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Infantile neuroaxonal dystrophy

INAD, INAD1, Seitelberger disease, Phospholipase A2-associated neurodegeneration

Overview

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.

Symptoms - Infantile neuroaxonal dystrophy

In most cases, the infants with Infantile neuroaxonal dystrophy appear to grow normally until at about 6-18 months of age, when the symptoms start appearing. Infants may experience delay in achieving psychomotor development. Infantile neuroaxonal dystrophy may be classical or atypical.

Classical Infantile neuroaxonal dystrophy presents between 6 months to 3 years with psychomotor delay and developmental regression. It is characterized by truncal hypotonia progressing to tetraparesis. Dementia is also seen. Visual signs include strabismus, pendular nystagmus, uncoordinated eye movement, optic atrophy and failing vision. Seizure episodes may be seen.

The progression of disease is usually rapid. Many affected children never learn to walk or lose this ability shortly after attaining it. During the end stages of disease, severe spasticity, progressive cognitive decline, and visual impairment result in a vegetative state. Death occurs as a result of secondary illnesses such as aspiration pneumonia, associated with bulbar dysfunction. Many affected children do not survive beyond their first decade, but some survive into their teens or later.

Onset of atypical neuroaxonal dystrophy can be seen in early childhood or in late teens. Speech delay and neurobehavioral disturbance is seen. Progressive dystonia and dysarthia is seen. Visual disturbances are same as seen in classical neuroaxonal dystrophy like nystagmus, squints and gradually optic atrophy and ultimately loss of vision. Tetraparesis occurs late in disease.
Neuropsychiatric disturbance include impulsivity, poor attention span, hyperactivity, and emotional liability. The disease progresses same like classical Infantile neuroaxonal dystrophy, leaving the child dependant.

Causes - Infantile neuroaxonal dystrophy

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 phospholipids. 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.

Prevention - Infantile neuroaxonal dystrophy

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Diagnosis - Infantile neuroaxonal dystrophy

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), 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.

Prognosis - Infantile neuroaxonal dystrophy

There are no symptoms at birth, however as the child grows from 6 months to 2 years, the symptoms become apparent. The condition worsens with age. Over several years, the child becomes dependant wholly and eventually loses all learned skills and intellect. Death occurs by the age of 5-10 years. The prognosis is thus poor.

Treatment - Infantile neuroaxonal dystrophy

Treatment is palliative and includes:

  • Pharmacologic treatment of spasticity and seizures
  • Oral or intrathecal baclofen for significant dystonia
  • Physiotherapeutic treatment of spasticity and measures such as gastric feeding tube or tracheostomy to prevent aspiration pneumonia.
  • Iron chelation therapy is not currently recommended.

Resources - Infantile neuroaxonal dystrophy

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