Dr. Prakash Gambhir*
Consultant Genetics, Pune Email: *
It has been 125 years since Warren Tay an ophthalmologist gave first description of a child with retinal abnormalities and poor motor abilities. This was the first report of a lysosomal storage disorder GM2 gangliosidosis now named Tay Sachs disease. The very next year in 1882, Philip Gaucher a medical student described epithelioma of spleen first description of the condition now named after him. The next decades saw clinical identifications of many disorders characterized by storage. In 1955, De Duve identified lysosomes (1) and in the following years importance of this organelle as recycling house for macromolecules was recognized.

Lysosomes are now known to contain approximately 60 acid hydrolases and over a dozen accessory proteins. This elaborate system is responsible for degradation of almost all macromolecules, lipids, glycosaminoglycans, oligosaccharides proteins and nucleic acids. This system is assisted by specific transport systems in cytoplasm as well as lysosomal membranes (2). Storage of a variety of macromolecules result from defects in enzymes or the transport systems resulting in a group of disorders called lysosomal storage disorders.

Identification of acid maltase as the enzyme responsible for Pompe disease came with postulation of enzyme replacement therapy as the cure for this group of disorders. Bone marrow transplant and gene therapy as other strategies for restoring the enzyme degradative function have also been tried. The failure of enzymatic macromolecules to cross blood brain barrier and lack of spectacular success for bone marrow transplant to reverse the neurologic disease still warrants search for alternate approaches. The ideal choice will be gene therapy but as a lot of hurdles need to be overcome before gene therapy becomes a reality, scientists are still looking for other approaches (2, 3). Small molecule therapy for substrate deprivation as therapeutic intervention or as an adjunct to other therapies is an exciting prospect under consideration presently.

Table 1. Lysosomal storage disorders classified according to the function affected

Lysosomal Function Affected


Defective metabolism of

MPS I to IX Aspartylglucosaminuria, fucosidosis, Mannosidosis, Schindler disease, sialidosis type I

Defective degradation of glycogen
Defective degradation of sphingolipid components

Fabry, Farber, Gaucher, GM1 Gangliosidosis, GM2
Gangliosidosis, Krabbe, Metachromatic leukodystrophy, Niemann Pick (A & B)

Defective degradation of polypeptides


Defective degradation or transport of cholesterol, esters or complex lipids

Ceroid lipofuscinosis, cholesterol ester storage
disease, Niemann Pick ©, Wolman disease

Multiple deficiencies of Lysosomal

Multiple sulfates deficiency, galactosialidosis,
mucolipidosis II and III

Transport and trafficking Defects

Cystinosis, mucolipidosis IV, sialic acid storage
disorder, Hermansky Pudlak, Chediak Higashi

Unknown defects

Geleophysic dysplasia, Marinesco Sjogren's syndrome

Treatment Strategies:
The lysosomal disorders are characterized by abnormal accumulation of a normal substance. This substance may be increased to thousand times the normal resulting into various manifestations of the disease. The treatment protocols can be divided into Etiology specific therapy and symptomatic measures. Etiology specific therapy consists of strategic measures directed towards increasing the enzyme function and decreasing the substrate accumulation. The comprehensive protocols should comprise of both types of measures.

Symptomatic and Palliative Therapy:
Though new strategies of controlling lysosomal storage disorders are becoming a reality, presently no strategy is as yet proving to be a radical cure for any of the disorders. Therefore symptomatic treatment has an important place in management of these relentless disorders. The manifestations of lysosomal disorders are protean and affect many systems in an individual. Hence, care of the patient will involve a team approach of experts from various disciplines. The team should be headed by a person usually a biochemical geneticist experienced in treating these disorders. The other members in the team will be orthopedic surgeons, ophthalmologist, neurosurgeon, dermatologist, nephrologists, cardiologists, chest physician, oncologists etc. This team should be assisted by genetic counselors, physical therapists, occupational therapists, speech therapists social workers etc (3). Though patient is the focus of attention the support needs of the near family and other caretakers should always be looked into for best results. Table 2 shows commonly required symptom specific measures for lysosomal storage disorders.

