Lysosomes are cytoplasmic organelles containing hydrolytic enzymes responsible for degrading and recycling macromolecules. These include compounds such as glycosaminoglycans, sphingolipids, and oligosaccharides. If lysosome function is defective, this leads to improper breakdown and subsequent buildup of undegraded substrates, destruction of cells, and organ damage.1–3 These rare metabolic defects are known as lysosomal storage diseases (LSDs). LSDs are caused by pathogenic variants in genes that encode lysosomal acid hydrolases, membrane and activator proteins, transporters, and other important products necessary for correct lysosome operations.4
There are more than 50 known LSDs, and their clinical presentations vary widely depending on the specific enzyme affected and degree of substrate accumulation. Within a single LSD, people who are affected may have different ages of onset and clinical severity.1,5 Common clinical findings include developmental delay, neurologic decline, facial dysmorphisms such as coarsening facies, organomegaly, and skeletal and muscle issues, but any organ system can be affected.1,5,6 Due to their broad clinical phenotypes and mostly slow, progressive symptoms, diagnosing LSDs can be challenging. Many people are born without any clear signs of an LSD,5 and they may not come to medical attention until more severe findings have manifested.
Due to the development of treatments for select LSDs and improved testing assays, there has been increasing interest in adding these conditions to universal newborn screening (NBS). The first available testing platform in the late 1990s was an immunoassay that detected increased lysosomal-associated membrane proteins. Later approaches include fluorescent-based assays and various tandem mass spectrometry assays, but there have been many challenges with analysis.5,7–9 In 2006, New York was the first state to mandate screening for Krabbe disease, an LSD caused by a deficiency in galactocerebrosidase enzyme activity.6,7 Additional states have since followed and have expanded their newborn screening to include certain LSDs; these are outlined in Table 1.1,6,10 Other states are piloting certain LSDs and/or have started legislative and logistical measures to eventually screen for select LSDs.
US States Fully Adopting Newborn Screening for Select Lysosomal Storage Diseases
Enzyme Replacement Therapy: Background and Clinical Use
Enzyme replacement therapy (ERT), or the replacement of an enzyme that is deficient, was first suggested as a method of treatment for LSDs in the 1960s by Christian de Duve11,12 and Roscoe Brady.13,14 This was based on the idea that patients with residual enzyme activity in LSDs were noted to have less severe symptoms compared to patients with complete enzyme deficiencies.15 ERT is not considered a cure as it cannot fix the inherent issue of improper production of the lysosomal enzyme. However, the theory behind ERT suggests if functional enzyme can be provided to patients with enzyme deficiencies, this will at least increase enzyme activity for a period of time and lead to some improvement in clinical symptoms.3
Due to the rare nature of LSDs and their initially poorly understood pathophysiology, treatment development was slow at the beginning of the late 20th century. The implementation of the US Orphan Drug Act of 198316 was key in to increasing development of treatments for rare disease including LSDs. Various financial incentives were offered to increase interest and investment into investigations of rare disease.16 After nearly 3 decades of research and development efforts, the first ERT (alglucerase) was approved under orphan drug status for Gaucher disease by the US Food and Drug Administration (FDA) in 1991.16 ERT has since been highly successful in treating Gaucher disease. ERT development for other LSDs followed. Table 21,6,15,17–19 summarizes the clinical features of LSDs that currently have FDA-approved ERT.
Lysosomal Storage Diseases Approved by the US Food and Drug Administration for Enzyme Replacement Therapy
Of note, although ERT has been primarily used to treat LSDs, it has also been used in other conditions such as hypophosphatasia20 and adenosine deaminase deficiency/severe combined immunodeficiency.21 Additionally, although ERT is now available for multiple disorders, not all conditions are screened for at NBS currently. Likewise, not all LSDs screened for at NBS have ERT available (Table 11,6,10 and Table 21,6,15,17–19), although these conditions, such as globoid cell leukodystrophy (Krabbe disease), have alternative methods of treatment. Adding any condition to NBS is a complicated process and requires state and legislative support, and there is variability between states in terms of the conditions that are ultimately selected for screening.
