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Infantile Neuroaxonal Dystrophy

NORD is very grateful to Robert E. Schmidt, MD, PhD, Professor of Pathology & Immunology, Department of Pathology and Immunology, Division of Neuropathology, Washington University School of Medicine, for assistance in the preparation of this report.

Synonyms of Infantile Neuroaxonal Dystrophy

  • INAD
  • neurodegeneration with brain iron accumulation 2A (NBIA2A)
  • Seitelberger Disease

Disorder Subdivisions

  • INAD, atypical
  • prenatal/connatal neuroaxonal dystrophy

General Discussion

Infantile neuroaxonal dystrophy (INAD) is an extremely rare, inherited degenerative disorder of the nervous system characterized by abnormalities of nerve endings (axon terminals) within the brain and spinal cord (central nervous system) and outside the central nervous system (peripheral nerves and terminals). In most cases, infants and children with INAD appear to develop normally until approximately 14 to 18 months of age, when they may begin to experience progressively increased difficulties in walking. In other cases, symptoms may begin at approximately six to eight months of age, at which time infants may experience delays or an arrest in the acquisition of skills requiring the coordination of mental and physical activities (delayed psychomotor development).

The symptoms and physical characteristics associated with infantile neuroaxonal dystrophy are the result of swelling and degeneration of individual nerve endings (dystrophic axonal swellings or "spheroids") within and outside the brain and spinal cord (central nervous system). In most cases, INAD is inherited as an autosomal recessive genetic trait.

Symptoms

Infantile neuroaxonal dystrophy is characterized neuropathologically by abnormalities of nerve endings (axons) within the brain and spinal cord (central nervous system or neuroaxis) and outside the central nervous system (peripheral nerves), resulting in loss of proper nerve function. Nerve terminals represent the sites of neuron-to-neuron or neuron-to-target communication.

In most cases, infants and children with the disorder appear to develop normally until approximately 14 to 18 months of age, when they may begin to experience progressively increased difficulties in walking, demonstrating unsteadiness and/or a tendency to fall. Few affected children attain the ability to walk completely independently before such symptoms appear. In other cases, the disorder may become apparent at approximately six to eight months of age, at which time affected infants may experience delays or an arrest in the acquisition of skills requiring the coordination of mental and physical activities (delayed psychomotor development). Affected children may then begin to lose previously acquired skills (psychomotor regression) such as the ability to sit, stand, or vocalize sounds and words. Affected children also demonstrate progressive neuromuscular impairment characterized by generalized muscle weakness, severely diminished muscle tone (hypotonia), abnormally exaggerated reflex responses (hyperreflexia), and/or unusually weak, depressed, or absent reflexes (areflexia). Affected children experience progressive mental retardation in association with gradual motor impairment. In addition, in infants and children with INAD, the head and brain may cease growing at the normal rate after the onset of symptoms. As a result, although the head circumference is normal at birth, it may appear moderately reduced (microcephaly) after symptoms become apparent.

According to the medical literature, infants and children with INAD rarely experience seizures, such as brief, shock-like muscle spasms of the arms, legs, or entire body (myoclonic seizures) or episodes of uncontrolled electrical disturbances in the brain that cause convulsive seizures (epilepsy). However, some affected infants and children may experience involuntary movements of the face and hands and/or sudden involuntary muscle spasms (spasticity) of the lower arms and legs (limbs). In addition, in some cases, affected children may also experience a diminished sensitivity to pain in the lower limbs and trunk and/or progressive paralysis of the legs and the lower portion of the body (paraplegia). Many also experience abnormal retention of urine.

As the disorder progresses, affected children may exhibit involuntary, rapid, side-to-side movements of the eyes (pendular nystagmus); crossing of the eyes (strabismus); and gradual deterioration of the nerves of the eyes (optic atrophy), progressing to blindness. Visual impairment may occur from approximately 10 months to two years after the initial onset of symptoms. As neurological deterioration progresses, affected children may also experience hearing impairment; progressive disorientation and loss of intellectual function (dementia); impaired response to touch (tactile stimulation); uncontrolled, rigid extensions and rotations of the arms, legs, fingers, and toes due to progressively degenerative brain abnormalities (decerebrate rigidity); and increased susceptibility to repeated infections of the respiratory tract. Life-threatening complications may develop by the end of the first decade.

