Laboratory Studies

Biochemical diagnosis can be made in the following ways:

N -acetylglucosaminyl-1-phosphotransferase activity can be measured in WBCs or in cultured fibroblasts.
Various lysosomal enzyme activities can be measured in serum and in cultured fibroblasts. The activities of beta-hexosaminidase, iduronate sulfatase, and arylsulfatase A are deficient in cultured fibroblasts, but their serum levels are 10-20 times the reference range. Assays for lysosomal enzymes in leukocytes are not reliable because of mannose-6-phosphate–independent targeting pathways.
Dried blood spot screening methodology has been reported. ^[12]

Radiography

The characteristic bone changes are similar to those observed in the mucopolysaccharidoses.^[9]There may be fractures, bone rarification, and other findings leading to confusion with rickets.^[13]

The classic finding is dysostosis multiplex, with a cloaking appearance of the long tubular bones, anterior beaking and wedging of the vertebral bodies, widening of the ribs, proximal pointing of the metacarpals, and bullet-shaped phalanges.

Brain imaging

Brain imaging is not necessary to diagnose I-cell disease, although it is often performed during evaluation of developmental delay.

MRI and CT scan findings can be variable and nonspecific and may not aid in the diagnosis. Reported MRI and CT scan findings include completely normal scans with normal myelination, occasionally accompanied by cerebral atrophy, and nonspecific white matter changes.

Histologic Findings

A unique finding in I-cell disease is the presence of numerous intracytoplasmic inclusions in cells of mesenchymal origin(i.e. fibroblasts) that are observed on electron microscopy. These inclusions are membrane-bound vacuoles filled with fibrillogranular material. The contents of these vacuoles have not been well characterized; however, they appear to contain various lipids, mucopolysaccharides, and oligosaccharides.

Treatment & Management

Dierks T, Schlotawa L, Frese MA, Radhakrishnan K, von Figura K, Schmidt B. 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. 2009 Apr. 1793(4):710-25. [QxMD MEDLINE Link].
Leroy JG, DeMars RI, Opitz JM. I-cell disease. Birth Defects Orig Artic Ser. 1969. 4:174-85.
Spranger JW, Wiedemann HR. The genetic mucolipidoses. Diagnosis and differential diagnosis. Humangenetik. 1970. 9(2):113-39. [QxMD MEDLINE Link].
De Pace R, Coutinho MF, Koch-Nolte F, et al. Mucolipidosis II-related mutations inhibit the exit from the endoplasmic reticulum and proteolytic cleavage of GlcNAc-1-phosphotransferase precursor protein(GNPTAB). Hum Mutat. March 2014. 35:368-376. [QxMD MEDLINE Link].
Kollmann K, Pestka JM, Kuehn SC, et al. Decreased bone formation and increased osteoclastogenesis cause bone loss in mucolipidosis II. EMBO Mol Med. December 2013. 5:1871-1876. [QxMD MEDLINE Link].
Poorthuis BJ, Wevers RA, Kleijer WJ, et al. The frequency of lysosomal storage diseases in The Netherlands. Hum Genet. 1999 Jul-Aug. 105(1-2):151-6. [QxMD MEDLINE Link].
Yokoi A, Niida Y, Kuroda M, Imi-Hashida Y, Toma T, Yachie A. B-cell-specific accumulation of inclusion bodies loaded with HLA class II molecules in patients with mucolipidosis II (I-cell disease). Pediatr Res. 2019 Jul. 86 (1):85-91. [QxMD MEDLINE Link].
Parker EI, Xing M, Moreno-De-Luca A, Harmouche E, Terk MR. Radiological and clinical characterization of the lysosomal storage disorders: non-lipid disorders. Br J Radiol. 2014 Jan. 87 (1033):20130467. [QxMD MEDLINE Link].
Lai LM, Lachman RS. Early characteristic radiographic changes in mucolipidosis II. Pediatr Radiol. 2016 Nov. 46 (12):1713-1720. [QxMD MEDLINE Link].
Otomo T, Higaki K, Nanba E, Ozono K, Sakai N. Lysosomal storage causes cellular dysfunction in mucolipidosis II skin fibroblasts. J Biol Chem. 2011 Oct 7. 286(40):35283-90. [QxMD MEDLINE Link]. [Full Text].
Coutinho MF, Santos LD, Girisha KM, Satyamoorthy K, Lacerda L, Prata MJ, et al. Mucolipidosis type II a/ß with a homozygous missense mutation in the GNPTAB gene. Am J Med Genet A. 2012 Apr 11. [QxMD MEDLINE Link].
Cobos PN, Steglich C, Santer R, et al. Dried blood spots allow trageted screening to diagnose mucopolysaccharidosis and mucolipidosis. JIMD Rep. May 2015. 15:123-132. [QxMD MEDLINE Link].
Lin MH, Pitukcheewanont P. Mucolipidosis type II (I-cell disease) masquerading as rickets: two case reports and review of literature. J Pediatr Endocrinol Metab. 2012. 25(1-2):191-5. [QxMD MEDLINE Link].
Krivan G, Timar L, Goda V, et al. Bone marrow transplantation in non-malignant disorders. Bone Marrow Transplant. 1998 Dec. 22 Suppl 4:S80-3. [QxMD MEDLINE Link].
Lund TC, Cathey SS, Miller WP, et al. Outcomes after hematopoietic stem cell transplantation for children with I-cell disease. Biol Blood Marrow Transplant. November 2014. 20:1847-1851. [QxMD MEDLINE Link].

Media Gallery

Profile view of 3-year-old with I-cell disease. Growth ceased more than one year earlier. Note small orbits, proptotic eyes, full and prominent mouth caused by gingival hypertrophy, short and broad hands, stiffening of small hand joints, prominent abdomen with umbilical hernia, and limited extension of the hips and knees.

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Author

Karl S Roth, MD Retired Professor and Chair, Department of Pediatrics, Creighton University School of Medicine

Karl S Roth, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Pediatric Society, American Society for Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, The Scientific Research Honor Society, Society for Pediatric Research, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Coauthor(s)

William B Rizzo, MD Professor, Department of Pediatrics, University of Nebraska Medical Center

William B Rizzo, MD is a member of the following medical societies: American Society of Human Genetics, Society for Inherited Metabolic Disorders

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Aldeyra Therapeutics (consultant)<br/>Received research grant from: Aldeyra Therapeutics.

Margaret M McGovern, MD, PhD Professor and Chair of Pediatrics, Stony Brook University School of Medicine

Margaret M McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Society of Human Genetics

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.

Chief Editor

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

Luis O Rohena, MD, PhD, FAAP, FACMG 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.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Grace Lee, MD, to the original writing and development of this article.