metabolites in lysosomes. All three of these disorders have later-onset forms that can be manifested clinically in adult life. In addition, Gaucher’s disease and NPD have severe, fatal infantile forms that are described briefly.



Fabry’s disease is an X-linked recessive inborn error of glycosphingolipid metabolism. The classic phenotype occurs in childhood and is characterized by angiokeratomas (telangiectatic skin lesions), hypohidrosis, corneal and lenticular opacities, acroparesthesias, and vascular disease of the kidney, heart, and brain. The disease has an estimated incidence of about 1 in 40,000 males. Later-onset affected males with residual α-galactosidase A activity may have cardiac or renal disease (or both), including hypertrophic cardiomyopathy and renal failure. Females heterozygous for the classic phenotype can be asymptomatic or as severely affected as males, the variability being due to random inactivation of the X chromosome. There is limited information available on the manifestations in heterozygotes for the later-onset phenotypes.


The disease results from mutations in the α-galactosidase A gene, which encodes lysosomal hydrolase α-galactosidase A ( Table 223-1 ). The enzyme deficiency in classically affected males leads to the accumulation of globotriaosylceramide and related glycosphingolipids with terminal α-galactosyl moieties in the plasma and lysosomes of endothelial, perithelial, and smooth muscle cells of blood vessels. These glycosphingolipid deposits are also prominent in epithelial cells of the cornea, in the glomeruli and tubules of the kidney, in muscle fibers of the heart, and in ganglion cells of the dorsal roots and autonomic nervous system. The skin lesions are telangiectases. The larger lesions are usually located in the upper dermis, where they may produce elevation, flattening, or hypertrophy of the epithelium along with keratosis, hence the term angiokeratoma. Ultrastructurally, the glycosphingolipid inclusions in lysosomes have a concentrically arranged lamellar or myelin-like structure. Later-onset patients lack the vascular endothelial glycosphingolipid deposition that is responsible for the early manifestations in the classic phenotype.

TABLE 223-1   — 

Disease Deficiency Substance Accumulated Site Complications
Fabry α-Galactosidase A Primarily globotriaosylceramide Most cells, particularly vascular endothelial and smooth muscle cells Ischemia, infarction
 Type 1 Acid β-glucosidase Primarily glucosylceramide Macrophage-monocyte system hepatosplenomegaly, skeletal complications Infiltration of bone marrow, progressive
 Type 2 Acid β-glucosidase Primarily glucosylceramide Macrophage-monocyte system, CNS hepatosplenomegaly, skeletal complications, neurodegeneration Infiltration of bone marrow, progressive
 Type 3 Acid β-glucosidase Primarily glucosylceramide Macrophage-monocyte system, CNS Progressive neurodegeneration
 Type A Acid sphingomyelinase Sphingomyelin Monocyte-macrophage system, CNS Hepatosplenomegaly, progressive neurodegeneration
 Type B Acid sphingomyelinase Sphingomyelin Monocyte-macrophage system Progressive hepatosplenomegaly, infiltrative lung disease
 Type C Abnormal cholesterol transport Primarily cholesterol Most cells, especially liver, CNS Hepatosplenomegaly, progressive neurodegeneration

CNS = central nervous system.

Clinical Manifestations

Affected males with the classic phenotype have the skin lesions, acroparesthesias, hypohidrosis, and ocular changes, whereas males with the later-onset phenotypes lack these findings and have cardiac or renal disease (or both) in adulthood. Angiokeratomas usually occur in childhood, which may lead to early diagnosis. They increase in size and number with age and range from barely visible to several millimeters in diameter. The lesions are punctate, dark red to blue-black, and flat or slightly raised. They do not blanch with pressure, and the larger ones may show slight hyperkeratosis. Characteristically, the lesions are most dense between the umbilicus and the knees, in the “bathing trunk area,” but they may occur anywhere, including the oral mucosa. The hips, thighs, buttocks, umbilicus, lower part of the abdomen, scrotum, and glans penis are common sites, and a tendency toward bilateral symmetry is noted. Variants without skin lesions have been described. Sweating is usually decreased or absent. Corneal opacities and characteristic lenticular lesions, observed by slit lamp examination, are present in affected male patients, as well as in about 70 to 80% of heterozygotes for the classic phenotype. Conjunctival and retinal vascular tortuosity is common and results from systemic vascular involvement.

