Infantile neuroaxonal dystrophy
Encyclopedia
Infantile neuroaxonal dystrophy is a rare pervasive developmental disorder
that primarily affects the nervous system
. Individuals with infantile neuroaxonal dystrophy typically do not have any symptoms at birth, but between the ages of about 6 and 18 months they begin to experience delays in acquiring new motor and intellectual skills, such as crawling or beginning to speak. Eventually they lose previously acquired skills.
Children with infantile neuroaxonal dystrophy experience progressive difficulties with movement. Generally they have muscles that are at first weak and "floppy" (hypotonic
), and then gradually become very stiff (spastic
). Eventually, affected children lose the ability to move independently. Lack of muscle strength causes difficulty with feeding and breathing problems that can lead to frequent infections, such as pneumonia. Seizures occur in some affected children.
Rapid, involuntary eye movements (nystagmus), eyes that do not look in the same direction (strabismus), and vision loss due to deterioration (atrophy) of the optic nerve are characteristic of infantile neuroaxonal dystrophy. Hearing loss may also develop. Children with this disorder experience progressive deterioration of cognitive functions (dementia
), and eventually lose awareness of their surroundings.
Infantile neuroaxonal dystrophy is characterized by the development of swellings called spheroid bodies in the axons, the fibers that extend from nerve cells (neurons) and transmit impulses to muscles and other neurons. A part of the brain called the cerebellum, which helps to control movements, may also be damaged. In some individuals with infantile neuroaxonal dystrophy, abnormal amounts of iron accumulate in a specific region of the brain called the basal ganglia.
s. Phospholipid metabolism is important for many body processes, including helping to keep the cell membrane
intact and functioning properly. Specifically, the A2 phospholipase produced from the PLA2G6 gene, sometimes called PLA2 group VI, helps to regulate the levels of a compound called phosphatidylcholine
, which is abundant in the cell membrane.
Mutations in the PLA2G6 gene impair the function of the PLA2 group VI enzyme. This impairment of enzyme function may disrupt cell membrane maintenance and contribute to the development of spheroid bodies in the nerve axons. Although it is unknown how changes in this enzyme's function lead to the signs and symptoms of infantile neuroaxonal dystrophy, phospholipid metabolism problems have been seen in both this disorder and a related disorder called pantothenate kinase-associated neurodegeneration
. These disorders, as well as the more common Alzheimer disease and Parkinson disease, also are associated with changes in brain iron metabolism. Researchers are studying the links between phospholipid defects, brain iron, and damage to nerve cells, but have not determined how the iron accumulation that occurs in some individuals with infantile neuroaxonal dystrophy may contribute to the features of this disorder.
A few individuals with infantile neuroaxonal dystrophy have not been found to have mutations in the PLA2G6 gene. The genetic cause of the condition in these cases is unknown; there is evidence that at least one other gene may be involved.
Mutations in the NAGA gene
, resulting in alpha-N-acetylgalactosaminidase deficiency, cause an infantile neuroaxonal dystrophy known as Schindler disease
.
This condition is inherited in an autosomal recessive pattern, which means two copies of the gene (PLA2G6) in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder each carry one copy of the altered gene but do not show signs and symptoms of the disorder.
Pervasive developmental disorder
Pervasive developmental disorders is a diagnostic category refers to a group of disorders characterized by delays or impairments in communication, social behaviors, and cognitive development.Pervasive developmental disorders include Autism, Asperger's syndrome, Rett's syndrome, Childhood...
that primarily affects the nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
. Individuals with infantile neuroaxonal dystrophy typically do not have any symptoms at birth, but between the ages of about 6 and 18 months they begin to experience delays in acquiring new motor and intellectual skills, such as crawling or beginning to speak. Eventually they lose previously acquired skills.
Diagnosis
In some cases, signs and symptoms of infantile neuroaxonal dystrophy first appear later in childhood or during the teenage years and progress more slowly.Children with infantile neuroaxonal dystrophy experience progressive difficulties with movement. Generally they have muscles that are at first weak and "floppy" (hypotonic
Hypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
), and then gradually become very stiff (spastic
Spastic
The word spastic is used differently depending on location which has led to some controversy and misunderstanding. Derived via Latin from the Greek spastikos , the word originally referred to a change in muscles affected by the medical condition spasticity, which is seen in spastic diplegia and...
