GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS 547 Movement disorders Key Terms Botulinum toxin Any of a group of potent bacterial toxins or poisons produced by different strains of the bacterium Clostridium botulinum. The toxins cause muscle paralysis, and thus force the relaxation of a muscle in spasm. Cerebral palsy A movement disorder caused by a permanent brain defect or injury present at birth or shortly after. It is frequently associated with prema- ture birth. Cerebral palsy is not progressive. Computed tomography (CT) An imaging technique in which cross-sectional x rays of the body are com- piled to create a three-dimensional image of the body’s internal structures. Encephalopathy An abnormality in the structure or function of tissues of the brain. Essential tremor An uncontrollable (involuntary) shaking of the hands, head, and face. Also called fa- milial tremor because it is sometimes inherited, it can begin in the teens or in middle age. The exact cause is not known. Fetal tissue transplantation A method of treating Parkinson’s and other neurological diseases by graft- ing brain cells from human fetuses onto the basal ganglia. Human adults cannot grow new brain cells but developing fetuses can. Grafting fetal tissue stim- ulates the growth of new brain cells in affected adult brains. Hereditary ataxia One of a group of hereditary de- generative diseases of the spinal cord or cerebellum. These diseases cause tremor, spasm, and wasting of muscle. Huntington’s disease A rare hereditary condition that causes progressive chorea (jerky muscle move- ments) and mental deterioration that ends in de- mentia. Huntington’s symptoms usually appear in patients in their 40s. There is no effective treatment. Levodopa (L-dopa) A substance used in the treat- ment of Parkinson’s disease. Levodopa can cross the blood-brain barrier that protects the brain. Once in the brain, it is converted to dopamine and thus can replace the dopamine lost in Parkinson’s disease. Magnetic resonance imaging (MRI) An imaging technique that uses a large circular magnet and radio waves to generate signals from atoms in the body. These signals are used to construct images of internal structures. Parkinson’s disease A slowly progressive disease that destroys nerve cells in the basal ganglia and thus causes loss of dopamine, a chemical that aids in transmission of nerve signals (neurotransmitter). Parkinson’s is characterized by shaking in resting muscles, a stooping posture, slurred speech, muscu- lar stiffness, and weakness. Positron emission tomography (PET) A diagnostic technique in which computer-assisted x rays are used to track a radioactive substance inside a patient’s body. PET can be used to study the biochemical ac- tivity of the brain. Progressive supranuclear palsy A rare disease that gradually destroys nerve cells in the parts of the brain that control eye movements, breathing, and muscle coordination. The loss of nerve cells causes palsy, or paralysis, that slowly gets worse as the disease pro- gresses. The palsy affects ability to move the eyes, relax the muscles, and control balance. Restless legs syndrome A condition that causes an annoying feeling of tiredness, uneasiness, and itching deep within the muscle of the leg. It is accompanied by twitching and sometimes pain. The only relief is in walking or moving the legs. Tourette syndrome An abnormal condition that causes uncontrollable facial grimaces and tics and arm and shoulder movements. Tourette syndrome is perhaps best known for uncontrollable vocal tics that include grunts, shouts, and use of obscene language (coprolalia). Wilson’s disease An inborn defect of copper me- tabolism in which free copper may be deposited in a variety of areas of the body. Deposits in the brain can cause tremor and other symptoms of Parkinson’s disease. progress, “sculpting” the barrage of voluntary commands into a tightly controlled, constantly evolving pattern. Cere- bellar disorders cause inability to control the force, fine positioning, and speed of movements (ataxia). Disorders of the cerebellum may also impair the ability to judge dis- tance so that a person under- or overreaches the target (dysmetria). Tremor during voluntary movements can also result from cerebellar damage. LetterM.qxd 10/1/04 11:07 AM Page 547 548 GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS Movement disorders THE BASAL GANGLIA Both the cerebellum and the motor cortex send information to a set of structures deep within the brain that help control involuntary components of movement (basal ganglia). The basal ganglia send out- put messages to the motor cortex, helping to initiate move- ments, regulate repetitive or patterned movements, and control muscle tone. Circuits within the basal ganglia are complex. Within this structure, some groups of cells begin the action of other basal ganglia components and some groups of cells block the action. These complicated feedback circuits are not entirely understood. Disruptions of these circuits are known to cause several distinct movement disorders. A portion of the basal ganglia called the substantia nigra sends electrical signals that block output from another structure called the subthalamic nucleus. The subthalamic nucleus sends signals to the globus pallidus, which in turn blocks the thalamic nuclei. Finally, the thalamic nuclei send signals to the motor cortex. The substantia nigra, then, begins movement and the globus pallidus blocks it. This complicated circuit can be disrupted at several points. For instance, loss of substantia nigra cells, as in Parkinson’s disease, increases blocking of the thalamic nu- clei, preventing them from sending signals to the motor cortex. The result is a loss of movement (motor activity), a characteristic of Parkinson’s. In contrast, cell loss in early Huntington’s disease de- creases blocking of signals from the thalamic nuclei, caus- ing more cortex stimulation and stronger but uncontrolled movements. Disruptions in other portions of the basal ganglia are thought to cause tics, tremors,dystonia, and a variety of other movement disorders, although the exact mechanisms are not well understood. Some movement disorders, including Huntington’s disease and inherited ataxias, are caused by inherited ge- netic defects. Some diseases that cause sustained muscle contraction limited to a particular muscle group (focal dys- tonia) are inherited, but others are caused by trauma. The cause of most cases of Parkinson’s disease is unknown, al- though genes have been found for some familial forms. Symptoms Abnormal movements are broadly classified as either hyperkinetic—too much movement—and hypokinetic— too little movement. Hyperkinetic