Clinical Information

Lysosomes are intracellular organelles that contain hydrolytic enzymes that degrade a variety of macromolecules. Lysosomal storage disorders are a diverse group of inherited diseases characterized by the intracellular accumulation of macromolecules due to defects in their transport mechanisms across the lysosomal membrane or due to defective lysosomal enzyme function. The accumulation of these macromolecules leads to cell damage and, eventually, organ dysfunction. More than 40 lysosomal storage disorders have been described with a wide phenotypic spectrum.

Gaucher disease, which is inherited as an autosomal recessive lysosomal storage disorder, is caused by a deficiency of acid beta-glucosidase (glucocerebrosidase: GBA), resulting in increased storage of glucocerebroside (D-glucosylceramide). The deposition of glucocerebroside in macrophages of the reticuloendothelial system (Gaucher cells) causes organ dysfunction and organomegaly. Gaucher cells, found in the spleen, bone marrow, lung, lymph nodes, and liver, are characteristic of the disease. There are 3 clinical types of Gaucher disease:

-Type 1: adult/chronic

-Type 2: acute neuropathic/infantile

-Type 3: subacute neuropathic/juvenile

Type 1, the most frequent form of the disease, is characterized by organomegaly, thrombocytopenia, and bone pain, and is frequent among the Ashkenazi Jewish population. Hepatosplenomegaly is usually present in all 3 types. Involvement of the central nervous system (CNS) is limited to the infantile type (type 2). Treatment is available in the form of enzyme replacement therapy, substrate reduction therapy, and/or chaperone therapy for types 1 and 3. Currently, only supportive therapy is available for type 2.

Niemann-Pick disease types A and B are caused by a deficiency of sphingomyelinase, which results in extensive storage of sphingomyelin and cholesterol in the liver, spleen, lungs, and, to a lesser degree, brain. Niemann-Pick type A disease is more severe than type B and characterized by early onset with feeding problems, dystrophy, persistent jaundice, development of hepatosplenomegaly, neurological deterioration, deafness, and blindness, leading to death by age 3. Niemann-Pick type B disease is limited to visceral symptoms with survival into adulthood. Some patients have been described with intermediary phenotypes. Characteristic of the disease are large lipid-laden foam cells. Approximately 50% of cases have cherry-red spots in the macula. Niemann-Pick types A and B are caused by mutations in the SMPD1 gene.

Pompe disease, also known as glycogen storage disease type II, is an autosomal recessive disorder caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA; acid maltase) due to mutations in the GAA gene. The estimated incidence is 1 in 40,000 live births. In Pompe disease, glycogen that is taken up by lysosomes during physiologic cell turnover accumulates, causing lysosomal swelling, cell damage, and, eventually, organ dysfunction. This leads to progressive muscle weakness, cardiomyopathy, and, eventually, death. The clinical phenotype appears to be dependent on residual enzyme activity. Complete loss of enzyme activity causes onset in infancy leading to death, typically within the first year of life. Juvenile and adult-onset forms, as the names suggest, are characterized by later onset and longer survival. Because Pompe disease is considered a rare condition that progresses rapidly in infancy, the disease, in particular the juvenile and adult-onset forms, is often considered late, if at all, during the evaluation of patients presenting with muscle hypotonia, weakness, or cardiomyopathy. Treatment by enzyme replacement therapy became available recently, making early diagnosis of Pompe disease desirable, as early initiation of treatment may improve prognosis.

Krabbe disease (globoid cell leukodystrophy) is an autosomal recessive disorder caused by mutations in the GALC gene resulting in a deficiency of galactocerebrosidase (GALC, galactosylceramide beta-galactosidase). Galactosylceramide (as with sulfated galactosylceramide) is a lipid component of myelin. The absence of GALC results in globular, distended, multinucleated bodies in the basal ganglia, pontine nuclei, and cerebral white matter. There is severe demyelination throughout the brain with progressive cerebral degenerative disease affecting primarily the white matter. Patients with this early infantile onset variant of Krabbe disease (<1 in 250,000 live births) die within 2 years. Late infantile-onset Krabbe disease manifests between 6 and 12 months of life and leads to death within a few years as well. Juvenile and adult onset variants present later in life, progress more slowly and, based on newborn screening experience in New York, appear to be more common than the earlier onset variants. Of note, Krabbe disease variants, including pseudodeficiency, may not be discriminated by enzyme activity measurement. Hematopoietic stem cell transplantation, particularly when performed within the first few weeks of life, has shown variable benefit.

Fabry disease, caused by mutations in the GLA gene, is an X-linked recessive disorder with an incidence of approximately 1 in 50,000 males. Symptoms result from a deficiency of the enzyme alpha-galactosidase A (GLA; ceramide trihexosidase). Reduced GLA activity results in accumulation of glycosphingolipids in the lysosomes of both peripheral and visceral tissues. Severity and onset of symptoms are dependent on the residual GLA activity. Males with <1% GLA activity have the classic form of Fabry disease. Symptoms can appear in childhood or adolescence and usually include acroparesthesias (pain crises), multiple angiokeratomas, reduced or absent sweating, and corneal opacity. Renal insufficiency, leading to end-stage renal disease and cardiac and cerebrovascular disease, generally occur in middle age. Males with >1% GLA activity may present with a variant form of Fabry disease. The renal variant generally has onset of symptoms in the third decade. The most prominent feature in this form is renal insufficiency and, ultimately, end-stage renal disease. Individuals with the renal variant may or may not share other symptoms with the classic form of Fabry disease. Individuals with the cardiac variant are often asymptomatic until they present with cardiac findings such as cardiomyopathy or mitral insufficiency in the fourth decade. The cardiac variant is not associated with renal failure. Females who are carriers of Fabry disease can have clinical presentations ranging from asymptomatic to severely affected.

Mucopolysaccharidosis I (MPS I) is an autosomal recessive disorder caused by a reduced or absent activity of the alpha-L-iduronidase enzyme. Deficiency of the alpha-L-iduronidase enzyme can result in a wide range of phenotypes further categorized into 3 syndromes: Hurler syndrome (MPS IH), Scheie syndrome (MPS IS), and Hurler-Scheie syndrome (MPS IH/S). Because there is no way to distinguish the syndromes biochemically, they are also referred to as MPS I and attenuated MPS I.

Clinical features and severity of symptoms of MPS I are widely variable, ranging from severe disease to an attenuated form that generally presents at a later onset with a milder clinical presentation. In general, symptoms may include coarse facies, progressive dysostosis multiplex, hepatosplenomegaly, corneal clouding, hearing loss, mental retardation or learning difficulties, and cardiac valvular disease. MPS-I is caused by mutations in the IDUA gene and has an estimated incidence of approximately 1 in 100,000 live births. Treatment options include hematopoietic stem cell transplantation and enzyme replacement therapy.