Newborn Screening for Lysosomal Storage Disorders

      Abstract

      Lysosomal storage disorders (LSDs) are a heterogeneous group of approximately 50 rare inherited metabolic conditions that result from enzyme deficiencies that interfere with lysosome function. Although often grouped together, there is great variability regarding age of onset, severity, treatment, and outcomes for each disorder and subtype. Currently, laboratory methods are available to test newborns for seven of these conditions. Although newborn screening programs remain state-based, each at a different phase of condition review and implementation, if newborn screening for LSDs has not yet been adopted by the state within which you practice, it likely will. Given the extremely low prevalence and limited provider familiarity with these conditions, this article provides an overview of LSDs and the seven conditions for which newborn screening is available. It offers information about each of the conditions including enzyme deficiency, mode of inheritance, incidence rates, types, clinical course, and available as well as potential treatment options.

      Key Words

      At the completion of this continuing education program, the participant will be able to:
      • 1.
        Describe the pathophysiology of lysosomal storage disorders.
      • 2.
        List the lysosomal storage disorders for which newborn screening is available and those included in the Recommended Uniform Screening Panel.
      • 3.
        Discuss the differences and similarities between these conditions.
      • 4.
        Explain current and potential future treatment options for lysosomal storage disorders.
      • 5.
        Identify the mode of inheritance, clinical course, and available treatment options for at least two of the most common conditions.
      • 6.
        Identify key (differentiating) features for at least two lysosomal storage disorders.
      Newborn screening saves lives and through early, often presymptomatic detection, has reduced disease-associated morbidity. Since the introduction of tandem mass spectrometry to newborn screening almost two decades ago, newborn screening has continued to expand exponentially. Processes and panels vary from state to state and as technology advances, the conditions screened, diagnostic testing, and treatments have grown in complexity, challenging providers to keep pace. This article offers an overview of newborn screening and lysosomal storage diseases and describes each of the lysosomal storage diseases for which screening is available to familiarize providers with these rare conditions should they encounter a newborn or child who has a positive screening result.

      Newborn Screening

      Under the auspices of the Advisory Committee on Heritable Disorders in Newborns and Children (Committee), the Recommended Uniform Screening Panel guides state-based newborn screening programs across the United States. Over the past several years, widespread adoption of filter paper screening for severe combined immunodeficiencies and pulse oximetry screening for critical congenital heart disease have been implemented. More recently, methodology to screen for seven lysosomal storage disorders and one peroxisomal disorder, X-linked adrenoleukodystrophy became available, prompting Committee review for panel inclusion. Of the conditions for which newborn screening methods are available, Pompe disease, mucopolysaccharoidosis type I disease (MPS I) and X-linked adrenoleukodystrophy (see Box) were reviewed by the Committee and met criteria for addition to the Recommended Uniform Screening Panel (
      U. S. Department of Health and Human Services, Advisory Committee on Heritable Disorders in Newborns and Children
      Recommended uniform screening panel.
      ). Before inclusion in the Recommended Uniform Screening Panel, however, several states began screening and/or passed legislation to screen for one or more of the LSDs. In 2006, the New York State Newborn Screening Program paved the way when it added Krabbe disease to the state panel. As laboratory methods became more available, Illinois and Missouri followed by legislating ambitious LSD screening panels (

      Illinois Department of Public Health, Genetics and Newborn Screening. (n.d.). Illinois Newborn Screening Panel. Springfield, IL: Author. Retrieved from http://www.idph.state.il.us/HealthWellness/disorderlist.htm

      ,

      Missouri Department of Health & Senior Services, State Public Health Laboratory (n.d.). Lysosomal storage disorders. Jefferson City, MO: Author. Retrieved from http://health.mo.gov/lab/lsd.php

      ). Despite efforts for standardization, state-based newborn screening varies across the country. As such, states are at different phases of review and implementation of newborn screening for LSDs (Table 1), but the inevitability of expanded screening looms.
      Despite efforts for standardization, state-based newborn screening varies across the country.
      Overview of X-linked adrenoleukodystrophy
      X-linked adrenoleukodystrophy (ALD) is a heterogeneous genetic condition of perixosomal fatty acid beta oxidation. It is the most common peroxisomal inborn error of metabolism, with an incidence between 1:20,000 and 1:50,000 (
      • Bezman L.
      • Moser A.B.
      • Raymond G.V.
      • Rinaldo P.
      • Watkins P.A.
      • Smith K.D.
      • Moser H.W.
      Adrenoleukodystrophy: Incidence, new mutation rate, and results of extended family screening.
      ,
      U. S. Department of Health and Human Services, National Institutes of Health, Genetics Home Reference
      X-linked adrenoleukodystrophy.
      ). Enzyme deficiency causes damage to nerve myelin sheaths, resulting in seizures. Because the condition is X-linked, it occurs most commonly in males. Heterozygote females, however, can develop neurologic symptoms of the milder form of disease, adrenomyeloneuropathy (AMN), later in life. Most patients present with severe cerebral disease in childhood. There is normal early development, followed by hyperactivity, and then rapid decline in cognition, behavior, vision, hearing, and motor function between ages 4 and 8 years. Although variable, patients typically progress to total disability within 2 years, and death follows at varying ages. Other forms of ALD range in severity and may include progressive paraparesis (AMN) and, less commonly, adrenal insufficiency (Addison only disease). Treatment for ALD is limited and primarily supportive. Dietary treatment may include restriction of very-long-chain fatty acids and, in asymptomatic patients, a combination of unsaturated fatty acids (Lorenzo's oil). For the cerebral form, allogenic hematopoietic stem cell transplantation is an option if detected early. It is not, however, recommended for individuals with severe neurologic and neuropsychologic dysfunction. Those with adrenal insufficiency respond to corticosteroids (
      • Steinberg S.J.
      • Moser A.B.
      • Raymond G.V.
      X-linked adrenoleukodystrophy.
      ,

