458 GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS Interferons For use in multiple sclerosis, interferon beta-1a is in- jected into the muscle (intramuscular injection), and beta- 1b is injected just below the skin (subcutaneous injection). The injections are usually given every other day. The recommended dose for beta-1a and 1b is 0.03 mg and 0.25 mg, respectively. Initial doses of beta-1b should be far less (i.e., 0.0625 mg), with a gradual in- crease in dose over six weeks. Precautions Patients who have had seizures or who are at risk for a seizure should be closely monitored following the in- jection of interferon, as should those with heart disorders such as angina, congestive heart failure, or an irregular heartbeat. It is not known if interferon can be expressed in breast milk. Concerned mothers may opt to cease breast-feeding while receiving interferon therapy. Side effects Interferon beta 1-a and 1-b commonly produce flu- like symptoms, including fever, chills, sweating, muscle aches, and tiredness. These side effects tend to diminish with time. Menstrual cycle changes have also been docu- mented in a significant number of women. Far less commonly, interferon beta 1-a and 1-b can produce suicidal feelings in someone who is already clin- ically depressed. Death of cells around an injection site (necrosis) can occur, as can swelling and bruising. Aller- gic reactions are possible. The massive and sometimes fatal allergic reaction termed anaphylaxis occurs rarely. Other side effects include liver and thyroid malfunction, and altered blood chemistry (fewer platelets and red and white blood cells). Interactions As of December 2003, drug interaction studies have not been conducted. Resources BOOKS Lotze, M. T., R. M. Dallal, J. M. Kirkwood, and J. C. Flickinger. “Cutaneous Melanoma.” In Principles and Practice of Oncology, edited by V. T. DeVita, S. A. Rosenberg, and S. Hellmon. Philadelphia: Lippincott, 2001. PERIODICALS Aguilar, R. F. “Interferons in Neurology.” Rev Invest Clin 52, no. 6 (2000): 665–679. Polman, C. H., and B. M. J. Uitdehaag. “Drug Treatment of Multiple Sclerosis.” BMJ 321 (2000): 490–494. OTHER National Multiple Sclerosis Society. Interferons. National Multiple Sclerosis Society Sourcebook. December 28, 2003. (May 22, 2004). <http://www.nationalmssociety.org/ %5Csourcebook-Interferons.asp>. ORGANIZATIONS National Multiple Sclerosis Society. 733 Third Avenue, New York, NY 10017. (800) 344-4867. <http:// www.nationalmssociety.org>. Brian Douglas Hoyle, PhD Intestinal lipodystrophy see Whipple’s disease Intracranial cysts see Arachnoid cysts LetterI.qxd 10/1/04 11:06 AM Page 458 GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS 459 J ❙ Joubert syndrome Definition Joubert syndrome is a well-documented but rare auto- somal recessive disorder. The syndrome is characterized by partial or complete absence of the cerebellar vermis (the connective tissue between the two brain hemispheres), causing irregular breathing and severe muscle weakness. Other features of the syndrome include jerky eye move- ments, abnormal balance and walking, and mental handi- cap. Additionally, there may be minor birth defects of the face, hands, and feet. Description Marie Joubert (whose name is given to the condition) gave a detailed description of the syndrome in 1969. She wrote about four siblings (three brothers, one sister) in one family with abnormal breathing, jerky eye movements (nystagmus), poor mental development, and ataxia (stag- gering gait and imbalance). X-ray examination showed that a particular section of the brain, called the cerebellar vermis, was absent or not fully formed. This specific brain defect was confirmed on autopsy in one of these individ- uals. Her initial report also described a sporadic (non-in- herited) patient with similar findings, in addition to polydactyly. Another name for Joubert syndrome is Jou- bert-Bolthauser syndrome. Demographics Joubert syndrome affects both males and females, al- though more males (ratio of 2:1) have been reported with the condition. The reason why more males have the con- dition remains unknown. Joubert syndrome is found worldwide, with reports of individuals of French Canadian, Swedish, German, Swiss, Spanish, Dutch, Italian, Indian, Belgian, Laotian, Moroc- can, Algerian, Turkish, Japanese, and Portuguese origin. In all, more than 200 individuals have been described with Joubert syndrome. Causes and symptoms Although the underlying genetic cause remains un- known, there have been numerous instances of siblings (brothers and sisters) with Joubert syndrome. The parents were normal. A few families have also been seen where the parents were said to be closely related (i.e., may have shared the same altered gene within the family). For these reasons, Joubert syndrome is classified as an auto- somal recessive disorder. Autosomal means that both males and females can have the condition. Recessive means that both parents carry a single copy of the res- ponsible gene. Autosomal recessive disorders occur when a person inherits a particular pair of genes that do not work correctly. The chance that this would happen to children of carrier parents is 25% (one in four) for each pregnancy. It is known that the cerebellum and brain stem begin to form between the sixth