Information on the following diseases can be found in the Related Disorders section of this report:

• Neuroaxonal Dystrophy, Infantile
• Seitelberger Disease
• Parkinson’s Disease
• Huntington Disease
• Joseph Disease
• Cerebral Palsy
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There are several descriptive terms for the neuromuscular symptoms associated with all forms of Neurodegeneration with Brain Iron Accumulation Type 1 (Hallervorden-Spatz syndrome). Dystonia is a group of disorders characterized by involuntary muscle contractions that may force certain body parts into unusual, and sometimes painful, movements and positions. Choreoathetosis is a condition characterized by involuntary, rapid, jerky movements (chorea) occurring in association with relatively slow, sinuous, writhing motions (athetosis). In addition, there may be stiffness in the arms and legs because of continuous resistance to muscle relaxing (spasticity) and abnormal tightening of the muscles (muscular rigidity). Spasticity and muscle rigidity usually begin in the legs and later develop in the arms. As affected individuals age, they may eventually lose control of voluntary movements. Muscle spasms combined with decreased bone mass can result in bone fractures (not caused by trauma or accident).

Dystonia affects the muscles in the mouth and throat, which may cause poor articulation and slurring (dysarthria) and difficulty swallowing (dysphagia). The progression of dystonia in these muscles can result in loss of speech as well as tongue-biting.

Specific forms of dystonia that may occur in association with Neurodegeneration with Brain Iron Accumulation Type 1 (Hallervorden-Spatz syndrome) include blepharospasm and torticollis. Blepharospasm is a condition in which the muscles of the eyelids do not function properly resulting in excessive blinking and involuntary closing of the eyelids. Torticollis is a condition in which there are involuntary contractions of neck muscles resulting in abnormal movements and positions of the head and neck.

Many of the delays in development pertain to motor skills (movement), although a small subgroup may have intellectual delays. Although intellectual impairment has often been described as a part of the condition in the past, it is unclear if this is a true feature. Intellectual testing may be hampered by the movement disorder; therefore, newer methods of studying intelligence are necessary to determine if there are any cognitive features of this condition.

The symptoms and physical findings associated with PKAN mutations can be distinguished between classical and atypical disease. Individuals with classical disease have a more rapid progression of symptoms. In most cases, atypical disease progresses slowly over several years. The symptoms and physical findings vary from case to case.

Classical PKAN develops in the first ten years of life (average age for developing symptoms is three and a half years). These children may initially be perceived as clumsy and later develop more noticeable problems with walking. Eventually, falling becomes a frequent feature. Because of the limited ability to protect themselves during falls, children may have repeated injury to the face and chin. Many individuals with the classic form of PKAN require a wheelchair by their mid-teens (in some cases earlier). Most lose the ability to move/walk independently between 10 and15 years after the beginning of symptoms.

Individuals with classical PKAN are more likely to have specific eye problems. Approximately two-thirds of these patients will have retinal degeneration. This is a progressive degeneration of the nerve-rich membrane lining the eyes (retina), resulting in tunnel vision, night blindness, and loss of peripheral vision. Loss of this peripheral vision may contribute to the more frequent falls and gait disturbances in the early stages. [For more information on this retinopathy (retinitis pigmentosa), choose "retinitis pigmentosa" as your search term in the Rare Disease Database]. Optic atrophy, a vision impairment caused by gradual degeneration of the nerves of the eyes, is only found in three percent of patients.

The atypical form of PKAN usually occurs after the age of ten years and progresses more slowly. The average age for developing symptoms is 13 years. Loss of independent ambulation (walking) often occurs 15 to 40 years after the initial development of symptoms. The initial presenting symptoms usually involve speech. Common speech problems are repetition of words or phrases (palilalia), rapid speech (tachylalia), and poor articulation/slurring (dysarthria). Psychiatric symptoms are more commonly observed and include impulsive behavior, violent outbursts, depression, or a tendency to rapid mood swings. While the movement disorder is a very common feature, it usually develops later. In general, atypical disease is less severe and more slowly progressive than early-onset PKAN.