Enzyme Replacement Therapy: Limitations
The success and effectiveness of ERT treatment depends on more than solely supplying additional enzyme to someone who is affected. Lysosomal enzymes are normally produced by the body in the endoplasmic reticulum, then sent to the Golgi apparatus where a mannose-6 phosphate (M6P) tag is placed.3 M6P is the key signal to target the protein's movement to the lysosomes. Thus, any ERT produced must also be targeted to lysosomes and be delivered to the correct tissues affected by the disorder.18 Modifications may be required as purified enzymes are not always targeted to the lysosomes.3
Another issue encountered with ERT is limited bioavailability in certain tissues. Recombinant enzymes may not be able to travel freely along membranes due to their large size, and the efficiency of ERT delivery is reduced for cells that do not have direct contact with the bloodstream.1,18 This is problematic in tissues such as skeletal muscle and bone. However, the greatest challenge is that enzyme given intravenously cannot cross into the brain due to the blood-brain barrier (BBB).18 Thus, neurologic symptoms, which are present in about two-thirds of LSDs,18 will not respond to treatment. Approaches to address this issue are under investigation. They include modifying molecules to facilitate its movement through the BBB, higher ERT doses (although this did not demonstrate neurologic improvement for patients in a type 3 Gaucher disease trial22), and giving the injections intrathecally.1,15,23,24 Giving ERT through lumbar punctures bimonthly is not practical in the long-term for patients who need treatment, but possible alternative methods for chronic delivery have been explored, such as intrathecal catheters connected to subcutaneous ports, which is a method that was used in an animal study.25
Logistics of treatment may also impact its effectiveness for patients. When symptoms are identified, ERT is typically given intravenously on a weekly or bimonthly schedule. However, the treatments are expensive—the cost of treating one person who is affected may be several hundred thousand dollars or more annually.1 This type of treatment also requires a life-long, dedicated commitment for maximum benefit, and compliance may be difficult for patients and families. Patients may also develop immune reactions to the exogenous enzyme, which reduces the effectiveness of ERT. The degree of reaction varies widely between people and diseases. With some success toward prevention, immune tolerance induction has been evaluated in Pompe disease.26
Alternative Treatments for LSDs
Alternative treatments have been investigated because ERT cannot ameliorate all the clinical issues of LSDs. Hematopoietic stem cell transplantation (HSCT) using peripheral blood, bone marrow, or umbilical cord derived cells has been used in certain LSDs with varying success.27 With this method, stem cells from the healthy donor repopulate tissues and release normally functioning lysosomal enzymes that are taken up by recipient cells, improving the enzyme defect through cross-correction.1 In contrast to ERT, microglial cells from the donor could theoretically engraft in the brain and produce enzyme locally, potentially helping neurologic symptoms.27,28 However, HSCT depends on finding compatible donors and successful engraftment of donor cells, and patients need to be immunosuppressed. Transplantation mortality has improved significantly in the last decade, but overall patients with more mild phenotypes who are transplanted at earlier periods have been shown to have better outcomes.27
Gene therapy in the setting of LSDs aims to deliver a normal functioning copy of the impaired gene to the affected tissues to improve or restore enzyme activity. Viral vectors such as adeno-associated virus or lentivirus are typically used as carriers for the therapeutic gene.1 Gene therapy may be done using an in vivo or ex vivo method. When done in vivo, the corrected gene is delivered systemically with a tissue-specific promotor to allow the correct protein to be produced in large quantities at that tissue site, or there is direct injection into a target organ.1,3,19 In the ex vivo method, cells from a patient are transduced with a viral vector to highly express the needed enzyme and then infused back to the patient to fix the defect by cross-correction.1,3,19 Successful delivery and distribution of the gene therapy to the targeted tissues and cells are key in this approach.
