I-cell disease

Last updated
I-cell disease
Other namesMucolipidosis II (ML II)
Specialty Medical genetics
CausesMutation in the N-acetylglucosamine-1-phosphotransferase gene (GNPTAB)

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. Mannose-6-phosphate serves as a marker for proteins to be targeted to lysosomes within the cell. Without this marker, proteins are instead secreted outside the cell, which is 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" seen microscopically. In addition, the defective lysosomal enzymes normally found only within lysosomes are instead found in high concentrations in the blood, but they remain inactive at blood pH (around 7.4) because they require the low lysosomal pH 5 to function.

Contents

Signs and symptoms

Mucolipidosis II (ML II) is a particularly severe form of ML that has a significant resemblance to another mucopolysaccharidosis called Hurler syndrome. Generally, only laboratory testing can distinguish the two as the presentation is so similar, with high plasma concentrations of lysosomal enzymes, often fatal in childhood. [4] Typically, by the age of six months, failure to thrive and developmental delays are obvious signs of this disorder. Some physical signs, such as abnormal skeletal development, coarse facial features (e.g. bulging scaphocephalic head, flat nose), 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 cells. Without mannose-6-phosphate to target them to the lysosomes, the enzymes are erroneously transported from the Golgi to the extracellular space. Consequently, lysosomes lack the requisite hydrolytic enzymes needed for catabolism of cellular debris, so this debris accumulates within them and forms the characteristic intracellular inclusions (hence the name of the disorder). [5] Hydrolases secreted into the blood stream cause little problem as they are inactivate at the near neutral pH of blood (7.4).

It can be associated with N-acetylglucosamine-1-phosphate transferase (GNPTA). [6] In a case report, I-cell disease 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 disease. [5] The presence of lipids, glycosaminoglycans (GAG's) and carbohydrates in the blood provide for the distinguishing characteristic to separate I-cell from Hurler Syndrome. In Hurler's, only glycosaminoglycans would be present.

Diagnosis

Diagnostic measures can include the following:

Before birth:

In infants:

Treatment

There is no cure for I-cell disease/Mucolipidosis II disease; treatment is limited to controlling or reducing symptoms. Nutritional supplements, particularly iron and vitamin B12, are often recommended. 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. [9] The Yash Gandhi Foundation is a US non-profit organization which funds research for I-Cell disease. [10]

Related Research Articles

<span class="mw-page-title-main">Lysosome</span> Cell organelle

A lysosome is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane proteins, and its lumenal proteins. The lumen's pH (~4.5–5.0) is optimal for the enzymes involved in hydrolysis, analogous to the activity of the stomach. Besides degradation of polymers, the lysosome is involved in various cell processes, including secretion, plasma membrane repair, apoptosis, cell signaling, and energy metabolism.

<span class="mw-page-title-main">Mucopolysaccharidosis</span> Medical condition

Mucopolysaccharidoses are a group of metabolic disorders caused by the absence or malfunctioning of lysosomal enzymes needed to break down molecules called glycosaminoglycans (GAGs). These long chains of sugar carbohydrates occur within the cells that help build bone, cartilage, tendons, corneas, skin and connective tissue. GAGs are also found in the fluids that lubricate joints.

<span class="mw-page-title-main">Lysosomal storage disease</span> Medical condition

Lysosomal storage diseases are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other parts of the cell for recycling. This process requires several critical enzymes. If one of these enzymes is defective due to a mutation, the large molecules accumulate within the cell, eventually killing it.

<span class="mw-page-title-main">Glycosaminoglycan</span> Polysaccharides found in animal tissue

Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units. The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case of the sulfated glycosaminoglycan keratan, where, in place of the uronic sugar there is a galactose unit. GAGs are found in vertebrates, invertebrates and bacteria. Because GAGs are highly polar molecules and attract water; the body uses them as lubricants or shock absorbers.

The terms glycans and polysaccharides are defined by IUPAC as synonyms meaning "compounds consisting of a large number of monosaccharides linked glycosidically". However, in practice the term glycan may also be used to refer to the carbohydrate portion of a glycoconjugate, such as a glycoprotein, glycolipid, or a proteoglycan, even if the carbohydrate is only an oligosaccharide. Glycans usually consist solely of O-glycosidic linkages of monosaccharides. For example, cellulose is a glycan composed of β-1,4-linked D-glucose, and chitin is a glycan composed of β-1,4-linked N-acetyl-D-glucosamine. Glycans can be homo- or heteropolymers of monosaccharide residues, and can be linear or branched.

<span class="mw-page-title-main">Mucolipidosis</span> Medical condition

Mucolipidosis is a group of inherited metabolic disorders that affect the body's ability to carry out the normal turnover of various materials within cells.

<span class="mw-page-title-main">Glucocerebrosidase</span> Mammalian protein found in humans

β-Glucocerebrosidase is an enzyme with glucosylceramidase activity that cleaves by hydrolysis the β-glycosidic linkage of the chemical glucocerebroside, an intermediate in glycolipid metabolism that is abundant in cell membranes. It is localized in the lysosome, where it remains associated with the lysosomal membrane. β-Glucocerebrosidase is 497 amino acids in length and has a molecular mass of 59,700 Da.

<span class="mw-page-title-main">Pseudo-Hurler polydystrophy</span> Medical condition

Pseudo-Hurler polydystrophy, also referred to as mucolipidosis III, is a lysosomal storage disease closely related to I-cell disease. This disorder is called Pseudo-Hurler because it resembles a mild form of Hurler syndrome, one of the mucopolysaccharide (MPS) diseases.