Hence the care of the patient will involve a team approach of experts from various disciplines.

Table 2. Symptomatic treatment in Lysosomal storage disorders



Neurologic : Seizures, Neuropathic pain,
Hydrocephalus, Spinal cord compression, Carpal tunnel syndrome, Disturbed sleep, Dysarthria
Anticonvulsants, Prophylactic low dose
Anticonvulsants, Shunt procedure, Laminectomy, Carpal tunnel release, Melatonin, Speech therapy

Ophthalmologic: Cataract, Corneal clouding, Glaucoma

Removal, Transplant if impairs vision, Medication or surgery

Ear Nose Throat: Recurrent Otitis media, Hearing Loss, Sleep apnea

Pressure equalization tubes, Hearing aids,

Dental Caries

Good Dental Care

Cardiac: Valvular disease, Arrhythmias

Replacement, Endocarditis prophylaxis, Medication, Pacemaker

Pulmonary: Infiltrative lung disease


Gastrointestinal: Abdominal pain and
Diarrhea, Poor nutrition

Diet modification, Loperamide, Nutritional

Renal: Tubulopathy, Renal Failure

Electrolyte replacements, ACE inhibitors, Diet
modification, Dialysis

Musculoskeletal: Joint stiffness, Weakness, Scoliosis, Odontoid hypoplasia

Physical therapy, Walker , wheelchair, Rod placement, Upper cervical fusion

Hematologic : Anemia, thrombocytopenia, hypersplenism


Etiology-specific treatment modalities:
The aim of etiology specific modalities including Bone marrow transplant, Enzyme replacement therapy and Gene therapy is to restore the enzyme activity and function. The other upcoming etiologic specific therapy of substrate deprivation aims to utilize the remaining or replaced enzyme activity most efficiently.

Bone marrow transplant (BMT):
Bone marrow transplants have enjoyed certain measure of success in lysosomal storage disorders over last two decades. The bone marrow of healthy donor contains hemopoietic stem cells that can produce the required enzyme. The diseases in which bone marrow transplantation is tried are MPS I (4, 5, 6, 7), MPS II (8, 9), MPS VI (10), alpha mannosidosis (11), Krabbe and metachromatic leukodystrophies (13, 14), and Wolman disease (12). In all these conditions this form of therapy has been partially successful.

Transplantation is tried are MPS I (4 5 6 7), MPS II (8, 9), MPS VI (10), alpha mannosidosis(11), Krabbe and metachromatic leukodystrophies (13, 14) and Wolman disease (12). In all these conditions, this form of therapy has been partially successful.

In MPS I, it has been shown that if done early BMT reduces neurologic deterioration, reduces hepatosplenomegaly, cardiac function and upper airway obstruction. Skeletal manifestations like dysostosis and joint stiffness are not helped greatly and may require surgical correction.

The main drawbacks of BMT are morbidity and mortality of the procedure itself, difficulty in findings a matched donor, graft failure and graft versus host disease (8) . BMT does not help to a great extent in CNS manifestations so has to be performed early in course of the disease.

It has been observed that post-BMT, normal cells integrate into many tissues including the CNS however this process of integration is slow. It is hoped that with better protocols, survival and outcome will improve in future.

Enzyme replacement therapy (ERT):
Candidate for ERT include gaucher's, Fabry's, MPSI, MPSII, MPSVI. When acid maltase deficiency was demonstrated to be the cause for Pompe disease it was postulated that replacing the absent enzyme will be the corrective treatment for the disease. Gaucher disease type I was supposed to be the ideal candidate for this as it was seen that the tissue macrophage was the only cell type that was involved in the pathophysiology of the disease. The trials for replacement were started in 1970s in the NIH.(15) Initial attempts were not so successful because the enzyme glucocerebrosidase was obtained from human placenta and was available in small quantities. Secondly it was seen that the uptake of glucocerebrosidase was greater in other cells like hepatocytes than macrophages. The second problem of the enzyme reaching the target macrophage was crucial one. It was solved later by replacing the terminal galactose moieties by mannose by in vitro methods in placental glucocerebrosidase. Later it was demonstrated that fibroblasts secrete similar mannose terminated glucocerebrosidase.(2) Animal experiments demonstrated that mannose-terminated glucocerebrosidase preferentially was taken up by the Kupffer cells than the hepatocytes (16). Mannose terminated glucocerebrosidase later was given to Gaucher type I patients and was seen to be very effective in reducing organomegaly, and correction of the hematologic abnormalities (17).

