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Interpretive Handbook

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Test 89678 :
Lysosomal and Peroxisomal Storage Disorders Screen, Blood Spot

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Lysosomes are intracellular organelles that contain hydrolytic enzymes to degrade a variety of macromolecules. Lysosomal storage disorders are a diverse group of inherited diseases where macromolecules accumulate due to defects in their transport mechanisms across the lysosomal membrane or due to defective lysosomal enzyme function. 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 I: adult/chronic

-Type II: acute neuropathic/infantile

-Type III: subacute neuropathic/juvenile


Type I, the most frequent form of the disease, is characterized by organomegaly, thrombocytopenia, and bone pain, and is frequent among the Ashkenazim. Hepatosplenomegaly is usually present in all 3 types. Involvement of the central nervous system (CNS) is limited to the infantile type (type II). Enzyme replacement therapy with alglucerase (Ceredase) is available for patients with Gaucher type I disease. Clinical trials of antimetabolites are in progress.


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. Sphingomyelinase is encoded by 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 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 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. The incidence of MPS I is approximately 1 in 100,000 live births. Treatment options include hematopoietic stem cell transplantation and enzyme replacement therapy.


Peroxisomes are organelles present in all human cells except mature erythrocytes. They carry out essential metabolic functions including beta-oxidation of very long-chain fatty acids (VLCFA), alpha-oxidation of phytanic acid, and biosynthesis of plasmalogen and bile acids. Peroxisomal disorders include 2 major subgroups: disorders of peroxisomal biogenesis and single peroxisomal enzyme/transporter defects. Peroxisome biogenesis defects such as Zellweger spectrum syndrome, are characterized by defective assembly of the entire organelle, whereas in single enzyme/transporter defects such as X-linked adrenoleukodystrophy, the organelle is intact, but a specific function is disrupted. These disorders are clinically diverse and range in severity from neonatal lethal to later onset milder variants.


Zellweger syndrome spectrum (ZSS) is a continuum of severe disorders affecting the nervous system, vision, hearing, and liver function. Most individuals present in infancy, but adult patients have been identified. The prevalence of ZSS is 1 in 50,000. ZSS follows autosomal recessive inheritance. At least 12 different genes have been implicated in ZSS, with approximately 60% to 70% of mutations occurring in PEX1. The clinical phenotypes include Zellweger syndrome, neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD). Individuals with Zellweger syndrome typically die within the first year of life without making any developmental progress. Individuals with NALD or IRD typically present in childhood with developmental delays, vision loss, and hearing loss, and have a much slower disease progression. There is no specific treatment for ZSS.


X-linked adrenoleukodystrophy (XALD) is a disorder affecting the nervous system, adrenal cortex, and testis. It is the most common of the peroxisomal disorders, affecting 1 in 17,000 to 1 in 21,000 males. At least 50% of all females who are heterozygotes for XALD are symptomatic. A defect in the ABCD1 gene is responsible for the disease. X-ALD shows a wide range of phenotypic expressions. The clinical phenotypes occurring in males can be subdivided in 4 main categories: cerebral inflammatory, adrenomyeloneuropathy (AMN), Addison only, and asymptomatic. The first 2 phenotypes account for almost 80% of the patients, while the frequency of the asymptomatic category diminishes with age and it is very rare after age 40. It is estimated that approximately 50% of heterozygotes develop an AMN-like syndrome. Treatment options are hormone replacement therapy, dietary intervention, or hematopoietic stem cell transplantation.

Useful For Suggests clinical disorders or settings where the test may be helpful

Evaluation of patients with a clinical presentation suggestive of a lysosomal storage disorder, specifically Gaucher, Niemann-Pick type A or type B, Pompe, Krabbe, Fabry disease, or mucopolysaccharidosis I; or a peroxisomal disorder, either X-linked adrenoleukodystrophy or Zellweger spectrum syndrome

Interpretation Provides information to assist in interpretation of the test results

An interpretive report is provided.


When abnormal results are detected, a detailed interpretation is given, including an overview of the results and of their significance, a correlation to available clinical information, elements of differential diagnosis, recommendations for additional biochemical testing, and in vitro confirmatory studies (enzyme assay, molecular analysis), name and phone number of key contacts who may provide these studies at Mayo Medical Laboratories or elsewhere, and a phone number to reach 1 of the laboratory directors in case the referring physician has additional questions.  


Abnormal results are not sufficient to conclusively establish a diagnosis of a particular disease. To verify a preliminary diagnosis based on the analysis, independent biochemical (eg, in vitro enzyme assay) or molecular genetic analyses are required.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Specimens exposed to heat >25 degrees C will be cancelled.


A positive test result is strongly suggestive of a diagnosis but needs follow-up by stand-alone biochemical or molecular assay.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.



Normal Range


Acid Beta-Glucosidase

> or =3.0 nmol/mL/hr

Niemann-Pick A/B


> or =5.5 nmol/mL/hr


Acid Alpha-Glucosidase

> or =4.0 nmol/mL/hr



> or =0.4 nmol/mL/hr



> or =4.0 nmol/mL/hr



> or =2.0 nmol/mL/hr


C20 Lysophosphatidylcholine

< or =0.26 mcg/mL


C22 Lysophosphatidylcholine

< or =0.11 mcg/mL


C24 Lysophosphatidylcholine

Female <0.10 mcg/mL

Female indeterminate = 0.10-0.20 mcg/mL

Male < or =0.20 mcg/mL


C26 Lysophosphatidylcholine

< or =0.30 mcg/mL

Clinical References Provides recommendations for further in-depth reading of a clinical nature

1. DeJesus VR, Zhou H, Vogt RF, Hannon WH: Changes in solvent composition in tandem mass spectrometry multiplex assay for lysosomal storage disorders do not affect assay results. Clin Chem 2009;55(3):596-598

2. Li Y, Scott CR, Chamoles NA, et al: Direct multiplex assay of lysosomal enzymes in dried blood spots for newborn screening. Clin Chem 2004;50(10):1785-1796

3. Hubbard WC, Moser AB, Liu AC, et al: Newborn screening for X-linked adrenoleukodystrophy (X-ALD): validation of a combined liquid chromatography-tandem mass spectrometric (LC-MS/MS) method. Mol Genet Metab 2009;97(3):212-220