movements include: • Dystonia: sustained muscle contractions, often causing twisting or repetitive movements and abnormal postures. Dystonia may be limited to one area (focal) or may affect the whole body (general). Focal dystonias may affect the neck (cervical dystonia or torticollis), the face (one-sided or hemifacial spasm, contraction of the eyelid or ble- pharospasm, contraction of the mouth and jaw or oro- mandibular dystonia, simultaneous spasm of the chin and eyelid or Meige syndrome), the vocal cords (laryngeal dystonia), or the arms and legs (writer’s cramp, occupa- tional cramps). Dystonia may be painful as well as inca- pacitating. •Tremor: uncontrollable (involuntary) shaking of a body part. Tremor may occur only when muscles are relaxed or it may occur only during an action or holding an ac- tive posture. •Tics: involuntary, rapid, nonrhythmic movement or sound. Tics can be controlled briefly. • Myoclonus:a sudden, shock-like muscle contraction. Myoclonic jerks may occur singly or repetitively. Unlike tics, myoclonus cannot be controlled even briefly. • Chorea: rapid, nonrhythmic, usually jerky movements, most often in the arms and legs. • Ballism: like chorea, but the movements are much larger, more explosive and involve more of the arm or leg. This condition, also called ballismus, can occur on both sides of the body or on one side only (hemiballismus). • Akathisia: restlessness and a desire to move to relieve uncomfortable sensations. Sensations may include a feel- ing of crawling, itching, stretching, or creeping, usually in the legs. • Athetosis. slow, writhing, continuous, uncontrollable movement of the arms and legs. Hypokinetic movements include: •Bradykinesia: slowness of movement. •Freezing: inability to begin a movement or involuntary stopping of a movement before it is completed. • Rigidity: an increase in muscle tension when an arm or leg is moved by an outside force. • Postural instability: loss of ability to maintain upright posture caused by slow or absent righting reflexes. Diagnosis Diagnosis of movement disorders requires a careful medical history and a thorough physical and neurological examination. Brain imaging studies are usually performed. Imaging techniques include computed tomography scan (CT scan), positron emission tomography (PET),or magnetic resonance imaging (MRI) scans. Routine blood and urine analyses are performed. A lumbar punc- ture (spinal tap) may be necessary. Video recording of the abnormal movement is often used to analyze movement patterns and to track progress of the disorder and its treat- ment. Genetic testing is available for some forms of move- ment disorders. LetterM.qxd 10/1/04 11:07 AM Page 548 GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS 549 Moyamoya disease Treatment Treatment of a movement disorder begins with deter- mining its cause. Physical and occupational therapy may help make up for lost control and strength. Drug therapy can help compensate for some imbalances of the basal ganglionic circuit. For instance, levodopa (L-dopa) or re- lated compounds can substitute for lost dopamine-pro- ducing cells in Parkinson’s disease. Conversely, blocking normal dopamine action is a possible treatment in some hyperkinetic disorders, including tics. Oral medications can also help reduce overall muscle tone. Local injections of botulinum toxin can selectively weaken overactive muscles in dystonia and spasticity. Destruction of periph- eral nerves through injection of phenol can reduce spas- ticity. All of these treatments may have some side effects. Surgical destruction or inactivation of basal gan- glionic circuits has proven effective for Parkinson’s dis- ease and is being tested for other movement disorders. Transplantation of fetal cells into the basal ganglia has produced mixed results in Parkinson’s disease. There are several alternative therapies that can be use- ful when treating movement disorders. The progress made will depend on the individual and his/her condition. Among the therapies that may be helpful are acupunc- ture, homeopathy, touch therapies, postural alignment therapies, and biofeedback. Prognosis The prognosis for a patient with a movement disorder depends on the specific disorder. Resources BOOKS Martini, Frederic. Fundamentals of Anatomy and Physiology. Englewood Cliffs, NJ: Prentice Hall, 1989. Watts, Ray L., and William C. Koller, eds. Movement Disorders: Neurologic Principles and Practice. New York: McGraw-Hill, 1997. ORGANIZATIONS Worldwide Education and Awareness for Movement Disorders. One Gustave L. Levy Place, Box 1052, New York, NY 10029. (800) 437-6683. <http://www.wemove.org>. Richard Robinson ❙ Moyamoya disease Definition Moyamoya disease is a rare disorder of blood vessels in the brain known as internal carotid arteries (ICA). The condition is characterized by stenosis (narrowing) or oc- clusion (blockage) of one or both ICA with subsequent formation of an abnormal network of blood vessels adja- cent to the ICA. Description Moyamoya disease was first described in Japan in 1955. The term moyamoya,a Japanese word that means “puff of smoke,” describes the appearance of the abnormal vessels that form adjacent to the internal carotid arteries. Alternate names for the disorder include spontaneous oc- clusion of the circle of Willis, and basal occlusive disease with telangiectasia. Moyamoya disease can occur in children (juvenile type) or in adults (adult type). Children tend to be less than age 10 and adults are usually between ages 30 and 49. Af- fected individuals typically present with signs of stroke or other types of cerebral ischemia (decreased blood flow to an area of the brain due to obstruction in an artery), cere- bral hemorrhage (bleeding), or seizures (mainly in chil- dren). Symptoms in an affected child or adult may include disturbed consciousness, speech deficits, sensory and cog- nitive impairment, involuntary movements, or vision prob- lems. Options for treatment for people with moyamoya disease consist of medications and brain surgery. Without treatment, repeated strokes, transient ischemic attacks, brain hemorrhages, or seizures can lead to serious cogni- tive impairment, physical disability, or death. Demographics Moyamoya disease occurs worldwide and is most prevalent in Asia, and especially in Japan. According to a report in 1998, more than 6000 cases had been described. The disease occurs in about one in a million people per year. Estimates of disease incidence in Japan are as much as ten times greater. Slightly more females than males are affected. The male-to-female ratio has been reported to be around 2:3. Approximately 10% of cases of moyamoya disease are familial. Causes and symptoms The cause