and twelfth week of pregnancy. The birth defects seen in Joubert syndrome must occur during this crucial period of development. The cerebellum is the second largest part of the brain. It is located just below the cerebrum, and is partially cov- ered by it. The cerebellum consists of two hemispheres sep- arated by a central section called the vermis. The cerebellum is connected to the spinal cord through the brain stem. The cerebellum (and vermis) normally works to mon- itor and control movement of the limbs, trunk, head, and eyes. Signals are constantly received from the eyes, ears, muscles, joints, and tendons. Using these signals, the cere- bellum is able to compare what movement is actually hap- pening in the body with what is intended to happen, then send an appropriate signal back. The effect is to either in- crease or decrease the function of different muscle groups, making movement both accurate and smooth. In Joubert syndrome, the cerebellar vermis is either absent or incompletely formed. The brain stem is some- times quite small. The absence or abnormal function of LetterJ.qxd 10/1/04 11:06 AM Page 459 460 GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS Joubert syndrome KEY TERMS Apnea An irregular breathing pattern character- ized by abnormally long periods of the complete cessation of breathing. Ataxia A deficiency of muscular coordination, es- pecially when voluntary movements are attempted, such as grasping or walking. Cerebellum A portion of the brain consisting of two cerebellar hemispheres connected by a narrow vermis. The cerebellum is involved in control of skeletal muscles and plays an important role in the coordination of voluntary muscle movement. It in- terrelates with other areas of the brain to facilitate a variety of movements, including maintaining proper posture and balance, walking, running, and fine motor skills, such as writing, dressing, and eating. Iris The colored part of the eye, containing pig- ment and muscle cells that contract and dilate the pupil. Nystagmus Involuntary, rhythmic movement of the eye. Polydactyly The presence of extra fingers or toes. Retina The light-sensitive layer of tissue in the back of the eye that receives and transmits visual signals to the brain through the optic nerve. Vermis The central portion of the cerebellum, which divides the two hemispheres. It functions to monitor and control movement of the limbs, trunk, head, and eyes. these brain tissues causes problems in breathing and vi- sion, and severe delays in development. One characteristic feature of Joubert syndrome is the pattern of irregular breathing. The individuals’s breathing alternates between deep rapid breathing (almost like pant- ing) and periods of severe apnea (loss of breathing). This is usually noticeable at birth. The rate of respiration may increase more than three times that of normal (up to 200 breaths per minute) and the apnea may last up to 90 sec- onds. The rapid breathing occurs most often when the in- fant is awake, especially when they are aroused or excited. The apnea happens when the infants are awake or asleep. Such abnormal breathing can cause sudden death or coma, and requires that these infants be under intensive care. For unknown reasons, the breathing tends to improve with age, usually within the first year of life. Muscle movement of the eye is also affected in Jou- bert syndrome. It is common for the eyes to have a quick, jerky motion of the pupil, known as nystagmus. The retina (the tissue in the back of the eye that receives and trans- mits visual signals to the brain) may be abnormal. Some individuals (most often the males) may have a split in the tissue in the iris of the eye. Each of these problems will af- fect their vision, and eye surgery may not be beneficial. The central nervous system problem affects the larger muscles of the body as well, such as those for the arms and legs. Many of the infants will have severe mus- cle weakness and delays in development. They reach nor- mal developmental milestones, such as sitting or walking, much later than normal. For example, some may learn to sit without support around 19–20 months of age (normal is six to eight months). Most individuals are not able to take their first steps until age four or older. Their balance and coordination are also affected, which makes walking difficult. Many will have an unsteady gait, and find it dif- ficult to climb stairs or run, even as they get older. Cognitive (mental) delays are also a part of the syn- drome, although this can be variable. Most individuals with Joubert syndrome will have fairly significant learning impairment. Some individuals will have little or no speech. Others are able to learn words, and can talk with the aid of speech therapy. They do tend to have pleasant and sociable personalities, but problems in behavior can occur. These problems most often are in temperament, hy- peractivity, and aggressiveness. Careful examination of the face, especially in infancy, shows a characteristic appearance. They tend to have a large head, and a prominent forehead. The eyebrows look high, and rounded, and the upper eyelids may be droopy (ptosis). The mouth many times remains open, and looks oval shaped in appearance. The tongue may protrude out of the mouth, and rest on the