Small-molecule based therapies are important because they can cross the BBB and could potentially impact neurological symptoms of LSDs.15 They are also less immunogenic compared to larger molecules involved in ERT and gene therapy.19 Examples include using pharmacologic chaperones that interact with abnormal proteins to help stabilize them and favor development of the correct protein conformation, enzyme substrate inhibitors to prevent formation of substrates thereby reducing their accumulation, and modulators of cytosolic molecules.1,19 Drawbacks include lack of information regarding long-term toxicity and lack of standardized dosing.3
Interest in genome editing has also been on the rise, particularly with the development of the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 system, a gene editing tool based on a prokaryotic immune system.29 CRISPR-Cas9 system has been suggested as a possible method to correct the abnormal gene at its original site instead of providing a working copy with other methods. Although this system holds promise and has been described as a potential treatment option for LSDs30 among other genetic disorders, long-term implications of using such technology are unknown and additional studies are needed.
LSDs are a highly heterogeneous group of disorders with varying clinical features and severity even within a single disorder. Over the last few decades, knowledge of the LSDs' molecular underpinnings and pathophysiology has increased dramatically and led to the development of treatments such as ERT and other techniques for select disorders. ERT use has been successful for many LSDs; however, all available treatments still only help slow the progressive symptoms. Presently, there is no true “cure” for LSDs. Management remains focused on early diagnosis and treatment, which has led to the implementation of NBS for select LSDs in certain states. LSD screening will likely expand to universal NBS, particularly as better treatments are developed that can address the prominent neurologic features of LSDs. Further long-term studies are needed to investigate the use of newer treatments such as gene-editing technologies, which may potentially be the key to truly correct genetic errors responsible for LSDs.
- Parenti G, Andria G, Ballabio A. Lysosomal storage diseases: from pathophysiology to therapy. Annu Rev Med. 2015;66(1):471–486. doi:. doi:10.1146/annurev-med-122313-085916 [CrossRef]
- Wang RY, Bodamer OA, Watson MS, Wilcox WR. Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals. Genet Med. 2011;13(5):457–484. doi:. doi:10.1097/GIM.0b013e318211a7e1 [CrossRef]
- Kelly JM, Bradbury A, Martin DR, Byrne ME. Emerging therapies for neuropathic lysosomal storage disorders. Prog Neurobiol. 2017;152:166–180. doi:. doi:10.1016/j.pneurobio.2016.10.002 [CrossRef]
- Sands MS, Davidson BL. Gene therapy for lysosomal storage diseases. Mol Ther. 2006;13(5):839–849. doi:. doi:10.1016/j.ymthe.2006.01.006 [CrossRef]
- Schielen P, Kemper E, Gelb M. Newborn screening for lysosomal storage diseases: a concise review of the literature on screening methods, therapeutic possibilities and regional programs. Int J Neonatal Screen. 2017;3(2):6. doi:. doi:10.3390/ijns3020006 [CrossRef]
- Saudubray J-M, van den Berghe G, Walter J. Inborn Metabolic Diseases. 5th ed. Berlin, Germany: Springer-Verlag; 2012. doi:10.1007/978-3-642-15720-2 [CrossRef]
- Orsini J, Aggana M. Newborn screening for Krabbe disease and other lysosomal storage disorders: broad lessons learned. Int J Neonatal Screening. 2017;3(1):3. doi:10.3390/ijns3010003 [CrossRef]
- Matern D, Oglesbee D, Tortorelli S. Newborn screening for lysosomal storage disorders and other neuronopathic conditions. Dev Disabil Res Rev. 2013;17(3):247–253. doi:. doi:10.1002/ddrr.1117 [CrossRef]
- Elliott S, Buroker N, Cournoyer JJ, et al. Pilot study of newborn screening for six lysosomal storage diseases using tandem mass spectrometry. Mol Genet Metab. 2016;118(4):304–309. doi:. doi:10.1016/j.ymgme.2016.05.015 [CrossRef]
- Conditions screened by state. Baby's First Test Web site. http://www.babysfirsttest.org/newborn-screening/states. Accessed April 26, 2018 Baby's first test.