      U. S. Department of Health and Human Services, National Institutes of Health, National Institute of Neurological Disorders and Stroke. (n.d.b). Adrenoleukodystrophy information page. Rockville, MD: Author. Retrieved from https://www.ninds.nih.gov/Disorders/All-Disorders/Adrenoleukodystrophy-Information-Page

      ).
      Table 1Status of newborn screening for lysosomal storage disorders
      StateLysosomal storage disorder
      Pompe disease
      These conditions are recommended on the Recommended Uniform Screening Panel.
      MPS I disease
      These conditions are recommended on the Recommended Uniform Screening Panel.
      Krabbe diseaseGaucher diseaseFabry diseaseNP diseaseMPS II disease
      IllinoisXXXXX
      KentuckyXXX
      MissouriXXXXX
      New YorkXX
      OhioX
      PennsylvaniaXXXXXX
      Note. This information is current as of January 17, 2017. To access the most up-to-date information, refer to the state website: http://babysfirsttest.org/, and/or https://www.newsteps.org/. MPS I = mucopolysaccharidosis type I; MPS II = mucopolysaccharidosis type II; NP = Niemann-Pick.
      a These conditions are recommended on the Recommended Uniform Screening Panel.

      Lysosomal Storage Disorders

      LSDs are a heterogeneous group of inherited metabolic diseases. Depending on the source, more than 50 different LSDs have been identified. Although each is individually quite rare, the combined incidence rate for LSDs is 1:7,000 to 1:8,000 live births (
      • Schneidereith T.A.
      Maternal-child nursing: Pediatrics.
      ). Most conditions are autosomal recessive, but several are X-linked. These generally progressive disorders result from a condition-specific enzyme deficiency that allows substances (lipids and carbohydrates) to accumulate in the lysosome (Figure). Symptoms result from the deposition of these metabolites in the cells of various organs, and disease severity depends on the rate and site of accumulation.
      Figure thumbnail gr1
      FigureLysosomes: form and function. Scattered within the cytoplasm, lysosomes are spherical, sac-like organelles that contain powerful enzymes to digest and dispose of cell waste (worn out organelles from within the cell, proteins, carbohydrates, lipids, and engulfed viruses and bacteria). When a digestive enzyme is deficient or absent, the lysosome is unable to degrade the product, and waste accumulates within the cell.
      Image from https://image.jimcdn.com/app/cms/image/transf/none/path/s79e2f60bf980ec19/image/iba744aa96c939c2c/version/1417044791/diagram-of-an-animal-cell.jpg. Download for free at http://cnx.org/content/col11496/latest/. This figure appears in color online at www.jpedhc.org.
      Although LSDs are categorized based on this similarity, they vary in severity, age of onset, treatment options, morbidity, and mortality (
      • Schneidereith T.A.
      Maternal-child nursing: Pediatrics.
      ). Each of the LSDs for which newborn screening is available is discussed below. Table 2 provides a summary of the conditions for comparison, and Table 3 provides an overview of available and potential future treatment options.
      Table 2Comparison of lysosomal storage disorders for which newborn screening is available
      DisorderTypes (% of cases)Presenting symptomsInheritanceIncidence rateAge at onsetAge at deathTreatment
      Krabbe
      InfantileNeurologic

      Muscular
      AR1:100,000 (United States and Europe)

      1:394,000 (New York State newborn screening program [Wasserstein et al., 2016])
      Before 6 months13 monthsPalliative care
      Palliative care may be used at some point for all of these conditions. When identified as a treatment in the table, it suggests its use as a primary intervention.
      (±) HSCT
      Late infantileNeurologic6–12 monthsYounger age of onset, faster disease progression (2–7 years from diagnosis)
      Later onsetOphthalmologic

      Muscular
      After 12 months
      Pompe
      Classic infantileLiver/spleen

      Muscular

      Respiratory

      Cardiac (cardiomyopathy)
      AR1:40,000 (United States)1 month (in utero)12 monthsERT
      Nonclassic infantileMuscular

      Respiratory

      Cardiac (cardiomegaly)
      12 monthsEarly childhood
      Late onsetMotor problems

      Respiratory
      Juvenile and adult onset30–70 years
      Gaucher1:40,000 (population)
      Type 1 (80–90%)Liver/spleen

      Hematologic

      Orthopedic
      AR1:450 to 1:1,000 (Ashkenazi Jewish)Adulthood (Juvenile rarely)Late adulthoodERT
      Type 2 (neuronopathic)Neurologic

      Liver/Spleen

      Respiratory
      1:100,000Infantile2–5 yearsPalliative care (±) ERT
      Type 3Neurologic

      Liver/Spleen
      1:50,000Before age 2 years30–40 years(±) ERT

      (±) Palliative care
      Niemann-Pick
      Type A (neuronopathic)Neurologic

      Liver/Spleen

      Ophthalmologic
      AR1:250,000 (combined)

      1:40,000 (Ashkenazi Jewish)
      3 monthsEarly childhood (3 years)(±) HSCT

      Palliative care
      Type BLiver/Spleen

      Respiratory

      Muscular
      Early childhood to adulthood (40–50 years)Adulthood
      Fabry1:80,000 to 1:117,000 (population)
      ClassicGastrointestinal

