I-cell disease
| I-cell disease | |
|---|---|
| Specialty | Endocrinology  |
Inclusion-cell (I-cell) disease, also referred to as mucolipidosis II (ML II),[1][2] is part of the lysosomal storage disease family and results from a defective phosphotransferase (an enzyme of the Golgi apparatus). This enzyme transfers phosphate to mannose residues on specific proteins, and serves as a marker for them to be targeted to lysosomes within the cell. Without this marker, the proteins are instead excreted outside the cell—the default pathway for proteins moving through the Golgi apparatus. Lysosomes cannot function without these proteins, which function as catabolic enzymes for the normal breakdown of substances (e.g. oligosaccharides, lipids, and glycosaminoglycans)[3] in various tissues throughout the body (i.e. fibroblasts). As a result, a buildup of these substances occurs within lysosomes because they cannot be degraded, resulting in the characteristic I-cells, or "inclusion cells." These cells can be identified under the microscope. In addition, the defective lysosomal enzymes normally found only within lysosomes are instead found in high concentrations in the blood.
Presentation
Mucolipidosis II (ML II) is a particularly severe form of ML that has a significant resemblance to another mucopolysaccharidoses called Hurler syndrome. Generally only laboratory testing can distinguish the two as the presentation is so similar. There are high plasma levels of lysosomal enzymes and are often fatal in childhood.[4] Typically, by the age of 6 months, failure to thrive and developmental delays are obvious symptoms of this disorder. Some physical signs, such as abnormal skeletal development, coarse facial features, and restricted joint movement, may be present at birth. Children with ML II usually have enlargement of certain organs, such as the liver (hepatomegaly) or spleen (splenomegaly), and sometimes even the heart valves. Affected children often have stiff claw-shaped hands and fail to grow and develop in the first months of life. Delays in the development of their motor skills are usually more pronounced than delays in their cognitive (mental processing) skills. Children with ML II eventually develop a clouding on the cornea of their eyes and, because of their lack of growth, develop short-trunk dwarfism (underdeveloped trunk). These young patients are often plagued by recurrent respiratory tract infections, including pneumonia, otitis media (middle ear infections), bronchitis and carpal tunnel syndrome. Children with ML II generally die before their seventh year of life, often as a result of congestive heart failure or recurrent respiratory tract infections.
Pathophysiology
I-cell disease is an autosomal recessive disorder caused by a deficiency of GlcNAc phosphotransferase, which phosphorylates mannose residues to mannose-6-phosphate on N-linked glycoproteins in the Golgi apparatus within the cell. Without mannose-6-phosphate to target them to the lysosomes, the enzymes are transported from the Golgi to the extracellular space, resulting in large intracellular inclusions of molecules requiring lysosomal degradation in patients with the disease (hence the name of the disorder).[5] Hydrolases secreted into the blood stream cause little problem as they are deactivated in the neutral pH of the blood.
It can be associated with GNPTA.[6] In a case report, it was complicated by severe dilative cardiomyopathy(DCM)[7]
Though rare, a deficiency of phosphodiesterase which would cleave GlcNAc from the Mannose 6 Phosphate tag will also cause I-Cell.[5]
The presence of lipids, glycosaminoglycans (GAG's) and carbohydrates in the blood provide for the distinguishing characteristic to separate I-Cell from Hurlers Syndrome, in Hurlers, only glycosaminoglycans would be present.
Treatment
A cure does not exist for I-Cell disease/Mucolipidosis II disease. Treatment is limited to controlling or reducing the symptoms that are associated with this disorder. Nutritional supplements, particularly iron and vitamin B12, are often recommended for individuals with I-Cell disease. Physical therapy to improve motor delays and speech therapy to improve language acquisition are treatment options. Surgery can remove the thin layer of corneal clouding to temporarily improve the complication. It is possible that bone marrow transplant may be helpful in delaying or correcting the neurological deterioration that occurs with I-Cell disease.[1]
References
- ^ "mucolipidosis II" at Dorland's Medical Dictionary
- ^ Plante M; Claveau S; Lepage P; et al. (March 2008). "Mucolipidosis II: a single causal mutation in the N-acetylglucosamine-1-phosphotransferase gene (GNPTAB) in a French Canadian founder population". Clin. Genet. 73 (3): 236–44. doi:10.1111/j.1399-0004.2007.00954.x. PMID 18190596.
{{cite journal}}: Unknown parameter|name-list-format=ignored (|name-list-style=suggested) (help) - ^ Bamshad, Lynn B. Jorde, John C. Carey, Michael J. (2010). Medical genetics (4th ed.). Philadelphia: Mosby/Elsevier. ISBN 9780323053730.
{{cite book}}: CS1 maint: multiple names: authors list (link) - ^ Le, Tao (2014). First Aid for the USMLE 2014. New York: McGraw Hill Education. p. 77. ISBN 9780071831420.
- ^ a b Champe, Pamela (2004). Lippincott's Illustrated Reviews: Biochemistry. Richard A Harvey, Denise R Ferrier (3rd ed.). Philadelphia, Pa.: Lippincott-Raven. p. 167. ISBN 0-7817-2265-9.
- ^ Tiede S; Storch S; Lübke T; et al. (2005). "Mucolipidosis II is caused by mutations in GNPTA encoding the alpha/beta GlcNAc-1-phosphotransferase". Nat. Med. 11 (10): 1109–12. doi:10.1038/nm1305. PMID 16200072.
{{cite journal}}: Unknown parameter|name-list-format=ignored (|name-list-style=suggested) (help) - ^ Sahha.gov.mt - 2006 Dec;29_1
External links
- mucolipidoses at NINDS — article derived from detail sheet available here
- I cell disease at NIH's Office of Rare Diseases
- GeneReview/NIH/UW entry on Mucolipidosis II
- Hide and Seek Foundation For Lysosomal Disease Research