Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Lipid Storage Disorders

  • Author: Lynne Ierardi-Curto, MD, PhD; Chief Editor: Luis O Rohena, MD  more...
 
Updated: Oct 16, 2014
 

Background

Lipid storage disorders are a family of diverse diseases related by their molecular pathology. In each disorder, a deficiency of a lysosomal hydrolase is inherited, which leads to lysosomal accumulation of the enzyme's specific sphingolipid substrate.[1, 2] Lipid substrates share a common structure, including a ceramide backbone (2-N -acyl-sphingosine), in which various sphingolipids are derived by substitution of hexoses, phosphorylcholine, or one or more sialic acid residues on terminal hydroxyl groups of the ceramide molecule.

Pathways of glycosphingolipid metabolism in both nervous tissue and visceral organs are elucidated, and for each catabolic step, a genetically determined metabolic derangement is identified.[3]

Disorders include GM1 gangliosidoses,[4] GM2 gangliosidoses,[4] Gaucher disease, sphingomyelinase deficiency or Niemann-Pick disease (NPD) types A and B,[5] Niemann-Pick disease type C, Fabry disease, fucosidosis, Schindler disease, metachromatic leukodystrophy (MLD), Krabbe disease, multiple sulfatase deficiency, Farber disease, Wolman disease, and cholesterol ester storage disease (CESD).

The biochemical basis of lipid storage disorders is well characterized and includes determining properties of enzymatic activities and various storage products. Research has led to development of diagnostic assays for identification of affected individuals, which usually rely on measurement of specific enzymatic activity in isolated leukocytes or cultured fibroblasts. For most disorders, carrier identification and prenatal diagnosis are available as well. Making a specific diagnosis in an affected individual is essential in order to provide accurate genetic counseling.

More recently, investigators have focused efforts on determining the molecular basis of each of these disorders. These studies have resulted in identifying specific disease-causing mutations and have led to improved clinical and laboratory diagnosis, prenatal diagnosis, and carrier identification. In addition, for some disorders (eg, Gaucher disease), making genotype-phenotype correlations that predict disease severity and allow more accurate genetic risk counseling is possible. Advances in understanding the molecular and biochemical basis include cloning and characterization of most genes that encode specific enzymes required for sphingolipid metabolism. These investigations permit development of improved therapeutic options, such as recombinant enzyme replacement therapy. Other therapeutic options, such as gene therapy and bone marrow transplantation, for selected lipidoses may also result in improved prognosis.

Next

Pathophysiology

Because glycosphingolipids are essential components of all cell membranes, inability to degrade these substances and their subsequent accumulation results in physiologic and morphologic alterations of specific tissues and organs that lead to characteristic clinical manifestations. In particular, progressive lysosomal accumulation of glycosphingolipids in the central nervous system can lead to a neurodegenerative course; whereas, storage in visceral cells can lead to organomegaly, skeletal abnormalities, bone marrow dysfunction, pulmonary infiltration, and other manifestations. In general, storage of any particular substrate in a specific tissue is dependent on the normal distribution of the compound in the body. Thus, various disorders of lipid metabolism have characteristic patterns of organ involvement and clinical history, depending on the particular substrate that is stored.

Previous
Next

Epidemiology

Frequency

United States

Lipid storage disorders are rare disorders, although some have an ethnic predilection with more appreciable frequency.

International

Frequency is similar to that in the United States.

Mortality/Morbidity

Infantile forms are usually fatal. Juvenile-onset and adult-onset disorders have variable survival rates that depend on particular manifestations.

Race

Most lipid storage disorders are panethnic; however, an ethnic predilection has been noted for Tay-Sachs disease, type 1 Gaucher disease, and sphingomyelinase deficiency (NPD type A), which all occur at increased frequency in Ashkenazi Jews. Guidelines for carrier screening for genetic disorders in individuals of Ashkenazi Jewish descent have been established.[6]

Other important ethnic predilections include the following:

  • NPD type C1 has a high incidence in Acadians from Nova Scotia, individuals of Hispanic descent in parts of the southwestern United States, and a Bedouin group in Israel.
  • Late-onset form of Fabry disease is found in increased incidence in Italy (1 in 4,600).
  • Gaucher disease type 3 is more common in the Norrbottnian region of Sweden (1 in 50,000).
  • Tay-Sachs disease has an increased incidence in French Canadians (1 in 10,000), Cajuns from Louisiana, and Old Order Amish in Pennsylvania.
  • Metachromatic leukodystrophy has an increased incidence in the Habbanite Jewish in Israel (1 in 75), Israeli and Christian Israeli Arabs (1 in 10,000), and the western portion of the Navajo nation in the United States (1 in 2,500).