Pain is the most debilitating symptom in childhood and adolescence. Fabry crises, lasting from minutes to several days, consist of agonizing, burning pain in the hands and feet and proximal parts of the extremities and are usually associated with exercise, fatigue, and fever. These painful acroparesthesias usually become less frequent in the third and fourth decades of life, although in some men they may become more frequent and severe. Attacks of abdominal or flank pain may simulate appendicitis or renal colic.

With increasing age, the major morbid symptoms result from progressive involvement of the vascular system. Early in the course of the disease, casts, red blood cells, and lipid inclusions with characteristic birefringent “Maltese crosses” appear in the urinary sediment. Proteinuria, isosthenuria, gradual deterioration in renal function, and the development of azotemia occur in the second to fourth decades. Cardiovascular findings may include hypertension, left ventricular hypertrophy, anginal chest pain, myocardial ischemia or infarction, and congestive heart failure. Mitral insufficiency is the most common valvar lesion. Abnormal electrocardiographic and echocardiographic findings are common. Cerebrovascular manifestations result primarily from multifocal small vessel involvement. Other features may include obstructive airway disease that increases with age, lymphedema of the legs without hypoproteinemia, episodic diarrhea, osteoporosis, retarded growth, and delayed puberty. Death most often results from uremia or vascular disease of the heart or brain. Before the advent of hemodialysis and renal transplantation, the mean age at death in affected men was 40 years.

Patients with later-onset cardiac variants and residual α-galactosidase A activity have cardiac disease and may have mild proteinuria but usually have normal renal function for age. The cardiac manifestations include hypertrophy of the left ventricular wall and interventricular septum and electrocardiographic abnormalities consistent with cardiomyopathy. Others have had hypertrophic cardiomyopathy or myocardial infarction, or both.


The diagnosis of Fabry’s disease in classically affected males should be pursued in individuals who have acroparesthesias, hypohidrosis, characteristic skin lesions, corneal opacities, or lenticular lesions. The diagnosis of classic and variant cases is confirmed biochemically by markedly decreased α-galactosidase A activity in plasma, isolated leukocytes, or cultured fibroblasts or lymphoblasts. Variants lack the early classic manifestations.

Females heterozygous for the classic phenotype may have corneal opacities, isolated skin lesions, and low to normal activities of α-galactosidase A in plasma or cell sources. Rare female heterozygotes may have manifestations as severe as those in affected male subjects. However, in asymptomatic, at-risk female members of families affected by Fabry’s disease, optimal diagnosis should be by direct analysis of the family’s specific mutation. Prenatal detection of affected male fetuses can be accomplished by demonstrating deficient α-galactosidase A activity or by detecting the family’s specific gene mutation in chorionic villi obtained in the first trimester of pregnancy or in cultured amniocytes obtained by amniocentesis in the second trimester.

Differential Diagnosis

Fabry’s disease is often misdiagnosed as rheumatic fever, erythromyalgia, or neurosis. The skin lesions must be differentiated from benign angiokeratomas of the scrotum (Fordyce’s disease) and from angiokeratoma circumscriptum. Angiokeratomas identical to those of Fabry’s disease have been reported in patients with fucosidosis, aspartylglycosaminuria, late-onset GM1 gangliosidosis, galactosialidosis, α-N-acetylgalactosaminidase deficiency, and sialidosis. Diagnosis of later-onset cardiac variants should be considered in individuals with left ventricular hypertrophy or cardiomyopathy. Recently, later-onset variants have been identified in chronic hemodialysis patients.