- de Duve C. Lysosomes. In: The Lysosome Concept. ; 1963:362–383.
- de Duve C. From cytases to lysosomes. Fed Proc. 1964;23:1045–1049.
- Brady RO, Kanfer JN, Shapiro D. Metabolism of glucocerebrosides II. Evidence of an enzymatic deficiency in Gaucher's disease. Biochem Biophys Res Commun. 1965;18(2):221–225. doi:. doi:10.1016/0006-291X(65)90743-6 [CrossRef]
- Brady RO, Kanfer JN, Mock MB, Fredrickson DS. The metabolism of sphingomyelin. II. Evidence of an enzymatic deficiency in Niemann-Pick disease. Proc Natl Acad Sci USA. 1966;55(2):366–369. doi:10.1073/pnas.55.2.366 [CrossRef]
- Ries M. Enzyme replacement therapy and beyond-in memoriam Roscoe O. Brady, M.D. (1923–2016). J Inherit Metab Dis. 2017;40(3):343–356. doi:. doi:10.1007/s10545-017-0032-8 [CrossRef]
- Mechler K, Mountford WK, Hoffmann GF, Ries M. Pressure for drug development in lysosomal storage disorders - a quantitative analysis thirty years beyond the US orphan drug act. Orphanet J Rare Dis. 2015;10(1):46. doi:. doi:10.1186/s13023-015-0262-5 [CrossRef]
- Pastores GM, Hughes DA. Gaucher disease. In: Adam MP, Ardinger HH, Pagon RA, , eds. GeneReviews. Seattle, WA: University of Washington; 2000.
- Lachmann RH. Enzyme replacement therapy for lysosomal storage diseases. Curr Opin Pediatr. 2011;23(6):588–593. doi:10.1097/MOP.0b013e32834c20d9 [CrossRef]
- Solomon M, Muro S. Lysosomal enzyme replacement therapies: historical development, clinical outcomes, and future perspectives. Adv Drug Deliv Rev. 2017;118:109–134. doi:. doi:10.1016/j.addr.2017.05.004 [CrossRef]
- Whyte MP, Madson KL, Phillips D, et al. Asfotase alfa therapy for children with hypophosphatasia. JCI Insight. 2016;1(9):e85971. doi:. doi:10.1172/jci.insight.85971 [CrossRef]
- Hershfield M. Adenosine deaminase deficiency. https://www-ncbi-nlm-nih-gov.archer.luhs.org/books/NBK1483/. Gene Rev. Accessed April 24, 2018.
- Vellodi A, Tylki-Szymanska A, Davies EH, et al. Management of neuronopathic Gaucher disease: revised recommendations. J Inherit Metab Dis. 2009;32(5):660–664. doi:. doi:10.1007/s10545-009-1164-2 [CrossRef]
- Muenzer J, Hendriksz CJ, Fan Z, et al. A phase I/II study of intrathecal idursulfase-IT in children with severe mucopolysaccharidosis II. Genet Med. 2016;18(1):73–81. doi:. doi:10.1038/gim.2015.36 [CrossRef]
- Munoz-Rojas MV, Vieira T, Costa R, et al. Intrathecal enzyme replacement therapy in a patient with mucopolysaccharidosis type I and symptomatic spinal cord compression. Am J Med Genet Part A. 2008;146:2538–2544. doi:. doi:10.1002/ajmg.a.32294 [CrossRef]
- Felice BR, Wright TL, Boyd RB, et al. Safety evaluation of chronic intrathecal administration of idursulfase-IT in cynomolgus monkeys. Toxicol Pathol. 2011;39(5):879–892. doi:. doi:10.1177/0192623311409595 [CrossRef]
- Banugaria SG, Prater SN, Patel TT, et al. Algorithm for the early diagnosis and treatment of patients with cross reactive immunologic material-negative classic infantile Pompe disease: a step towards improving the efficacy of ERT. PLoS One. 2013;8(6):e67052. doi:. doi:10.1371/journal.pone.0067052 [CrossRef]
- Boelens JJ, Van Hasselt PM. Neurodevelopmental outcome after hematopoietic cell transplantation in inborn errors of metabolism: current considerations and future perspectives. Neuropediatrics. 2016;47(5):285–292. doi:. doi:10.1055/s-0036-1584602 [CrossRef]
- Kim S. Lysosomal storage diseases: stem cell-based cell- and gene-therapy [published online ahead of print May 21, 2014]. Cell Transpl. doi:10.3727/096368914X681946 [CrossRef].