lower lip. The tongue may also quiver slightly. These are all signs of the underlying brain abnormality and muscle weakness. Occasionally, the ears look low-set on the face. As they get older, the fea- tures of the face become less noticeable. Less common features of the syndrome include minor birth defects of the hands and feet. Some individuals with Joubert syndrome have extra fingers on each hand. The extra finger is usually on the pinky finger side (poly- dactyly). It may or may not include bone, and could just be a skin tag. A few of these patients will also have extra toes on their feet. Diagnosis The diagnosis of Joubert syndrome is made on the following features. First, there must be evidence of the cerebellar vermis either being absent or incompletely formed. This can be seen with a CT scan or MRI of the brain. Second, the physician should recognize that the in- LetterJ.qxd 10/1/04 11:06 AM Page 460 GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS 461 Joubert syndrome This child is diagnosed with Joubert syndrome. Common symptoms of this disorder include mental retardation, poor coordination, pendular eye movement, and abnormal breathing patterns. (Photo Researchers, Inc.) fant has both muscle weakness and delays in development. In addition, there may be irregular breathing and abnormal eye movements. Having four of these five criteria is enough to make the diagnosis of Joubert syndrome. Most individuals are diagnosed by one to three years of age. Treatment team A pediatric neurologist usually sees children with Joubert syndrome. Physical, occupational, and speech and language therapists are important members of the treat- ment team. Treatment During the first year of life, many of these infants re- quire a respiratory monitor for the irregular breathing. For the physical and mental delays, it becomes necessary to provide special assistance and anticipatory guidance. Speech, physical, and occupational therapy are needed throughout life. Prognosis The unusual pattern of breathing as newborns, espe- cially the episodes of apnea, can lead to sudden death or coma. A number of individuals with Joubert syndrome have died in the first three years of life. For most individ- uals, the irregular breathing becomes more normal after the first year. However, many continue to have apnea, and require medical care throughout their life. Although the true life span remains unknown, there are some individu- als with Joubert syndrome who are in their 30s. Resources ORGANIZATIONS Joubert Syndrome Foundation Corporation. c/o Stephanie Frazer, 384 Devon Drive, Mandeville, LA 70448. OTHER Alliance of Genetic Support Groups. <http://www.genetic alliance.org.htm>. Joubert Syndrome Foundation Corporation. <http:// www.joubertfoundation.com>. Kevin M. Sweet, MS, CGC Rosalyn Carson-DeWitt, MD LetterJ.qxd 10/1/04 11:06 AM Page 461 GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS 463 K ❙ Kennedy’s disease Definition Kennedy’s disease is a rare genetic neurodegenerative disorder that affects the motor neurons (cells that are im- portant for normal function of the brain and spinal cord). It is a progressive disorder that leads to increasing sever- ity of motor dysfunction and subsequent deterioration of muscle strength, muscle tone, and motor coordination. It was first described by the American physician William R. Kennedy in 1966. Description As Kennedy’s disease is a progressive neurodegener- ative disorder, affected individuals have physical, mental, and emotional impacts. Physically, the neurological de- generative process results in muscle weakness and even- tual muscle wasting that can affect the patient’s ability to walk or move. Kennedy’s disease is also called spinal bul- bar muscular atrophy, or SBMA, because both the spinal and bulbar neurons are affected. Demographics Kennedy’s Disease is inherited through the X chro- mosome, and since males only have one X chromosome inherited from their carrier mother, they are usually af- fected while females are usually carriers. Therefore, sons of carrier mothers will be affected and all her daughters have a 50% chance of being a carrier. Although affected males often have a low sperm count or are infertile, if they are capable of reproducing, all male children will be un- affected and all female children will be unaffected carriers. In some cases, women who are carriers also exhibit clini- cal symptoms, although they are generally less severe. Kennedy’s disease is a rare disease, with only one in 50,000 males affected and no particular pattern among various races or ethnic groups. Causes and symptoms Symptoms do not usually develop until between the second and fourth decades of life, although an earlier (and a later) age of onset have been documented. Symptoms initially are mild and include tremors while stretching hands, muscle cramps after exertion, and fasciculations (visible muscle twitches). Muscle weakness often devel- ops in the arms and legs, beginning usually in the shoul- der or midsection. It is most noticeable in the legs and the arms. Breathing, swallowing, and talking are func- tions that require bulbar muscles controlled by motor nerves that communicate with the brain. The effects of bulbar muscle dysfunction can be manifested by slurred speech and dysphagia (swallowing