54 Lesch-Nyhan Disease Steven G. Little and Jennifer E. Rodemaker Overview Lesch-Nyhan disease (Lesch & Nyhan, 1964) is a rare condition caused by a defective gene on the X chromosome resulting in below-average cog- nitive functioning, spastic cerebral palsy, choreoathetosis (rapid jerky in- voluntary muscle movements accompanied by slow sinuous writhing movements, usually in the hands), and self-mutilation. The condition is usually inherited but may occur through spontaneous genetic mutation (Davidson et al., 1991). The disorder has generally been thought to affect males only; however, a recent study (Yukawa et al., 1992) has documented the syndrome in a female, and the cause is believed to be spontaneous mutation. The approximate incidence of the disorder is 1 in 380,000 and is distributed evenly among races and geographic locales (Matthews, So- lan, & Barabas, 1995). The disease is expressed in the almost complete absence of activity of the enzyme hypoanthine guanine phosphoribosyl transferase (HGPRT), which is responsible for purine metabolism (Page & Nyhan, 1990). The metabolic consequence is an enormous overproduc- tion of uric acid in body fluids. Interestingly, correction of the metabolic defect does not affect the physical and psychological characteristics of these children (Clements, 1988). Children with Lesch-Nyhan disease appear normal at birth and may achieve gross motor milestones appropriately for the first 6 to 8 months. A very early finding may be the appearance of orange crystalline material in the diapers as a result of high uric acid concentrations. All individuals with Lesch-Nyhan disease have cerebral palsy, and the first sign of the onset of the disease is the development of involuntary muscle movements between 8 and 12 months and the resultant loss of achieved motor mile- stones. The disturbance i n motor development is so severe that individuals with Lesch-Nyhan are unable to stand without assistance, and none learn to walk (Breese, Mueller, & Schroeder, 1987). The magnitude of these in- voluntary motor behaviors is increased with tension or excitement. Ulti- mately, development of excessive muscle tone occurs. One particular char- acteristic of this disorder is sudden spasms during which the head is thrown back suddenly and forcehlly. For this reason it is recommended that others refrain from standing directly behind these individuals. In addition, these children should not be placed on hard surfaces because 386 LESCH-NYHAN DISEASE 387 this may lead to head injuries. Communication is characterized by poor articulation, although individuals with Lesch-Nyhan appear to compre- hend quite well (Matthews et al., 1995). Mental retardation has been cited as a fundamental component of the disease (Page & Nyhan, 1990), but recent evidence suggests that the I& of children with this condition may reach the low-average range (Matthews et al., 1995). These individuals also tend to be difficult to feed, and they vomit frequently. Consequently, most are markedly underweight and short in stature. Aggressive, self-mutilating behavior is the most distinctive feature of this disorder (Hatanaka et al., 1990). With the eruption of teeth, patients begin biting themselves, and biting and other self-injurious behaviors such as head banging continue throughout the life span. Most individuals with Lesch-Nyhan disease bite both their lips and fingers destructively. Finger biting may result in partial self-induced amputations of the fingers, and lip biting results in marked tissue loss around the lips. In addition, these individuals cut themselves on available sharp objects (e.g., metal edges of their wheelchair), burn themselves with hot water, bang their heads, or bite and pick at their injuries. However, individuals with Lesch-Nyhan are not insensitive to pain. They scream in pain when they injure them- selves and may become agitated or fearful at the anticipation of self-injury. Biting is frequently controlled only when the primary teeth are extracted early in development. Aggression can also be directed toward other people, although their ability to hurt others is limited by their motor deficits. They may attempt to bite, kick, or hit others when not restrained. In addition, they often spit or vomit at others in a semivoluntary, aggressive manner (Page & Nyhan, 1990).With puberty, sexually oriented grabbing, pinching, or touching may develop; verbalizing obscenities is common. As with their self-injurious be- haviors, these aggressive actions appear compulsive, and they frequently apologize after successfully completing an aggressive act toward others. Most individuals with Lesch-Nyhan require some form of physical restraint both day and night. They appear happy, content, and good na- tured and laugh easily when securely restrained (Page & Nyhan, 1990). When the restraints are removed, however, their behavior changes dra- matically. They appear terrified, scream, and call for help. Older children sometimes attempt to put themselves back in restraints. Outcomes Individuals with Lesch-Nyhan disease have hyperuricemia (high uric acid concentrations) and, as such, are subject to all of the clinical features found in people with gout. Acute attacks of arthritis develop after a num- ber of years of untreated hyperuricemia. Infantile colic and recurrent ab- dominal pain may indicate insoluble material in the urine. Renal failure is the most common cause of early death. Tophi, a sodium deposit around joints or appearing as bumps in tissue of the external ear, also develop. Treatment appears to have little effect on cerebral palsy, choreoathetosis, 388 LITTLE AND RODEMAKER or other central nervous system manifestations of this disease. However, those aspects directly