of moyamoya disease is unknown. Possible explanations for the disorder include injuries to the brain, infection, multifactorial inheritance, genetic factors, or other causes. For example, moyamoya disease has been associated with meningitis, radiation therapy to the skull in children, and genetic conditions such as Down syn- drome, neurofibromatosis, and sickle cell anemia. Also, there have been reports linking a region on chromosome 3 (named MYM1) and a region on chromosome 17 (named MYM2) to moyamoya disease in some families. The initial symptoms of moyamoya disease are some- what different in children and adults. In children, there is ischemia due to stenosis and occlusion of the circle of LetterM.qxd 10/1/04 11:07 AM Page 549 550 GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS Moyamoya disease Key Terms Stroke Interruption of blood flow to a part of the brain with consequent brain damage. A stroke may be caused by a blood clot or by hemorrhage due to a burst blood vessel. Also known as a cerebrovas- cular accident. Transient ischemic attacks A brief interruption of the blood supply to part of the brain that causes a temporary impairment of vision, speech, or move- ment. Usually, the episode lasts for just a few mo- ments, but it may be a warning sign for a full-scale stroke. Willis, a ring of arteries at the base of the brain. In chil- dren, the disease tends to cause repeated “mini-strokes” known as transient ischemic attacks (TIAs) or, less often, seizures. The TIAs usually manifest as weakness of one side of the body (hemiparesis), speech disturbances, and sensory deficits. TIAs may be made worse by hyperventi- lation, such as with intense crying. Involuntary movements may occur. Mental retardation may be present. Adults with moyamoya disease typically present with bleeding in the brain (cerebral hemorrhage) or strokes. Cerebral hemorrhage occurs as a result of breakdown of the coexisting blood vessels that formed earlier in life due to stenosis or occlusion of the ICA. The cerebral hemor- rhages are commonly located in the thalamus, basal gan- glia, or deep white matter of the brain. Symptoms can include disturbance of consciousness and/or hemiparesis. Adult patients with moyamoya disease may go on to have further hemorrhages and strokes which can result in sig- nificant and irreversible brain damage. Diagnosis A diagnosis of moyamoya disease is based on find- ings from neuroradiologic studies and on clinical signs consistent with this diagnosis. Neuroradiologic studies used to establish the diagnosis of moyamoya disease in- clude cerebral angiography, magnetic resonance im- aging (MRI),magnetic resonance angiography (MRA), and computed tomography (CT) scan. Cerebral angiogra- phy is the most common means of confirming a diagnosis of moyamoya disease. There are reports indicating that MRI and MRA, which are less invasive procedures, may be used instead of cerebral angiography. CT scan findings tend to be non-specific and not as useful as CA, MRI, and MRA in making the diagnosis. Characteristic brain findings in moyamoya disease include narrowing or occlusion of the end portion of one or both internal carotid arteries, an abnormal network or blood vessels at the base of the brain, and presence of these findings on both sides of the brain. In about 10% of cases, cerebral aneurysms may also be found. Nuclear medicine studies such as Xenon-enhanced CT, posi- tron emission tomography (PET),orsingle photon emission computed tomography (SPECT) may be per- formed in order to evaluate cerebral blood flow (CBF) patterns. The information obtained from CBF studies helps the neurologist and/or neurosurgeon to devise a treatment plan. Treatment There is no cure for moyamoya disease. Early treat- ment is important to avoid mental and physical impair- ment. Treatment options include medications and surgical revascularization. Medications. Individuals having TIAs and stroke may be given antiplatelet drugs, vasodilators, or anticoagulants to help prevent future attacks. Steroid therapy may be prescribed for a person who has involuntary movements. For a patient with a cerebral hemorrhage, treatment may include management of hypertension, if present. Surgery. The purpose of revascularization surgery in moyamoya disease is to augment or redirect blood flow in the brain. Surgical revascularization has been reported to improve cerebral blood flow, to reduce ischemic attacks, and, in children, to increase IQ. The optimal method of surgery depends on the patient’s history and clinical status. There are various direct and indirect methods of restoring blood supply in the brain. Examples of direct bypass sur- gery include techniques known as superficial temporal artery to middle cerebral artery bypass, and extracranial- intracranial bypass to anterior or posterior cerebral artery. Examples of indirect bypass surgery include techniques known as encephaloduroarteriosynangiosis, encephalo- myosynangiosis, and encephaloarteriosynangiosis. Treatment team Management of moyamoya disease requires a multi- disciplinary approach. In addition to the patient’s primary health care professionals, medical professionals involved in the care of patients with moyamoya disease generally include specialists in neurology, neurosurgery, neuroradi- ology, and anesthesiology. Specialists in orthopedic sur- gery, ophthalmology, rehabilitation, physical therapy, occupational therapy, speech therapy, and mental health may also be involved in the care of affected individuals. Psychological counseling and contact with other affected LetterM.qxd 10/1/04 11:07 AM Page 550 GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS 551 Mucopolysaccharidoses patients may assist families in coping with this condition, especially given it’s rarity. Recovery and rehabilitation The potential for rehabilitation in moyamoya disease depends in part on the degree of impairment caused by complications such as strokes, cerebral hemorrhages, and seizures. Interventions such as physical, occupational, and speech therapy may be recommended for management of problems such as hemiparesis, speech problems, and sen- sory deficits. Some patients may require assistance with daily living. In cases in which there is significant disabil- ity, consideration may be given to in-home nursing care or placement in a residential care facility that can provide 24- hour care and support services. Clinical trials As of 2004, there were no clinical trials specifically for patients with moyamoya disease. As more is learned about the causes of moyamoya disease, it is hoped that novel therapies may be developed in the future. As of 2004, one laboratory listed on the GeneTests web site (www. genetests.org) was conducting genetic research on moya- moya disease. Interested patients may discuss the feasibil- ity of participating in this research with their physician. Prognosis As of 2004, the prognosis for moyamoya disease was not well defined. The prognosis depends in part on the ex- tent of brain injury present at the time of diagnosis and the success of treatment. For example, a person who had a major stroke or cerebral hemorrhage may already be per- manently impaired, both physically and mentally. Reports of clinical outcome after treatment are mixed. Some indi- viduals experience improvement of symptoms while oth- ers continue to show progressive decline. Moyamoya disease tends to be more progressive in children than in adults. In those patients who don’t stabilize clinically, sig- nificant disability or death may occur. Special concerns Children with moyamoya disease may have learning disabilities or mental retardation. They may also experi- ence physical disabilities that impact academic perform- ance. Such children may be eligible to have an Individual Education Plan (IEP). An IEP provides a framework from which administrators, teachers, and parents can meet the educational needs of a child with special learning needs. Depending upon severity of symptoms and the degree of learning difficulties, some children with moyamoya dis- ease may be best served by special education classes or a private educational setting. Resources BOOKS Ikezaki, Kiyonobu and Christopher M. Loftus, eds. Moyamoya Disease. Rolling Meadows, IL: American Association of Neurological Surgeons, 2001. Parker, James N., and Philip M. Parker, eds. The Official Parent’s Sourcebook on Moyamoya Disease: A Revised and Updated Directory for the Internet Age. San Diego, CA: ICON Health Publications, 2002. PERIODICALS Ikezaki, K. “Rational approach to treatment of moyamoya dis- ease in childhood.” Journal of Child Neurology 15 (November 2000): 350–6. Kobayashi, E., N. Saeki, H. Oishi, S. Hirai, and A. Yamaura. “Long-term natural history of hemorrhagic moyamoya disease in 42 patients.” Journal of Neurosurgery 93 (December 2000): 976–80. Lamphere, K. “Moyamoya disease. An uncommon cause of stroke in the young.” Adv Nurse Pract 11 (2003): 63–6. Shetty-Alva, N., and S. Alva. “Familial moyamoya disease in Caucasians.” Pediatric Neurology 23 (November 2000): 445–7. Yonekawa, Y., and N. Kahn. “Moyamoya disese.” Advances in Neurology 92 (2003): 113–118. WEBSITES The National Institute of Neurological Disorders and Stroke (NINDS). Moyamoya Disease Information Page. <http://www.ninds.nih.gov/health_and_medical/ disorders/moyamoya.htm>. Online Mendelian Inheritance In Man (OMIM). Moyamoya Disease 1. <http://www.ncbi.nlm.nih.gov:80/entrez/ dispomim.cgi?id=252350htm>. ORGANIZATIONS Children’s Hemiplegia and Stroke Association (CHASA). 4101 West Green Oaks Blvd., PMB #149, Arlington, TX 76016. (817) 492-4325. info5@chasa.org. <http://www.hemikids.org>. Families with Moyamoya Support Network. 4900 McGowan Street SE, Cedar Rapids, IA 52403. National Stroke Association. 9707 East Easter Lane, Englewood, CO 80112-3747. (303) 649-9299 or 800- STROKES (787-6537); Fax: (303) 649-1328. info@stroke.org. <http://www.stroke.org>. Dawn J. Cardeiro, MS, CGC ❙ Mucopolysaccharidoses Definition The mucopolysaccharidoses (MPS) are a number of metabolic disorders that follow a chronic and progressive course and involve many body systems. LetterM.qxd 10/1/04 11:07 AM Page 551 552 GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS Mucopolysaccharidoses 14 15 16 13 12 11 11 12 13 2 1 HD: Huntington disease MPS: Mucopolysaccharidoses Achondroplasia RIEG: Rieger syndrome p q 25 27 31 33 34 35 32 28 24 26 23 22 21 3 1 LQT4: Long QT syndrome 4 alpha-synuclein: Parkinson’s disease Chromosome 4 EVC: Ellis-van Creveld Mucopolysaccharidoses, on chromosome 4. (Gale Group.) Description Though the symptoms and severity vary for each MPS disorder, common features include enlarged organs (organomegaly), dysostosis multiplex (abnormal bone for- mation), and a characteristic facial appearance. Hearing, vision, breathing, heart function, joint mobility, and men- tal capacity may also be affected. As of 2003, seven types of MPS have been classified. The MPS disorders are caused by absent or insufficient production of proteins known as lysosomal enzymes The specific enzyme that is deficient or absent distinguishes one type of MPS from an- other. However, before these enzymes were identified, the signs and symptoms expressed by an affected individual led to the diagnosis. The discovery of these enzymes re- sulted in a reclassification of some of the MPS disorders. These conditions are often referred to as MPS I, MPS II, MPS III, MPS IV, MPS VI, MPS VII, and MPS IX and may also referred to by their original names, which are Hurler (MPS I H), Hurler-Scheie (MPS I H/S), Scheie (MPS I S), Hunter (MPS II), Sanfilippo (MPS III), Morquio (MPS IV), Maroteaux-Lamy (MPS VI), Sly (MPS VII), and Hyaluronidase deficiency (MPS IX). Demographics The MPS syndromes are considered to be rare. San- filippo syndrome appears to be the most common MPS with a reported incidence of one in 70,000. The incidence of Hyaluronidase deficiency is not yet known. The inci- dence of the remaining six classes of MPS are estimated to be: one in 100,000 for Hurler syndrome; one in 500,000 for Scheie syndrome; one in 115,000 for Hurler/Scheie disease; one in 100,000 (male live births) for Hunter syn- drome (mild and severe combined); one in 100,000 to one in 300,000 for Morquio syndrome (types A and B in- cluded); one in 215,000 for Maroteaux-Lamy syndrome; and less than one in 250,000 for Sly syndrome. These fig- ures are general; more exact figures have been reported for individual MPS disorders in certain countries. Causes and symptoms All of the MPS are genetic conditions. MPS I, MPS III, MPS IV, MPS VI, MPS VII, and MPS IX are inherited in an autosomal recessive manner which means that af- fected individuals have two altered or non-functioning genes, one from each parent, for a specific enzyme that is needed to break down mucopolysaccharides. MPS II (Hunter syndrome) is inherited in an X-linked manner which means that the gene for MPS II is located on the X chromosome, one of the two sex chromosomes. Hunter syndrome primarily affects males because they have only one X chromosome and therefore lack a second, normal copy of the gene responsible for the condition. Carriers for the autosomal recessive forms of MPS have one normal copy and one non-working copy of the MPS gene in ques- tion. Female carriers of the X-linked MPS (MPS II) have one X chromosome with a normal gene for the condition (the IDS gene) and one X chromosome