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Inclusion-cell (I-cell) disease, also referred to as mucolipidosis II (ML II), is part of the lysosomal storage disease family and results from a defective phosphotransferase (an enzyme of the
Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles i ...
). This enzyme transfers phosphate to
mannose Mannose is a sugar monomer of the aldohexose series of carbohydrates. It is a C-2 epimer of glucose. Mannose is important in human metabolism, especially in the glycosylation of certain proteins. Several congenital disorders of glycosylat ...
residues on specific proteins. Mannose-6-phosphate serves as a marker for proteins to be targeted to
lysosome 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 p ...
s 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 The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles i ...
. Lysosomes cannot function without these proteins, which function as catabolic enzymes for the normal breakdown of substances (e.g. oligosaccharides, lipids, and glycosaminoglycans) 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.


Signs and symptoms

Mucolipidosis II (ML II) is a particularly severe form of ML that has a significant resemblance to another
mucopolysaccharidosis 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 cel ...
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. Typically, by the age of 6 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 A motor skill is a function that involves specific movements of the body's muscles to perform a certain task. These tasks could include walking, running, or riding a bike. In order to perform this skill, the body's nervous system, muscles, and br ...
are usually more pronounced than delays in their
cognitive Cognition refers to "the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought ...
(mental processing) skills. Children with ML II eventually develop a clouding on the
cornea The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Along with the anterior chamber and lens, the cornea refracts light, accounting for approximately two-thirds of the eye's total optical ...
of their eyes and, because of their lack of growth, develop short-trunk
dwarfism Dwarfism is a condition wherein an organism is exceptionally small, and mostly occurs in the animal kingdom. In humans, it is sometimes defined as an adult height of less than , regardless of sex; the average adult height among people with dw ...
(underdeveloped trunk). These young patients are often plagued by recurrent respiratory tract infections, including
pneumonia Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severit ...
,
otitis media Otitis media is a group of inflammatory diseases of the middle ear. One of the two main types is acute otitis media (AOM), an infection of rapid onset that usually presents with ear pain. In young children this may result in pulling at the ear, ...
(middle ear infections), bronchitis and
carpal tunnel syndrome Carpal tunnel syndrome (CTS) is the collection of symptoms and signs associated with median neuropathy at the carpal tunnel. Most CTS is related to idiopathic compression of the median nerve as it travels through the wrist at the carpal tunn ...
. Children with ML II generally die before their seventh year of life, often as a result of
congestive heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...
or recurrent respiratory tract infections.


Pathophysiology

I-cell disease is an autosomal recessive disorder caused by a deficiency of
GlcNAc phosphotransferase N-acetylglucosamine-1-phosphate transferase is a transferase enzyme. Function It is made up of two alpha (α), two betas (β), and two gammas (γ) subunits. ''GNPTAB'' produces the alpha and beta subunits, ''GNPTG'' produces the gamma subunit. ...
, which phosphorylates
mannose Mannose is a sugar monomer of the aldohexose series of carbohydrates. It is a C-2 epimer of glucose. Mannose is important in human metabolism, especially in the glycosylation of certain proteins. Several congenital disorders of glycosylat ...
residues to
mannose-6-phosphate 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. M6P is a key targeting signal for acid hydrolase precursor proteins that are destined for tran ...
on N-linked glycoproteins in the
Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles i ...
within cells. Without
mannose-6-phosphate 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. M6P is a key targeting signal for acid hydrolase precursor proteins that are destined for tran ...
to target them to the lysosomes, the enzymes are erroneously transported from the Golgi to the
extracellular space Extracellular space refers to the part of a multicellular organism outside the cells, usually taken to be outside the plasma membranes, and occupied by fluid. This is distinguished from intracellular space, which is inside the cells. The compos ...
. 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). 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 N-acetylglucosamine-1-phosphate transferase is a transferase enzyme. Function It is made up of two alpha (α), two betas (β), and two gammas (γ) subunits. ''GNPTAB'' produces the alpha and beta subunits, ''GNPTG'' produces the gamma subunit. ...
(GNPTA). In a case report, I-cell disease was complicated by severe dilative cardiomyopathy (DCM). Though rare, a deficiency of
phosphodiesterase A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, ''phosphodiesterase'' refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many ot ...
which would cleave GlcNAc from the
mannose-6-phosphate 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. M6P is a key targeting signal for acid hydrolase precursor proteins that are destined for tran ...
tag will also cause I-cell disease. The presence of lipids,
glycosaminoglycans Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units (i.e. two-sugar units). The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case ...
(GAG's) and carbohydrates in the blood provide for the distinguishing characteristic to separate I-cell from Hurler Syndrome. In Hurler's, only
glycosaminoglycans Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units (i.e. two-sugar units). The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case ...
would be present.


Diagnosis

Diagnostic measures can include the following. Before birth: * Abnormally low concentrations of UDP-N-acetylglucosamine-1-phosphotransferase enzyme activity in amniotic fluid cells or chorionic villi In infants: * Elevated plasma lysosomal enzyme concentrations * Decreased concentration of lysosomal enzymes in cultured
fibroblast A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells ...
s and increased in the surrounding medium * Presence of inclusion bodies in peripheral blood
lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic a ...
s * Low concentrations of UDP-N-acetylglucosamine-1-phosphotransferase enzyme activity as measured in white blood cells


Treatment

There is no cure for I-Cell disease/Mucolipidosis II disease; treatment is limited to controlling or reducing symptoms. Nutritional supplements, particularly
iron Iron () is a chemical element with symbol Fe (from la, ferrum) and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, right in ...
and vitamin B12, are often recommended.
Physical therapy Physical therapy (PT), also known as physiotherapy, is one of the allied health professions. It is provided by physical therapists who promote, maintain, or restore health through physical examination, diagnosis, management, prognosis, pat ...
to improve motor delays and
speech therapy Speech is a human vocal communication using language. Each language uses phonetic combinations of vowel and consonant sounds that form the sound of its words (that is, all English words sound different from all French words, even if they are th ...
to improve language acquisition are treatment options. Surgery can remove the thin layer of
cornea The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Along with the anterior chamber and lens, the cornea refracts light, accounting for approximately two-thirds of the eye's total optical ...
l 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. The Yash Gandhi Foundation is a US
non-profit organization A nonprofit organization (NPO) or non-profit organisation, also known as a non-business entity, not-for-profit organization, or nonprofit institution, is a legal entity organized and operated for a collective, public or social benefit, in co ...
which funds research for I-Cell disease


References


External links

* — article derived from detail sheet available here *
GeneReview/NIH/UW entry on Mucolipidosis II
{{Posttranslational modification disorders Glycoprotein metabolism disorders