Journal of Child Neurology

Rett syndrome was first described in 1966 by Dr Andreas Rett, who reported in German his findings in 22 patients. Recognition of the syndrome grew slowly until 1983, when a series of 35 patients from several countries was reported in English. By 1987, the number of known cases had grown to over 1,250 worldwide, the International Rett Syndrome Association had been founded, and international conferences on the syndrome were being held regularly. Although a developmental staging system has been devised, many questions remain concerning the course of the disease. Rett syndrome poses a challenge to the physicians, therapists, psychologists, educators, and families involved with affected patients, as well as to researchers investigating the syndrome. (J Child Neurol 1988;3(Suppl):S3-S5).

Rett syndrome (RS) is characterized by progressive loss of intellectual functioning and fine and gross motor skills as well as development of stereotypic hand movement abnormalities, occurring after 6 to 18 months of normal development. Rett syndrome has been previously reported only in girls, but the possibility of the syndrome existing in male children cannot be currently excluded. Although the syndrome is thought to be relatively common, it was only described in the English literature 5 years ago. There is currently no marker for the syndrome; diagnosis is based on clinical criteria. The newly developed diagnostic criteria for RS are reviewed, with special attention given to the historical aspects of the diagnosis in the prenatal, perinatal, neonatal, and early childhood periods. Rett syndrome is characterized by a predictable, orderly progression of signs and symptoms. Four stages of RS have been described; each stage has special characteristics and offers different diagnostic challenges for the neurologist. Infantile autism is the most common incorrect diagnosis made for children with RS. The simultaneous regression of both motor and language skills, as well as the stereotypic hand movements, hyperventilation, bruxism, and seizures in early childhood are all typical in RS and help distinguish RS from infantile autism. (J Child Neurol 1988;3(Suppl):S6-S16).

Current data indicate that Rett syndrome is an important contributor to the total burden of idiopathic mental retardation. Studies from Sweden suggest that among girls the prevalence of Rett syndrome may be twice the prevalence of phenylketonuria. Successful epidemiologic studies of idiopathic mental retardation syndromes will require both large sample sizes and homogeneous populations. Because Rett syndrome is a relatively homogeneous and common syndrome of idiopathic mental retardation, epidemiologic methods may be more productive in the study of Rett syndrome than in other syndromes of mental retardation that are less clinically homogeneous. The approaches used in studying Rett syndrome epidemiologically may later be useful in the study of other syndromes of idiopathic mental retardation. (J Child Neurol 1988;3(Suppl):S17-S20).

We report preliminary studies in 18 girls with Rett syndrome (15 typical, three atypical cases) who were studied using a number of neuropsychologic measures. Results indicate a relative preservation of gross motor and daily living skills at the developmental level of the age of onset of the condition. Other adaptive functions were more depressed. Higher levels of object permanency were found in this population than reported previously. Our results indicate that islands of motor and intellectual function persist in Rett syndrome patients. These data may be useful for therapeutic intervention. (J J Child Neurol 1988;3(Suppl):S20-S24).

Sural nerve and peroneus brevis muscle biopsies were studied in 12 patients with Rett syndrome, ten with the typical form of the disorder according to 1985 criteria, and two with atypical features. Ages ranged from 23 months to 25 years. All stages of the disease were represented. There was evidence of a mild axonal neuropathy in seven of 12 patients. Degenerative and occasional regenerative changes were seen in five sural nerve biopsies, including one from the youngest patient in the series, who was normally nourished and fully ambulatory. Occasional nonspecific ultrastructural abnormalities were present, including accumulation of pi granules in Schwann cells and Hirano bodies within axons. However, morphometric analysis of the four nerves in which these alterations were most prominent showed a normal density and size distribution of myelinated fibers. Enzyme histochemistry of the peroneus brevis biopsies demonstrated abnormal predominance of type II muscle fibers in three of the 12 biopsies and atrophy of type I fibers in one patient. (J Child Neurol 1988;3(Suppl):S25-S30).