with a non-work- ing IDS gene. The enzymes that are deficient in the MPS disorders normally break down a type of mucopolysaccharide (a long chain of sugar molecules) in the body known as gly- cosaminoglycans (GAGs). Glycosaminoglycans are es- sential for building the bones, cartilage, skin, tendons, and other tissues in the body. Normally, the human body con- tinuously breaks down and builds GAGs. There are several enzymes involved in breaking down each GAG and a de- ficiency or absence of any of the essential enzymes can cause one or more GAGs to accumulate in the tissues and organs in the body. When too much GAG is stored, organs and tissues can be damaged or not function properly. The LetterM.qxd 10/1/04 11:07 AM Page 552 GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS 553 Mucopolysaccharidoses accumulating material is stored in cellular structures called lysosomes, and these disorders are also known as lysoso- mal storage diseases. MPS I Mutations in the alpha-L-iduronidase (IDUA) gene located on chromosome 4 cause the MPS I disorders (Hurler, Hurler-Scheie, and Scheie syndromes). Initially, these three disorders were believed to be separate because each was associated with different physical symptoms and prognoses. However, once the underlying cause of these conditions was identified, it was recognized that all three were variants of the same disorder. MPS I H (HURLER SYNDROME) Individuals with Hurler syndrome tend to have the most severe form of MPS I. Hurler syndrome may also be referred to as severe MPS I. Infants with Hurler syndrome appear normal at birth and typically begin to develop normally. Symptoms of Hurler syndrome are often evident within the first year or two after birth. Many of these infants may initially grow faster than expected, but their growth slows and typically stops by age three. Facial features also begin to appear coarse; affected children develop a short nose, flatter face, thicker skin, and a protruding tongue. Additionally, their heads become larger and they develop more hair on their bodies with the hair becoming coarser. Affected children with Hurler syndrome lose previously attained skills (milestones) and eventually suffer from profound mental retardation. Progressive abnormal development of all bones of the body (dysostosis multiplex) occurs in all chil- dren with Hurler syndrome. Children usually develop joint contractures (stiff joints), kyphosis (a “hunchback” curve of the spine), and broad hands with short fingers. Many of these children experience breathing difficulties, and res- piratory infections are common. Other common problems include heart valve dysfunction, cardiomyopathy (weak- ness of the heart muscle), hepatosplenomegaly (enlarged spleen and liver), clouding of the cornea, hearing loss, and carpal tunnel syndrome. Children with Hurler syndrome typically die within the first ten years of life. MPS I H/S (HURLER-SCHEIE SYNDROME) Hurler- Scheie syndrome is felt to be the intermediate form of MPS I, meaning that the symptoms are not as severe as those in individuals who have Hurler syndrome but not as mild as those with Scheie syndrome. Hurler-Scheie syndrome may also be referred to as intermediate MPS I. Individuals with Hurler-Scheie syndrome tend to be shorter than expected and may develop some of the physical features seen in Hurler syndrome, but usually they are not as severe. Intel- lectual ability varies; individuals have normal or near nor- mal intelligence. The prognosis for children with Hurler-Scheie syndrome is variable with some individuals dying during childhood and others living to adulthood. MPS I S (SCHEIE SYNDROME) Scheie syndrome is con- sidered the mild form of MPS I. Individuals with Scheie syndrome usually have normal intelligence, but there have been some reports of affected individuals developing psy- chiatric problems. Common physical problems include corneal clouding, heart abnormalities, and orthopedic dif- ficulties involving the hands and back. Individuals with Scheie syndrome do not develop the facial features seen with severe MPS I. Usually life span is normal. MPS II (Hunter syndrome) Mutations in the iduronate-2-sulphatase (IDS) gene cause both forms of MPS II (mild and severe). Nearly all individuals with Hunter syndrome are male, because the gene that causes the condition is located on the X chro- mosome. The severe form is associated with progressive mental retardation and physical disability, with most indi- viduals dying before age 15. Males with the mild form of Hunter syndrome usually have have normal or near normal intelligence. They tend to develop physical differences similar to males with the severe form, but not as quickly. Most males with Hunter syndrome develop joint stiffness, chronic diarrhea, enlarged liver and spleen, heart valve problems, hearing loss, kyphosis, and tend to be shorter than expected. Men with mild Hunter syndrome can have a normal life span and some have had children. MPS III (Sanfilippo syndrome) MPS III is a variable condition with symptoms be- ginning to appear between ages two and six years of age. The condition is characterized by developmental delay, be- havioral problems, and mild physical problems (as com- pared to other types of MPS). Specific problems include: seizures, sleeplessness, thick skin, joint contractures, en- larged tongues, cardiomyopathy, hyperactivity, and men- tal retardation. The life expectancy in MPS III is also variable. On average, individuals with MPS III live until adolescence. Initially, the diagnosis of MPS III, like the other MPS conditions, was clinical; the diagnosis was made by observation of certain physical characteristics. It was later discovered that a deficiency in one of four en- zymes could lead to the developmental delay and physical symptoms associated with MPS III. Each type of MPS III is now subdivided into four groups, labeled A-D, accord- ing to the specific enzyme deficiency. All four of these en- zymes help to break down the same GAG, heparan sulfate. MPS IIIA (SANFILIPPO SYNDROME TYPE A) MPS IIIA is caused by a deficiency of the enzyme heparan sulfate sulfamidase, due to mutations in the SGSH gene on chro- mosome 17. Type IIIA is felt to be the most severe of the four types, in which symptoms appear and death occurs at an earlier age. LetterM.qxd 10/1/04 11:07 AM Page 553 554 GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS Mucopolysaccharidoses Key Terms Carpal tunnel syndrome A condition caused by compression of the median nerve in the carpal tun- nel of the hand, characterized by pain. Cornea The clear, dome-shaped outer covering of the eye that lies in front of the iris and pupil. The cornea lets light into the eye. Gene A