Researchers have reported rare instances in which symptoms associated with INAD have begun before or soon after birth (prenatal or neonatal). According to the medical literature, such cases are often referred to as "Prenatal or Connatal Neuroaxonal dystrophy." As opposed to classical INAD, affected infants are more likely to experience seizures and more rapid progression of motor and neurological impairment and life-threatening complications. According to the medical literature, such cases may also be characterized by abnormalities of the hypothalamus, the region of the brain that activates and coordinates certain hormonal (endocrine) functions, body temperature, and several other bodily functions. For example, affected infants may experience chronic fevers, suggesting abnormalities of temperature regulation. In addition, abnormally decreased activity of the thyroid gland and underproduction of thyroid hormones (hypothalamic hypothyroidism) may contribute to generalized weakness, growth delays, and/or psychomotor retardation. The hypothalamus also coordinates the function of the pituitary gland, a small structure at the base of the brain, by controlling the gland's release of certain hormones. In affected infants with "Prenatal or Connatal Neuroaxonal dystrophy," the pituitary gland may fail to release sufficient levels of a certain hormone (antidiuretic hormone [ADH]). This hormone helps to regulate normal urine production. As a result, affected infants and children may have diabetes insipidus, a disorder characterized by excessive excretion of urine (polyuria) and excessive thirst (polydipsia).

Causes

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.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.

All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Pathological findings suggest that the symptoms and physical characteristics associated with INAD are in some complex way related to the characteristic swellings at the end of the nerve fibers (axons). These are known as dystrophic axonal swellings or "spheroids". These spheroids appear to block transmission of nerve impulses between nerve cells (synaptic transmissions), which leads to the loss of proper nerve function. Both myelinated and nonmyelinated nerve endings (axons) in certain areas (focal axonal swelling) may be affected. Axons carry nerve impulses away from nerve cell bodies. Many have a sheath of myelin, a fatty substance that forms a protective covering around certain nerve fibers, which serves as an electrical insulator that protects the nerve and allows for the effective transmission of certain nerve signals.

In many cases of INAD, such swellings and the degeneration of nerve endings (spheroids) are found to be widely distributed in the outer layer of the brain (cerebral cortex); the lowest part of the brain (brain stem); the spinal cord; and the peripheral nerves that extend from the brain and spinal cord to various areas of the body (e.g., the skin, the conjunctiva of the eyes) The brain stem serves as a "gateway" for messages passing between the spinal cord and other areas of the brain and also contains neurons which project to various structures in the head (for example, eye, jaw and facial muscles, tongue). The basal ganglia help to produce smooth coordinated movements. In some cases, the INAD spheroids have also been widely distributed in nerve endings (axons) of the hypothalamus; the back portion (posterior lobe) of the pituitary gland (neurohypophysis), including the short stalk of nerve fibers that connects the pituitary gland to the hypothalamus ("pituitary stalk").

Affected Populations

Infantile neuroaxonal dystrophy is an extremely rare genetic disorder and the incidence and prevalence is not known with any certainty. One source suggests that the prevalence is 1 per 200,000 children.

Related Disorders

Symptoms of the following disorders may be similar to those of infantile neuroaxonal dystrophy. Comparisons may be useful for a differential diagnosis:

Neurodegeneration with brain iron accumulation type 1 (NBIA1), also known as Hallervorden-Spatz disease, or Pantothenate kinase associated neurodegeneration (PKAN), is an extremely rare inherited disorder characterized by progressive degeneration of the nervous system and abnormal accumulation of iron pigment in certain areas of the brain. Symptoms typically become apparent during the first or second decade of life, with approximately 50 percent of cases occurring by 10 years of age and about 80 percent of cases occurring by 15 years of age. Symptoms tend to include uncontrolled tightening and stiffness of the muscles (rigidity), initially affecting the lower extremities and then progressing to the upper extremities; impaired coordination of voluntary movements (ataxia); slow, involuntary, writhing movements, particularly of the face, head, neck, and limbs (athetosis); irregular, rapid jerking movements (chorea); and/or difficulties speaking, chewing, and swallowing. Affected individuals may also experience progressive confusion, disorientation, and/or deterioration of intellectual abilities (dementia) and/or visual impairment. Life-threatening complications may develop within the second or third decade of life. NBIA1 is inherited as an autosomal recessive genetic trait in many cases caused by a mutation in the pantothenate kinase 2 (PANK2) gene.

Because the symptoms associated with late-onset cases of INAD may sometimes be difficult to distinguish from NBIA1, in the past some researchers have speculated that they may in fact represent the same disorder. However, other researchers caution that they should be considered two distinct disorders, stressing that there are striking differences between the two disorders including some major variances in characteristic symptoms (i.e., primarily extrapyramidal symptomatology in NBIA1). Recently, it has been shown that most cases of INAD and NBIA1 with PLA2G6 and PANK2 gene defects, respectively, which suggests the diseases may not represent the same disorder. In addition, individuals with NBIA1 exhibit heavy deposits of iron pigment in the brain; fewer, less widespread spheroids; less severe loss of brain tissue (cerebellar atrophy); and a juvenile onset with a longer course. (For more information on this disorder, choose " NBIA1" as your search term in the Rare Disease Database.)

