Gene dosage is a mechanism for Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited peripheral neuropathy in humans, characterized electrophysiologically by decreased nerve conduction velocities (NCVs). CMT1A is associated with a large submicroscopic DNA duplication in proximal 17p. In this report we demonstrate that a patient with a cytogenetically visible duplication, dup(17)(p11.2p12), has decreased NCV. Molecular analysis demonstrated this patient was duplicated for all the DNA markers duplicated in CMT1A as well as markers both proximal and distal to the CMT1A duplication. These data support the hypothesis that the CMT1A phenotype can result from a gene dosage effect.

Microarray based comparative genomic hybridization testing in deletion bearing patients with Angelman syndrome: genotype-phenotype correlations.

BACKGROUND: Angelman syndrome (AS) is a neurodevelopmental disorder characterised by severe mental retardation, dysmorphic features, ataxia, seizures, and typical behavioural characteristics, including a happy sociable disposition. AS is caused by maternal deficiency of UBE3A (E6 associated protein ubiquitin protein ligase 3A gene), located in an imprinted region on chromosome 15q11-q13. Although there are four different molecular types of AS, deletions of the 15q11-q13 region account for approximately 70% of the AS patients. These deletions are usually detected by fluorescence in situ hybridisation studies. The deletions can also be subclassified based on their size into class I and class II, with the former being larger and encompassing the latter. METHODS: We studied 22 patients with AS due to microdeletions using a microarray based comparative genomic hybridisation (array CGH) assay to define the deletions and analysed their phenotypic severity, especially expression of the autism phenotype, in order to establish clinical correlations. RESULTS: Overall, children with larger, class I deletions were significantly more likely to meet criteria for autism, had lower cognitive scores, and lower expressive language scores compared with children with smaller, class II deletions. Children with class I deletions also required more medications to control their seizures than did those in the class II group. CONCLUSIONS: There are four known genes (NIPA1, NIPA2, CYFIP1, & GCP5) that are affected by class I but not class II deletions, thus raising the possibility of a role for these genes in autism as well as the development of expressive language skills.

Elevated myelin basic protein levels in the cerebrospinal fluid of children with acute lymphoblastic leukemia.

Cerebrospinal fluid was examined from 70 children with acute lymphoblastic leukemia for evidence of active myelin breakdown based on the release of myelin basic protein (MBP). Fifty-three asymptomatic children were followed from diagnosis with serial MBP determinations. Eight (15.1%) of 53 children had abnormal elevations of MBP, six of eight before receiving presymptomatic central nervous system therapy. Long-term observations are in progress. For comparison, six children with clinical and radiologic findings of leukoencephalopathy had abnormal MBP determinations, whereas no abnormalities were detected in 11 children with meningeal leukemia.

Rett's syndrome. Correlation of electroencephalographic characteristics with clinical staging.

Rett's syndrome is a progressive disorder in female patients, characterized by autistic behavior, dementia, ataxia, loss of purposeful use of the hands, and seizures. The electroencephalographic (EEG) characteristics of 17 patients with Rett's syndrome, studied between the ages of 1 and 16 years, are reported and correlated with a recently proposed system of clinical staging. Although a specific diagnostic EEG pattern was not seen in these patients, we did observe a progressive deterioration in the EEG, characterized by a slowing of EEG activity, a loss of normal sleep EEG characteristics, and the appearance of multifocal epileptiform abnormalities, followed by a pattern of generalized slow spike-wave activity. These characteristics appear to be typically seen in patients with Rett's syndrome and can be correlated with clinical staging. The EEG may be of benefit in identifying variations or subgroups in patients with Rett's syndrome as a complement to the clinical examination.

Effect of tetrabenazine on tics and sleep of Gilles de la Tourette's syndrome.

Supersensitivity of dopaminergic receptors may be responsible for the tics of Tourette's syndrome. Symptoms improve after treatment with dopamine blockers, but side effects limit use of these drugs. We evaluated tetrabenazine (which has both presynaptic monoamine-depleting effects and postsynaptic blocking action) in nine patients. Marked and lasting (more than 6 months) improvement occurred in four patients (ages 10 to 14 years), mild or transient (less than 6 months) improvement occurred in three patients (ages 11 to 20 years), and two patients (age 48 years) had minimal or no response. Side effects included drowsiness in six, "nervousness" in two, depression in two, parkinsonism in one, and oculogyric crises in one, but all undesirable effects cleared with maintenance or reduction of the dosage.

