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eMedicine Journal
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Pediatrics
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Genetics And Metabolic Disease
Sialidosis (Mucolipidosis I) Synonyms, Key Words, and Related Terms: sialidosis, mucolipidosis type I, ML I, neuraminidase deficiency, sialidosis type I & II, sialidosis types I and II, sialidase deficiency, lipomucopolysaccharidosis, deficiency of alpha-N-acetyl neuraminidase |
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 | AUTHOR INFORMATION | Section 1 of 11    |
Authored by Karl S Roth, MD, Chair, Professor, Department of Pediatrics, Creighton University School of Medicine
Coauthored by William B Rizzo, MD, Professor, Department of Pediatrics, University of Nebraska Medical Center; Grace Y Lee, MD, Assistant Professor of Pediatrics, Department of Pediatrics, Le Bonheur Children's Medical Center; Margaret McGovern, MD, PhD, Vice Chair, Professor, Department of Human Genetics, Mount Sinai School of Medicine
Karl S Roth, MD, is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Association for the Advancement of Science, American College of Nutrition, American Pediatric Society, American Society for Clinical Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, and Southern Society for Pediatric Research
Edited by Edward Kaye, MD, Vice President of Clinical Research, Genzyme Corporation; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Margaret McGovern, MD, PhD, Vice Chair, Professor, Department of Human Genetics, Mount Sinai School of Medicine; Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center
| Author's Email: | Karl S Roth, MD |  |
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| Editor's Email: | Edward Kaye, MD |
eMedicine Journal, July 7 2006, VOLUME 7,
Number 7
| INTRODUCTION | Section 2 of 11  |
Background: Mucolipidosis type I (ML I) is a rare inherited lysosomal storage disease that has clinical and histologic findings similar to the mucopolysaccharidoses and the sphingolipidoses. In the late 1960s, a small number of patients with mild Hurlerlike facies, skeletal dysplasia, psychomotor retardation, and normal excretion of urinary mucopolysaccharides were reported. Initially called a lipomucopolysaccharidosis, this disease was later classified into the group of similar diseases now known as the mucolipidoses. Patients with ML I were subsequently found to have an isolated deficiency of alpha-N-acetyl neuraminidase (sialidase) in leukocytes and cultured fibroblasts and, thus, have increased amounts of sialyloligosaccharide in the urine.
Because of the neuraminidase deficiency, ML I is now categorized with the sialidoses, a group of biochemically distinct disease entities due to an isolated neuraminidase deficiency. Although the names are synonymous, this chapter will refer to ML I by the newer name, sialidosis.
Two major clinical phenotypes of sialidosis exist that are distinguished by the presence or absence of dysmorphic features and other somatic changes. Patients with type I disease have been referred to as having "cherry-red spot-myoclonus" syndrome. These patients typically develop symptoms of myoclonic epilepsy, visual problems, and ataxia in the second or third decade of life. Macular cherry red spots are always present. The myoclonus is aggravated by smoking and menses, among other factors, and may become debilitating.
Myoclonic seizures are poorly controlled by the standard antiepileptics. Patients with the type II form of sialidosis have an earlier onset of symptoms and exhibit dysmorphic and somatic features that progressively worsen. Type II patients can be further divided into an infantile onset and a more severe congenital onset. The infantile form presents in the first year of life with the appearance of coarse, Hurlerlike facies; hepatomegaly; bony changes of dysostosis multiplex; and early developmental delay. The reported incidence of cherry-red spots is less than 75%, in contrast to the virtual 100% in patients with the type I form. The more severe congenital form of type II sialidosis has onset in utero and results in hydrops fetalis, hepatomegaly, and either still birth or death within a period of months.
Some patients have been described with a clinical phenotype consistent with type II sialidosis and a combined deficiency of neuraminidase and beta-galactosidase. The biochemical basis for the combined enzyme deficiency, however, is a loss of a protective protein that interacts with both enzymes to produce catalytic activity. Hence, this is a genetically and biochemically distinct entity from sialidosis. Sialidosis should not be confused with disorders of free sialic acid storage, which are caused by a defect in the lysosomal transport of free sialic acid due to mutations in the AST (anion and sugar transporter) gene.
Pathophysiology: In lysosomal storage disorders, the deficiency of a specific lysosomal enzyme interrupts the normal catabolic pathway, resulting in the cellular accumulation of substrates ordinarily degraded by that enzyme. The specificity of these accumulated materials to the distinct enzyme defect is striking in the lysosomal disorders, and the accumulation then leads to abnormal cell architecture. Precisely how the changes in cellular structure due to storage translates into adverse effects on cell function remains enigmatic.
The clinical course of the disease depends on the associated effects of progressive storage in the organ systems where these substrates are highly concentrated. In sialidosis, the deficiency of lysosomal alpha-N-acetyl neuraminidase prevents the normal degradation of glycoproteins containing sialic acid residues. This results in intracellular storage of excess sialyloligosaccharides and is histologically observed as abnormal vacuolization of various cell types. While bone marrow and circulating lymphocytes are highly vacuolated in type II sialidosis, these findings are conspicuously absent in type I disease. The organ systems mostly involved in sialidosis include the CNS, the skeletal system, and the reticuloendothelial system.
Frequency:
Mortality/Morbidity:
Race: Sialidosis is panracial.