Guidelines for providing therapy intervention for persons with Rett syndrome are presented according to the four stages of the disease. In describing various aspects of Rett syndrome the differences between Rett syndrome, cerebral palsy, and autism are discussed. The role of the therapist in maintaining functional skills is emphasized. The changing nature of the therapist's involvement in relation to the progression of the disease is briefly addressed. (J Child Neurol 1988;3(Suppl): S31-S34).

Nutrition is a major problem for the Rett patient. We have studied 21 girls with Rett syndrome (19 typical, two atypical). We report our experience in this population with the nutritional aspects of Rett syndrome, the typical dietary habits, and various nutritional deficiencies. Further experience with the use of high fat diets is reported. (J Child Neurol 1988;3(Suppl):S35-S42).

Musculoskeletal deformity sufficiently severe to require orthopedic surgery is a significant problem in Rett syndrome. Preliminary results from the study of 16 patients suggest deformity in nearly all patients. Eight patients in stage III and seven patients in stage IV showed clinical evidence of scoliosis. Radiographic studies confirmed a structural curve in nine of ten patients studied. Heel cord tightening was seen in nine of 16 patients. Hip instability was identified as an area of potential concern in the Rett patient. (J Child Neurol 1988;3(Suppl):S43-S48).

It is well recognized that children with "autistic features" constitute a very heterogeneous population. There is a growing consensus that the core symptoms seen in autism include deficits in: (1) social/affective/behavioral functions, (2) developmental language disorders with concomitant deficits in interpersonal communication, and (3) play/preferred activities/ preoccupations which have a repetitive or stereotypic quality. The definition of the boundaries of "autism" as opposed to other related pervasive developmental disorders is widely debated among clinicians and research investigators alike. In the present paper, it is argued that autism is a cover term for a spectrum disorder with similarities and differences in the clinical presentation of preschool children. A model for subtyping the autistic spectrum disorders is suggested. (J Child Neurol 1988;3(Suppl):S48-S56).

Autism is a severe form of childhood psychopathology first described by Leo Kanner in 1943. While over the years there has been substantial controversy about many features of the syndrome, there is today some consensus as to the behavioral characteristics associated with the diagnosis. These include onset of the disorder in the early preschool years, severe and pervasive deficits in social behavior and attachments, deficits in speech and language, insistence for the preservation of sameness, unusual responsiveness to the sensory environment, self-stimulation, self-injurious behavior, isolated skill areas, and inappropriate affect. Another associated feature of many cases of autism is mental retardation. The present article describes these behavioral features as well as the application of the diagnosis and differentiation of autism from other disorders including primary mental retardation, childhood schizophrenia, developmental aphasia, and pervasive developmental disorder. (J Child Neurol 1988;3(Suppl):S57-S64).

Patients with Rett syndrome appear to fulfill the Rendle-Short criteria for the diagnosis of autism, but the pattern of their behavior is qualitatively different from children with autism. Until a biologic marker is identified, diagnosis is based on clinical assessment. In order to standardize this clinical assessment and to provide objective criteria for the evaluation of potential therapeutic modalities, motor and behavioral characteristics of 15 Rett patients were analyzed. The patients with Rett syndrome differed from autistic children in having ataxia, breath-holding, hyperventilation, bruxism, simplicity of stereotypies, and hand apposition. The children with autism demonstrated complex stereotypies and verbal but not motor regression. The more typical features of autism, namely, poor eye contact, lack of sustained interest, speech disturbance, and repetitive truncal rocking motions were poor discriminators between the two groups. (J Child Neurol 1988;3(Suppl): S65-S67).