Schindler disease type I is an extremely rare inherited metabolic disorder characterized by a deficiency of the lysosomal enzyme alpha-N-acetylgalactosaminidase (alpha-NAGA) in which there is widespread spheroid formation. This disorder belongs to a group of diseases known as lysosomal storage disorders. Lysosomes are particles bound in membranes within cells that break down certain fats and carbohydrates. Low levels of the alpha-NAGA enzyme lead to the abnormal accumulation of certain complex compounds (glycosphingolipids) consisting of fatty materials and carbohydrates (glycolipids) in many tissues of the body. Schindler disease type I, which is considered the classic form of the disease, has an infantile onset. Affected children appear to develop normally until approximately one year of age, when they begin to lose previously acquired physical and mental abilities (developmental regression). Neurological symptoms then begin to appear, which may include muscular weakness, visual impairment, and/or seizures. Neurological impairment continues to progress in affected children and may include sudden involuntary muscle spasms (spasticity), impairment of voluntary movements (immobility), severe mental retardation, and a lack of response to stimuli in the environment. Affected individuals may also exhibit an increased susceptibility to repeated infections of the respiratory tract, potentially leading to life-threatening complications. Schindler disease type I is inherited as an autosomal recessive genetic trait. Patients with INAD do not show defects in the acetylgalactosaminidase gene. (For more information on this disorder, choose "Schindler" as your search term in the Rare Disease Database.)

Late infantile metachromatic leukodystrophy (MLD) is a rare inherited neurometabolic disorder affecting the white matter of the brain (leukoencephalopathy). It is a lysosomal storage disorder characterized by the accumulation of a fatty substance known as sulfatide in the brain and other areas of the body (e.g., liver, gall bladder, kidneys). The fatty protective covering on nerve fibers (myelin) is lost from certain areas of the central nervous system (CNS) due to the buildup of sulfatide. Infants and children with the disorder may appear to develop normally until approximately two years of age, when they may begin to experience symptoms such as muscle weakness, diminished muscle tone (hypotonia), muscle rigidity, poor balance, crossing of the eyes (strabismus), and/or involuntary, rapid, side-to-side movements of the eyes (pendular nystagmus). As the disorder progresses, affected children may experience psychomotor regression, impaired speech, spasticity, dementia, depressed or absent reflex responses (areflexia), and/or, in some cases, involuntary, rhythmic shaking (tremors) or slow, involuntary, writhing movements (athetosis) of the arms and legs. Additional features may include abdominal pain, unexplained fevers, and visual impairment leading to blindness. Life-threatening complications may develop within approximately six months to four years after the onset of symptoms. Late infantile metachromatic leukodystrophy is inherited as an autosomal recessive genetic trait and represents a gene defect in arylsulfatase A and deficiency of its enzyme product which helps turnover a myelin constituent. Patients with INAD do not have a defect in arylsulfatase A. (For more information on this disorder, choose "Metachromatic Leukodystrophy" as your search term in the Rare Disease Database.)

There are several additional neurological, neuromuscular, and/or neurometabolic disorders that may become apparent within the first months or years of life and be characterized by psychomotor retardation, arrest, and regression; progressive neuromuscular and neurological impairment; and/or other abnormalities similar to those occurring in association with INAD. (For more information on such disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
INAD is diagnosed during the first years of life by means of a thorough clinical evaluation, a detailed patient history, identification of characteristic physical findings, and a variety of specialized tests. The presence of a defect in the PLA2G6 gene provides a diagnosis in 80% of patients with INAD. In addition, microscopic examination (i.e., light and electron microscopy) of samples (biopsies) of peripheral nerve tissue from the skin or the transparent membrane covering the whites of the eyes (conjunctivae) may reveal swelling and degeneration of nerve endings (dystrophic axonal swellings or "spheroids").