Sex: Sialidosis is inherited as an autosomal recessive trait. Both sexes are affected with equal frequency.
Age:
| CLINICAL | Section 3 of 11 |
History:
Physical:
Causes: Sialidosis is an autosomal recessive disorder caused by an isolated deficiency of the enzyme, alpha-N-acetyl neuraminidase (also called sialidase). Three distinct human neuraminidases are known to exist, which are specifically localized to the cytosol, plasma membrane, and lysosome. The lysosomal enzyme is selectively deficient in human sialidosis. The lysosomal neuraminidase gene maps to chromosome 6p21 and has been cloned. A variety of enzyme-inactivating mutations have been identified in sialidosis patients.
The variability of disease manifestation due to this enzyme deficiency, as evidenced by the 3 disease subtypes, has indicated that genotype-phenotype correlation may exist. Recent research has shown that the type of gene mutation affects not only enzyme activity but also whether the enzyme localizes to the lysosome. Preliminary studies indicate that both of these properties have positively correlated with the clinical subtype of sialidosis. However, the wide variability of clinical presentation in these patients cannot be fully explained by alpha-N-acetyl neuraminidase mutations. Therefore, other environmental or genetic factors probably account for the varying degrees of disease severity.
| DIFFERENTIALS | Section 4 of 11 |
I-Cell Disease (Mucolipidosis Type II)
Mucopolysaccharidosis Type IH
Other Problems to be Considered:
GM1 gangliosidosis
| WORKUP | Section 5 of 11 |
Lab Studies:
Imaging Studies:
| TREATMENT | Section 6 of 11 |
Medical Care:
Consultations:
| MEDICATION | Section 7 of 11 |
No specific pharmacologic therapy is available at this time.
| FOLLOW-UP | Section 8 of 11 |
Complications:
Prognosis:
Patient Education:
| MISCELLANEOUS | Section 9 of 11 |
Special Concerns:
| TEST QUESTIONS | Section 10 of 11 |
CME Question 1: The definitive diagnosis of mucolipidosis type I (ML I, sialidosis) is made by which of the following?
A: Demonstrating an abnormal excretion of mucopolysaccharides in the urine
B: Finding intracytoplasmic vacuolization in tissue fibroblasts
C: Demonstrating a deficiency of alpha-N-acetyl neuraminidase in leukocytes or cultured fibroblasts
D: Finding radiographic evidence of dysostosis multiplex
E: The presence of cherry-red spots on ophthalmologic examination
The correct answer is C: The definitive diagnosis of ML I is made by demonstrating a deficiency of alpha-N-acetyl neuraminidase in leukocytes or cultured fibroblasts. Although not diagnostic, the detection of an abnormal pattern of urinary oligosaccharides can be used as an initial screening test. The urinary excretion of mucopolysaccharides is normal in ML I. Patients with ML I have evidence of dysostosis multiplex on radiography, but this is also observed in patients with mucolipidosis types II and III and the various mucopolysaccharidoses. Cherry-red spots are observed in patients with ML I but are also observed in other lysosomal storage diseases.
CME Question 2: Which of the following is correct for a couple that has a child with mucolipidosis type I (ML I)?
A: Each parent has a 25% chance of being a carrier for ML I.
B: The parents have a 25% chance of having another child affected with ML I.
C: The chance of having another child affected with ML I is the same as in the general population.
D: The parents have a 25% chance of having a clinically healthy child.
E: The parents have a 50% chance of having another child affected with ML I.
The correct answer is B: ML I is inherited in an autosomal recessive fashion; therefore, if a couple has a child with ML I, each parent is an obligate carrier for the disease. In each subsequent pregnancy they have a 25% chance of having another affected child, a 50% chance of having a child who is a carrier for the disease but is otherwise healthy, and a 25% chance of conceiving a child who does not carry the gene for the disease.
Pearl Question 1 (T/F): Because the enzyme responsible for mucolipidosis type I (ML I) is known, the disease can be treated with enzyme replacement therapy.
The correct answer is False: Although the deficient enzyme in ML I has been identified and the gene cloned, enzyme replacement therapy is currently not available for this disease.
Pearl Question 2 (T/F): Prenatal diagnosis is available for couples at risk for having a child with mucolipidosis type I (ML I).
The correct answer is True: The diagnosis of ML I can be made prenatally by the measurement of alpha-N-acetyl neuraminidase in fresh or cultured amniotic fluid cells or chorionic villi samples.
Pearl Question 3 (T/F): Finding an abnormal pattern of urinary oligosaccharides is diagnostic of mucolipidosis type I (ML I).
The correct answer is False: Urine oligosaccharides are useful as an initial screen for ML I; however, they are also abnormal in a number of other lysosomal storage diseases. The best diagnostic test for ML I is the measurement of alpha-N-acetyl neuraminidase activity. Mutation analysis affords an alternate diagnostic approach.
Pearl Question 4 (T/F): Mucolipidosis type I (ML I) is more common in males.
The correct answer is False: ML I is inherited as an autosomal recessive trait; therefore, it affects both sexes with equal frequency. Often, it is confused with Hunter syndrome, which is an X-linked recessive disorder.
| BIBLIOGRAPHY | Section 11 of 11 |
| NOTE: |
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