). Eventually, affected children lose the ability to move independently. Lack of muscle strength causes difficulty with feeding and breathing problems that can lead to frequent infections, such as pneumonia. Seizures occur in some affected children.
Rapid, involuntary eye movements (nystagmus), eyes that do not look in the same direction (strabismus), and vision loss due to deterioration (atrophy) of the optic nerve are characteristic of infantile neuroaxonal dystrophy. Hearing loss may also develop. Children with this disorder experience progressive deterioration of cognitive functions (dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
), and eventually lose awareness of their surroundings.
Infantile neuroaxonal dystrophy is characterized by the development of swellings called spheroid bodies in the axons, the fibers that extend from nerve cells (neurons) and transmit impulses to muscles and other neurons. A part of the brain called the cerebellum, which helps to control movements, may also be damaged. In some individuals with infantile neuroaxonal dystrophy, abnormal amounts of iron accumulate in a specific region of the brain called the basal ganglia.
Pathophysiology
Mutations in the PLA2G6 gene have been identified in most individuals with infantile neuroaxonal dystrophy. The PLA2G6 gene provides instructions for making an enzyme called an A2 phospholipase. This enzyme family is involved in metabolizing phospholipidPhospholipid
Phospholipids are a class of lipids that are a major component of all cell membranes as they can form lipid bilayers. Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from...
s. Phospholipid metabolism is important for many body processes, including helping to keep the cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
intact and functioning properly. Specifically, the A2 phospholipase produced from the PLA2G6 gene, sometimes called PLA2 group VI, helps to regulate the levels of a compound called phosphatidylcholine
Phosphatidylcholine
Phosphatidylcholines are a class of phospholipids that incorporate choline as a headgroup.They are a major component of biological membranes and can be easily obtained from a variety of readily available sources such as egg yolk or soy beans from which they are mechanically extracted or chemically...
, which is abundant in the cell membrane.
Mutations in the PLA2G6 gene impair the function of the PLA2 group VI enzyme. This impairment of enzyme function may disrupt cell membrane maintenance and contribute to the development of spheroid bodies in the nerve axons. Although it is unknown how changes in this enzyme's function lead to the signs and symptoms of infantile neuroaxonal dystrophy, phospholipid metabolism problems have been seen in both this disorder and a related disorder called pantothenate kinase-associated neurodegeneration
Pantothenate kinase-associated neurodegeneration
Pantothenate kinase-associated neurodegeneration , also known as neurodegeneration with brain iron accumulation 1 and formerly called Hallervorden-Spatz syndrome Pantothenate kinase-associated neurodegeneration (PKAN), also known as neurodegeneration with brain iron accumulation 1 (NBIA1) and...
. These disorders, as well as the more common Alzheimer disease and Parkinson disease, also are associated with changes in brain iron metabolism. Researchers are studying the links between phospholipid defects, brain iron, and damage to nerve cells, but have not determined how the iron accumulation that occurs in some individuals with infantile neuroaxonal dystrophy may contribute to the features of this disorder.
A few individuals with infantile neuroaxonal dystrophy have not been found to have mutations in the PLA2G6 gene. The genetic cause of the condition in these cases is unknown; there is evidence that at least one other gene may be involved.
Mutations in the NAGA gene
NAGA (gene)
Alpha-N-acetylgalactosaminidase is an enzyme that in humans is encoded by the NAGA gene.-Further reading:...
, resulting in alpha-N-acetylgalactosaminidase deficiency, cause an infantile neuroaxonal dystrophy known as Schindler disease
Schindler disease
Schindler disease, also known as Kanzaki disease and Alpha-N-acetylgalactosaminidase deficiency is a rare congenital metabolic disorder in humans...
.
Inheritance
External links
- GeneReview/NIH/UW entry on Infantile Neuroaxonal Dystrophy
- National Library of Medicine. Genetics Home Reference - Infantile neuroaxonal dystrophy