Mucolipidosis type IV
Encyclopedia
Mucolipidosis type IV is an autosomal
recessive lysosomal storage disorder. Individuals with the disorder have many symptoms including delayed psychomotor development and various ocular aberrations. The disorder is caused by mutations in the MCOLN1 gene, which encodes a non-selective cation channel
, mucolipin1. These mutations disrupt cellular functions and lead to a neurodevelopmental disorder through an unknown mechanism. Researchers dispute the physiological role of the protein product and which ion it transports.
l opacity, retina
l degeneration and other ophthalmological abnormalities. Other symptoms include agenesis of the corpus callosum
, iron deficiency
resulting from an absence of acid secretion in the stomach, achlorhydria
. Achlorhydria in these patients results in an increase in blood gastrin
levels. These symptoms typically manifest early in life (within the first year). Retinal degeneration progresses slowly.
Mucolipin1 is thought to be localized in endosome
s. An important property of mucolipin1 is that decreasing pH (acidification) results in deactivation of the protein, likely through an assembly defect. There are at least 29 known mutations in MCOLN1, located throughout the gene. Many of the known mutations result in no expression of mucolipin1. Milder mutations, such as ΔF408 and V446L, produce a dysfunctioning form of the cation channel. Mutations that alter only the C-terminal of the protein also result in a mild phenotype of the disorder, usually sparing the brain. ML IV causes affected cells to accumulate auto-fluorescent vacuoles considered to be aberrant lysosomes. Several evidences exist for a defect in both exocytosis
and endocytosis
. There are conflicting indications of abnormal lysosomal pH in MLIV. It is not yet clear why these abnormalities will cause incomplete development of the brain, achlorhydria, and failure in the maintenance of retinal tissue.
See the equivalent section in the main mucolipidosis article.
. In the Ashkenazi Jewish population there are two severe mutations with a higher carrier frequency of 1:90 to 1:100.
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
recessive lysosomal storage disorder. Individuals with the disorder have many symptoms including delayed psychomotor development and various ocular aberrations. The disorder is caused by mutations in the MCOLN1 gene, which encodes a non-selective cation channel
Channel
Channel, Channels, and similar terms may refer to:* Channels , a rock band fronted by ex-Jawbox singer/guitarist J. Robbins* Channels , a 2008 film* Channel, synonym for pre-chorus in popular song structure...
, mucolipin1. These mutations disrupt cellular functions and lead to a neurodevelopmental disorder through an unknown mechanism. Researchers dispute the physiological role of the protein product and which ion it transports.
Symptoms and Signs
Most patients with ML IV show psychomotor retardation (i.e., delayed development of movement and coordination), corneaCornea
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...
l opacity, retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
l degeneration and other ophthalmological abnormalities. Other symptoms include agenesis of the corpus callosum
Agenesis of the corpus callosum
Agenesis of the corpus callosum is a rare birth defect in which there is a complete or partial absence of the corpus callosum. Agenesis of the corpus callosum occurs when the corpus callosum, the band of white matter connecting the two hemispheres in the brain, fails to develop normally,...
, iron deficiency
Iron deficiency (medicine)
Iron deficiency is one of the most common of the nutritional deficiencies. Iron is present in all cells in the human body, and has several vital functions...
resulting from an absence of acid secretion in the stomach, achlorhydria
Achlorhydria
Achlorhydria or hypochlorhydria refers to states where the production of gastric acid in the stomach is absent or low, respectively. It is associated with various other medical problems.-Signs and symptoms:...
. Achlorhydria in these patients results in an increase in blood gastrin
Gastrin
In humans, gastrin is a peptide hormone that stimulates secretion of gastric acid by the parietal cells of the stomach and aids in gastric motility. It is released by G cells in the antrum of the stomach, duodenum, and the pancreas...
levels. These symptoms typically manifest early in life (within the first year). Retinal degeneration progresses slowly.
Pathophysiology
Endosome
In biology, an endosome is a membrane-bound compartment inside eukaryotic cells. It is a compartment of the endocytic membrane transport pathway from the plasma membrane to the lysosome. Molecules internalized from the plasma membrane can follow this pathway all the way to lysosomes for...
s. An important property of mucolipin1 is that decreasing pH (acidification) results in deactivation of the protein, likely through an assembly defect. There are at least 29 known mutations in MCOLN1, located throughout the gene. Many of the known mutations result in no expression of mucolipin1. Milder mutations, such as ΔF408 and V446L, produce a dysfunctioning form of the cation channel. Mutations that alter only the C-terminal of the protein also result in a mild phenotype of the disorder, usually sparing the brain. ML IV causes affected cells to accumulate auto-fluorescent vacuoles considered to be aberrant lysosomes. Several evidences exist for a defect in both exocytosis
Exocytosis
Exocytosis , also known as 'The peni-cytosis', is the durable process by which a cell directs the contents of secretory vesicles out of the cell membrane...
and endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
. There are conflicting indications of abnormal lysosomal pH in MLIV. It is not yet clear why these abnormalities will cause incomplete development of the brain, achlorhydria, and failure in the maintenance of retinal tissue.
Treatment/Management
There is no specific treatment to this disorder. However, several symptoms may be alleviated. For instance, anemia is treated by iron supplements. Some of the movement deficiencies may be corrected with orthopedic intervention. The corneal clouding can be, at least, temporarily corrected by corneal transplantation.See the equivalent section in the main mucolipidosis article.
Epidemiology
Mucolipidosis type IV is severely under-diagnosed. It is often misdiagnosed as cerebral palsyCerebral palsy
Cerebral palsy is an umbrella term encompassing a group of non-progressive, non-contagious motor conditions that cause physical disability in human development, chiefly in the various areas of body movement....
. In the Ashkenazi Jewish population there are two severe mutations with a higher carrier frequency of 1:90 to 1:100.