Sleep in Gilles de la Tourette's syndrome: disorder of arousal.

Overnight polygraphic sleep studies, which included accelerometry and video monitoring, were performed on 14 Tourette patients before therapy and on 11 age-matched controls. Tourette patients less than 23 years old had a significantly increased percentage of stage 3/4 sleep, had an increased number of awakenings, had a decreased percentage of REM sleep, experienced paroxysmal events during stage 4 sleep, and had motor tics during all stages of sleep. Three patients were treated with tetrabenazine and subsequently showed significant decreases in percentage of total sleep, number of awakenings, and number of tics during sleep. These findings suggest a disorder of arousal in Tourette patients.

Extrapyramidal involvement in Rett's syndrome.

Extrapyramidal dysfunction is poorly characterized in Rett's syndrome, a neurodegenerative disorder in girls. We studied the motor and behavioral findings in 32 Rett's syndrome patients, 21 months to 30 years old. In addition to the typical stereotyped movements and scoliosis, other motor disturbances included bruxism, sialorrhea, ocular deviations, parkinsonian findings, dystonia, myoclonus, and athetosis. The types of movement disorders seemed to be age-related, with the hyperkinetic disorders occurring in the younger patients and the bradykinetic disorders occurring more frequently in the older patients.

Tics and vocalizations in children treated with carbamazepine.

Three patients are reported who, following the initiation of carbamazepine therapy for seizure control, either experienced the onset of Tourette's syndrome or a worsening of their tics and vocalizations. Blood levels of carbamazepine were within the therapeutic range, and no patient showed clinical signs of intoxication. Tics and vocalizations did not resolve following discontinuation of carbamazepine therapy. Carbamazepine may trigger the onset of Tourette's syndrome in susceptible patients.

Epidemiology of Rett syndrome: a population-based registry.

The Texas Rett Syndrome Registry maintains the largest population-based registry of cases and potential cases of Rett syndrome in the world. The most precise estimate of the prevalence of Rett syndrome of 1 per 22800 (0.44/10000) females aged 2 through 18 years of age was generated from this Registry. In addition, the first prevalence figures for black and Hispanic female cases were estimated. Registry cases are actively ascertained from multiple sources. Registry staff identify presumptive cases from review of information provided to the Registry by the parent or guardian. Preliminary diagnostic evaluation includes standardized review of medical records and videotape of key behaviors. Diagnosis is confirmed at clinical evaluation. The active surveillance system is monitored with the two-source capture-recapture methodology and case ascertainment is projected. The 1990 prevalence estimate of Rett syndrome indicates that the syndrome occurs less frequently than previously estimated. Until a biologic marker for Rett syndrome is identified or a standard definition for an incident case of Rett syndrome is designated, the prevalence of Rett syndrome will remain a major investigative issue of its epidemiology, and the Registry will be an important, systematic mean to gather case material for clinical and laboratory studies providing the foundation for the development of preventive interventions.

A de novo X;3 translocation in Rett syndrome.

Rett syndrome is a neurodegenerative disorder that occurs exclusively in females. The syndrome is sporadic in most cases with the exception of a few familial cases with an inheritance pattern through maternal lines. These observations raised the possibility that Rett syndrome may be due to an X-linked dominant mutation which is lethal in the male. To evaluate this hypothesis, we have systematically performed high-resolution chromosome analysis on 28 patients with Rett syndrome searching for deletions and/or translocations. In one patient, a de novo balanced translocation was observed with the chromosome constitution of 46,X,t(X;3) (p22.11;q13.31). This finding supports the hypothesis of an X-linked dominant mutation and suggests that the Rett gene might map to distal Xp21 or proximal Xp22.

Population-based registries using multidisciplinary reporters: a method for the study of pediatric neurologic disorders.