      Pain

      Integumentary

      Renal

      Cardiac

      Ophthalmologic

      Cerebrovascular
      X-linked1:50,000 (Males)4–8 years30–50 yearsERT

      Hemodialysis
      RenalRenal

      Cardiac
      >25 years>40 yearsERT

      Hemodialysis
      CardiacCardiac>60 years60–80 yearsERT
      MPS
       MPS I
      SevereCoarse facies

      Neurologic

      Liver/Spleen

      Respiratory

      Cardiac

      Orthopedic

      Ophthalmologic

      Growth problems
      AR1:100,0006–12 months10 yearsERT (±) HSCT (by 2 years)
      AttenuatedGenerally, milder onset of symptoms associated with severe MPS I (typically normal intelligence and height)1:500,0003-10 years20–30 years to normal lifespan
       MPS II
      SevereCoarse facies

      Neurologic

      Liver/Spleen

      Respiratory

      Cardiac

      Orthopedic

      Growth problems
      X-linked1:100,000 to 1:170,000 (Males)18 months to 4 years10–20 yearsERT (±) HSCT
      AttenuatedGenerally, milder onset of symptoms associated with severe MPS II, absent or less severe cognitive problemsAdolescence to adulthoodAdulthood
      Note. This table provides an overview of the seven lysosomal storage diseases for which there is available newborn screening technology. It presents an overview of the various types, presenting symptoms, inheritance pattern, incidence rate, age of onset, average age of death, and available treatment options. (±) = may or may not be used/indicated; AR = autosomal recessive; ERT = enzyme replacement therapy; HSCT = hematopoietic stem cell transplantation; MPS = mucopolysaccharidosis(es).
      a Palliative care may be used at some point for all of these conditions. When identified as a treatment in the table, it suggests its use as a primary intervention.
      Table 3Present and possible future treatments for lysosomal storage disorders
      TreatmentsExplanation
      Enzyme replacement therapyIntravenous

      Intravenous infusion of a modified version of the enzyme to break down the accumulating substance. Infusions may be weekly to monthly depending on the condition and severity.

      Intrathecal

      Intrathecal infusion of a different formulation of enzyme specifically developed to be distributed throughout the central nervous system and penetrate the brain and meninges.
      Gene therapySeveral approaches to gene therapy include (a) replacing the mutated gene, (b) developing a way to inactivate the mutated gene, and (c) introducing a new gene to help treat disease.
      Hematopoietic stem cell transplantationIntravenous infusion of stem cells collected from bone marrow, peripheral blood, or umbilical cord blood of an unaffected donor to reestablish hematopoietic function. Although treatment-associated mortality rates are improving, this remains a dangerous procedure with severe complications and mortality rates. As such, it is reserved for those with life-threatening disease. Additionally, there is delayed/inadequate engraftment of cells in the central nervous system when administered intravenously.
      Oligodendrocyte-like cell transplantIntrathecal administration of oligodendrocyte-like cells used as an adjunctive therapy to hematopoietic stem cell transplant to speed engraftment of cells in the central nervous system and prevent disease progression.
      Pharmacologic chaperone therapyOral, small molecule medication that helps the misfolded protein fold properly to reactivate the enzyme and break down the accumulated material.
      Substrate reduction therapyOral medication that partially blocks the production of the accumulating substance, which allows the small amount of residual enzyme to process the accumulating substance. This treatment is effective only in certain types of patients (those with some residual enzyme activity).