With recombinant technology, the problem of quantity and purity was solved. However glucocerebrosidase being a large molecule does not cross the blood brain barrier and is not of much use in acute infantile and CNS manifestations of chronic neuronopathic types of Gaucher Disease. As perivascular storage cells in brain express mannose receptor, high dose ERT may work for neuronopathic form of Gaucher Disease (2, 3).

Apart from Gaucher disease, enzyme replacement therapy is now available commercially for Fabry disease and MPSI. In Fabry disease the response was quite satisfactory (18, 19, 20, 21). Though the enzyme does not cross the blood brain barrier even in severe MPS I ERT was rewarding as it resulted in reduced organomegaly, better joint mobility, reduced sleep apnea and better pulmonary function tests. This definitely improved the quality of life for these patients (23). ERT is also tried for Pompe disease with beneficial results and is on the way for MPS II and MPS VI (24) .
Apart from Gaucher disease, enzyme replacement therapy is now available commercially for Fabry disease and MPSI.

The major concern regarding ERT was the acceptance by the patients immunologically. Contrary to the fears even in immunologically naïve patients ERT seems to work efficiently even after prolonged treatment. In an analysis of 2462 patients of Gaucher disease on ERT during first 5 years of therapy only 3 patients developed neutralizing antibodies and less than 10 patients discontinued therapy because of adverse reactions (25, 26, 27) . In Fabry disease though many patient seroconvert the efficacy of ERT is not lost (19, 28) . The few symptoms like flu-like reaction that may occur because of complement release are easily treated with antihistaminics.

Gene therapy
Gene therapy holds the promise of complete cure for lysosomal disorders like any other genetic disorder.

Initial studies have shown that the gene therapy is possible but there are a lot of hurdles still to be overcome.
The problems that are to be solved are gene delivery to the target cells and the target tissue in the affected organs.

The gene after delivery should result into sustained that adequate expression (2, 3).
The safety concerns have been aroused by recent experiences in apparently successful gene therapy instances (29, 30).

For lysosomal disorders one of the approaches can be introduction of viral vectors directly into the CNS.
Other approach that is under consideration is generally altering the hemopoietic stem cells from the patient
to express the missing enzyme and returning the altered cells by BMT (3) . Both have been successful in animal models.
In one experiment, neural stem cells from human fetus were introduced in the brain of neonate MPS VII mice
and these stem cells were found to integrate into the host brain producing large quantities of beta glucuronidase
with clearing of lysosomal storage (31).

In other experiment, CD34+ cells from adult Gaucher patients were transduced with glucocerebrosidase gene
and immediately transfused. The cells persisted for at least 3 months but levels of corrected cells were found
to be too low for clinical benefit (32) .

Small Molecule Therapy:
Inaccessibility of the CNS because of the blood brain barrier and limitations of available forms of therapy bone marrow transplantation and enzyme replacement therapy prompted scientists to think of alternative strategies. One of the lysosomal storage disorders nephropathic cystinosis already has a drug regimen in the form of cysteamine systemically and topically in the eye. Cysteamine forms complexes with cystine accumulated in the lysosomes and this can escape lysosomes via the intact lysine transporter (33) .