Clinical trials with recombinant α-galactosidase (Fabrazyme, Genzyme Corporation, Cambridge, MA; Replagal, TKT Corporation, Cambridge, MA) have revealed the safety and effectiveness of enzyme replacement therapy for Fabry’s disease at a dose of 1 mg/kg every other week.[1] The enzyme replacement therapy is available in Europe and has been approved by the U.S. Food and Drug Administration. Renal transplantation and long-term hemodialysis have also become life-saving procedures for patients with renal failure.



Gaucher’s disease is a glycolipid storage disease characterized by the deposition of glucocerebroside in cells of the macrophage-monocyte system. Three clinical subtypes are delineated by the absence or presence and progression of neurologic involvement: type 1, the adult non-neuronopathic form; type 2, the infantile or acute neuronopathic form; and type 3, the juvenile or subacute neuronopathic form. All three subtypes are inherited as autosomal recessive traits.


Type 1 disease is the most common lysosomal storage disease and the most prevalent genetic disorder in Ashkenazi Jewish individuals, with an incidence of about 1 in 1000 and a carrier frequency of about 1 in 16 to 18.



All three subtypes of Gaucher’s disease result from deficient activity of lysosomal hydrolase acid β-glucosidase (see Table 223-1 ). The molecular basis of Gaucher’s disease has been identified for more than 95% of Ashkenazi Jewish patients ( Table 223-2 ). Genotype/phenotype correlations have been noted for the different subtypes, particularly type 1 Gaucher’s disease. Presumably, the amount of residual enzymatic activity determines the disease subtype and severity. For example, type 1 patients homozygous for the milder N370S mutation tend to have a later onset and milder course than do patients with one N370S allele and another mutant allele. However, the wide variability in clinical findings among patients with Gaucher’s disease cannot be fully explained by the nature of the underlying acid β-glucosidase mutations. The lesions causing the severe type 2 (infantile) disease express little if any enzymatic activity in vitro.

TABLE 223-2   — 

Disease Chromosome Assignment Molecular Characteristics Comments
Fabry Xq22.1 cDNA, entire genomic sequences, >450 mutant alleles known More than 450 private mutations detected in a single or a few families
Gaucher 1q21 cDNA, functional and pseudogenomic sequences, >200 mutant alleles known Four mutations (N370S, L444P, 84insG, IVS2+1) account for 90 to >95% of mutant alleles in Ashkenazi Jewish patients
 Types A and B 11p15.1 to p15.4 cDNA, entire genomic sequence, >100 mutant alleles known Four mutations account for >95% of mutant alleles in Ashkenazi Jewish patients with type A disease
 Type C 18q11-q12 region cDNA, entire genomic sequence, >100 mutant alleles known More than 100 mutations in the NPC1 gene

cDNA = complementary DNA; mRNA = messenger RNA.


The pathologic hallmark is the presence of Gaucher cells in the macrophage-monocyte system, particularly in the bone marrow. These cells, which are 20 to 100 μm in diameter, have a characteristic wrinkled-paper appearance resulting from intracytoplasmic substrate deposition. These cells stain strongly positive with periodic acid–Schiff stain, and their presence in bone marrow or other tissues suggests the diagnosis ( Fig. 223-1 ). The accumulated glycolipid glucosylceramide is derived primarily from the phagocytosis and degradation of senescent leukocytes and to a lesser extent from erythrocyte membranes. Glycolipid storage results in organomegaly and pulmonary infiltration. Neuronal cell loss in patients with type 2 and 3 disease is presumably caused by accumulation of the cytotoxic glycolipid glucosylsphingosine in the brain as a result of the severe deficiency of acid β-glucosidase activity. Accumulation of glucosylceramide in the bone marrow, liver, spleen, lungs, and kidney leads to pancytopenia, massive hepatosplenomegaly, and occasionally, diffuse infiltrative pulmonary disease and nephropathy or glomerulonephritis. The progressive infiltration of Gaucher cells into bone marrow causes thinning of the cortex, pathologic fractures, bone pain, bony infarcts, and osteopenia. Central nervous system involvement occurs only in patients with type 2 and 3 disease.

FIGURE 223-1  Niemann-Pick disease. Gaucher cell (A) and a foam cell (B) seen in a case of Niemann-Pick disease. Both are viewed under phase microscopy with unstained smears of aspirated bone marrow. Magnification can be estimated from adjacent red blood cells.