building block of inheritance, which contains the instructions for the production of a particular protein, and is made up of a molecular sequence found on a section of DNA. Each gene is found on a precise location on a chromosome. Hydrops fetalis A condition in which a fetus or newborn baby accumulates fluids, causing swollen arms and legs and impaired breathing. Metabolic Refers to the chemical reactions in liv- ing organisms. Mucopolysaccharide A complex molecule made of smaller sugar molecules strung together to form a chain. It is found in mucous secretions and inter- cellular spaces. Mutation A permanent change in the genetic ma- terial that may alter a trait or characteristic of an in- dividual, or manifest as disease. This change can be transmitted to offspring. MPS IIIB (SANFILIPPO SYNDROME TYPE B) MPS IIIB is due to a deficiency in N-acetyl-alpha-D-glu- cosaminidase due to mutations in the NAGLU gene, also located on chromosome 17. This type of MPS III is not felt to be as severe as Type IIIA and the characteristics vary. Type IIIB is the most common of the four types of MPS III in southeastern Europe. MPS IIIC (SANFILIPPO SYNDROME TYPE C) A defi- ciency in the enzyme acetyl-CoA-alpha-glucosaminide acetyltransferase causes MPS IIIC. This is considered a rare form of MPS III. The gene involved in MPS IIIC is believed to be located on chromosome 14. MPS IIID (SANFILIPPO SYNDROME TYPE D) MPS IIID is caused by a deficiency in the enzyme N-acetylglu- cosamine-6-sulfatase, due to mutations in the GNS gene lo- cated on chromosome 12. This form of MPS III is also rare. MPS IV (Morquio syndrome) Morquio syndrome is characterized by severe skele- tal deformities and their secondary effects on the nervous system. Intelligence is usually normal. One of the earliest symptoms seen in this condition is a difference in the way the child walks. Skeletal abnormalities can be extreme and include dwarfism, kyphosis (outward-curved spine), prominent breastbone, flat feet, and genu-valgum (knock- knees). A bone deformity known as odontoid hypoplasia (improper formation of the bones that stabilize the head and neck) can result in compression of the spinal cord, a potentially serious and life-threatening complication. As with several of the MPS disorders, Morquio syndrome was originally diagnosed by the presence of particular signs and symptoms. However, it is now known that the defi- ciency of two different enzymes can result in MPS IV. These two types of MPS IV are called MPS IV A and MPS IV B. MPS IV is variable in its severity. MPS IV A is the classic (typical) or the severe form of the condition and is caused by a deficiency in the enzyme galactosamine-6-sul- phatase. The gene involved with MPS IV A (GALNS) is located on chromosome 16. MPS IV B is considered the milder form of the condition. The enzyme, beta-galac- tosidase, is deficient in MPS IV B. The gene involved with MPS IV B (GLB1) is located on chromosome 3. MPS VI (Maroteaux-Lamy syndrome) MPS VI is caused by deficiency of the enzyme N- acetylglucosamine-4-sulphatase (arylsulfatase B), due to mutations in the ARSD gene located on chromosome 5. Affected individuals may have a mild or severe form of the condition. Typically, the nervous system and intelligence are not affected. Individuals with a more severe form of MPS VI can develop airway obstruction, hydrocephalus (extra fluid accumulating in the brain), and abnormal growth and formation of the bones. Additionally, individ- uals with a severe form of MPS VI are more likely to die while in their teens. With a milder form of the condition, individuals tend to be shorter than expected for their age, develop corneal clouding, and live longer. MPS VII (Sly syndrome) MPS VII, an extremely rare form of MPS, results from a deficiency of the enzyme beta-glucuronidase due to mutations in the GUSB gene on chromosome 7. MPS VII is also highly variable, but symptoms are generally simi- lar to those seen in individuals with Hurler syndrome. In severe cases, infants may be born with hydrops fetalis. MPS IX (Hyaluronidase deficiency) MPS IX is a condition that was first described in 1996 and has been grouped with the other MPS conditions by some researchers. MPS IX is caused by the deficiency of the enzyme hyaluronidase due to mutations in the HYAL1 gene on chromosome 3. In the few individuals described with this condition, the symptoms are variable, but some develop soft-tissue masses (growths under the skin). Also, these individuals are shorter than expected for their age. LetterM.qxd 10/1/04 11:07 AM Page 554 GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS 555 Mucopolysaccharidoses Diagnosis Identification of symptoms is usually the first step in making an MPS diagnosis. Doctors will then use labora- tory tests to establish an accurate diagnosis. They may first use a screening test that looks for glycosaminoglycans in the urine. The definitive diagnosis of an MPS is made using a biochemical test that measures the specific enzyme (known to be reduced or absent) in the individual’s tissues or bodily fluids. Genetic testing may also be used to con- firm a suspected diagnosis and, in some cases, to provide limited information about potential disease severity. Ge- netic testing is accomplished by looking for specific changes known as mutations in the gene responsible for the MPS disorder. Genetic testing is available for all of the MPS disorders except MPS IIIC, MPS IVB, and MPS IX. If the gene mutation(s) have been found in an affected in- dividual, the same genetic test may be used for carrier screening in unaffected family members, such as adult sib- lings, and for prenatal diagnosis. If the DNA mutations are not found or if genetic testing is not available, carrier screening and prenatal diagnosis may be accomplished using biochemical methods. Preimplantation genetic di- agnosis (PGD) is available on a research basis for MPS I and MPS II. More information on PGD for these types of MPS can be found by contacting the Reproductive Genet- ics Institute at (773) 472-4900 or at rgi@flash.net. Treatment team Treatment of MPS disorders requires a multidiscipli- nary approach. In addition to the patient’s primary health care professionals, medical professionals involved in the care of patients with an MPS usually includes specialists in neurology, neurosurgery, ophthalmology (eyes), otolaryn- gology (ear-nose-throat), audiology (hearing), cardiology, pulmonology (lungs), anesthesiology, gastroenterology, nutrition, orthopedic surgery, rehabilitation (physical, oc- cupational, and speech therapy) and genetics. Some pa- tients with MPS may receive comprehensive services through a specialty clinic such as metabolic or neuroge- netics