difficulties). In later stages, patients often develop aspiration pneumonia (pneumonia caused by food and fluids traveling down the bronchial tubes instead of the trachea due to poor ability to swallow). Kennedy’s disease is caused by a trinucleotide repeat expansion in the androgen receptor gene. This means that three letters in the DNA alphabet (cytosine-adenine-gua- nine, or CAG) that are normally repeated 10–36 times ex- pand to produce a larger repeat size of approximately a 40–62 repeated trinucleotide sequence. This sequence is unstable and can change from one generation to the next leading to further expansions. The specific mechanism ex- plaining how this trinucleotide repeat expansion (which leads to an increased length in the protein it encodes) causes the disease is unknown. Diagnosis Patients with Kennedy’s disease usually receive a de- finitive diagnosis in a clinical molecular genetics labora- tory. This requires DNA extraction from blood, followed by testing the gene that causes Kennedy’s disease for a mutation. Kennedy’s disease can be misdiagnosed as spinal muscular atrophy and Lou Gehrig’s disease due to similar symptoms displayed. LetterK.qxd 10/1/04 11:06 AM Page 463 464 GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS Klippel Feil syndrome Key Terms Dysphagia Difficulty swallowing. Fasciculations Fine muscle tremors. X-linked disorder A disorder resulting from a ge- netic mutation on the X chromosome. Usually, males, having only one X chromosome, are affected with X-linked disorders; females are usually carriers. Treatment team The treatment team caring for a patient with Kennedy’s disease includes a neurologist, physical ther- apists, occupational therapists, gastroenterologists, and ge- netic counselors. Treatment Although research efforts are underway, currently there is no treatment for Kennedy’s disease. Medical treat- ment is based on lessening the symptoms. Physical ther- apy is useful in reducing the side affects from the progressive muscle weakness. Recovery and rehabilitation In the absence of a cure, patients usually do not re- cover and the symptoms progress during their lifetime. Lifestyle changes may become necessary, especially late in the disease. These changes, in more severe cases, can include (but are not limited to) help eating, wheelchair ac- cess at home, and help with using the restroom and chang- ing clothes. Prognosis Kennedy’s disease is a neurodegenerative disorder that is slow in its progression. It is likely that individuals will become wheelchair bound during the later stages of the disease. Although individuals will have certain difficulties in motor function and may have special needs, the lifespan of affected individuals is not thought to be shortened. Special concerns Genetic counseling is important in this disorder since the presence of one affected offspring means that it is likely the disease gene was inherited and that there is a risk that there will be affected offspring in subsequent gener- ations. The possibility of infertility due to low sperm count should also be discussed during the counseling, especially in cases that develop early. Also, gynecomastia (enlarged breasts) in males due to reduced virilization can also have psychosocial consideration and need to be addressed. Erectile dysfunction and/or testicular atrophy may also af- fect males. Resources BOOKS Cooper, D. N., M. Krawczak, and S. E. Antonarakis. “The Nature and Mechanisms of Human Gene Mutation.” In The Metabolic and Molecular Basis of Inherited Disease, 7th ed. Edited by C. R. Scriver, A. L. Beaudet, W. S. Sly, and D. Valle. NY: McGraw-Hill, 1995. Icon Group Publications. The Official Parent’s Sourcebook on Spinal Muscular Atrophy: A Revised and Updated Directory for the Internet Age. San Diego: Icon Group International, 2002. Panzarino, Connie. Me in the Mirror. Seal Press, 1994. OTHER “NINDS Kennedy’s Disease Information Page.” National Institute of Neurological Disorders and Stroke. (April 24, 2004). <http://www.ninds.nih.gov/health_and_medical/ disorders/kennedy’s.htm>. “What Is Kennedy Disease?” Kennedy Disease Association. (April 24, 2004). <http://www.kennedysdisease.org/ about.html>. ORGANIZATIONS National Organization of Rare Disorders. PO Box 8923, New Fairfield, CT 06812-8925. (203) 746-6518 or (800) 999- 6673; Fax: (203) 746-6481. orphan@rarediseases.org. <http://www.rarediseases.org>. Kennedy’s Disease Association. PO Box 2050, Simi Valley, CA 93062-2050. (805) 577-9591. tswaite@ pacbell.net. <http://www.kennedysdisease.org/ about.html>. Bryan Richard Cobb, PhD Kinsbourne syndrome see Opsoclonus myoclonus ❙ Klippel Feil syndrome Definition Klippel Feil syndrome is a rare congenital (present at birth) disorder in which there is abnormal fusion of some of the cervical (neck) vertebrae. Description People with Klippel Feil syndrome are often identi- fied due to three major characteristics: a short neck, a low hairline, and restricted neck mobility due to the fused cer- vical vertebrae. Klippel Feil syndrome can occur as a lone defect, or in association with other abnormalities, includ- ing scoliosis (curved spine), spina bifida (a birth defect LetterK.qxd 10/1/04 11:06 AM Page 464 GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS 465 Klippel Feil syndrome 23 22 12 