      Krabbe Disease

      Krabbe disease is an autosomal recessive, progressive neurodegenerative leukodystrophy caused by a deficiency of the enzyme ß-galactosidase (galactocerebrosidase) that inhibits myelin production. Before the implementation of newborn screening, the disease incidence rate in the United States and Europe was estimated to be 1:100,000 (
      • Wenger D.A.
      Krabbe disease.
      ). Based on data from New York State Newborn Screening Program,
      • Wasserstein M.P.
      • Andriola M.
      • Arnold G.
      • Aron A.
      • Duffner P.
      • Erbe R.W.
      • Caggana M.
      Clinical outcomes of children with abnormal newborn screening results for Krabbe disease in New York State.
      report an actual incidence of 1:394,000.
      There are several types of Krabbe, including early infantile, late infantile, and later onset disease. Before information shared by the New York State Newborn Screening Program, 85% to 90% of diseased individuals were diagnosed with severe, infantile onset disease. Data compiled after 8 years of newborn screening in New York, however, suggests a much greater incidence of infants with later onset than early infantile disease. Interestingly, it is estimated that the percentages are almost completely reversed, with 90% of infants having later onset disease (
      • Wasserstein M.P.
      • Andriola M.
      • Arnold G.
      • Aron A.
      • Duffner P.
      • Erbe R.W.
      • Caggana M.
      Clinical outcomes of children with abnormal newborn screening results for Krabbe disease in New York State.
      ).
      Presenting symptoms of early infantile onset Krabbe include irritability, shrill cry, spasticity, hypotonia, feeding difficulties, and mental and physical developmental delay and regression. As the disease progresses, hypotonia worsens, limiting physical mobility and the ability to eat, swallow, and breathe. Other symptoms may include vision and hearing loss and seizures. The average age of death for infantile onset Krabbe is 13 months (
      • Schneidereith T.A.
      Maternal-child nursing: Pediatrics.
      ;
      U. S. Department of Health and Human Services, National Institutes of Health, Genetics Home Reference
      Krabbe disease.
      ,
      • Wang R.Y.
      • Bodamer O.A.
      • Watson M.S.
      • Wilcox W.R.
      ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Disease
      Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals.
      ,
      • Wenger D.A.
      Molecular genetics of Krabbe disease (globoid cell leukodystrophy): Diagnostic and clinical implications.
      ,
      • Wenger D.A.
      Krabbe disease.
      ).
      The clinical course for late infantile and later onset childhood/adolescent forms of Krabbe can vary considerably. Those with late infantile Krabbe typically become symptomatic between 6 and 12 months of age, and a rapid neurodegenerative course follows. Individuals with later onset disease present with vision and ambulation difficulties. There may also be cognitive decline and muscle weakness. Generally, the younger the age of onset, the faster the disease progression and age of death, usually within 2 to 7 years of diagnosis (
      U. S. Department of Health and Human Services, National Institutes of Health, Genetics Home Reference
      Krabbe disease.
      ,
      • Wang R.Y.
      • Bodamer O.A.
      • Watson M.S.
      • Wilcox W.R.
      ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Disease
      Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals.
      ,
      • Wenger D.A.
      Molecular genetics of Krabbe disease (globoid cell leukodystrophy): Diagnostic and clinical implications.
      ,
      • Wenger D.A.
      Krabbe disease.
      ).
      Currently, there is no cure for Krabbe, and treatment is primarily symptomatic and palliative (
      U. S. Department of Health and Human Services, National Institutes of Health, Genetics Home Reference
      Krabbe disease.
      ,
      • Wang R.Y.
      • Bodamer O.A.
      • Watson M.S.
      • Wilcox W.R.
      ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Disease
      Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals.
      ,
      • Wenger D.A.
      Molecular genetics of Krabbe disease (globoid cell leukodystrophy): Diagnostic and clinical implications.
      ,
      • Wenger D.A.
      Krabbe disease.
      ). Researchers are pursuing hematopoietic stem cell transplantation (HSCT) for newborns and those with late onset disease. It is hypothesized that HSCT in presymptomatic infants and those with milder disease will improve disease-associated morbidity and mortality (
      • Wang R.Y.
      • Bodamer O.A.
      • Watson M.S.
      • Wilcox W.R.
      ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Disease
      Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals.
      ; see ClinicalTrials.gov). Although HSCT may not cure the disease, it may delay symptom onset and disease progression and improve quality of life.
      Based on follow-up of the first newborns identified through the New York State Newborn Screening Program over the first 8 years,
      • Orsini J.
      • Kay D.M.
      • Saavedra-Matiz C.A.
      • Wenger D.A.
      • Duffner P.K.
      • Erbe R.W.
      • Caggana M.
      the New York State Krabbe Disease Consortium
      Newborn screening for Krabbe disease in New York State: The first eight years' experience.
      and
      • Wasserstein M.P.
      • Andriola M.
      • Arnold G.
      • Aron A.
      • Duffner P.
      • Erbe R.W.
      • Caggana M.
      Clinical outcomes of children with abnormal newborn screening results for Krabbe disease in New York State.
      report the clinical outcomes for four of the five newborns identified with infantile Krabbe who received HSCT. Of the four infants treated (one family declined), two survived with moderate to severe developmental delay, and two died from transplantation-related complications. Outcomes suggest that it remains unclear whether HSCT will become a mainstream therapy for Krabbe, but it is clear that ongoing assessment of patient and treatment outcomes of those receiving HCST is essential. Intrathecal administration of oligodendrocyte-like cells is currently being studied. Other treatments such as enzyme replacement therapy and gene therapy are also in the early stages of development (see ClinicalTrials.gov).

      Pompe Disease

      Pompe disease is an autosomal recessive, glycogen storage disorder caused by acid α-glucosidase enzyme deficiency that allows accumulation of glycogen primarily in cardiac and skeletal muscle (
      • Clayton N.P.
      • Nelson C.A.
      • Weeden J.
      • Taylor K.M.
      • Moreland R.J.
      • Scheule R.K.
      • Wentworth B.M.
      Antisense oligoneucleotide-mediated suppression of muscle glycogen synthase/synthesis as an approach for substrate reduction therapy of Pompe disease.
      ). The incidence rate varies from 1:14,000 among African Americans to 1:100,000 for individuals of European descent. The average incidence rate in the United States is 1:40,000 (
      U. S. Department of Health and Human Services, National Institutes of Health, Genetics Home Reference
      Pompe disease.
      ,
      • Hirschhorn R.
      • Reuser A.J.J.
      Glycogen storage disease type II: Acid alpha-glucosidase (acid maltase) deficiency.
      ,

      U. S. Department of Health and Human Services, National Institutes of Health, National Institute of Neurological Disorders and Stroke. (n.d.a). Pompe disease information page. Rockville, MD: Author. Retrieved from https://www.ninds.nih.gov/Disorders/All-Disorders/Pompe-Disease-Information-Page

      ). As is true with most LSDs, there are several types of Pompe that include infantile, nonclassic infantile, and two types of late onset disease.
      Although disease symptoms may be apparent in utero, most infants with classic infantile onset Pompe present with hypotonia, hypertrophic cardiomyopathy, respiratory insufficiency with frequent infections, hepatomegaly, macroglossia, and failure to thrive within the first month of life. There is progressive muscle weakness with hyperlordosis and scoliosis. Without prompt diagnosis and treatment, infantile onset Pompe results in death from progressive cardiomyopathy and heart failure by the first year of life (

      U. S. Department of Health and Human Services, National Institutes of Health, National Institute of Neurological Disorders and Stroke. (n.d.a). Pompe disease information page. Rockville, MD: Author. Retrieved from https://www.ninds.nih.gov/Disorders/All-Disorders/Pompe-Disease-Information-Page

      ,
      • Tinkle B.T.
      • Leslie N.
      Glycogen storage disease type II (Pompe disease).
      ,
      • Wang R.Y.
      • Bodamer O.A.
      • Watson M.S.
      • Wilcox W.R.
      ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Disease
      Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals.
      ).
      Nonclassic infantile Pompe presents in the first year of life with motor delays and progressive muscle weakness including cardiomegaly (without heart failure) and serious respiratory insufficiency. Most children live into early childhood (
      U. S. Department of Health and Human Services, National Institutes of Health, Genetics Home Reference
      Pompe disease.
      ,