- Xiao-Jie L, Hui-Ying X, Zun-Ping K, Jin-Lian C, Li-Juan J. CRISPR-Cas9: a new and promising player in gene therapy. J Med Genet. 2015;52(5):289–296. doi:. doi:10.1136/jmedgenet-2014-102968 [CrossRef]
- Christensen C, Choy F. A prospective treatment option for lysosomal storage diseases: CRISPR/Cas9 gene editing technology for mutation correction in induced pluripotent stem cells. Diseases. 2017;5(1):e6. doi:. doi:10.3390/diseases5010006 [CrossRef]
US States Fully Adopting Newborn Screening for Select Lysosomal Storage Diseasesa
||Fabry, Gaucher, MPS1, NPD,b Pompec
||GLDd (also called Krabbe disease), MPS1, Pompec
||Fabry, Gaucher, MPS1, Pompec
||GLD,d MPS1, Pompec
||Fabry, Gaucher, GLD,d MPS1, NPD,b Pompec
||Fabry, Gaucher, GLD,d MPS1, Pompec
Lysosomal Storage Diseases Approved by the US Food and Drug Administration for Enzyme Replacement Therapy
||Enzyme Replacement Therapy a
||Imiglucerase, taliglucerase alfa, velaglucerase alpha
||Type I: Majority of cases. Most commonly presents in adulthood but can present earlier. Varied clinical presentations from asymptomatic to symptoms such as osteopenia or sclerotic lesions, bone crisis, hepatosplenomegaly, anemia and thrombocytopenia, pulmonary disease, and abdominal pain. Usually lacks neurologic symptoms
Type II: Acute neuronopathic disease. Typically presents in early infancy with progressive neurologic dysfunction, bulbar and pyramidal signs, feeding difficulties and failure to thrive, pulmonary disease, splenomegaly, and intellectual disability. Survival not common beyond 2–4 years
Type III: Subacute or chronic neuronopathic disease. Slower progression compared to type II. Average age of onset is around 5 years, although it can present from infancy to adulthood. Severe end has systemic involvement. May see developmental delay, horizontal gaze palsy, hearing impairment along with hepatosplenomegaly, pulmonary disease and cytopenias. Can also have mild systemic disease with neurologic findings such as myoclonic encephalopathy, seizures, and dementia.