Sex

Each disorder is transmitted as an autosomal recessive trait, except Fabry disease, which is an X-linked recessive trait.

Age

Congenital presentation

The perinatal lethal form of Gaucher disease is associated with nonimmune hydrops fetalis, arthrogryposis, ichthyosiform or collodion skin abnormalities, hepatosplenomegaly, and pancytopenia.

Perinatal forms of GM1 gangliosidosis, NPD type C, Wolman disease, and Farber disease are associated with nonimmune hydrops fetalis.

Presentation in infancy

GM1 gangliosidosis type 1 and sphingomyelinase deficiency (NPD type A) usually appear in early infancy. GM2 gangliosidoses, which include Tay-Sachs disease and Sandhoff disease, have infantile forms.

The clinical phenotypes for MLD widely vary. Patients who are severely affected usually present in the first year of life with developmental delay and somatic features, similar to those of mucopolysaccharidoses. Late infantile forms of MLD, which is most common, usually present in infants aged 12-18 months with irritability, inability to walk, and hyperextension of the knee, causing genu-recurvatum.

Infantile forms of Krabbe disease are rapidly progressive and present early in infancy with irritability, seizures, and hypertonia. Optic atrophy is evident in the first year of life and mental development is severely impaired. A second, late infantile form of Krabbe disease is also observed and presents in children older than 2 years. Affected individuals have a disease course similar to early infantile form.

Wolman disease is a fatal disorder of infancy. Clinical features become apparent in the first week of life and include failure to thrive, relentless vomiting, abdominal distention, and hepatosplenomegaly.

Multiple sulfatase deficiency is typically diagnosed in infancy and childhood. Affected patients have ichthyosis, dysostosis multiplex, and symptoms of MLD due the deficient activity of several sulfatases.

The few reported cases of Farber disease describe the presence of irritability, hoarse cry, and nodular, erythematous swelling of the wrists during the first few weeks of life, with severe motor and mental retardation and death by 2 years of age.

Patients with Schindler disease type 1 have infantile onset of neuroaxonal dystrophy, developmental delay, and rapidly progressive psychomotor deterioration without organomegaly.

Sphingomyelinase deficiency (NPD type A) is a fatal disorder of infancy. Hepatosplenomegaly develops by 6 months of age and development does not progress beyond 12 months. A relentless neurodegenerative course then follows with death by 21 months of age.

Presentation in childhood

GM1 and GM2 gangliosidoses type 2 are juvenile-onset forms.

Sphingomyelinase deficiency (NPD type B) has a variable age of presentation but frequently appears early in childhood when hepatosplenomegaly is detected.

Angiokeratomas that appear in Fabry disease usually occur in childhood and can lead to early diagnosis.

Juvenile forms of MLD have more indolent courses and onset can occur in persons as old as 20 years. This form presents with gait disturbances, mental deterioration, urinary incontinence, and emotional difficulties.

Gaucher disease types 2 and 3 (neuronopathic) and more severe cases of type 1 (non-neuronopathic) present during childhood.

Cholesterol ester storage disease (CESD) is the milder form of Wolman disease, with later onset in childhood, less severe symptoms, and lifespan into adulthood.

Schindler disease type III has milder neurologic manifestations and later onset in childhood.

Patients with classic NPD type C develop normally for the first 2 years of life, followed by the onset of ataxia, grand mal seizures, loss of speech, impaired vertical gaze, and other neurologic manifestations leading to death in mid to late childhood.

Patients with sphingomyelinase deficiency (NPD type B) primarily have visceral involvement, sometimes massive, without neurologic symptoms and often survive into adulthood.

Presentation in adulthood

Adult forms of MLD, which present after the second decade of life, are similar to juvenile forms in clinical manifestations, although emotional difficulties and psychosis are more prominent features. Late-onset and variant forms with onset or diagnosis in adulthood due to milder symptoms include Krabbe, NPD type C, Gaucher disease type 1, and Schindler disease type II (Kanzaki disease).

Previous
 
 
Contributor Information and Disclosures
Author

Lynne Ierardi-Curto, MD, PhD Attending Physician, Division of Metabolism, Children's Hospital of Philadelphia

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Eric T Rush, MD, FAAP, FACMG Clinical Geneticist, Munroe-Meyer Institute for Genetics and Rehabilitation; Assistant Professor of Pediatrics and Internal Medicine, University of Nebraska Medical Center

Eric T Rush, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American College of Physicians, Nebraska Medical Association

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Alexion Pharmaceuticals<br/>Honoraria for: Alexion Pharmaceuticals and Biomarin Pharmaceuticals.