The main attraction drug therapy is that the small molecules can easily cross the blood brain barrier unlike the enzymes. The principle of using small molecules in enzymopathies of lysosomal storage disorders is different. The idea is to keep the production of substrate only so much as to match its impaired catabolic rate. Thus the accumulation of the substrate and its disease causing effects because of accumulation can be avoided. This principle is variously named as substrate deprivation, substrate reduction or substrate inhibition (2, 3).

The idea is to keep the production of substrate only so much as to match its impaired catabolic rate

Two classes of drugs have been described. These drugs inhibit the activity of glucosyl ceramide synthetase, the enzyme that catalyzes the transfer of glucose to ceramide first step in the biosynthesis of glucosphingolipids. Prototype PDMP and its potent analogues have been evaluated in animal models. Studies in knockout mouse model for Fabry disease have shown that oral administration of these compounds results in reduction of accumulation of globotriaosylceramide (34).

The other class of drugs are iminosugars. These molecules were already known to inhibit N-glycan processing enzymes. The drug NB-DNJ was being evaluated as antiretroviral drug when it was recognized that it was capable of inhibiting glycosyl ceramide synthetase at micromolar concentrations (35). The researchers pursuing this lead showed that NB-DNJ could decrease glycosphingolipid storage in animal models of GM2 gangliosidosis (36). However the side effect of diarrhea probably because of inhibition of disacchridases of intestinal brush border was prominent. Galactose analogue of NB-DNJ N-butyldeoxygalactonojirimycin (OCT-918) was shown to be devoid of this side effect while retaining the pharmacological efficacy. N-butyldeoxygalacronojirimycin(OCT-918) was shown to reduce the liver and spleen volumes in adult patients of Gaucher disease who were not on ERT (37). It is now approved I Europe and U.S. in adults in whom ERT is not an available option. Further studies on OCT-918 in patients of Gaucher Disease, Fabry, Tay-Sachs Disease, Sandoff Disease GM2 activator variety, Niemann Pick type C are underway (2, 3).

OGT-918 in patients of Gaucher Disease, Fabry, Tay-Sachs Disease, Sandoff Disease, GM2 activator variety, Niemann Pick type C are underway (2)

A major factor that may determine the utility of these agents is that they require some residual activity of the enzyme under question that has to be answered is that whether long term inhibition of sphingolipid synthesis will be safe. However when the drugs will be used in conjunction with other therapies like ERT or BMT the comprehensive therapy is likely to be ore effective (2, 3).

Indian Scenario:
Lysosomal disorders are now frequently diagnosed in our country and excellent diagnostic facilities are available at few centers. However ERT is not still available to the patients and BMT and ERT will be out of reach for most of the people of our country. Till such time that effective therapy can be offered to the common man prenatal diagnosis is the resource that is available to people of India.