12 13 11 21 11 1 2 p q 23 24 22 21 1 2 Cohen syndrome Klippel Feil syndrome Hereditary spherocytosis Chromosome 8 MYC: Burkitt lymphoma LGS: Langer-Giedon syndrome WRN: Werner syndrome Klippel Feil syndrome, on chromosome 8. (Gale Group.) involving the spinal column and cord), cleft palate, and a variety of defects involving the ribs, urinary tract, kidneys, heart, muscles, brain, and skeleton. Facial defects and problems with hearing and breathing may also occur in Klippel Feil syndrome. Klippel Feil syndrome has been organized into three basic types. In type I, all of the cervical and upper thoracic vertebrae are fused together into one block. In type II, one or two pairs of cervical vertebrae are fused together. In type III, there is lower thoracic or lumbar fusion as well as cervical fusion. Demographics Although not a lot of data has been collected regard- ing how often Klippel Feil syndrome occurs, the informa- tion available suggests that the incidence of this condition ranges from about one in 42,400 births to about three in 700 births. Boys are slightly more likely than girls to have this condition (1.5:1). Causes and symptoms Klippel Feil syndrome is believed to occur during very early fetal development, when the cervical vertebrae do not segment normally. The exact mechanism that causes the defect is unkown. Although most cases of Klippel Feil syndrome occur spontaneously, there have been a few reports of Klippel Feil syndrome that showed a pattern of inheritance within a family. In some cases, maternal alcoholism and subse- quent fetal alcohol syndrome seems to be associated with Klippel Feil syndrome. Many individuals with Klippel Feil syndrome have no symptoms. Individuals who have more minimal degrees of fusion can live completely normally and partake in all ac- tivities. They may never become aware that they have any abnormality at all. Individuals with more severe degrees of fusion will be obviously impaired in terms of their neck mobility. Some individuals will suffer from torticollis or wry neck, a condition in which the neck muscles pull the neck to one side. If the spinal cord is constricted by the ab- normal vertebrae, neurological symptoms (weakness, numbness, tingling) may result. A full 30–40% of all individuals with Klippel Feil syndrome will have significant structural abnormalities of their urinary tract. These often lead to chronic kidney in- fections (pyelonephritis), and a high risk of kidney failure. Diagnosis Diagnosis is usually established through a variety of imaging techniques, such as plain x-ray films of the neck and spine, CT scan,orMRI. Other diagnostic studies should be done to uncover associated defects. For exam- ple, children diagnosed with Klippel Feil syndrome should have a thorough hearing screening performed, due to the high risk of associated hearing problems. The cardiovas- cular system and the kidneys and urinary tract may also re- quire evaluation. Treatment team The treatment team will depend on the degree of dis- ability brought on by the vertebral defects, and the pres- ence of any associated problems. In more mildly affected individuals, a pediatrician and orthopedic surgeon may collaborate to achieve a diagnosis. In more severely af- fected individuals, a neurologist or neurosurgeon may need to be involved as well. Depending on what other body systems are involved, a cardiologist, nephrologist, urologist, and orofacial surgeon may be consulted. An au- diologist can consult about hearing issues. A physical ther- apist and occupational therapist can be very helpful in helping with issues of mobility and ability to tend to ac- tivities of daily living. Treatment More mildly affected individuals will require no treat- ment. Other individuals may need surgery to improve cer- vical stability, correct scoliosis, and improve any LetterK.qxd 10/1/04 11:06 AM Page 465 466 GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS Krabbe disease Key Terms Cervical Referring to the neck. Cervical vertebrae are the first seven bones of the spine. Cleft palate A birth defect in which the roof of the mouth (palate) has an abnormal opening (cleft). Congenital A condition that is present at birth. Lumbar Referring to the lower back. There are five lumbar vertebrae. Spina bifida A birth defect in which there is an ab- normal opening of the spinal column. The disabil- ity caused by this opening depends on the degree of the opening, and whether there are associated ab- normalities of the development of the spinal cord and nerves. Thoracic Referring to the area of the torso com- monly called the chest. There are 12 thoracic ver- tebrae. Torticollis A condition in which the muscles of the neck are abnormally contracted, pulling the neck off to one side. Vertebrae The stacked bones of the spinal col- umn. There are seven cervical vertebrae, twelve thoracic vertebrae, five lumbar vertebrae, five sacral vertebrae (normally fused into the sacrum in adults), and four coccygeal vertebrae (normally fused into the coccyx in adults). constriction of the spinal cord. Depending on the degree of scoliosis, a brace may be helpful. Physical therapy can be very helpful in order to im- prove strength and mobility. Occupational therapy can help more severely restricted individuals learn how to best perform