related to uric acid itself can be effectively treated using the same medication used to treat gout in adults. In early descriptions, severe mental retardation was thought to be one of the “cardinal features” of the disease (Nyhan, 1972, p. 186).The physical disabilities, self-injurious behaviors, and the need for restraints all make standardized cognitive assessment of these individuals difficult. It has been observed, however, that these individuals appear more intelligent than test scores indicate. Anderson, Ernst, and Davis (1992) attempted to avoid the difficulties associated with traditional assessment methods by having parents or caregivers describe the cognitive abilities of their chil- dren. Their results led them t o conclude that most individuals with Lesch-Nyhan disease are not mentally retarded. Matthews et al. (1995) attempted to clarify the issue by evaluating seven hospitalized individuals with Lesch-Nyhan disease using formal cog- nitive assessment instruments. Participants were administered subtests from each of the four areas measured by the Stanford-Binet Intelligence Scale: Fourth Edition (Thorndike, Hagen, & Sattler, 1986),with minor mod- ifications to account for the participant’s limited motor functioning. Results indicated a range of functioning from moderate mental retardation to low average intelligence. Overall, group mean performance on verbal and visual subtests did not differ, although the authors noted that some individuals showed a strong preference for one modality over another. The greatest impairments were found in the areas of attention and higher intellectual functioning. Specifically, it was noted that they (a) were limited in the amount of information they could attend to or organize, (b) had difficulty sustaining short-term memory traces long enough to perform mental manip- ulations, and (c) exhibited conceptual limitations. The results led the authors to conclude that although cognitive impairment could be considered to be characteristic of Lesch-Nyhan disease, mental retardation “isnot an invar- l, iable component of Lesch-Nyhan syndrome” (Matthews et a . 1995, p. 721). Many children with developmental disorders have symptoms in com- mon with Lesch-Nyhan disease. For example, children with autism or nonspecific mental retardation may engage in self-injurious behavior. The pattern of self-mutilation is much different from that of Lesch-Nyhan disease, however. Head banging is the most common form of self-injurious behavior found in non-Lesch-Nyhan children, whereas biting and picking are much less common. The damage inflicted is much less severe and usu- ally consists of enlargement of the damaged area (e.g., cauliflower ear) rather than the tissue loss characteristic of Lesch-Nyhan disease. In ad- dition, the self-injurious behavior of non-Lesch-Nyhan children is much more amenable to treatment using operant techniques than it is for indi- viduals with the disease. Psychoeducational Implications No treatment has been shown to have any effect on the central nervous system manifestations of the disease. Although the goutlike symptoms are LESCH-I" DISEASE 389 easily controlled chemically, the physical handicaps associated with the disease follow a predictable course, beginning with a lack of muscle tone and followed by muscle rigidity and uncontrolled movements of the arms and body. Physical growth is retarded, and these individuals are unable to walk or sit without support. Feeding is a problem; many children with this disease have inefficient mouths as a result of self-mutilation or re- moval of the teeth. The most remarkable feature of this disorder is the extreme, chronic self-mutilation that begins early in development. For these reasons, children with Lesch-Nyhan disease are unlikely to be placed in a regular school environment. Placement is much more likely to be in a chronic care facility or in the home with supportive services pro- vided to the parents. Although little can be done to alter the course of the disease, environ- mental modifications can be made t o increase the likelihood that these individuals can participate in their environment. It is preferable to have them sitting up in a chair most of the day. They enjoy television, radio, and recordings. They also enjoy interacting with others, provided they are in restraints. The placement of securely tied restraints in the chair is important. Once it is determined which restraints work with the individ- ual patient, he or she may be able to play with toys or move around in a wheelchair. Cloth diapers have been found to function well as restraints. They are ideally tied rather than pinned, because pins can easily come apart. The thighs and forearms should be secured to the chair with the hands left free. Hands must be wrapped in a soft material in such a way as to allow the individual freedom of use without the risk of biting. Ties should be placed around the chest. All hard surfaces must be padded. At night, most individuals with Lesch-Nyhan disease require tying all four extremities to the bed using cloth diapers. When the child is not physically restrained, more than one adult should be present to provide manual re- straint. Bathing requires at least two people, and all protruding objects around the tub or sink should be padded. Self-mutilative behaviors in individuals with mental retardation are usually considered a learned response and subject to behavior modification using operant techniques. Attempts at behavior modification in children with Lesch-Nyhan disease have led to equivocal results, however. Some evidence suggests that positive social reinforcement and time-out (i.e., withdrawal of attention) can be effective in reducing self-injurious