<span class="mw-page-title-main">Insulin-like growth factor 2 receptor</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor 2 receptor (IGF2R), also called the cation-independent mannose-6-phosphate receptor (CI-MPR) is a protein that in humans is encoded by the IGF2R gene. IGF2R is a multifunctional protein receptor that binds insulin-like growth factor 2 (IGF2) at the cell surface and mannose-6-phosphate (M6P)-tagged proteins in the trans-Golgi network.

<span class="mw-page-title-main">Mannose 6-phosphate</span> Chemical compound

Mannose-6-phosphate (M6P) is a molecule bound by lectin in the immune system. M6P is converted to fructose 6-phosphate by mannose phosphate isomerase.

The mannose 6-phosphate receptors (MPRs) are transmembrane glycoproteins that target enzymes to lysosomes in vertebrates.

N-acetylglucosamine-1-phosphate transferase is a transferase enzyme.

Uridine diphosphate <i>N</i>-acetylglucosamine Chemical compound

Uridine diphosphate N-acetylglucosamine or UDP-GlcNAc is a nucleotide sugar and a coenzyme in metabolism. It is used by glycosyltransferases to transfer N-acetylglucosamine residues to substrates. D-Glucosamine is made naturally in the form of glucosamine-6-phosphate, and is the biochemical precursor of all nitrogen-containing sugars. To be specific, glucosamine-6-phosphate is synthesized from fructose 6-phosphate and glutamine as the first step of the hexosamine biosynthesis pathway. The end-product of this pathway is UDP-GlcNAc, which is then used for making glycosaminoglycans, proteoglycans, and glycolipids.

<span class="mw-page-title-main">N-acetylglucosamine-6-phosphate deacetylase</span>

In enzymology, N-acetylglucosamine-6-phosphate deacetylase (EC 3.5.1.25), also known as GlcNAc-6-phosphate deacetylase or NagA, is an enzyme that catalyzes the deacetylation of N-acetylglucosamine-6-phosphate (GlcNAc-6-P) to glucosamine-6-phosphate (GlcN-6-P):

In enzymology, an UDP-N-acetylglucosamine—lysosomal-enzyme N-acetylglucosaminephosphotransferase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">NAGPA</span> Protein-coding gene in the species Homo sapiens

N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase is an enzyme that in humans is encoded by the NAGPA gene.

<i>N</i>-linked glycosylation Attachment of an oligosaccharide to a nitrogen atom

N-linked glycosylation, is the attachment of an oligosaccharide, a carbohydrate consisting of several sugar molecules, sometimes also referred to as glycan, to a nitrogen atom, in a process called N-glycosylation, studied in biochemistry. The resulting protein is called an N-linked glycan, or simply an N-glycan.

<span class="mw-page-title-main">Cation-dependent mannose-6-phosphate receptor</span> Protein-coding gene in the species Homo sapiens

In the fields of biochemistry and cell biology, the cation-dependent mannose-6-phosphate receptor (CD-MPR) also known as the 46 kDa mannose 6-phosphate receptor is a protein that in humans is encoded by the M6PR gene.

O-linked glycosylation is the attachment of a sugar molecule to the oxygen atom of serine (Ser) or threonine (Thr) residues in a protein. O-glycosylation is a post-translational modification that occurs after the protein has been synthesised. In eukaryotes, it occurs in the endoplasmic reticulum, Golgi apparatus and occasionally in the cytoplasm; in prokaryotes, it occurs in the cytoplasm. Several different sugars can be added to the serine or threonine, and they affect the protein in different ways by changing protein stability and regulating protein activity. O-glycans, which are the sugars added to the serine or threonine, have numerous functions throughout the body, including trafficking of cells in the immune system, allowing recognition of foreign material, controlling cell metabolism and providing cartilage and tendon flexibility. Because of the many functions they have, changes in O-glycosylation are important in many diseases including cancer, diabetes and Alzheimer's. O-glycosylation occurs in all domains of life, including eukaryotes, archaea and a number of pathogenic bacteria including Burkholderia cenocepacia, Neisseria gonorrhoeae and Acinetobacter baumannii.

<span class="mw-page-title-main">GNPTG</span> Protein-coding gene in the species Homo sapiens

GNPTG is a gene in the human body. It is one of three genes that were found to correlate with stuttering.

References

  1. ↑ " mucolipidosis II " at Dorland's Medical Dictionary
  2. ↑ 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" (PDF). Clin. Genet. 73 (3): 236–44. doi:10.1111/j.1399-0004.2007.00954.x. PMID   18190596. S2CID   20999105.
  3. ↑ 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)
  4. ↑ Le, Tao (2014). First Aid for the USMLE 2014. New York: McGraw Hill Education. p. 77. ISBN   9780071831420.
  5. 1 2 Champe, Pamela (2004). Lippincott's Illustrated Reviews: Biochemistry. Richard A Harvey, Denise R Ferrier (3rd ed.). Philadelphia, Pa.: Lippincott-Raven. p. 167. ISBN   978-0-7817-2265-0.
  6. ↑ 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. S2CID   24959938.
  7. ↑ Sahha.gov.mt - 2006 Dec;29_1
  8. 1 2 3 4 5 "I Cell Disease - NORD (National Organization for Rare Disorders)". NORD (National Organization for Rare Disorders). Retrieved 2017-11-02.
  9. ↑ "Inherited Metabolic Storage Diseases and BMT - MED - PEDS - Blood and Marrow Transplantation Program, University of Minnesota". Archived from the original on 2010-06-20. Retrieved 2009-12-01.
  10. ↑ "Yash Gandhi Foundation". Yash Gandhi Foundation. Retrieved 2023-09-25.
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