Infantile neuroaxonal dystrophy (INAD): Description, Causes and Risk Factors:
A rare, familial disorder of early childhood manifested as progressive psychomotor deterioration, increased reflexes, Babinski sign, hypotonia and progressive blindness. Pathologically, eosinophilic spheroids of swollen axoplasm are found in various central nervous system nuclei.
INAD is a rare autosomal-recessive Neurodegenerative disorder with onset in the first and second year of life. Frequency is unknown. It is characterized by a progressive motor and mental deterioration, bilateral pyramidal tract signs, marked hypotonia, and early visual disturbances without epileptic seizures. The pathological hallmark of the disease is the presence of axonal swellings and spheroid bodies throughout central and peripheral system, evidenced by skin, nerve, conjunctiva, and rectum biopsy.
INAD is an extremely rare genetic disorder and the incidence and prevalence is not known with any certainty. It prevalence is estimated at 1 per 200,000 children.
In most cases, INAD is inherited as an autosomal-recessive trait. Researchers have determined that disruptions or changes (mutations) of the PLA2G6 gene cause INAD in a large number of affected individuals. The PLA2G6 gene is located on chromosome 22 (22q13.1).
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short-arm designated "p" and a long-arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 22q13.1" refers to band 13.1 on the long arm of chromosome 22. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Researchers believe that the PLA2G6 gene carries instructions to create (encode) an enzyme that breaks down certain fats known as lipids. When the PLA2G6 gene is mutated the breakdown of lipids is affected, which may result in the excess accumulation of membranes in the nerve terminal and, ultimately, in a build up of iron in the brain.
The onset of the disease is usually occurs between the age of six months and 3 years. The initial symptoms is a slowing of the rate of motor and mental development followed by definite regression with loss of previously acquired milestones. Psychomotor regression is associated with increased hypotonia with muscular weakness of such a degree as to suggest a diagnosis of myopathy
or a spinal muscular atrophy
Electrophysiological and radiological studies may be helpful for the diagnosis, which is based on the combination of clinical and pathological aspects.
A definite diagnosis of infantile neuroaxonal dystrophy requires the demonstration of axonal spheroids by the histological study of brain, nerve, and muscle, skin or conjunctival biopsy. Electron microscopy shows that spheroids contain granular and tubulogranular material, degenerated cytoplasmic organelles and glycogen accumulation. The presence of spheroid bodies in both myelinated and unmyelinated axons is the most typical finding although not specific to infantile neuroaxonal dystrophy since it appears in other conditions including NBIA (neurodegeneration with brain iron accumulation), infantile GM2 gangliosidosis, Menkes disease, chronic vitamin E deficiency. Neurophysiological studies may help clinical diagnosis. The presence of high amplitude, non-reactive, fast rhythms at 16 to 22 Hz in the EEG both in sleep and waking state, although not specific is highly suggestive for infantile neuroaxonal dystrophy is an appropriate clinical setting.
Due to lack of knowledge about etiology no specific treatment is available. A Rehabilitation program including physiotherapy and orthopedic management might be helpful and should be started early in the course of the disease. The main task of these therapies is to prevent development of contractures and fixed deformities. Symptomatic pharmacological treatment of spasticity and seizures with myorelaxant and antiepileptic drugs may be of some benefit.
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