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.

Circadian rhythm abnormalities of melatonin in Smith-Magenis syndrome.

BACKGROUND: Smith-Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation syndrome associated with a hemizygous deletion of chromosome 17, band p11.2. Characteristic features include neurobehavioural abnormalities such as aggressive and self-injurious behaviour and significant sleep disturbances. The majority of patients have a common deletion characterised at the molecular level. Physical mapping studies indicate that all patients with the common deletion are haploinsufficient for subunit 3 of the COP9 signalosome (COPS3), which is conserved from plants to humans, and in the plant Arabidopis thaliana regulates gene transcription in response to light. Haploinsufficiency of this gene is hypothesised to be potentially involved in the sleep disturbances seen in these patients. Melatonin is a hormone secreted by the pineal gland. SMS patients are reported to have fewer sleep disturbances when given a night time dose of this sleep inducing hormone. METHODS: Urinary excretion of 6-sulphatoxymelatonin (aMT6s), the major hepatic metabolite of melatonin, in 19 SMS patients were measured in conjunction with 24 hour sleep studies in 28 SMS patients. Five of the 28 patients did not have the common SMS deletion. To investigate a potential correlation of COPS3 haploinsufficiency and disturbed melatonin excretion, we performed fluorescence in situ hybridisation (FISH) using two BACs containing coding exons of COPS3. RESULTS: All SMS patients show significant sleep disturbances when assessed by objective criteria. Abnormalities in the circadian rhythm of aMT6s were observed in all but one SMS patient. Interestingly this patient did not have the common deletion. All patients studied, including the one patient with a normal melatonin rhythm, were haploinsufficient for COPS3. CONCLUSIONS: Our data indicate a disturbed circadian rhythm in melatonin and document the disturbed sleep pattern in Smith-Magenis syndrome. Our findings suggest that the abnormalities in the circadian rhythm of melatonin and altered sleep patterns could be secondary to aberrations in the production, secretion, distribution, or metabolism of melatonin; however, a direct role for COPS3 could not be established.

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.

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.

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.

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.

Multi-disciplinary clinical study of Smith-Magenis syndrome (deletion 17p11.2)

Smith-Magenis syndrome (SMS) is a multiple congenital anomaly, mental retardation (MCA/MR) syndrome associated with deletion of chromosome 17 band p11.2. As part of a multi-disciplinary clinical, cytogenetic, and molecular approach to SMS, detailed clinical studies including radiographic, neurologic, developmental, ophthalmologic, otolaryngologic, and audiologic evaluations were performed on 27 SMS patients. Significant findings include otolaryngologic abnormalities in 94%, eye abnormalities in 85%, sleep abnormalities (especially reduced REM sleep) in 75%, hearing impairment in 68% (approximately 65% conductive and 35% sensorineural), scoliosis in 65%, brain abnormalities (predominantly ventriculomegaly) in 52%, cardiac abnormalities in at least 37%, renal anomalies (especially duplication of the collecting system) in 35%, low thyroxine levels in 29%, low immunoglobulin levels in 23%, and forearm abnormalities in 16%. The measured IQ ranged between 20-78, most patients falling in the moderate range of mental retardation at 40-54, although several patients scored in the mild or borderline range. The frequency of these many abnormalities in SMS suggests that patients should be evaluated thoroughly for associated complications both at the time of diagnosis and at least annually thereafter.

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.

Hand and foot growth failure in Rett syndrome.

Growth failure is a major aspect of the developmental arrest in Rett syndrome. Small hands and feet have been reported anecdotally, but the pattern of hand and foot growth has not been studied rigorously. The aims of this study were to characterize the hand and foot growth of 28 girls with Rett syndrome and to examine the relationship between their hand or foot size and height. Median hand length deviated to the 5th percentile at 11 years of age whereas median foot length and height deviated below the 5th percentile at 5.5 years of age. After adjusting for height-age, a greater proportion of foot lengths than hand lengths was less than the 50th percentile. In conclusion, the rate of hand and foot growth of girls with Rett syndrome is slower than that of the normal female. Moreover, the rate of deceleration of foot, but not hand, growth relative to height growth is greater. Thus, many girls with Rett syndrome have "small" feet, but not hands, for their height.

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.

Substance P immunoreactivity in the enteric nervous system in Rett syndrome.

Rett syndrome is associated with profound mental retardation and motor disability in girls. It has a characteristic clinical phenotype which includes abnormalities of the autonomic nervous system. Feeding impairment and severe constipation are two symptoms of this autonomic dysfunction. Substance P, an important peptide in the autonomic nervous system, is decreased in the cerebrospinal fluid of Rett syndrome. We have demonstrated that substance P immunoreactivity is significantly decreased in Rett syndrome brain-stem and may be related to the autonomic dysfunction. In this study, we have continued the investigation of substance P in the enteric nervous system. We immunohistochemically examined the normal developing bowel in 22 controls (ages, 14 gestational weeks to 31 years) using formalin fixed tissue, with antibodies to substance P, tyrosine hydroxylase and vasoactive intestinal peptide. We compared the immunoreactivity of normal controls with 14 cases of Rett syndrome (ages, 5-41 years) and observed that the expression of substance P, tyrosine hydroxylase and vasoactive intestinal peptide immunoreactivity in the bowel in Rett syndrome was not significantly different from that of controls. This suggests that the feeding impairment and constipation in Rett syndrome relate to dysfunction of the autonomic nervous system originating outside of the bowel, in the brain-stem, as suggested by our previous study.

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.