A survey of approximately 4,000 questionnaires completed by parents of autistic children provided ratings on a variety of treatments and interventions. Among the biomedical treatments, the use of high-dosage vitamin B6 and magnesium (n = 318) received the highest ratings, with 8.5 parents reporting behavioral improvement to every one reporting behavioral worsening. Deanol (n = 121) was next most highly rated, with 1.8 parents reporting improvement to each one reporting worsening. Fenfluramine (n = 104) was third, with a ratio of 1.5:1. Thioridazine hydrochloride (Mellaril), by far the most often used drug on the list (n = 724), was fourth with a helped-worsened ratio of 1.4:1. The research literature on the use of vitamin B6-magnesium is briefly reviewed, and mention is made of recent findings regarding high-dosage folic acid in autism and biotin in Rett syndrome. (J Child Neurol 1988;3(Suppl):S68-S72).

Past, present, and future research activities in Rett syndrome are described. Studies to this point have failed to define a biologic or chemical marker. It is hoped that heightened activity in this unique syndrome will provide guidance for the diagnosis of this disorder, and with it, better understanding. (J Child Neurol 1988;3(Suppl):S72-S75).

To date over 1,000 cases of Rett syndrome have been described in females exclusively. Some of these cases, less than 2 in 100, are familial. The inheritance through maternal lines in the familial cases suggests that Rett syndrome is an X-linked disorder lethal in males. Hypotheses about the genetic mechanisms involved in this syndrome along with suggestions to approach the molecular basis of this disorder are presented. (J Child Neurol 1988;3(Suppl):S76-S78).

The research strategy presented here involves four assumptions: (1) Rett syndrome exists; (2) a single cause will eventually be found to account for the majority of cases presently assigned to this disease category; (3) it is genetically determined; and (4) it represents a neurodegenerative disorder that can be defined by quantitative studies of nervous system structure and function. The strategy proposed here involves the comprehensive study of 100 patients with the classic Rett syndrome phenotype. Studies include the (1) search for a diagnostic marker; (2) high-resolution cytogenetic banding techniques, (3) quantitative morphologic studies of postmortem brain tissue as well as neurochemical analyses including autoradiographic techniques, radioimmunoassays, and in situ hybridization; and (4) positron emission tomography studies of cerebral glucose metabolism and neurotransmitters. (J Child Neurol 1988;3(Suppl):S78-S86).

Since 1984, the International Rett Syndrome Association has brought together families of girls with Rett syndrome, disseminated information about the syndrome, and supported research efforts. Through its computerized records, the Association can match parents most able to provide support for one another, refer parents to physicians familiar with Rett syndrome, keep accurate statistical records of the disease, and connect researchers with subjects willing to participate in investigations. The Association helps families adjust emotionally and practically to living with a Rett syndrome patient and works toward long-term answers by promoting understanding and improved treatment for the condition. (J Child Neurol 1988;3(Suppl):S87-S88).

Information about Rett syndrome should be imparted to parents of newly diagnosed children by a physician who is familiar with the disease and the care of affected children. Symptomatic treatment should be discussed and a follow-up schedule planned. Parents should be referred to a support group for parents of similarly afflicted children and should be informed about current research efforts. The contribution to knowledge about Rett syndrome that can be made by allowing postmortem examination of the child should be emphasized; parents can thereby be enlisted as co-investigators into this poorly understood disease (J Child Neurol 1988;3(Suppl):S89-S90).

In order to maximize biochemical, neurochemical, molecular, and pathologic information from patients with Rett syndrome, a uniform procedure has been developed for the conduct of the postmortem examination. Tissue should be prepared for freezing, for electron microscopy studies, and for standard histologic examination. For the purposes of uniformity, three central repositories for necropsy materials have been established and are available at all times. In the event of the death of a patient with Rett syndrome, parents who consent to necropsy should request that materials be handled according to the protocol and transported under appropriate conditions to the central repository. The National Neurological Research Bank (Los Angeles), the Brain Tissue Bank (Belmont, Mass), and the Department of Neuropathology at Johns Hopkins Hospital (Batimore) have agreed to serve as repositories for tissues. A committee of the International Rett Syndrome Association medical advisory panel will monitor this process in cooperation with the directors of the respective tissue banks. (J Child Neurol 1988;3(Suppl):S91-S93).