In cases of neurodegeneration with brain iron accumulation (NBIA) that are not caused by PKAN, the movement-related symptoms (such as dystonia) may be very similar. The symptoms in NBIA are more varied because there are probably several different causes of neurodegeneration in this group. There is a subgroup of patients with moderate to severe mental retardation. Also, seizure disorders are more common among non-PKAN individuals.
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Individuals with Neurodegeneration with Brain Iron Accumulation Type 1 (Hallervorden-Spatz syndrome) often have abnormal accumulation of iron in certain areas of the brain. This is especially seen in regions of the basal ganglia called the globus pallidus and the substantia nigra. The basal ganglia is a collection of structures deep within the base of the brain that assist in regulating movements. The exact relationship between iron accumulation and the symptoms of Hallervorden-Spatz syndrome is not fully understood.

PKAN is an autosomal recessive condition. Many other cases of NBIA are presumed to be autosomal recessive as well. In autosomal recessive disorders, a person has received a non-working gene from both parents. Following is a brief review of some of the basic genetic terminology.

A person carries a complete set of genetic material in most cells of his body. The total amount of information is contained on 46 chromosomes. These exist in 23 pairs, where one chromosome from each pair comes from the mother and the other from the father. Chromosomes are like miniature filing cabinets for the thousands of genes that control normal health and development.

Because all of our genes exist in pairs (one coming from the mother and one coming from the father), we normally carry two functioning copies of each gene. When one copy of a recessive gene has an alteration (mutation) in it, the person should still have normal health. That person is called a carrier. Recessive diseases only occur when both parents are carriers for the same condition and then pass their altered gene on to their child. Statistically, there is a 1 in 4 chance that two carriers would have an affected child, a 2 in 4 chance to have a child who is also a carrier, and a 1 in 4 chance to have a child who did not receive the gene mutation.

PKAN is due to mutations of the PANK2 gene on chromosome 20. This gene encodes the enzyme pantothenate kinase. Current research is investigating how this missing enzyme results in damage to neurons in the brain as well as the characteristic iron buildup. It is hypothesized that some cysteine-containing chemicals accumulate in high levels causing damage to the neurons in the basal ganglia. No genes have been found for other forms of NBIA.
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Neurodegeneration with Brain Iron Accumulation Type 1 (Hallervorden-Spatz syndrome) affects males and females in equal numbers. The symptoms typically develop during childhood, although occasionally they begin during late adolescence or adulthood.

The frequency of Neurodegeneration with Brain Iron Accumulation Type 1 (Hallervorden-Spatz syndrome) in the general population is estimated between one and three in a million individuals. Because rare disorders like Hallervorden-Spatz disease often go unrecognized, these disorders may be under-diagnosed or misdiagnosed, making it difficult to determine the accuracy of these estimates.
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Symptoms of the following disorders can be similar to those of Neurodegeneration with Brain Iron Accumulation Type 1 (Hallervorden-Spatz syndrome). Comparisons may be useful for a differential diagnosis:

Seitelberger disease, also known as infantile neuroaxonal dystrophy (INAD), is an extremely rare inherited degenerative disorder of the nervous system characterized by abnormalities of nerve endings (axons) within the brain and spinal cord (central nervous system) and outside the central nervous system (peripheral nerves). In most cases, infants and children with Seitelberger disease 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). Affected infants and children may then begin to lose previously acquired skills (psychomotor regression) including sitting and standing and may 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. In some cases, as the disorder progresses, affected children may also experience involuntary movements of the face and hands, sudden involuntary muscle spasms (spasticity) of the lower arms and legs (limbs), and progressive paralysis of the legs and lower part of the body (paraplegia). Progressive mental retardation occurs in association with gradual motor impairment. In most cases, Seitelberger disease is inherited as an autosomal recessive trait. (For more information on this disorder, choose "Seitelberger" as your search term in the Rare Disease Database.)

Parkinson disease is a slowly progressive neurologic condition characterized by involuntary trembling (tremor), muscular stiffness or inflexibility (rigidity), slowness of movement and difficulty carrying out voluntary movements. Degenerative changes occur in areas deep within the brain (substantia nigra and other pigmented regions of the brain), causing a decrease in dopamine levels in the brain. Dopamine is a neurotransmitter, which is a chemical that sends a signal in the brain. Parkinsonian symptoms can also develop secondary to hydrocephalus (a condition in which the head is enlarged and areas of the brain accumulate excessive fluids, resulting in an increase in pressure on the brain), head trauma, inflammation of the brain (encephalitis), obstructions (infarcts) or tumors deep within the cerebral hemispheres and the upper brain stem (basal ganglia), or exposure to certain drugs and toxins. Parkinson's disease is slowly progressive and may not become incapacitating for many years. (For more information on this disorder, choose "Parkinson's" as your search term in the Rare Disease Database.)