clinic. A genetic specialist, such as a clinical geneti- cist or a genetic counselor, may be helpful to the patient and family, especially at the time of diagnosis or prior to genetic testing. Psychological counseling and MPS sup- port groups may also assist families in coping with this condition. Treatment Treatment of the MPS disorders primarily consists of supportive care and management of complications. Bone marrow transplant (BMT) and enzyme replacement are two promising therapies that offer the possibility of alter- ing the course of these conditions. Due to the progressive nature of the MPS disorders, regular evaluations by pri- mary care providers and specialists is required to detect problems early. Treatment for the most common problems found in the MPS disorders is listed below. Symmtomatic care and treatment HYDROCEPHALUS Hydrocephalus (increased fluid in the ventricles of the brain) commonly occurs in MPS I, MPS II, MPS VI, and MPS VII due to a blocked circulation of cerebral spinal fluid in the brain. If the hydrocephalus is detected early, a surgical procedure known as ventricu- loperitoneal shunting or a VP shunt may afford the affected individual with a better outcome. Periodic CT or MRI scans may be recommended to monitor for hydrocephalus in a child with MPS. In MPS III, enlarged ventricles (spaces in the brain) may occur but here the enlargement is thought to be due to cortical atrophy (loss of brain cells). It has been reported that shunting may decrease behavior problems associated with this form of MPS. SEIZURES Seizures are a problem found in severe forms of MPS and especially in MPS III (Sanfilippo syn- drome). Patients with seizures are given a type of pre- scription medication known as an anticonvulsant. VISION AND HEARING Regular evaluation by an oph- thalmologist is recommended to look for common eye problems including changes in the retina, glaucoma, and corneal clouding. Retinal degeneration, an eye problem that leads to night blindness and loss of peripheral vision, is common in MPS I, MPS II, and MPS III. Adding a night light to a hall or bedroom may help with this. Glaucoma is especially common in MPS I and is usually treated with medications. Corneal clouding is found in MPS I, MPS IV, MPS VI and MPS VII. People with corneal clouding have photophobia (the inability to tolerate bright light). Caps with a visor or sunglasses may be recommended to help reduce this problem. Corneal transplantation is possible for people with significantly reduced vision yet transplants may not always result in improved vision in the long term. Hearing problems are common in the MPS disorders. Regular hearing evaluations are important so that children with hearing loss can be treated early. Hearing aids may provide some degree of improvement. Recurrent otitis media (middle ear infections) significantly contribute to hearing loss in individuals with MPS. Prescription med- ications are used to treat otitis media. Ventilating tubes in the ears may be used to minimize the long term effects of these infections. CARDIOVASCULAR Many individuals with MPS show some signs of heart disease. Common problems include abnormal heart valves, narrowing of the blood vessels in the heart, and weak heart muscles (cardiomyopathy). Pa- tients with MPS I H and the severe form of MPS II usually LetterM.qxd 10/1/04 11:07 AM Page 555 556 GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS Mucopolysaccharidoses have damage to the mitral valve. In MPS I H/S, MPS IS, MPS IV, and MPS VI, aortic valvular disease is more com- mon. Medications may be prescribed for congestive heart failure and hypertension associated with underlying heart disease. Valve replacement surgery is possible and has been reported in the MPS disorders. AIRWAY DISEASE Obstruction of the airway is a com- mon and significant problem for individuals with MPS. This problem can be due to a narrowed trachea (wind pipe), thickened vocal cords, large adenoids or tonsils, de- creased rib movement with breathing, and a large tongue. A condition known as obstructive sleep apnea (temporary cessation of breathing while asleep) is the most common airway problem in MPS. Treatment for sleep apnea may include: removal of adenoids and tonsils, CPAP or BiPAP treatment, or a tracheostomy. CPAP (continuous positive airway pressure) and BiPAP (bilevel positive airway pres- sure) are treatments that help to keep the airway open at nighttime. A tracheostomy, an permanent opening through the neck into the trachea, may be needed in severe cases of sleep apnea. FEEDING PROBLEMS For many individuals with MPS, neurological problems eventually lead to significant prob- lems with chewing and swallowing. Surgical placement of gastrostomy tube (G-tube) or a jejunostomy tube (J-tube) may be recommended when feeding problems cause weight loss, choking, gagging, or episodes of pneumonia. SKELETAL DEFORMITIES Bony problems, especially of the neck, spine, and hips may require orthopedic inter- vention. Problems of the cervical spine due to odontoid hypoplasia (improper formation bones that stabilize the head and neck) can be quite serious. Odontoid hypoplasia can lead to slippage of the bones in the neck and com- pression of the spine in the cervical (neck) region. In se- vere cases, this spinal cord compression may result in nerve damage, paralysis or death. Odontoid hypoplasia is common in MPS IV (Morquio syndrome). Treatment in- cludes regular monitoring with MRI or X-rays and cervi- cal fusion surgery for severe cases. Other bony problems seen in the MPS disorders include progressive scoliosis or kyphosis (curvatures of the spine ) and hip dysplasia (ab- normal hip joint). Bracing and sometimes surgery may be used to treat spine curvature. A surgical procedure known as spinal fusion may be considered in patients with sig- nificant curvature. Patients with hip dysplasia may be given non-steroidal anti-inflammatory medications. CARPAL TUNNEL SYNDROME Carpal tunnel syn- drome is a common problem in MPS. Although many in- dividuals with MPS may not have typical symptoms (numbness, tingling, pain), the carpal tunnel syndrome can and may be severe. Treatment options include splint- ing, anti-inflammatory medications and surgery. Bone marrow transplantation (BMT) Bone marrow transplants have been used to treat chil- dren with MPS I, MPS II, MPS III, and MPS VI. Some success has been achieved with BMT in MPS I and in MPS VI; however, this treatment is not a cure and is con- sidered experimental due to the associated risks, including death. Some children who have undergone BMT have shown reduced progression of some disease symptoms. It remains uncertain whether BMT can prevent brain dam- age. BMT is