Infantile Neuroaxonal Dystrophy (INAD)
What is Infantile Neuroaxonal Dystrophy (INAD)?
Infantile neuroaxonal dystrophy (INAD) is a rare, genetic neurological disorder. Symptoms usually present between 6 and 18 months of age. There is often rapid onset of motor and intellectual regression. Diminished muscle tone, called hypotonia, is also present. Hypotonia means the infant will be weak and ‘floppy’. Later on, spasticity develops. Spasticity is when the muscle tone increases and the muscles stiffen. Spasticity causes abnormal stiff, jerky movements, particularly of the legs. There are also problems with vision and the eyes, the autonomic nervous system, and, in a minority of individuals, seizures. Usually, the progression is very fast and the disorder can be fatal in childhood. There are atypical forms of INAD that have been recognized with onset as late as the teen-aged years; this is an even rarer condition and the prognosis or life span is not known.
INAD is part of a spectrum of disease called PLA2G6-associated neurodegeneration. INAD is the severe end of this spectrum. The spectrum itself is further classified as part of a group of disorders called neurodegeneration with brain iron accumulation or NBIA.
Synonyms
- Infantile Neuroaxonal Dystrophy
- Seitelberger disease
- Neurodegeneration with Brain Iron Accumulation, PLA2G6-associated
- Neurodegeneration with Brain Iron Accumulation 2A
Infantile neuroaxonal dystrophy (INAD) is a rare, genetic neurological disorder. Symptoms usually present between 6 and 18 months of age. There is often rapid onset of motor and intellectual regression. Diminished muscle tone, called hypotonia, is also present. Hypotonia means the infant will be weak and ‘floppy’. Later on, spasticity develops. Spasticity is when the muscle tone increases and the muscles stiffen. Spasticity causes abnormal stiff, jerky movements, particularly of the legs. There are also problems with vision and the eyes, the autonomic nervous system, and, in a minority of individuals, seizures. Usually, the progression is very fast and the disorder can be fatal in childhood. There are atypical forms of INAD that have been recognized with onset as late as the teen-aged years; this is an even rarer condition and the prognosis or life span is not known.
INAD is part of a spectrum of disease called PLA2G6-associated neurodegeneration. INAD is the severe end of this spectrum. The spectrum itself is further classified as part of a group of disorders called neurodegeneration with brain iron accumulation or NBIA.
The prevalence of INAD is not known. It is believed to be a very rare disorder. The prevalence for PLA2G-associated neurodegeneration as a group is estimated to be about 1 in 1,000,000 in the general population.
| Name | Abbreviation |
|---|---|
| Infantile Neuroaxonal Dystrophy | INAD |
| Seitelberger disease | INAD |
| Neurodegeneration with Brain Iron Accumulation, PLA2G6-associated | NBIA |
| Neurodegeneration with Brain Iron Accumulation 2A | NBIA2A |
INAD is caused by a mutation or genetic alteration in the PLA2G6 gene. This gene produces an enzyme called A2 phospholipase. This enzyme is necessary to break down a type of fat called lipids. Because the PLA2G6 gene is altered, affected people do not have enough functional copies of this enzyme and cannot properly breakdown (metabolize) these fats. This can cause problems including excess build up of membranes in nerve cells, or the build up of iron in the brain.
INAD is an autosomal recessive disease. This means that individuals must have two copies of the altered gene, one received from the mother and the other from the father. If an individual receives one normal gene and one affected gene, the person will become a carrier for the condition but not affected with it. This case is known as a heterozygous gene pattern. Thus, the risk for two carrier parents to pass on the altered gene and produce an affected offspring is 25% per pregnancy. The risk of the child being a carrier is 50% and the chances of the child inherited two unaltered copies of the gene are 25%. The risk of inheritance is the same for both males and females.
At or around 6 to 18 months of age, infants begin to have delays in reaching developmental milestones and then begin to lose previously acquired skills. There may be a progressive loss of intellectual abilities.
Infants have weak or diminished muscle tone, but later muscles stiffen. The stiffening of muscles can become severe and can cause difficulty feeding, an inability to initiate voluntary movements, and breathing problems that can lead to repeated respiratory infections or pneumonia.