Huntington's disease is a genetic, progressive, neurodegenerative disorder characterized by the gradual development of involuntary muscle movements affecting the hands, feet, face, and trunk and progressive deterioration of cognitive processes and memory (dementia). Neurologic movement abnormalities may include uncontrolled, irregular, rapid, jerky movements (chorea) and athetosis, a condition characterized by relatively slow, writhing involuntary movements. Dementia is typically associated with progressive disorientation and confusion, personality disintegration, impairment of memory control, restlessness, agitation, and other symptoms and findings. In individuals with the disorder, disease duration may range from approximately 10 years up to 25 years or more. Life-threatening complications may result from pneumonia or other infections, injuries related to falls, or other associated developments. Huntington's disease is inherited as an autosomal dominant trait. (For more information on this disorder, choose "Huntington" as your search term in the Rare Disease Database.)

Joseph's disease is a rare inherited disorder affecting the central nervous system that is characterized by the slow degeneration of certain areas of the brain. Symptoms typically begin during adulthood and may include an unsteady gait (ataxia), slurred speech (dysarthria), muscle rigidity, impaired muscle tone, slow involuntary movements of the arms and legs (athetosis), and/or irregular eye movements. Mental alertness and intellectual capacities are not affected. This disorder primarily affects people of Portuguese heritage. Joseph's disease is inherited as an autosomal dominant trait. (For more information on this disorder, choose "Joseph" as your search term in the Rare Disease Database.)

Cerebral palsy is a general term that covers a group of disorders that involve impairment of muscle control or coordination resulting from injury to the brain during its early stages of development (the fetal, perinatal or early childhood stages). There may be problems associated with involuntary movements, vision, hearing, communication skills, perception levels, intellect and seizures. Individuals with cerebral palsy often experience delays in reaching developmental milestones. The specific symptoms associated with cerebral palsy vary greatly from case to case. (For more information on this disorder, choose "Cerebral Palsy" as your search term in the Rare Disease Database.)
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Diagnosis
The diagnosis of Neurodegeneration with Brain Iron Accumulation Type 1 (Hallervorden-Spatz syndrome) is made based upon a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. The diagnosis can be made by MRI (magnetic resonance imaging). This imaging technique shows the characteristic iron accumulation in certain areas of the brain (globus pallidus and pars reticulata of the substantia nigra). Individuals with PKAN have a characteristic feature called the "eye-of-the-tiger" sign. This is not seen in other forms of NBIA1. MRI should be useful in distinguishing PKAN and non-PKAN individuals and may also help to determine which families should have DNA testing for PKAN.

Treatment
There is no specific treatment for individuals with Neurodegeneration with Brain Iron Accumulation Type 1 (Hallervorden-Spatz syndrome). Treatment is directed towards the specific symptoms that appear in each individual. Research is focusing on a better understanding of the underlying cause of this disorder, which may eventually help to find a more comprehensive treatment.

Treatment may require the coordinated efforts of a team of specialists. Physicians that the family may work with include the pediatrician or internist, neurologist, opthalmologist, and geneticist. A team approach to supportive therapy may include physical therapy, exercise physiology, occupation therapy, and speech pathology. In addition, many families may benefit from genetic counseling.

One of the most consistent forms of relief from disabling dystonia is baclofen. This medication has been taken orally, although recently a baclofen pump has been used to administer regular doses automatically into the nervous system.

Levodopa/carbidopa, bromocriptine, and trihexyphenidyl do not appear to help patients with PKAN. These treatments may have a role in the treatment of other causes of NBIA1; however, their overall effectiveness is unknown and the responsiveness in individual cases is unpredictable.

Drugs that reduce the levels of iron in the body (iron chelation) have been attempted to treat individuals with Neurodegeneration with Brain Iron Accumulation Type 1 (Hallervorden-Spatz syndrome). These agents have proven ineffective.