Few registries are available for evaluating population differences for rare, newly, or ill-defined pediatric neurologic disorders. The purpose of this article is to present standard methodologies for establishing a population-based registry and evaluating the completeness of a registry's case ascertainment. The Texas Rett Syndrome Registry (TRSR) is used as a model. The combination of health care and education resources has identified approx. 89-100% of the Rett syndrome cases in Texas. Cases reported by non-physician sources, although older on average (10.7 vs 7.7 years of age), did not differ by other demographic characteristics from those reported by physicians. Non-physician health and education professionals participated with the TRSR at a significantly higher rate than physicians, 89 and 37% (p < 0.05), respectively. Capture-recapture techniques, both two-sample and log-linear modeling, were used to quantitatively evaluate case ascertainment. Standardized national and international population-based registries could be the basis of an initiative to identify the etiology and perhaps preventive measures for pediatric neurologic disorders.

Coupling of focal electrical seizure discharges with infantile spasms: incidence during long-term monitoring in newly diagnosed patients.

To investigate the coupling of focal electrical seizure discharges (FS) and infantile spasms, we analyzed the video/polygraphic monitoring studies performed on 96 consecutive patients newly diagnosed with infantile spasms and hypsarrhythmic EEGs. A FS was considered to be coupled with infantile spasms if it occurred during a cluster of spasms (a series of individual spasms separated by < 1 min) or within 10 s of spasm onset or cessation. Ten patients demonstrated FS. In five patients (5% of the entire population) an apparent coupling of some FS with infantile spasms was observed during the baseline monitoring study. However, in three patients (only 3% of the entire population) was the observed coupling of FS and infantile spasms significant (p < 0.05). These results indicate that coupling of FS and infantile spasms occurs rarely, and that, in some instances, apparent couplings of FS and infantile spasms are best explained by chance coincidence. These findings do not support the hypothesis that the generation of infantile spasms at a subcortical level is dependent on a focal cortical discharge.

Alpha rhythm slowing during initiation of carbamazepine therapy: implications for future cognitive performance.

A prospective study comparing the immediate changes in occipital electroencephalographic (EEG) frequency following institution of carbamazepine therapy to long-term alterations of neuropsychological performance is reported. The patient group consisted of 16 previously untreated children in the 5-14-year age range who had recent onset partial seizures and were managed for at least 1 year with carbamazepine monotherapy. EEG changes following initiation of carbamazepine therapy, as compared to baseline, were determined by a computer-based quantitative method. Neuropsychological factors were assessed at baseline and after 1 year of therapy. While the alpha frequency decreased following institution of carbamazepine in most subjects, a greater decline (typically > 0.5 Hz) was observed in the subset who subsequently demonstrated decreased neuropsychological performance at 1 year. The major effects could be attributed to the Arithmetic and Picture Completion subtests of the Wechsler Intelligence Scale for Children-Revised (WISC-R). The findings suggest that quantitative EEG analysis may be useful for identifying individuals at increased risk for developing anticonvulsant-related long-term cognitive changes.

Altered energy balance may account for growth failure in Rett syndrome.

To determine whether alterations in energy balance account for growth failure in Rett syndrome, we measured dietary energy intakes, fecal fat losses, activity patterns, and sleeping as well as quietly and actively awake metabolic rates in Rett syndrome girls and healthy controls. Dietary energy intakes and fecal fat losses did not differ between the groups. Metabolic rates while sleeping and quietly awake were 23% lower (P < .05) in Rett syndrome girls than in controls; metabolic rates while actively awake did not differ between the groups. However, because of the 2.4-fold greater time (P < .001) spent in involuntary motor movement, energy expenditure associated with activity was twofold greater (P < .05) in Rett syndrome girls than in controls. Although total daily energy expenditure of the two groups did not differ significantly, energy balance was less positive in the Rett syndrome girls than in the controls. This small difference in energy balance, if sustained over months to years, is sufficient to account for growth failure in Rett syndrome girls.

Rett syndrome: discrimination of typical and variant forms.

Eighteen female patients are described with the clinical features of Rett syndrome. Fifteen patients fulfill the criteria established by Hagberg et al hereas three represent clinical variants. Detailed biochemical and neurodiagnostic assessment was conducted in all patients. Reduction in cerebrospinal biogenic amine metabolites and characteristic alterations in respiratory, sleep, and EEG patterns were helpful in supporting the clinical diagnosis in the fifteen patients with typical features of Rett syndrome. In the remaining three patients, the modalities were much less helpful in establishing the diagnosis. Until a molecular marker is defined, diagnosis must depend on careful clinical assessment.

Computed tomography in infantile spasms: effects of hormonal therapy.