Neonatal Screening For Lysosomal Storage disorders
As effective therapies for Lysosomal Storage disorders are sought after, early detection may be an important intervention measure in future. A pilot neonatal screening program is initiated in Australia with test for LAMP1 (Lysosome associated membrane protein) (38, 39). When rational therapies become available for lysosomal storage disorders in future the choice of neonatal screening and subsequent treatment may supercede that of prenatal diagnosis.
References :
  1. De Duve C, Pressman B, Gianetto R, Wattiaux R, Appelmans F. Tissue fractionation studies. Intracellular distribution patterns of enzymes in rat liver. Biochem J 1955;60:604.
  2. Aerts JM, Hollk C, Boot R, Groener A. Biochemistry of glycosphingolipid storage disorders: implications for therapeutic intervention. Phil Trans R Soc Lond B 2003;358:905-914.
  3. Wilcox WR. Lysosomal storage disorders: The need for better pediatric recognition and comprehensive care. J Pediatr 2004;144:S3-S14.
  4. Peters C, Balthazor M, Shapiro EG, King RJ, Kollman C, Hegland JD, et al. Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome. Blood 1996;87:4894-902.
  5. Guffon N, Souiller G, Mairel, Straczek J, Guibaud P. Follow-up of nine patients with Hurler syndrome after bone marrow transplantation. J Pediatr 1998;133:119-25.
  6. Hite SH, Peters C, Krivit W. Correction of odontoid dysplasia following bone-marrow transplantation and engraftment (in Hurler syndrome MPS1H). Pediatr Radio 2000;30:464-70.
  7. Kachur E, Del Maestro R. Mucopolysaccharidoses and spinal cord compression: case report and review of the literature with implications of bone marrow transplantation. Neurosurgery 2000;47:223-228; discussion 89.
  8. Hoogerbrugge PM, Brouwer OF, Bordigoni P, Ringden O, Kapaun P, Ortega JJ, et al. Allogenic born marrow transplantation for lysosomal storage diseases. The European Group for Bone Marrow Transplantation. Lancet 1995;345:1398-402.
  9. Vellodi A, Young E, Cooper A, Lidchi V, Winchester B, Wraith JE. Long-term follow-up following bone marrow transplantation for Hunter disease. J Inherit Metab Dis 1999;22:638-48.
  10. Herskhovitz E, Young E, Rainer J, Hall CM, :Lidchi V, Chong K, et al. Bone marrow transplantation for Maroteaux-Lamy syndrome (MPSVI): long term follow-up. J Inherit Metab Dis 1999;22:50-62.
  11. Wall DA, Grange DK, Goulding P, Daines M, Luisiri A, Kotagal S. Bone marrow transplantation for the treatment of alpha-mannosidosis. J Pediatr 1998;133:282-5.
  12. Krivit W, Peters C, Dusenbery K, Ben-Yoseph Y, Ramsay NK, Wagner JE, et al. Wolman disease successfully treated by bone marrow transplantation. Bone Marrow Transplant2000-26:567-70.
  13. Krivit W, Shapiro E, Kennedy W, Lipton M, Lockman L, Smith S, et al. Treatment of late infantile metachromatic leukodystrophy by bone marrow transplantation. N Engl J Med 1990;322:28-32.
  14. Krivit W, Peters C, Shapiro EG. Bone marrow transplantation as effective treatment of central nervous system disease in globoid cell leukodystrophy, metachromatic leukodystrophy, adrenoleukodystrophy, mannosidosis, fucosidosis, Aspartylglucosaminuria, Hurler, Maroteaux-Lamy, and Sly syndromes, and Gaucher disease type III. Current Opin Neurol 1999;12:167-76.
  15. Braddy RO. Enzyme replacement therapy. Concept Chaos and Gulmination. Phil Trans Roy Soc Lond B 2003;358:915-919.
  16. Furbish FS, Ster CJ, Kret NL, Barranger JA. Uptake and distribution of placental glucocerebrosidase in rat hepatic cells and effects of sequential deglycosylation. Biochemistry Biophys ata 1981;673:425-434.
  17. Barton Net al Replacement therapy for inherited enzyme deficiency: macrophage targeted glucocerebrosidase for Gaucher's disease. N EnG J Med. 1991;324:1464-1470.
  18. Eng CM, Guffon N, Wilcox WR, Germain DP, Lee P, Waldek S, et al. Safety and efficacy of recombinant human alpha-galactosidase A replacement therapy in Fabry's disease. N Engl J Med 2001;345:9-16.