not recommended as a treatment for MPS II or MPS III. Enzyme replacement therapy Enzyme replacement therapy is available for MPS I. A pharmaceutical form of alpha-L-iduronidase known as laronidase is available in the United States. More infor- mation may be obtained at<http://www.aldurazyme.com>. Enzyme therapy may be an option in the future for indi- viduals with MPS IV. Recovery and rehabilitation Rehabilitation for the MPS disorders consists of phys- ical, occupational, and possibly speech therapy. For ex- ample, physical therapy may help preserve joint function for individuals with joint stiffness. Joint stiffness is pres- ent in all of the MPS disorders except MPS IV and MPS IX. In physical therapy, patients may undergo range-of- motion exercises (passive bending and stretching of the arms and legs). Also, physical therapy after neck, spine or knee surgery can help patients (who could walk prior to surgery) to walk again. Occupational therapy can teach pa- tients to use adaptive techniques and devices that may help compensate for loss of mobility and/or for loss of speech. Speech therapy may be indicated for individuals with MPS; however, this intervention may not be useful in cases in which the mental condition is rapidly deteriorating. Hyperactivity can be a severe problem in individuals with MPS, especially in MPS III and MPS II. Medications may or may not be successful in treating this problem. Be- havior modification programs may be helpful for some hy- peractive MPS children. It may also be necessary to adapt the house and yard to the child. Clinical trials As of December 2003, there were four clinical trials related to the MPS disorders that were recruiting patients. A phase II/II trial to determine whether the administration of iduronate-2-sulfatase enzyme is safe and efficacious in patients with MPS II will be conducted in the United States, Brazil, Germany and England. Information on this trial can be found at <http://www.clinicaltrials.gov> or by contacting Transkaryotic Therapies at 617-613-4499. A LetterM.qxd 10/1/04 11:07 AM Page 556 [...]... National Institute on Aging (NIA) 31 Center Drive, Rm 5C27 MSC 22 92, Bethesda, MD 20 8 9 2- 229 2 (301) 49 6-1 7 52 or (800) 22 2 -2 2 25 niainfo@nih.gov National Institute of Mental Health (NIMH) 6001 Executive Blvd Rm 8184, MSC 9663, Bethesda, MD 20 8 9 2- 9663 (301) 44 3-4 513 or (866) 61 5-6 464; Fax: (301) 44 3- 427 9 nimhinfo@nih.gov Brian Douglas Hoyle,... Muscular Dystrophy Association 3300 East Sunrise Drive, Tucson, AZ 8571 8- 320 8 ( 520 ) 529 -2 0 00 or (800) 5 721 717; Fax: ( 520 ) 529 -5 300 mda@mdausa.org American Heart Association 727 2 Greenville Avenue, Dallas, TX 7 523 1-4 596 (21 4) 37 3-6 300 or (800) 24 2-8 721 ; Fax: (21 4) 37 3- 026 8 inquire@heart.org Francisco de Paula Careta Iuri Drumond... 5801, Bethesda, MD 20 824 (301) 49 6-5 751 (800) 3 5 2- 9 424 National Organization for Rare Disorders (NORD) 55 Kenosia Avenue, Danbury, CT 0681 3-1 968 (20 3) 74 4-0 100 or (800) 99 9-6 673; Fax: (20 3) 798 -2 2 91 orphan@rare diseases.org Myasthenia Gravis Foundation of America, Inc 1 821 University Ave W., Suite S256, St Paul, MN 55104 (651) 574 S Myasthenia... Study of CellCept in the Treatment of MG: This is a multicenter, placebo-controlled study testing CellCept and prednisone as the initial form of immunotherapy in the treatment of MG The purpose of the study is to determine if the combination of these two medications provides better control of MG symptoms compared with prednisone alone • Study of Etanercept Among Individuals With MG: The purpose of the. .. disease, and symptoms worsen over time 566 Atrophy The progressive wasting and loss of function of any part of the body Cerebellum The part of the brain involved in the coordination of movement, walking, and balance Neurodegeneration tissues The deterioration of nerve Parkinsonism is the initial symptom in almost half of all patients The classic symptoms of Parkinson’s disease (PD)—tremor, stiffness or... cause the breakdown in tolerance that leads to GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS 575 Myasthenia gravis an immune-mediated attack on AChR in this disease The thymus contains all the necessary elements for the beginnings of MG: myoid cells that express the AChR antigen, antigen presenting cells, and immunocompetent T-cells However, it is still uncertain whether the role of the thymus in the pathogenesis... nerve to muscle The genetic abnormalities can be present in the fetus at the moment of conception or may occur during fetal development This genetic cause of the disease separates the congenital form of myasthenia from myasthenia gravis and Lambert-Eaton myasthenic syndrome, both of which are caused by the malfunctioning of the immune system Demographics Congenital myasthenia occurs in the young, and... most types of congenital myasthenia typically involves the use of drugs that help promote the transmission of nerve impulses Drugs that retard the breakdown of acetylcholine can be used An example of an acetylcholinesterase is mestinon Other drugs that show merit in some cases include guanidine, ephedrine sulfate, GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS 573 Myasthenia, congenital S Myasthenia, congenital... laboratory analysis Ultrasound studies of the carotid artery may also be performed Diagnosis most often involves the non-destructive imaging of the brain by means of computed tomography (CT) or magnetic resonance imaging (MRI) to reveal blood clots or the characteristic damaged regions of the brain GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS Key Terms Dementia A chronic loss of mental capacity due to an organic... 733 Third Avenue, 6th floor, New York, NY 10017 (21 2) 98 6- 324 0 or (800) 34 4-4 867; Fax: (21 2) 98 6-7 981 nat@nmss.org It is generally very difficult to predict the course of MS The disorder varies greatly in each individual, but most people with MS can expect to live 95% of the normal GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS Marcos do Carmo Oyama Iuri Drumond Louro . (NIA). 31 Center Drive, Rm. 5C27 MSC 22 92, Bethesda, MD 20 8 9 2- 229 2. (301) 49 6-1 7 52 or (800) 22 2 -2 2 25. niainfo@nih.gov. <http://www.nia.nih.gov>. National Institute of Mental Health (NIMH) 565 566 GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS Multiple system atrophy Key Terms Atrophy The progressive wasting and loss of func- tion of any part of the body. Cerebellum The part of the brain. distribution of MS, with the highest prevalence in the northern and cen- tral Europe, northern North America and southeastern LetterM.qxd 10/1/04 11:07 AM Page 561 5 62 GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS Multiple