      U. S. Department of Health and Human Services, National Institutes of Health, National Institute of Neurological Disorders and Stroke. (n.d.a). Pompe disease information page. Rockville, MD: Author. Retrieved from https://www.ninds.nih.gov/Disorders/All-Disorders/Pompe-Disease-Information-Page

      ).
      There are two types of late onset Pompe, juvenile and adult onset. Juvenile onset Pompe presents with milder symptoms including progressive muscle weakness that primarily affects the legs, torso, and respiratory system. Unlike infantile onset Pompe, the heart is typically not involved. Death results from respiratory failure. Individuals with adult onset Pompe present in the third to seventh decades of life with muscle weakness and elevation of creatine kinase level (
      U. S. Department of Health and Human Services, National Institutes of Health, Genetics Home Reference
      Pompe disease.
      ,

      U. S. Department of Health and Human Services, National Institutes of Health, National Institute of Neurological Disorders and Stroke. (n.d.a). Pompe disease information page. Rockville, MD: Author. Retrieved from https://www.ninds.nih.gov/Disorders/All-Disorders/Pompe-Disease-Information-Page

      ).
      Treatment for Pompe rests with symptomatic treatment, anticipatory guidance, ongoing surveillance, and enzyme replacement therapy (ERT). It is purported that early treatment of asymptomatic infants identified by newborn screening or family history will improve outcomes and, perhaps, change the course of the disease. Long-term data are unfolding to confirm or refute this hypothesis (

      U. S. Department of Health and Human Services, National Institutes of Health, National Institute of Neurological Disorders and Stroke. (n.d.a). Pompe disease information page. Rockville, MD: Author. Retrieved from https://www.ninds.nih.gov/Disorders/All-Disorders/Pompe-Disease-Information-Page

      ,
      • Tinkle B.T.
      • Leslie N.
      Glycogen storage disease type II (Pompe disease).
      ,
      • Wang R.Y.
      • Bodamer O.A.
      • Watson M.S.
      • Wilcox W.R.
      ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Disease
      Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals.
      ). Treatments in development include pharmacologic chaperone, substrate reduction, and gene therapies (
      • Clayton N.P.
      • Nelson C.A.
      • Weeden J.
      • Taylor K.M.
      • Moreland R.J.
      • Scheule R.K.
      • Wentworth B.M.
      Antisense oligoneucleotide-mediated suppression of muscle glycogen synthase/synthesis as an approach for substrate reduction therapy of Pompe disease.
      ; see ClinicalTrials.gov).

      Gaucher Disease

      Gaucher disease is an autosomal recessive sphingolipidosis that results from β-glucosidase (glucocerebrosidase, glucosylceramidase) enzyme deficiency and deposit of glucocerebroside (glycosylceramide). In the general population, the incidence rate is 1:40,000 (1:20,000 live births in the United States) and, depending on the source, as frequent as 1:450 to 1:1,000 among individuals of Ashkenazi Jewish descent (

      U.S. National Library of Medicine, PubMed Health (n.d.a). Gaucher Disease. Retrieved from https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0029639/

      ,
      • Ibrahim J.
      Genetics of glycogen-storage disease Type II (Pompe disease).
      ,
      U. S. Department of Health and Human Services, National Institutes of Health, Genetics Home Reference
      Gaucher disease.
      ,
      • Pastores G.M.
      • Hughes D.A.
      Gaucher disease.
      ,
      • Schneidereith T.A.
      • Anderson G.
      Maternal-child nursing: Adult health and illness and medical-surgical nursing.
      ,
      • Wang R.Y.
      • Bodamer O.A.
      • Watson M.S.
      • Wilcox W.R.
      ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Disease
      Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals.
      ).
      There are three types of Gaucher. Accounting for 80% to 90% of case, Type 1 is a visceral form and is most common. This non-neuronopathic type generally presents in adulthood with infiltration of the bone marrow, liver, and spleen. Patients develop nonspecific symptoms such as fatigue, easy bruising, and hepatosplenomegaly. Over time, infiltration of the bone increases risk for fracture, infarction, necrosis (Erlenmeyer deformity, aseptic necrosis of the femoral head), and pain/pain crisis. Infiltration of the spleen causes thrombocytopenia, anemia, and immune compromise. Although children have been identified with Type 1 Gaucher, it is more slowly progressive than Types 2 and 3 (
      • Ibrahim J.
      Genetics of glycogen-storage disease Type II (Pompe disease).
      ,
      U. S. Department of Health and Human Services, National Institutes of Health, Genetics Home Reference
      Gaucher disease.
      ,
      • Pastores G.M.
      • Hughes D.A.
      Gaucher disease.
      ,
      • Schneidereith T.A.
      • Anderson G.
      Maternal-child nursing: Adult health and illness and medical-surgical nursing.
      ,
      • Wang R.Y.
      • Bodamer O.A.
      • Watson M.S.
      • Wilcox W.R.
      ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Disease
      Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals.
      ).
      The onset of Types 2 and 3 Gaucher are characterized by neurologic disease in infancy. Classic Type 2 (neuropathic) is the severe form, which causes deposition of glucosylceramidase, which inhibits myelin formation, resulting in cerebral injury and death between 2 and 5 years of age. Infants present with stridor, hoarse cry, respiratory distress, and feeding difficulties. There is opisthotonos and trismus, followed by decerebrate rigidity. Type 3 presents before 2 years of age and progresses more slowly. Affected individuals may survive to the third or fourth decades of life (
      • Ibrahim J.
      Genetics of glycogen-storage disease Type II (Pompe disease).
      ,
      U. S. Department of Health and Human Services, National Institutes of Health, Genetics Home Reference
      Gaucher disease.
      ,
      • Pastores G.M.
      • Hughes D.A.
      Gaucher disease.
      ,
      • Schneidereith T.A.
      • Anderson G.
      Maternal-child nursing: Adult health and illness and medical-surgical nursing.
      ,
      • Wang R.Y.
      • Bodamer O.A.
      • Watson M.S.
      • Wilcox W.R.
      ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Disease
      Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals.
      ).
      Treatment for Gaucher entails symptomatic treatment (bone pain for Type 1, respiratory distress/feeding difficulties for Types 2 and 3), anticipatory guidance, ongoing surveillance, ERT, and/or substrate reduction therapy (available for adults with Type 1 only). ERT can reduce liver and spleen size, improve skeletal abnormalities, and treat nonneurologic symptoms of Gaucher. HSCT is not a mainstay treatment, but it may be offered to select individuals. In some patients, blood transfusion may be necessary, and partial splenectomy may be performed to reverse thrombocytopenia and anemia. Those with later onset Types 1 and 3 Gaucher have improved outcomes with treatment. Because ERT does not cross the blood–brain barrier, children with infantile onset Gaucher (primarily Type 2) suffer progressive neurologic damage and die in early childhood despite treatment (
      • Ibrahim J.
      Genetics of glycogen-storage disease Type II (Pompe disease).
      ,
      • Pastores G.M.
      • Hughes D.A.
      Gaucher disease.
      ,
      • Wang R.Y.
      • Bodamer O.A.
      • Watson M.S.
      • Wilcox W.R.
      ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Disease
      Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals.
      ). ERT may be offered as a palliative measure but does not cross the blood–brain barrier and, as such, does not greatly alter the disease course. For those with neuronopathic Gaucher, research efforts are focused on identifying a way to deliver enzyme replacement across the blood–brain barrier. Additionally, the use of substrate reductase therapy, pharmaceutical chaperone, and gene therapy are being considered (see ClinicalTrials.gov).