Chief Editor

Luis O Rohena, MD Chief, Medical Genetics, San Antonio Military Medical Center; Assistant Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Assistant Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Additional Contributors

Edward Kaye, MD Vice President of Clinical Research, Genzyme Corporation

Edward Kaye, MD is a member of the following medical societies: American Academy of Neurology, Society for Inherited Metabolic Disorders, American Society of Gene and Cell Therapy, American Society of Human Genetics, Child Neurology Society

Disclosure: Received salary from Genzyme Corporation for management position.

References
  1. Jenkins RW, Canals D, Hannun YA. Roles and regulation of secretory and lysosomal acid sphingomyelinase. Cell Signal. 2009 Jun. 21(6):836-46. [Medline].

  2. Sasaki H, Arai H, Cocco MJ, White SH. pH dependence of sphingosine aggregation. Biophys J. 2009 Apr 8. 96(7):2727-33. [Medline]. [Full Text].

  3. Saini-Chohan HK, Mitchell RW, Vaz FM, Zelinski T, Hatch GM. Delineating the role of alterations in lipid metabolism to the pathogenesis of inherited skeletal and cardiac muscle disorders: Thematic Review Series: Genetics of Human Lipid Diseases. J Lipid Res. 2012 Jan. 53(1):4-27. [Medline]. [Full Text].

  4. Steczkowska M, Gergont A, Kroczka S, Nowak A. [Clinical features of GM1 and GM2 gangliosidosis in own observation]. Przegl Lek. 2008. 65(11):819-23. [Medline].

  5. Ambrosio C, Serra S, Alexandre M, Malcata A. [Arthralgia, bone pain, positive antinuclear antibodies and thrombocytopenia...diagnosis: Niemann-Pick disease]. Acta Reumatol Port. 2009 Jan-Mar. 34(1):102-5. [Medline].

  6. [Guideline] Langlois S, Wilson RD. Carrier screening for genetic disorders in individuals of Ashkenazi Jewish descent. J Obstet Gynaecol Can. 2006 Apr. 28(4):324-43. [Medline]. [Full Text].

  7. Wasserstein M, Godbold J, McGovern MM. Skeletal manifestations in pediatric and adult patients with Niemann Pick disease type B. J Inherit Metab Dis. 2012 Jun 21. [Medline].

  8. Tsuboi K, Suzuki S, Nagai M. Descriptive epidemiology of Fabry disease among beneficiaries of the Specified Disease Treatment Research Program in Japan. J Epidemiol. 2012. 22(4):370-4. [Medline].

  9. Goldim MP, Garcia Cda S, de Castilhos CD, Daitx VV, Mezzalira J, Breier AC, et al. Screening of high-risk Gaucher disease patients in Brazil using miniaturized dried blood spots and leukocyte techniques. Gene. 2012 Oct 25. 508(2):197-8. [Medline].

  10. Aerts JM, Kallemeijn WW, Wegdam W, Joao Ferraz M, van Breemen MJ, Dekker N, et al. Biomarkers in the diagnosis of lysosomal storage disorders: proteins, lipids, and inhibodies. J Inherit Metab Dis. 2011 Jun. 34(3):605-19. [Medline]. [Full Text].

  11. Arora P, Tullu MS, Muranjan MN, et al. Congenital and inherited ophthalmologic abnormalities. Indian J Pediatr. 2003 Jul. 70(7):549-52. [Medline].

  12. Brunetti-Pierri N, Scaglia F. GM1 gangliosidosis: review of clinical, molecular, and therapeutic aspects. Mol Genet Metab. Aug 2008. 94(4):391-396. [Medline].

  13. Burton BK. Inborn errors of metabolism: the clinical diagnosis in early infancy. Pediatrics. 1987 Mar. 79(3):359-69. [Medline].

  14. Caciotti A, Donati MA, d'Azzo A, et al. The potential action of galactose as a "chemical chaperone": increase of beta galactosidase activity in fibroblasts from an adult GM1-gangliosidosis patient. Eur J Paediatr Neurol. Mar 2009. 13(2):160-164. [Medline].

  15. Dierks T, Schlotawa L, Frese MA, et al. Molecular basis of multiple sulfatase deficiency, mucolipidosis II/III and Niemann-Pick C1 disease - Lysosomal storage disorders caused by defects of non-lysosomal proteins. Biochim Biophys Acta. Apr 2009. 1793(4):710-725. [Medline].