activities of daily living, despite the limitations of their condition. Prognosis The prognosis is excellent for very mildly affected people with Klippel Feil syndrome. With careful medical attention, the prognosis can be good for more severely af- fected individuals as well. Resources BOOKS Thompson, George H. “The Neck.” In Nelson Textbook of Pediatrics, edited by Richard E. Behrman, et al. Philadelphia: W.B. Saunders Company, 2004. Maertens, Paul, and Paul Richard Dyken. “Storage Diseases: Neuronal Ceroid-Lipofuscinoses, Lipidoses, Glycogenoses, and Leukodystrophies.” In Textbook of Clinical Neurology, edited by Christopher G. Goetz. Philadelphia: W.B. Saunders Company, 2003. Warner, William C. “Pediatric Cervical Spine” In Campbell’s Operative Orthopedics, edited by S. Terry Canale. St. Louis: Mosby Company, 2003. WEBSITES National Institute of Neurological Disorders and Stroke (NINDS). NINDS Klippel Feil Syndrome Information Page. May 6, 2003. <http://www.ninds.nih.gov/ health_and_medical/disorders/klippel_feil.htm>. Rosalyn Carson-DeWitt, MD ❙ Krabbe disease Definition Krabbe disease is an inherited enzyme deficiency that leads to the loss of myelin, the substance that wraps nerve cells and speeds cell communication. Most affected indi- viduals start to show symptoms before six months of age and have progressive loss of mental and motor function. Death occurs at an average age of 13 months. Other less common forms exist with onset in later childhood or adulthood. Description Myelin insulates and protects the nerves in the central and peripheral nervous system. It is essential for effi- cient nerve cell communication (signals) and body func- tions such as walking, talking, coordination, and thinking. As nerves grow, myelin is constantly being built, broken down, recycled, and rebuilt. Enzymes break down, or me- tabolize, fats, carbohydrates, and proteins in the body in- cluding the components of myelin. Individuals with Krabbe disease are lacking the en- zyme galactosylceramidase (GALC), which metabolizes a myelin fat component called galactosylceramide and its by-product, psychosine. Without GALC, these substances are not metabolized and accumulate in large globoid cells. For this reason, Krabbe disease is also called globoid cell leukodystrophy. Accumulation of galactosylceramide and psychosine is toxic and leads to the loss of myelin- producing cells and myelin itself. This results in impaired nerve function and the gradual loss of developmental skills such as walking and talking. Demographics Approximately one in every 100,000 infants born in the United States and Europe will develop Krabbe disease. A person with no family history of the condition has a one LetterK.qxd 10/1/04 11:06 AM Page 466 GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS 467 Krabbe disease 12 13 11 11 1 p q 21 32 31 13 12 22 23 24 1 3 2 Chromosome 14 PS1(AD3): Alzheimer’s disease Krabbe disease Krabbe disease, on chromosome 14. (Gale Group.) in 150 chance of being a carrier. Krabbe disease occurs in all countries and ethnic groups but no cases have been re- ported in the Ashkenazi Jewish population. A Druze com- munity in Northern Israel and two Moslem Arab villages near Jerusalem have an unusually high incidence of Krabbe disease. In these areas, about one person in every six is a carrier. Causes and symptoms Krabbe disease is an autosomal recessive disorder. Affected individuals have two nonfunctional copies of the GALC gene. Parents of an affected child are healthy car- riers and therefore have one normal GALC gene and one nonfunctional GALC gene. When both parents are carri- ers, each child has a 25% chance to inherit Krabbe disease, a 50% chance to be a carrier, and a 25% chance to have two normal GALC genes. The risk is the same for males and females. Brothers and sisters of an affected child with Krabbe disease have a 66% chance of being a carrier. The GALC gene is located on chromosome 14. Over 70 mutations (gene alterations) known to cause Krabbe disease have been identified. One specific GALC gene deletion accounts for 45% of disease-causing mutations in those with European ancestry and 35% of disease-causing mutations in those with Mexican ancestry. Ninety percent of individuals with Krabbe disease have the infantile type. These infants usually have normal development in the first few months of life. Before six months of age, they become irritable, stiff, and rigid. They may have trouble eating and may have seizures. Devel- opment regresses leading to loss of mental and muscle function. They also lose the ability to see and hear. In the end stages, these children usually cannot move, talk, or eat without a feeding tube. Ten percent of individuals with Krabbe disease have juvenile or adult type. Children with juvenile type begin having symptoms between three and ten years of age. They gradually lose the ability to walk and think. They may also have paralysis and vision loss. Their symptoms usually progress slower than in the infantile type. Adult Krabbe disease has onset at any time after age 10. Symp- toms are more general including weakness, difficulty walking, vision loss, and diminished mental abilities. Diagnosis There are many tests that can be performed on an in- dividual with symptoms of Krabbe disease. The most