      Niemann-Pick Disease

      The four main types of Niemann-Pick disease, Types A (NP-A), B (NP-B), and C (Types C1 and C2), are inherited in an autosomal recessive manner. Currently, laboratory methodology is available to screen newborns for NP-A and NP-B, both of which result from acid sphingomyelinase deficiency, and causes cell death. The combined incidence rate for NP-A and NP-B is 1:250,000. The incidence among Ashkenazi Jewish populations, however, is as frequent as 1:40,000 (
      U. S. Department of Health and Human Services, National Institutes of Health, Genetics Home Reference
      Niemann-Pick disease.
      ).
      Individuals with neuronopathic (severe infantile) NP-A have severe enzyme deficiency that results in hepatosplenomegaly and failure to thrive by 3 months of age. Infants are initially floppy and, over time, develop spasticity. Although not present in all patients at the time of diagnosis, ophthalmologic examination will eventually show a cherry red macule. There is progressive neurologic impairment, and most die in early childhood, usually by 3 years of age (
      • Wasserstein M.P.
      • Schuchman E.H.
      Acid sphingomyelinase deficiency.
      ).
      Non-neuronopathic NP-B has a later onset, milder presentation characterized by hepatosplenomegaly with hypersplenism, thrombocytopenia, hyperlipidemia and interstitial pulmonary infiltration, recurrent pulmonary infection, and gradual deterioration of pulmonary function. There may also be cardiac, growth, and skeletal problems. After normal early development, individuals present with psychomotor regression and, over time, develop ataxia and peripheral neuropathy (
      • McGovern M.M.
      • Lippa N.
      • Bagiella E.
      • Schuchman E.H.
      • Desnick E.H.
      • Wasserstein M.P.
      Morbidity and mortality in type B Niemann-Pick disease.
      ,
      • Wasserstein M.P.
      • Schuchman E.H.
      Acid sphingomyelinase deficiency.
      ). In contrast to NP-A, there is a wide range of disease severity among individuals with NP-B, who may present in early childhood or as late as the fourth to fifth decades of life (
      • McGovern M.M.
      • Lippa N.
      • Bagiella E.
      • Schuchman E.H.
      • Desnick E.H.
      • Wasserstein M.P.
      Morbidity and mortality in type B Niemann-Pick disease.
      ). Individuals with NP-B typically survive into adulthood.
      Currently, there is no universally accepted treatment for NP-A and NP-B, and care is primarily supportive. Those with NP-A may receive physical therapy, occupational therapy, nutritional treatments, sedatives for irritability, and sleep disturbance. Those with NP-B may require blood transfusions, oxygen, and treatment for hyperlipidemia and nutritional deficits (
      • Wasserstein M.P.
      • Schuchman E.H.
      Acid sphingomyelinase deficiency.
      ). On rare occasions, those without neurologic injury may be offered HSCT, and those with hepatic failure may be offered liver transplantation (
      • Ierardi-Curto L.
      Sphingomyelinase deficiency.
      ,
      • McGovern M.M.
      • Schuchman E.H.
      Acid sphingomyelinase deficiency.
      ,
      • Wang R.Y.
      • Bodamer O.A.
      • Watson M.S.
      • Wilcox W.R.
      ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Disease
      Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals.
      ,
      • Wasserstein M.P.
      • Schuchman E.H.
      Acid sphingomyelinase deficiency.
      ). Future treatments such as ERT and intrathecal administration of oligodendrocyte-like cells are being studied (
      • Wasserstein M.P.
      • Schuchman E.H.
      Acid sphingomyelinase deficiency.
      ; see ClinicalTrials.gov).

