I-cell disease
Encyclopedia
Inclusion-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). 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 throughout the body. As a result, a build up 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.
. 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.
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). 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.
In a case report, it was complicated by severe dilative cardiomyopathy(DCM)
Lysosomal storage disease
Lysosomal storage diseases are a group of approximately 50 rare inherited metabolic disorders that result from defects in lysosomal function...
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 throughout the body. As a result, a build up 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
ML II is a particularly severe form of ML that resembles one of the mucopolysaccharidoses called Hurler syndromeHurler syndrome
Hurler syndrome, also known as mucopolysaccharidosis type I , Hurler's disease, also gargoylism, is a genetic disorder that results in the buildup of glycosaminoglycans due to a deficiency of alpha-L iduronidase, an enzyme responsible for the degradation of mucopolysaccharides in lysosomes...
. 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
Joint
A joint is the location at which two or more bones make contact. They are constructed to allow movement and provide mechanical support, and are classified structurally and functionally.-Classification:...
movement, may be present at birth. Children with ML II usually have enlargement of certain organs, such as the liver (hepatomegaly
Hepatomegaly
Hepatomegaly is the condition of having an enlarged liver. It is a nonspecific medical sign having many causes, which can broadly be broken down into infection, direct toxicity, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdominal mass...
) or spleen (splenomegaly
Splenomegaly
Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any...
), 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
Cornea
The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Together with the lens, the cornea refracts light, with the cornea accounting for approximately two-thirds of the eye's total optical power. In humans, the refractive power of the cornea is...
of their eyes and, because of their lack of growth, develop short-trunk dwarfism
Dwarfism
Dwarfism is short stature resulting from a medical condition. It is sometimes defined as an adult height of less than 4 feet 10 inches , although this definition is problematic because short stature in itself is not a disorder....
(underdeveloped trunk). These young patients are often plagued by recurrent respiratory tract infections, including pneumonia
Pneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
, otitis media (middle ear infections), bronchitis
Bronchitis
Acute bronchitis is an inflammation of the large bronchi in the lungs that is usually caused by viruses or bacteria and may last several days or weeks. Characteristic symptoms include cough, sputum production, and shortness of breath and wheezing related to the obstruction of the inflamed airways...
and carpal tunnel syndrome
Carpal tunnel syndrome
Carpal Tunnel Syndrome is an entrapment idiopathic median neuropathy, causing paresthesia, pain, and other symptoms in the distribution of the median nerve due to its compression at the wrist in the carpal tunnel. The pathophysiology is not completely understood but can be considered compression...
. Children with ML II generally die before their seventh year of life, often as a result of congestive heart failure
Congestive heart failure
Heart failure often called congestive heart failure is generally defined as the inability of the heart to supply sufficient blood flow to meet the needs of the body. Heart failure can cause a number of symptoms including shortness of breath, leg swelling, and exercise intolerance. The condition...
or recurrent respiratory tract infections.
Pathophysiology
I-cell disease is an autosomal recessive disorder caused by a deficiency of GlcNAc phosphotransferase, which phosphorylates mannoseMannose
Mannose is a sugar monomer of the aldohexose series of carbohydrates. Mannose is a C-2 epimer of glucose. It is not part of human metabolism, but is a component of microbial cell walls, and is therefore a target of the immune system and also of antibiotics....
residues to mannose-6-phosphate
Mannose-6-phosphate
Mannose-6-phosphate is a molecule bound by lectin in the immune system. M6P is converted to fructose 6-phosphate by mannose phosphate isomerase....
on N-linked glycoproteins
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
in the Golgi apparatus
Golgi apparatus
The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....
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). 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.
In a case report, it was complicated by severe dilative cardiomyopathy(DCM)