Advanced imaging techniques may also be used to detect, confirm, and/or characterize specific abnormalities of the central nervous system that may be associated with INAD. Magnetic resonance imaging (MRI), which uses a magnetic field and radio waves to create cross-sectional images of the brain, may reveal progressive, generalized degeneration (diffuse atrophy) of tissue of the outer portion of the cerebellum (cerebellar cortex). Affected infants with prenatal or connatal neuroaxonal dystrophy may tend to exhibit less marked degeneration of the cerebellum. Specialized imaging tests may also reveal degeneration of the portion of the brain that helps pass messages between the spinal cord and other areas of the brain (brain stem) and varying degeneration of the nerve tracts of the spinal cord that pass sensory information up toward the brain (ascending tracts) and pass motor signals downward toward the trunk, arms, and legs (descending tracts).

In infants and children with INAD, specialized testing may also be conducted to evaluate electrical activity (electrophysiological studies) of certain areas of the body. For example, electromyograms (EMG), tests that record electrical activity in skeletal muscles at rest and during muscle contraction, may indicate that, although nerve signals may be transmitted at normal speed to muscles (normal nerve conduction velocities), there is failed communication of such signals to the muscles (denervation). Electroencephalography (EEG), which records the brain's electrical impulses, may reveal abnormally high amplitude and fast activity within brain wave patterns. INAD results in a decreased or absent response when the eye is stimulated by light (visually evoked potential [VEP]), confirming defects in optic pathways in the brain.

Treatment
The treatment of infantile neuroaxonal dystrophy is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who diagnose and treat neurological disorders (neurologists), eye specialists (ophthalmologists), and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment.

The treatment of INAD is symptomatic and supportive. Thorough preventive measures may be taken to help prevent respiratory tract infections. Medications that help treat such infections (e.g., antibiotic therapy) and other supportive measures may be used to aggressively treat such infections should they occur. Genetic counseling will be of benefit for affected individuals and their families.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Contact for additional information about infantile neuroaxonal dystrophy:

Robert E. Schmidt, M.D., Ph.D.
Professor of Pathology & Immunology
Department of Pathology and Immunology
Division of Neuropathology
reschmidt@pathology.wustl.edu

Organizations related to Infantile Neuroaxonal Dystrophy

(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., neurological abnormalities, neuromuscular impairment, optic atrophy, etc.].)

References

TEXTBOOKS
Schmidt RE. Infantile Neuroaxonal Dystrophy. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:634-35.

Rowland LP. Ed. Merritt's Neurology. 10th ed. Lippincott Williams & Wilkins. Philadelphia, PA. 2000:556-57, 560.

JOURNAL ARTICLES
Morgan NV, Westaway SK, Morton JE, et al., PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nat Genet. 2006;38:752-4.
Potts R, Leech RW. Thalamic dementia: an example of primary astroglial dystrophy of Zeitelberger. Clin Neuropathol. 2005;24:271-75.

Egan RA, Weleber RG, Hogarth P, et al. Neuro-ophthalmologic and electroretinographic findings in pantothenate kinase-associated neurodegeneration (formerly Hallervorden-Spatz syndrome). Am J Ophthalmol. 2005;140:267-74.

Wieczorek SW, Epplen JT. Gene symbol: PANK2. Disease: Pantothenate kinase-associated neurodegeneration (PKAN). Hum Genet. 2005;116:545.

Pelecchia MT, Valente EM, Cif L, et al. The diverse phenotype and genotype of pantothenate kinase-associated neurodegeneration. Neurology. 2005;64:1810-12.
Kobor J, Javaid A, Omojola MF. Cerebellar hypoperfusion in infantile neuroaxonal dystrophy. Pediatr Neurol. 2005;32:137-39.

Saleheen D, Frossard P, Ozair MZ, Kazmi MA, Khlaid H, Khealani B. The "eye of the tiger" sign. CMAJ. 2005;172:38.

Hortnagel K, Nardocci N, Zorzi G, et al. Infantile neuroaxonal dystrophy and pantothenate-kinase-associated neurodegeneration: locus heterogeneity. Neurology. 2004;63:922-24.

FROM THE INTERNET
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Neurodegeneration with Brain Iron Accumulation 2A;NBIA2A. Entry No: 256600. Last Edited October 12, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed October 24, 2011.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Osteopetrosis and Infantile Neuroaxonal Dystrophy. Entry No: 600329. Last Edited June 29, 2010. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed October 24, 2011.

NINDS Infantile Neuroaxonal Dystrophy Information Page. www.ninds.nih.gov/disorders/neuroaxonal_dystrophy/neuroaxonal_dystrophy.htm. Last updated February 14, 2007. Accessed October 24, 2011.

Nardocci N. Infantile Neuroaxonal Dystrophy. Orphanet encyclopedia, November 2004. Available at: http://www.orpha.net/data/patho/GB/uk-INAD.pdf. Accessed October 24, 2011.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2011/10/27 00:00:00 GMT+0

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