      Fabry Disease

      Fabry disease is an X-linked genetic disorder that results from α-galactosidase A enzyme deficiency, which allows progressive lysosomal deposition of glycosphingolipids (globotriaosylceramide) that accumulate in endothelium of the skin and cells in the renal, cardiac, and nervous systems (
      U. S. Department of Health and Human Services, National Institutes of Health, Genetics Home Reference
      Fabry disease.
      ). The incidence rate is estimated to be 1:50,000 males, with a population estimate from 1:80,000 to 1:117,000 (
      • Desnick R.J.
      • Ioannou Y.A.
      • Eng C.M.
      α-Galactosidase A deficiency: Fabry disease.
      ). Although primarily seen in males, X chromosome inactivation may result in asymptomatic, or classic, severe phenotype in carrier females. The prevalence in females is unknown (
      U. S. Department of Health and Human Services, National Institutes of Health, Genetics Home Reference
      Fabry disease.
      ).
      The classic presentation for males with Fabry occurs during late childhood or adolescence and includes periodic severe pain crises in the extremities (acroparasthesias), angiokeratomas, hypohidrosis, corneal opacity, gastrointestinal problems, tinnitus, and hearing loss. Without treatment, there is gradual deterioration of kidney function, which leads to end-stage renal disease by the third to fifth decades of life. Eventually, individuals develop cardiovascular and cerebrovascular disease, which leads to death.
      In addition to the classic form, there are two atypical phenotypes of Fabry. Individuals with the renal variant present in their mid-20s with severe left ventricular hypertrophy and renal insufficiency requiring hemodialysis or renal transplant. In contrast to classic Fabry and some with the renal variant who present with integumentary and ophthalmologic findings, individuals with the cardiac variant present between 60 and 80 years of age with left ventricular hypertrophy, hypertrophic cardiomyopathy, and conduction disturbances/arrhythmias. These individuals may develop proteinuria, but they do not develop renal failure as is seen in the other types (
      • Mehta A.
      • Hughes D.A.
      Fabry disease.
      ).
      Treatment for Fabry focuses on symptomatic treatment of pain crises (which can be difficult to treat), angiokeratomas, hypertension, hyperlipidemia, renal failure, and gastrointestinal disturbances. In addition to aggressive management of pain crisis and associated medical problems, therapies include hemodialysis and ERT (
      U. S. Department of Health and Human Services, National Institutes of Health, Genetics Home Reference
      Fabry disease.
      ,
      • Mehta A.
      • Hughes D.A.
      Fabry disease.
      ,
      • Wang R.Y.
      • Bodamer O.A.
      • Watson M.S.
      • Wilcox W.R.
      ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Disease
      Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals.
      ). Other treatments being explored include pharmacologic chaperone, substrate reduction, and gene therapies (
      • Motabar O.
      • Sidransky E.
      • Goldin E.
      • Zheng W.
      Fabry disease–Current treatment and new drug development.
      ; see ClinicalTrials.gov).

      Mucopolysaccharidoses

      There are several types of MPS that vary in clinical severity. Although individually quite rare, the combined incidence rate of all MPS conditions is as frequent as 1:25,000 (
      • Schneidereith T.A.
      Maternal-child nursing: Pediatrics.
      ). MPS Types I and II are characterized by the accumulation of glycosaminoglycans (dermatan and heparan sulfate) in the lysosomes and deposited primarily in connective tissue, bone, viscera, heart, brain, and spinal cord (
      • Lashley F.R.
      Inherited biochemical disorders.
      ).

      MPS Type I

      MPS Type I are a spectrum of progressive multisystem conditions with some clinical overlap and considerable variability and phenotype. Formerly referred to as Hurler (severe), Hurler-Scheie (intermediate), Scheie (mild) syndromes, MPS I is an autosomal recessive condition caused by α-l-iduronidase deficiency. The estimated incidence for MPS I is 1:100,000 live births (
      • Beck M.
      • Arn P.
      • Giugliani R.
      • Muenzer J.
      • Okuyama T.
      • Taylor J.
      • Fallet S.
      The natural history of MPS I: Global perspectives from the MPS I Registry.
      ). Others estimate a prevalence of 1:100,000 for the severe form and 1:500,000 for the smaller subset of individuals with the less severe, attenuated form (
      • Clarke L.A.
      Mucopolysaccharidosis Type I.
      ,
      U. S. Department of Health and Human Services, National Institutes of Health, Genetics Home Reference
      Mucopolysaccharoidosis type I.
      ).
      The most severe presentation of MPS I occurs the first year of life (between 6 and 12 months) with developmental delay, frequent respiratory infections, and coarsening of facial features. Infants may be exceptionally large, with umbilical or inguinal hernias and macroglossia. Cognitive disabilities, hepatosplenomegaly, and cardiomyopathy develop over time. Additional findings may include skeletal (Gibbus deformity of the lower spine) and joint deformities, thickening of most of the long bones and ribs (dysostosis multiplex), corneal clouding, and hearing loss. There is progressive and profound intellectual decline. Most die from cardiorespiratory failure within the first 10 years of life (
      • Clarke L.A.
      Mucopolysaccharidosis Type I.
      ,
      • Schneidereith T.A.
      Maternal-child nursing: Pediatrics.
      ).
      Children with attenuated disease present between 3 and 10 years with normal intelligence and height but with stiffness and other joint deformities, coarse facies, and corneal clouding. Over time there are progressive musculoskeletal and cardiorespiratory problems. If left untreated, some children die by the second to third decade of life, but others have a normal lifespan (
      • Clarke L.A.
      Mucopolysaccharidosis Type I.
      ,
      • Scarpa M.
      Mucopolysaccharidosis Type II.
      ,
      • Wang R.Y.
      • Bodamer O.A.
      • Watson M.S.
      • Wilcox W.R.
      ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Disease
      Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals.
      ).
      Treatment for MPS I rests with symptom management, anticipatory guidance, and ongoing surveillance. In the absence of neurologic symptoms, ERT is available. When performed before the age of 2 years, HSCT has proven successful for those with severe MPS I to slow cognitive decline and neurologic manifestations. Because ERT does not cross the blood–brain barrier, it does not prevent cognitive deterioration (
      • Clarke L.A.
      Mucopolysaccharidosis Type I.
      ,
      • Scarpa M.
      Mucopolysaccharidosis Type II.
      ,
      • Wang R.Y.
      • Bodamer O.A.
      • Watson M.S.
      • Wilcox W.R.
      ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Disease
      Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals.
      ). Intrathecal ERT is being considered as a future treatment option (see ClinicalTrials.gov).