Pallidotomy and thalamotomy have been investigational attempts at controlling dystonia. These are both surgical techniques which destroy (ablate) very specific regions of the brain, the pallidus and thalamus, respectively. Some families have reported some immediate and temporary relief. However, most patients return to their pre-operative level of dystonia within one year of the operation. Pallidotomy is used for the treatment of disorders that are characterized by changes in muscle tone, postural disturbances, abnormalities in conducting certain voluntary movements, and the development of abnormal involuntary movements (i.e., extrapyramidal disorders). Thalamotomy is usually only used in cases of severe, progressive dystonia that fails to respond to other treatments (intractable).

Individuals experiencing seizures usually benefit from standard anti-convulsive drugs. In addition, standard approaches to pain management are generally recommended where there is no identifiable treatment for the underlying cause of pain.

With the recent discovery of the association between pantothenate kinase and NBIA1, there is a new potential therapy that focuses on the underlying chemical defect. Supplemental pantothenate (pantothenic acid, calcium pantothenate) can be taken orally. Pantothenate is another name for vitamin B5, a water soluble vitamin. Theoretically, this is most likely to assist individuals with very low levels of pantothenate kinase activity. It is hypothesized that classical disease results from complete absence of the enzyme pantothenate kinase, whereas atypical disease results from a severe deficiency, although the individuals still may have some level of enzyme activity. Clinical trials will soon be underway to investigate the effectiveness of this treatment with various forms of NBIA1.

The benefits and limitations of any of the above treatments should be discussed in detail with a physician.
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The National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health (NIH) supports research on neurodegenerative movement disorders such as Neurodegeneration with Brain Iron Accumulation Type 1 (Hallervorden-Spatz syndrome). The goals of this research are to increase understanding of these disorders, and to find ways to prevent, treat, and cure them.

Researchers at Oregon Health & Science University (OHSU) and University of California, San Francisco (UCSF) are doing research specific to Neurodegeneration with Brain Iron Accumulation Type 1 (Hallervorden-Spatz syndrome). They maintain a registry to be used for international research. To be included in the registry and to receive information about possible study participation, please contact:

Susan J. Hayflick, M.D. or
Jason Coryell, M.S.
Oregon Health & Science University
3181 S.W. Sam Jackson Park Road, L103A
Portland, OR 97201-3098
(ph) (503) 494-4344
(fax) (503) 494-4411
e-mail: coryellj@ohsu.edu
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REVIEW ARTICLES
Hayflick SJ. First scientific workshop on Hallervorden-Spatz syndrome: executive summary. Pediatr Neurol. 2001;25:99-101.

Koeppen AH, Dickson AC. Iron in the Hallervorden-Spatz syndrome. Pediatr Neurol. 2001;25:148-55.

Swaiman KF, Hallervorden-Spatz syndrome. Pediatr Neurol. 2001;25:102-8.

Connor JR, Menzies SL, Burdo JR, et al., Iron and iron management proteins in neurobiology. 2001;25;148-55.

JOURNAL ARTICLES
Hayflick SJ, Penzien JM, Michl W, et al. Cranial MRI changes may precede symptoms in Hallervorden-Spatz syndrome. Pediatr Neurol. 2001;25:166-69.

Hayflick SJ, Westaway SK, Levinson B, et al. Pantothenate kinase associated neurodegeneration: clinical and radiolographic delineation, submitted 2002.

Ching KHL, Westaway SK, Levinson B et al. HARP syndrome is allelic with pantothenate kinase associated neurodegeneration; Neurology 2002; 58(11): 1673-1674

Senior K. New genes reveal major role for iron in neurodegeneration. Lancet. 2001;358:302.

Zhou B, Westaway SK, Levinson B, et al. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat Genet. 2001;28:345-49.

Dressler D, Wittstock M, Benecke R. Botulinum toxin for treatment of jaw opening dystonia in Hallervorden-Spatz syndrome. Eur Neurol. 2001;45:287-88.

Keegan MT, et al., Anesthetic management for two-stage computer-assisted, stereotactic thalamotomy in a child with Hallervorden-Spatz disease. J Neurosurg Anesthesiol. 2000;12:107-11.

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