Most children are never able to walk, or lose the ability to walk shortly after achieving this milestone. There may be problems with the autonomic nervous system, which controls involuntary actions such as breathing or regulating the heartbeat. Infants or children may have constipation, cold hands or feet, and, sometimes, fluctuations in core body temperature.
Several conditions affecting the eyes can be seen including rapid, involuntary movements of the eyes, crossed-eyes, and degeneration of the optic nerve, the main nerve of the eye that carries nerve impulses to the brain. They may also have problems moving their eyes to where they want (hypometric saccades).
Hearing loss has also been reported. A minority of infants or children will experience seizures.
The disease often progresses until children experience signs of dementia and lose awareness of their surroundings. The disorder is often fatal by the end of the first decade.
There are atypical forms of INAD and researchers do not yet know what the severity or life expectancy of these forms are.
A diagnosis may be suspected because of characteristic signs and symptoms. However, many of these signs and symptoms are common to other neurodegenerative disorders. A diagnosis may be confirmed through molecular genetic testing. Such testing may involve looking at the PLA2G6 gene to see whether a mutation is present. This can provide a diagnosis in about 80% of infants.
Additional testing may done to help obtain a diagnosis, or after a diagnosis to establish the extent of the disease. Biopsies of nerve tissue from the skin or conjunctiva may reveal characteristic changes. Magnetic resonance imaging called an MRI or other imaging techniques may reveal characteristic changes in the brain like cerebellar atrophy.
Other tests that may be performed can include an electromyography, which measures the electrical activity of muscle tissue; an electroencephalography (EEG), which measures the electrical activity in different parts of the brain; visual evoked potential, which assesses the eyes when they are exposed to a test pattern; and nerve conduction velocity, which measures the speed of conduction of electrical impulses through a nerve.
Molecular genetic testing is used to confirm a diagnosis. These testing involving looking at the PLA2G6 gene to see whether a mutation is present. This can provide a diagnosis in about 80% of infants.
Additional testing that may done to help obtain a diagnosis, or after a diagnosis is made to establish the extent of the disease. Biopsies of nerve tissue from the skin or conjunctiva may reveal characteristic changes. Magnetic resonance imaging called an MRI or other imaging techniques may reveal characteristic changes in the brain like cerebellar atrophy.
Other tests that may be performed can include an electromyography, which measures the electrical activity of muscle tissue; an electroencephalography (EEG), which measures the electrical activity in different parts of the brain; visual evoked potential, which assesses the eyes when they are exposed to a test pattern; and nerve conduction velocity, which measures the speed of conduction of electrical impulses through a nerve.
There are no disease-specific treatments or cure. Treatment is aimed at the symptoms that are present and include antibiotics for infections or anti-convulsants medications for seizures. Supportive services including occupational therapy, physical therapy, speech therapy and other such services may be recommended.
INAD is a progressive disorder and is often fatal between 5 and 10 years of age. However, there are atypical forms of the disorder and researchers do not know what the life expectancy of these are. INAD is the severe end of a spectrum of disease and individuals with altered PLA2G6 genes can have less severe forms.
Genetic counseling is recommended for families affected by INAD. There are supportive services like early intervention programs that can provide assistance.
Gregory A, Kurian MA, Maher ER, Hogarth P, Hayflick SJ. PLA2G6-Associated Neurodegeneration. GeneReviews website. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1675/. Updated: March 23, 2017.
Illingworth MA, Meyer E, Chong WK, et al. PLA2G6-associated neurodegeneration (PLAN): Further expansion of the clinical, radiological and mutation spectrum associated with infantile and atypical childhood-onset disease. Mol Genet Metab. 2014;112(2):183–189.
Infantile neuroaxonal dystrophy. Genetics Home Reference website. Available at: https://ghr.nlm.nih.gov/condition/infantile-neuroaxonal-dystrophy. Updated: September 2012.
Infantile Neuroaxonal Dystrophy Information Page. National Institute of Neurological Disorders and Stroke website. Available at: https://www.ninds.nih.gov/Disorders/All-Disorders/Infantile-Neuroaxonal-Dystrophy-Information-Page.
Infantile Neuroaxonal Dystrophy. National Organization for Rare Disorders website. Available at: https://rarediseases.org/rare-diseases/infantile-neuroaxonal-dystrophy/. Updated: 2011.
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