      MPS Type II

      MPS Type II (Hunter syndrome) is an X-linked condition caused by iduronate-2-sulfatase deficiency, an enzyme that degrades glycosaminoglycans. Reduced or absent enzyme levels allow accumulation of glycosaminoglycans in various organs and tissues, including the central nervous system. The incidence rate is between 1:100,000 to 1:170,000 males (
      • Baehner F.
      • Schmiedeskamp C.
      • Krummenauer F.
      • Miebach E.
      • Bajbouj M.
      • Whybra C.
      • Beck M.
      Cumulative incidence rates of the mucopolysaccharidoses in Germany.
      ,
      U. S. Department of Health and Human Services, National Institutes of Health, Genetics Home Reference
      Mucopolysaccharoidosis type II.
      ,
      • Nelson J.
      • Crowhurst J.
      • Carey B.
      • Greed L.
      Incidence of the mucopolysaccharidoses in Western Australia.
      ). Like MPS I, there is a mild (attenuated) and more severe presentation.
      A progressively debilitating disease, severe MPS II typically presents between 18 months and 4 years of age with developmental delay and short stature, hepatosplenomegaly, joint contractures, and coarse facies. Macrocephaly and umbilical or inguinal hernias may be present. Enlarged vocal cords cause a deep, hoarse voice. In those with severe disease, communicating hydrocephalus may develop, and central nervous system involvement results in progressive loss of cognitive function. There are also behavioral changes such as anxiety, hyperactivity, sleep disturbances, impulsivity, and aggression. There may be multiple skeletal abnormalities and dysostosis multiplex. As the disease advances, there is cardiac and respiratory decompensation, and death usually occurs in the first or second decade of life (
      U. S. Department of Health and Human Services, National Institutes of Health, Genetics Home Reference
      Mucopolysaccharoidosis type II.
      ,
      • Roberts J.
      • Stewart C.
      • Kearney S.
      Management of the behaviourial manifestations of Hunter syndrome.
      ,
      • Scarpa M.
      Mucopolysaccharidosis Type II.
      ,
      • Schneidereith T.A.
      Maternal-child nursing: Pediatrics.
      ,
      • Wang R.Y.
      • Bodamer O.A.
      • Watson M.S.
      • Wilcox W.R.
      ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Disease
      Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals.
      ).
      Presentation for individuals with attenuated disease is highly variable and may occur between adolescence to adulthood. Affected individuals present with similar findings as those with severe disease, but the progressive organ involvement including hepatosplenomegaly, skeletal and joint problems, and cardiac and airway disease is slower than in those with severe disease (
      • Muenzer J.
      • Bodamer O.
      • Burton B.
      • Clarke L.
      • Frenkling G.S.
      • Giugliani R.
      • Harmatz P.
      The role of enzyme replacement therapy in sever Hunter syndrome—An expert panel consensus.
      ). Those with milder disease do not have severe intellectual disability and typically live into adulthood. Life expectancy varies from the fourth through the seventh decades.
      Treatment for MPS II includes disease-specific symptom management (antipsychotics, benzodiazepines, and anticonvulsants), anticipatory guidance, ongoing surveillance, and ERT for some individuals. ERT, however, has not been studied in children under 5 years of age and does not cross the blood–brain barrier. There is potential for HSCT to be effective, but outcome data are pending (
      • Scarpa M.
      Mucopolysaccharidosis Type II.
      ,
      • Wang R.Y.
      • Bodamer O.A.
      • Watson M.S.
      • Wilcox W.R.
      ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Disease
      Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals.
      ). Other treatments on the horizon may include intrathecal ERT, intrathecal administration of oligodendrocyte-like cells, and gene therapy (see ClinicalTrials.gov).

      Conclusion

      LSDs are a heterogeneous group of genetic conditions that result from enzyme deficiency in the lysosome. Because each condition results from a different enzyme and different genetic changes cause varying degrees of enzyme activity, disorders for which newborn screening is available have unique presentations, ages of onset, and recommended and available treatments. Although individually rare, the combined incidence rate for these conditions is higher than one might expect. As such, it is imperative that providers
      Although individually rare, the combined incidence rate for these conditions is higher than one might expect.
      become familiar with newborn screening panels within their own and neighboring states and maintain a basic understanding of these rare complex conditions should they encounter them in clinical practice.

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      Biography

      Sharon Anderson, Advanced Practice Nurse, Rutgers Robert Wood Johnson Medical School, Pediatric Genetics, Child Health Institute of New Jersey, New Brunswick, NJ and Assistant Professor, Rutgers School of Nursing, Newark, NJ.

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