Clinical Manifestations

A broad spectrum of clinical expression is seen in patients with type 1 disease, in part because of a combination of different mutant alleles and unidentified modifier genes. The onset of clinical manifestations occurs from early childhood to late adulthood. At examination, patients may display easy bruisability because of thrombocytopenia, chronic fatigue secondary to anemia, hepatomegaly with or without elevated liver function test results, splenomegaly, and bone pain or pathologic fractures. Occasional patients have pulmonary involvement. Patients whose disease is diagnosed in the first 5 years of life are frequently non-Jewish and typically have a more malignant disease course. Patients with milder disease are discovered later in life during evaluation for hematologic or skeletal problems or are found to have splenomegaly on routine examination. In symptomatic patients, the splenomegaly is progressive and can become massive. Clinically apparent bone involvement, which occurs in more than 20% of patients, can be manifested as bone pain or pathologic fractures. Most patients have radiologic evidence of skeletal involvement, including an Erlenmeyer flask deformity of the distal end of the femur and osteopenia, which are early skeletal changes. In patients with symptomatic bone disease, lytic lesions can develop in the long bones, ribs, and pelvis, and osteosclerosis may be evident at an early age. Bone crises with severe pain and swelling can occur. Bleeding secondary to thrombocytopenia may be manifested as epistaxis and bruising and is frequently overlooked until other symptoms become apparent. Children with massive splenomegaly are short in stature because of the energy expenditure required by the enlarged organ.

Type 2 disease, which is rare and panethnic in distribution, is characterized by a rapid neurodegenerative course with extensive visceral involvement and death within the first 2 years of life. The disease occurs in infancy and is associated with increased tone, strabismus, and organomegaly. Failure to thrive and stridor from laryngospasm are typical. The progressive psychomotor degeneration leads to death, usually secondary to an intercurrent respiratory infection and respiratory compromise.

Type 3 disease is noted in infancy or childhood. In addition to the organomegaly and bone involvement, patients have neurodegenerative manifestations. Type 3 disease is most frequent in Sweden (1 in 50,000), where it has been traced to a common founder in the 17th century. Type 3 has been further subclassified as types 3a and 3b based on the extent of neurologic involvement and whether progressive myotonia and dementia (type 3a) or isolated supranuclear gaze palsy (type 3b) is present.


Gaucher’s disease should be considered in the differential diagnosis of patients with unexplained organomegaly, easy bruisability, or bone pain. Bone marrow examination usually reveals the presence of Gaucher cells; however, all suspected diagnoses should be confirmed by demonstration of deficient acid β-glucosidase activity in isolated leukocytes or cultured cells. For possible genotype/phenotype correlations, the specific acid β-glucosidase mutation may be determined, particularly in Ashkenazi Jewish patients. Carrier identification is best achieved by DNA testing in Jewish families. Testing should be offered to all family members, but it should be kept in mind that heterogeneity, even among members of the same kindred, can be so great that cases may be diagnosed in asymptomatic affected individuals during such testing. Prenatal diagnosis is possible by determining the enzymatic activity or specific mutations in chorionic villi or cultured amniotic fluid cells.


Enzyme replacement with recombinant acid β-glucosidase is available for the treatment of symptomatic patients with type 1 disease. Clinical trials have demonstrated that most extraskeletal symptoms are reversed within 12 to 36 months by an initial debulking dose of enzyme (60 IU/kg) administered by intravenous infusion every other week. Early treatment may be efficacious in normalizing linear growth and bone morphology in affected children. Efforts are also under way to develop gene therapy for type 1 disease. Although enzyme replacement does not alter the neurologic progression of patients with types 2 and 3 Gaucher’s disease, it has been used in selected patients as a palliative measure, particularly in type 3 patients with severe visceral involvement. Alternative treatments are also being evaluated, including the use of agents designed to decrease the synthesis of glucosylceramide by chemical inhibition of glucosylceramide synthase.

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