spe- cific test is done by measuring the level of GALC enzyme activity in blood cells or skin cells. A person with Krabbe disease has GALC activity levels that are zero to 5% of the normal amount. Individuals with later onset Krabbe disease may have more variable GALC activity levels. This testing is done in specialized laboratories that have experience with this disease. The fluid of the brain and spinal cord (cerebrospinal fluid) can also be tested to measure the amount of protein. This fluid usually contains very little protein but the pro- tein level is elevated in infantile Krabbe disease. Nerve- conduction velocity tests can be performed to measure the speed at which the nerve cells transmit their signals. Indi- viduals with Krabbe disease will have slowed nerve con- duction. Brain imaging studies such as computed tomography (CT scan) and magnetic resonance imag- ing (MRI) are used to get pictures from inside the brain. These pictures will show loss of myelin in individuals with Krabbe disease. DNA testing for GALC mutations is not generally used to make a diagnosis in someone with symptoms but it can be performed after diagnosis. If an affected person has identifiable known mutations, other family members can be offered DNA testing to find out if they are carriers. This is helpful since the GALC enzyme test is not always accurate in identifying healthy carriers of Krabbe disease. If an unborn baby is at risk to inherit Krabbe disease, prenatal diagnosis is available. Fetal tissue can be obtained through chorionic villus sampling (CVS) or amniocente- sis. Cells obtained from either procedure can be used to measure GALC enzyme activity levels. If both parents have identified known GALC gene mutations, DNA test- ing can also be performed on the fetal cells to determine if the fetus inherited one, two, or no GALC gene mutations. LetterK.qxd 10/1/04 11:06 AM Page 467 468 GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS Kuru Key Terms Globoid cells Large cells containing excess toxic metabolic “waste” of galactosylceramide and psy- chosine. Motor function The ability to produce body movement by complex interaction of the brain, nerves, and muscles. Mutation A permanent change in the genetic ma- terial that may alter a trait or characteristic of an in- dividual, or manifest as disease, and can be transmitted to offspring. Some centers offer preimplantation diagnosis if both parents have known GALC gene mutations. In-vitro fer- tilization (IVF) is used to create embryos in the laboratory. DNA testing is performed on one or two cells taken from the early embryo. Only embryos that did not inherit Krabbe disease are implanted into the mother’s womb. This is an option for parents who want a biological child but do not wish to face the possibility of terminating an af- fected pregnancy. Treatment team The treatment team for a child with Krabbe disease should include a neurologist, general surgeon to place cer- tain types of feeding tubes, and a hematologist if bone mar- row or stem cell transplants are being considered. Physical and occupational therapists can help plan for daily care of the child and provide exercises to decrease muscle rigidity. Treatment Once a child with infantile Krabbe disease starts to show symptoms, there is little effective treatment. Sup- portive care can be given to keep the child as comfortable as possible and to counteract the rigid muscle tone. Med- ications can be given to control seizures. When a child can no longer eat normally, feeding tubes can be placed to pro- vide nourishment. Affected children who are diagnosed before develop- ing symptoms (such as through prenatal diagnosis) can un- dergo bone marrow transplant or stem cell transplant. The goal of these procedures is to destroy the bone marrow which produces the blood and immune system cells. After the destruction of the bone marrow, cells from a healthy donor are injected. If successful, the healthy cells travel to the bone marrow and reproduce. Some children have received these transplants and had a slowing of their symp- tom’s progression or even improvement of their symptoms. However, these procedures are not always successful and research is being done in order to reduce complications. Scientists are also researching gene therapy for Krabbe disease. This involves introducing a normal GALC gene into the cells of the affected child. The goal is for the cells to integrate the new GALC gene into its DNA and copy it, producing functional GALC enzyme. This is still in research stages and is not being performed clinically. Prognosis Prognosis for infantile and juvenile Krabbe disease is very poor. Individuals with infantile type usually die at an average age of 13 months. Death usually occurs within a year after the child shows symptoms and is diagnosed. Children with juvenile type may survive longer after di- agnosis but death usually occurs within a few years. Adult Krabbe disease is more variable and difficult to predict but death usually occurs two to seven years after diagnosis. Resources BOOKS Wenger, D. A., et al. “Krabbe Disease: Genetic Aspects and Progress Toward Therapy.” Molecular Genetics and Metabolism 70 (2000): 1-9. ORGANIZATIONS Hunter’s Hope Foundation. PO Box 643, Orchard Park, NY 14127. (877) 984-HOPE. Fax: (716) 667-1212. <http://www.huntershope.org>. United Leukodystrophy Foundation. 