behav- iors (Clements, 1988). It is clear, however, that aversive techniques have been totally ineffective and may lead to a worsening of the behaviors tar- geted for reduction. When working with a child with Lesch-Nyhan dis- ease, it is best to analyze functionally the self-injurious behavior. It is possible that it may be maintained through the responses of others in the environment. It is important to remember that children with Lesch- Nyhan disease enjoy social interactions, and the attention necessitated by responding to injuries may be reinforcing to the child. The results of be- havior modification trials are mildly encouraging, but complete remission of the self-injurious behaviors should not be expected. School professionals may provide services to children with Lesch- 390 LIlTLEANDRODEMAKER Nyhan disease either in a residential setting or through homebound ser- vices. In terms of the Individuals With Disability Education Act, they are likely t o be classified as Other Health Impaired. Because this is a very rare disorder, little research has been conducted on the psychosocial ad- justment of family members, although one would suspect similar re- sponses to those found in families of children with other chronic diseases. This research indicates that these families are at risk for adjustment prob- lems, particularly maternal distress and marital discord (Varni & Wallan- der, 1988).Providing emotional support for families, coordinating and fa- cilitating support services, and making necessary referrals are all ways the mental health professional can assist in family adjustment. Annotated Bibliography Anderson, L., Ernst, M., & Davis, S. V. (1992). Cognitive abilities of patients with Lesch-Nyhan syndrome. Journal of Autism and Developmental Disorders, 22, 189-203. Mathews, W. S., Solan, A., & Barabas, G. (1995). Cognitive functioning in Lesch- Nyhan syndrome. Developmental Medicine and Child Neurology, 37, 715-722. These two articles provide an excellent review of cognitive outcomes and subse- quent psychoeducational implications. Resources Association for Neuro-Metabolic Disorders, 5223 Brooklield Lane, Sylvania, OH 43560-1809; 4 19-885-1497 This is a national not-for-profitvoluntary organization that is composed of families with children who have metabolic disorders that affect the central nervous system. The association produces educational materials, including a brochure and a reg- ular newsletter. International Lesch-Nyhan Disease Association, 11402 Ferndale Street, Phila- delphia, PA 19116; 215-677-4206 This is a not-for-profit, self-help organization dedicated to providing information and support to families of children diagnosed with Lesch-Nyhan disease. National Organization for Rare Disorders, Post Office Box 8923, New Fairfield, CT 06812-1783; 800-999-6673 http.J/www.pcnet.com/-orphan Purine Research Society, 5424 Beech Avenue, Bethesda, MD 20814-1730; 301-530-0354; 301-564-9597 (fax); Email: email@example.com http~lwww2.dgsys.com/-purinel This is a national nonprofit charitable organization dedicated to funding research and treatments for purine-related metabolic diseases. They provide appropriate referrals to affected individuals and offer educational pamphlets and brochures. LESCH-NYHAN DISEASE 391 References . Anderson, L., Emst, M., & Davis, S. V (1992).Cognitive abilities of patients with Lesch- Nyhan Syndrome. Journal of Autism and Developmental Disorders, 22, 189-203. Breese, G. R., Mueller, R. A., & Schroeder, S. R. (1987).The neurochemical basis of symp- toms in the Lesch-Nyhan syndrome: Relationship to central symptoms in other devel- opmental disorders. In E. Schopler & G. B. Mesibov (Eds.), Neurobiological issues in autism (pp. 145- 160).New York Plenum Press. Clements, J. (1988). Early childhood. In J. L. Matson &A. Marchetti (Eds.), Developmental 6) disabilities: A lifespan perspective ( pp. 127- 1 5 . Philadelphia: Grune & Stratton. Davidson, B. L., Tarle, S. A., Van Antwerp, M., Gobbs, D. A, Watts, R. W., Kelley, W. N., & Palella, T. D. (1991).Identification of 17 independent mutations responsible for human hypoxanthineguanine phosphoribosyl-transferase (HGPRT) deficiency. American Jour- nal of Human Genetics, 48,951-958. Hatanaka, T., Higashino, T., Woo, M., Yasuhara, A,, Sugimoto, T., & Kobayahi, Y. (1990). Lesch-Nyhan syndrome with delayed onset of self-mutilation: Hyperactivity of inter- neurons at the brainstem and blink reflex. Acta Neurologica Scandinavia, 81,184-187. Lesch, M., & Nyhan, W. I. (1964).A familial disorder of uric acid metabolism and central nervous system function. American Journal of Medicine, 36, 561-570. Matthews, W. S.,Solan, A., & Barabas, G. (1995).Cognitive functioning in Lesch-Nyhan syndrome. Developmental Medicine and Child Neurology, 37, 715-722. Nyhan, W. L. (1972). Clinical features of the Lesch-Nyhan syndrome. Archives of Internal Medicine, 130, 186-192. Page, T., & Nyhan, W. L. (1990).Biochemical correlates of auto-aggressive behavior: Infer- ences from Lesch-Nyhan syndrome. In s. I. Deutch, A. Weizman, & R. Weizman (Eds.), Application of basic neuroscience to child psychiatry (pp. 297-311). New York Plenum Medical Book Company. Thorndike, R. L., Hagen, E. P., & Sattler, J. M. (1986). Stanford-Binet Intelligence Scale: Fourth Edition. Chicago: Riverside. Varni,J. W., & Wallander, J. L. (1988). Pediatric chronic disabilities: Hemophilia and spina bifida as examples. In D. K. Routh (Ed.), Handbook of pediatric psychology (pp. 190- 221). New York Guilford Press. Yukawa, T., Akazawa, H., Miyake, Y., Takahashi, Y., Nagao, H., & Takeda, E. (1992).A female patient with Lesch-Nyhan syndrome. Developmental Medicine and Child Neu- rology, 34, 543-546.
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