  19. Schiffmann R, Kopp JB, Austin HA3rd, Sabnis S, Moore DF, Weibel T, et al. Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA 2001;285:2743-9.
  20. Eng CM, Banikjazemi M, Gordon RE, Goldman M, Phelps R, Kim L, et al. A phase ½ clinical trial of enzyme replacement in Fabry disease: pharmacokinetic, substrate clearance, and safety studies. Am J Hum Gene 2001;68:711-22.
  21. Chiffmann R, Murray GJ, Treco D, Daniel P, Sellos Moura M, Myers M, et al. Infusion of alpha-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease. Proc Natl Acad Sci USA 2000;97:365-70.
  22. Wraith JE, Clarke LA, Beck M, Kolodny EH et al. Enzyme replacement Therapy for mucopolysaccharidosis I A randomized double blinded placebo controlled multinational study of Human alpha 1 iduronidase (laronidase). J Pediatr 2004:581-588.
  23. Kakkis ED, Muenzer J, Tiller GE, Waber L, Belmont J, Passage M, et al. Enzyme-replacement therapy in mucopolysaccharidosis I. N Engl J Med 2001;344:182-8.
  24. VandenHout JM, Reuser AJ, de Klerk JB, Arts WF, Smeitink JA, Van der Ploeg AT. Enzyme therapy for Pompe disease with recombinant human alpha-glucosidase from rabbit milk. J Inherit Metab Dis 2001;24:266-74.
  25. Grabowski GA, Leslie N, Wenstrup R. Enzyme therapy for Gaucher disease: the first 5 years. Blood Rev 1998;12:115-33.
  26. Ponce E, Moskovitz J, Grabowski G. Enzyme therapy in Gaucher disease type I : effect of neutralizing antibodies to acid beta-glucosidase. Blood 1997;90:43-8.
  27. Brady RO, Murray GJ, Oliver KL, Leitman SF, Sneller MC, Fleisher TA, et al. Management of neutralizing antibody to Ceredase in a patient with type 3 Gaucher disease. Pediatrics 1997;100:E11.
  28. Eng CM, Guffon N, Wilcox WR, Germain DP, Lee P, Waldek S, et al. Safety and efficacy of recombinant human alpha-galactosidase A replacement therapy in Fabry's disease. N Engl J Med 2001;345:9-16.
  29. Raper SE, Chirmule N, Lee FS, Wivel NA, Bagg A, Gao G, et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Gene Metab 2003;80:148-58.
  30. Kohm DB, Sadelain M, Glorioso JC. Occurrence of leukemia following gene therapy of X-linked SCID. Nar Rev Cancer 2003;3:477-88.
  31. Eto Y, ShenJ-S, X-I, Ohashi T. Treatment of lysosomal disorders : Cell therapy and Gene therapy. J inherit metabol dis 2004;27:411-415.
  32. Dunbar CE, Kohn DB, Schiffmann R, Barton NW, Nolta JA, Esplin JA, et al. Retroviral transfer of the glucocerebrosidase gene into CD 34+ cells from patients with Gaucher disease : in vivo detection of transduced cells without myeloablation. Hum gene ther 1998;9:2629-40.
  33. Schneider JA, Clark KF, Greene AA, Reisch JS, Markello TC, Gahl WA, et al. Recent advances in the treatment of cystinosis. J Inherit Metab Dis 1995;18387-97.
  34. Abe A, Gregory S, lee L, Killen PD, et al. Reduction of Globotriaosylceramide in Fabry disease mice by substrate deprivation. J clin invest 2000;105:1563-1567.
  35. Platt FM, Neises GR, Dwek RA, Butters TD. N-Butyl- deoxynojirimycin is a novel inhibitor of glycosphingolipid synthesis. J Biol Chem 1994;269:8362-8365.
  36. Jeyakumar M, Butters TD, Corrina-Borja M, et al. Delayed symptom onset and increased life expectancy in Sandoff mice treated with N-Butyl-deoxynojirimycin. Proc. Natl Acad. Sci USA 1999;96:6388-6393.
  37. Cox T, Lachmann R, Hollak C, Aerts J, van Weely S, Hrebicek M, et al. Novel oral treatment of Gaucher's disease with N-Butyldeoxynojirimycin (OGT918) to decrease substrate biosynthesis. Lancet 2000;355:1481-5.
  38. Meikle PJ, Ranieri E, Ravenscroft EM, Hua CT, Brooks DA, Hopwood JJ. Newborn screening for lysosomal storage disorders. Southeast Asian J Trop Med Public Health 1999;30 Suppl 2:104-10.
  39. Ranierri E, Gerace RL, Ravenscroft EM, Hopwood JJ, Meikle PJ. Pilot neonatal screening program for lysosomal storage disorders, using lamp-1. Southeast Asian J Trop Med Public Health 1999;30 Suppl 2:111-3.
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