  16. Galanaud D, Tourbah A, Lehericy S, et al. 24 month-treatment with miglustat of three patients with Niemann-Pick disease type C: follow up using brain spectroscopy. Mol Genet Metab. Feb 2009. 96(2):55-58. [Medline].

  17. Grabowski GA. Phenotype, diagnosis, and treatment of Gaucher's disease. Lancet. Oct 2008. 372(9645):1263-1271. [Medline].

  18. Kooper AJ, Janssens PM, de Groot AN, et al. Lysosomal storage diseases in non-immune hydrops fetalis pregnancies. Clin Chim Acta. Sep 2006. 371(1-2):176-182. [Medline].

  19. Kraoua I, Sedel F, Caillaud C, Froissart R, Stirnemann J, Chaurand G, et al. A French experience of type 3 Gaucher disease: Phenotypic diversity and neurological outcome of 10 patients. Brain Dev. 2010 Mar 20. [Medline].

  20. Maegawa GH, Banwell BL, Blaser S, Sorge G, Toplak M, Ackerley C, et al. Substrate reduction therapy in juvenile GM2 gangliosidosis. Mol Genet Metab. 2009 Sep-Oct. 98(1-2):215-24. [Medline].

  21. Maegawa GH, van Giersbergen PL, Yang S, et al. Pharmacokinetics, safety and tolerability of miglustat in the treatment of pediatric patients with GM2 gangliosidosis. Mol Genet Metab. Aug 2009. 97(4):284-291. [Medline].

  22. Mehta A, Clarke JT, Giugliani R, et al. Natural course of Fabry disease: changing pattern of causes of death in FOS - the Fabry Outcome Survey. J Med Genet. May 2009. Epub:[Medline].

  23. Mignot C, Gelot A, Bessieres B, et al. Perinatal-lethal gaucher disease. Am J Med Genet A. 2003. 120:338-344.

  24. Mistry PK, Smith SJ, Ali M, Hatton CS, McIntyre N, Cox TM. Genetic diagnosis of Gaucher's disease. Lancet. 1992 Apr 11. 339(8798):889-92. [Medline].

  25. Pastores GM, Giraldo P, Chérin P, Mehta A. Goal-oriented therapy with miglustat in Gaucher disease. Curr Med Res Opin. 2009 Jan. 25(1):23-37. [Medline].

  26. Pierson TM, Bonnemann CG, Finkel RS, Bunin N, Tennekoon GI. Umbilical cord blood transplantation for juvenile metachromatic leukodystrophy. Ann Neurol. 2008 Nov. 64(5):583-7. [Medline]. [Full Text].

  27. Ramsubir S, Nonaka T, Girbés CB, Carpentier S, Levade T, Medin JA. In vivo delivery of human acid ceramidase via cord blood transplantation and direct injection of lentivirus as novel treatment approaches for Farber disease. Mol Genet Metab. 2008 Nov. 95(3):133-41. [Medline]. [Full Text].

  28. Schneiderman J, Thormann K, charrow J, Kletzel M. Correction of enzyme levels with allogeneic hematopoietic progenitor cell transplantation in Niemann-Pick type B. Pediatr Blood Cancer. Dec 2007. 49(7):987-989. [Medline].

  29. Schuchman EH. The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann-Pick disease. J Inherit Metab Dis. Oct 2007. 30(5):654-663. [Medline].

  30. Stein J, Garty BZ, Dror Y, et al. Successful treatment of Wolman disease by unrelated umbilical cord blood transplantation. Eur J Pediatr. Jul 2007. 166(7):663-666. [Medline].

  31. Tolar J, Petryk A, Khan K, et al. Long-term metabolic, endocrine, and neuropsychological outcome of hematopoietic cell transplantation for Wolman disease. Bone Marrow Transplant. Jan 2009. 43(1):21-27. [Medline].

  32. Wraith JE, Vecchio D, Jacklin E, Abel L, Chadha-Boreham H, Luzy C, et al. Miglustat in adult and juvenile patients with Niemann-Pick disease type C: long-term data from a clinical trial. Mol Genet Metab. 2010 Apr. 99(4):351-7. [Medline].

  33. Cerdelga (eliglustat) prescribing information [package insert]. IDA Industrial Park, Old Kilmeaden Road, Waterford, Ireland: Genzyme Ireland, Ltd. August 2014. Available at [Full Text].

 
Previous
Next
 
Autosomal recessive inheritance pattern.
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.