Perinatal-lethal sub-type: Nonimmune hydrops, icthyosiform skin changes, arthrogryposis, hepatosplenomegaly, pancytopenia
Cardiovascular subtype: Presents with calcification of mitral and aortic valves and mild hepatosplenomegaly. Survival can occur to third or fourth decade
||Agalsidase alfa, agalsidase beta
||X-linked disorder so classic form appears in males; however, female presentations vary from asymptomatic to severe disease as seen in males
Classic presentation: Childhood with severe pain crises in extremities (acroparethesias), sweating issues, temperature and exercise intolerance, cutaneous vascular lesions called angiokeratomas, proteinuria, and corneal opacities. Kidney dysfunction progresses by mid-adulthood with end-stage renal disease and renal failure. Hearing loss and various gastrointestinal and pulmonary symptoms have also been reported
Additional presentations include: A primarily cardiac phenotype in late adulthood with conduction abnormalities, cardiomyopathy, and proteinuria but not end stage renal failures, cerebrovascular disease with onset of stroke or transient ischemic attack, or primarily renal phenotype with end-stage renal failure but no skin findings or pain crisis
|Lysosomal acid lipase deficiency
||Lysosomal acid lipase
||Infantile-onset (Wolman disease): May present with abdominal distension and emesis, loose stools, failure to thrive, anemia, and hepatosplenomegaly. May also see calcification of adrenal glands that can cause adrenal cortical insufficiency.
Later-onset cholesterol ester storage disease: Can have early presentation similar to infantile-onset or later presentation in childhood. Will see lipid abnormalities, hepatosplenomegaly, elevated liver enzymes, and complications from liver disease and atherosclerosis
|Mucopolysaccharidosis type I (Hurler syndrome)
||Traditionally was classified on a spectrum from Hurler (most severe), Hurler-Scheie (moderate) to Scheie disease (most mild); however, no distinct biochemical way to distinguish so best thought of as severe and attenuated
Severe: Nonspecific features in early infancy such as upper respiratory infections and hernias. Facies coarsen more noticeably after 1 year. Will see progressive skeletal dysplasia and joint deformities (dysostosis multiplex), slowed growth, and short stature. May see macrocephaly, hearing loss, hepatosplenomegaly, corneal clouding, progressive intellectual disability, and cardiac abnormalities such as valvular disease. Survival is usually not past 10 years
Attenuated: Less severe and later onset typically between toddler years to early childhood. Can have overlapping features seen in severe form and varying levels of neurologic and intellectual disabilities. Range of lifespan from young adulthood to normal.
|Mucopolysaccharidosis type II (Hunter syndrome)
||X-linked recessive but female heterozygotes do not usually show symptoms. Presentation and disease progression varies widely among males. Similar features to Mucopolysaccharidosis type I but corneas typically remain clear
|Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome)
||Onset and presentation varies. Findings similar to previously listed mucopolysaccharidosis disorders: coarse facies, hepatosplenomegaly, bone issues and dysostosis multiplex, short stature, corneal clouding, cardiac abnormalities. Intelligence is usually normal
|Mucopolysaccharidosis type IV (Morquio syndrome)
||Type A: Ranges from severe to more slowly progressive disease. Severe cases typically present in early infancy-toddler age and less severe forms later in childhood. Will see bony involvement and skeletal dysplasia, kyphoscoliosis, hip dysplasia, and genu valgum. May also have respiratory issues, valvular heart disease, hearing loss, corneal clouding, and hepatomegaly. Intelligence is normal
Type B: Of note, there is a type B form caused by deficiency of beta-galactosidase. Clinical features are similar to type A, but enzyme replacement therapy is not available for this form. May only be distinguishable from type A by biochemical and molecular testing
|Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome)
||Onset and presentation varies. Findings similar to previously listed mucopolysaccharidosis disorders: coarse facies hepatosplenomegaly, bone issues and dysostosis multiplex, short stature, corneal clouding, cardiac abnormalities. Intelligence is usually normal
||Infantile-onset (classic): Onset in first year of life with failure to thrive, hypotonia, respiratory difficulties, and hypertrophic cardiomyopathy
Late-onset: Presentations after first year of life or infants with onset before 1 year without heart involvement. Slower progression compared to infantile-onset. Primary findings are muscle weakness and respiratory difficulties that may eventually necessitate use of wheelchairs and/or ventilator. Any cardiac complications usually occur later in life. Can also present in adulthood with affected trunk and proximal limb muscles, similar to limb-girdle muscle dystrophies