2304 Highland Dr., Sycamore, IL 60178. (815) 895-3211 or (800) 728-5483. Fax: (815) 895-2432. <http://www. ulf.org>. WEBSITES Wenger, David A. “Krabbe Disease.” GeneClinics. <http:// www.geneclinics.org/profiles/krabbe/details.html>. Amie Stanley, MS Rosalyn Carson-DeWitt, MD Kugelberg-Welander disease see Spinal muscular atrophy ❙ Kuru Definition Kuru is the name of a progressively disabling and ul- timately fatal brain infection caused by a unique protein particle called a prion. LetterK.qxd 10/1/04 11:06 AM Page 468 [...]... Lesch-Nyhan Disease Association 11 4 Winchester Way, Shamong, NJ 0808 8-9 398 ( 215 ) 6774206 Lesch-Nyhan Syndrome Registry New York University School of Medicine, Department of Psychiatry, 550 First Ave., New York, NY 10 012 ( 212 ) 26 3-6 458 National Organization for Rare Disorders (NORD) PO Box 8923, New Fairfield, CT 06 812 -8 923 (203) 74 6-6 518 or (800) 99 9-6 673 Fax: (203) 74 6-6 4 81 ... Baltimore, MD 212 05 88 8-5 5 4-2 080 MLD Foundation 213 45 Miles Drive, West Linn, OR 9706 8-2 878 80 0- 617 -8 387; Fax: 50 3- 212 - 015 9 National Tay-Sachs and Allied Diseases Association, Inc 20 01 Beacon Street, Boston, MA 0 213 5 80 0-9 0 6-8 723 NIH/NINDS Brain Resources and Information Network PO Box 58 01, Bethesda, MD 20824 80 0-3 5 2-9 424... develop inflammation of the joints (gout) as they get older Causes and symptoms ORGANIZATIONS Lennox-Gastaut Syndrome Group 3872 Lyceum Avenue, Los Angeles, CA 90066 ( 310 ) 3 9 1- 0335; Fax: ( 310 ) 3972687 CandaceLGS@aol.com Epilepsy Foundation 43 51 Garden City Drive, Suite 500, Landover, MD 2078 5-7 223 (3 01) 45 9-3 700 or (800) EFA -1 0 00 (332 -1 0 00); Fax: (3 01) 57 7-2 684 postmaster@ efa.org ... age Sand-like crystals of uric acid in the diapers may be one of the first symptoms of the disease The baby may be unusually irritable Typically, the first sign of nervous system impairment is the inability to lift their GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS 485 Lesch-Nyhan syndrome with safety concerns, children with LGS are often dependent for personal care such as toileting, management of behavioral... abnormalities in the body at a distance from the actual site of the malignancy) In the case of Lambert-Eaton myasthenic syndrome, it is thought that the immune system produces immune cells in response to the presence of early cancer cells These immune cells cross-react with the calcium channels on nerve cells, resulting in the symptoms of Lambert-Eaton myasthenic syndrome Demographics Lambert-Eaton myasthenic... North America 20, no 2 (June 2002) Spivak, Jeffery M “Degenerative Lumbar Spinal Stenosis.” The Journal of Bone and Joint Surgery 80-A:7 (July 19 98) GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS The American Back Society 2647 International Boulevard, Suite 4 01, Oakland, CA 946 01 ( 510 ) 53 6-9 929; Fax: ( 510 ) 536 -1 8 12 info@americanbacksoc.org Laith Farid Gulli, MD Robert Ramirez,... Pryse-Phillips.“Infectious diseases of the nervous system.” Noble: Textbook of Primary 470 Sy, Man-Sun, Pierluigi Gambetti, and Wong Boon-Seng “Human Prion Diseases” Medical Clinics of North America 86 (May 2002) 5 51 5 71 WEBSITES National Institute of Neurological Disorders and Stroke (NINDS) Kuru Fact Sheet Bethesda, MD: NINDS, 2003 Rosalyn Carson-DeWitt, MD GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS. .. diagnosis A board-certified geneticist is most likely to make the correct diagnosis, using the fewest tests in the least amount of time Levetiracetam Schiffmann, Raphael and Marjo S van der Knaap The latest on leukodystrophies.” Current Opinions in Neurology 17 (April 2004): 18 7 -1 9 2 ORGANIZATIONS Association for Neuro-Metabolic Disorders 5223 Brookfield Lane, Sylvania, OH 43560 -1 8 09 419 -8 85 -1 4 97 Kennedy... the involved nerve root To expose the nerve root(s), the surgeon removes the ligament joining the vertebrae along all or part of the lamina The nerve root is pulled back toward the center of the spinal column, and all or part of the disc is removed Muscle is placed to protect the nerve root(s) and the incision is closed In-home recovery Preparation Weeks before surgery, the surgeon (a neurosurgeon or... two to three years of the onset of their initial symptoms of LambertEaton myasthenic syndrome Other types of cancer associated with Lambert-Eaton myasthenic syndrome include non-small-cell lung cancer; lymphosarcoma; malignant thymoma; and carcinoma of the breast, stomach, colon, prostate, bladder, kidney, or gallbladder Because of the strong connection between LambertEaton myasthenic syndrome and . birth defect LetterK.qxd 10 /1/ 04 11 :06 AM Page 464 GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS 465 Klippel Feil syndrome 23 22 12 12 13 11 21 11 1 2 p q 23 24 22 21 1 2 Cohen syndrome Klippel. ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS 467 Krabbe disease 12 13 11 11 1 p q 21 32 31 13 12 22 23 24 1 3 2 Chromosome 14 PS1(AD3): Alzheimer’s disease Krabbe disease Krabbe disease, on chromosome 14 . (Gale. MD LetterK.qxd 10 /1/ 04 11 :06 AM Page 470 GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS 4 71 L ❙ Lambert-Eaton myasthenic syndrome Definition Lambert-Eaton myasthenic syndrome is an autoim- mune disease