During a prospective double-blind, crossover study of ACTH versus prednisone therapy, serial computed tomography (CT) scans were performed on 16 children with infantile spasms. Pre-treatment scans revealed four findings: normal (6 patients), generalized atrophy (bilaterally enlarged ventricles and/or subarachnoid space) (2 patients), predominantly focal atrophy (3 patients), and congenital anomalies (5 patients). Within 2 weeks of initiating relatively low therapeutic dosages of ACTH or prednisone, a significant number of the infants (63%) had CT findings consistent with decreased cortical volume; in many cases (44%), these findings had not reversed 4 to 6 weeks after discontinuing therapy. Duration of therapy did not correlate significantly with the persistence of CT changes.

Substance P immunoreactivity in Rett syndrome.

Severe autonomic dysfunction occurs in Rett syndrome (RS). Substance P, a tachykinin peptide that localizes to several brain regions, including the autonomic nervous system, is reduced in the cerebrospinal fluid of patients with RS. The anatomic localization and intensity of substance P immunoreactivity and glial fibrillary acidic protein-positive astrocytes in the brains of 14 patients with RS were compared with those in the brains of 10 age-matched normal patients. Substance P immunoreactivity expression was significantly decreased in RS tissue compared with control tissue in the following regions: dorsal horns, intermediolateral column of the spinal cord, spinal trigeminal tract, solitary tract and nucleus, parvocellular and pontine reticular nuclei, and locus ceruleus. A less significant decrease of substance P immunoreactivity occurred in the substantia nigra, central gray of the midbrain, frontal cortex, caudate, putamen, globus pallidus, and thalamus. Antiglial fibrillary acidic protein-positive astrocytes were increased in the areas in which substance P immunoreactivity was decreased and in other brain regions. Because many of the brain regions with the greatest decrease in substance P immunoreactivity are involved in the control of the autonomic nervous system, especially the solitary tracts and reticular formation, reduced substance P may contribute to the autonomic dysfunction in RS.

Organ growth in Rett syndrome: a postmortem examination analysis.

Rett syndrome is a disorder of unknown etiology in females that manifests as severe mental and motor retardation during the first years of life. A postnatal pattern of altered growth is its earliest clinical expression. Head growth decelerates during the first year of age and is followed by a decline in somatic (height/weight) growth. The decreased occipitofrontal circumference (OFC) is reflected in decreased brain size, and measurements of the dendrites of cortical neurons suggest that a developmental and growth arrest have occurred. To further document growth in Rett syndrome, measurements of organ weights, as recorded in 39 postmortem examination studies were compared with normal organ weights for females of comparable age and height. These organ weights suggest that the pattern of growth failure in Rett syndrome, as compared with other forms of mental handicap, such as Down syndrome and Turner's syndrome, may be unique. In Rett syndrome the rate of brain growth, as derived from OFC, decelerates after birth. The increment in normal brain weight after 4 years of age, the age of the first postmortem examinations, is not observed in the Rett brain. The heart, kidneys, liver, and spleen grow at the normally defined rate until 8-12 years of age, when their growth rate decelerates, but their growth continues achieving organ weights that are appropriate for the height of the female. Adrenal weights are normal. These observations suggest that despite a generalized decreased growth in Rett syndrome the brain may be preferentially affected in this syndrome.

Clinical severity and quality of life in children and adolescents with Rett syndrome.

OBJECTIVE: The clinical features and genetics of Rett syndrome (RTT) have been well studied, but examination of quality of life (QOL) is limited. This study describes the impact of clinical severity on QOL among female children and adolescents with classic RTT. METHODS: Cross-sectional and longitudinal analyses were conducted on data collected from an NIH-sponsored RTT natural history study. More than 200 participants from 5 to 18 years of age with classic RTT finished their 2-year follow-up at the time of analysis. Regression models after adjustment for their MECP2 mutation type and age at enrollment were used to examine the association between clinical status and QOL. RESULTS: Severe clinical impairment was highly associated with poor physical QOL, but worse motor function and earlier age at onset of RTT stereotypies were associated with better psychosocial QOL; conversely, better motor function was associated with poorer psychosocial QOL. CONCLUSIONS: Standard psychosocial QOL assessment for children and adolescents with RTT differs significantly with regard to their motor function severity. As clinical trials in RTT emerge, the Child Health Questionnaire 50 may represent one of the important outcome measures.