Alan K. Percy

Specific mutations in Methyl-CpG-Binding Protein 2 confer different severity in Rett syndrome

Objective: To determine if a relationship exists between the clinical features of Rett syndrome, an X-linked dominant neurodevelopmental disorder, and specific mutations in MECP2. Method: Cross-sectional study of 245 girls and women with typical Rett syndrome seen between 1990 and 2004 in tertiary academic outpatient specialty clinics and who had complete MECP2 mutation analysis. A structured clinical evaluation was completed for each participant. The results were grouped by MECP2 mutation and compared. Results: Participants with the R133C mutation are less severely affected than those with R168X or large DNA deletions (p < 0.05). Likewise, individuals with the R168X mutation are more severely affected than those with R294X and late carboxy-terminal truncating mutations (p < 0.05). Clinical differences are notable in ambulation, hand use, and language (p < 0.004), three cardinal features of Rett syndrome. Individuals with R168X are less likely to walk (p = 0.008), retain hand use (p = 0.002), or use words (p = 0.001). In contrast, those with carboxy-terminal truncations are more likely to walk (p = 0.007) and use words (p < 0.001). The R306C mutation, previously found to confer milder features, adversely affects only one clinical feature, language (p < 0.05). Conclusions: Specific mutations in MECP2 confer different severity. These results allow the design of therapies targeted toward the amelioration of expected problems. Furthermore, the distinct effects of MECP2 mutations on clinical severity must be considered in clinical intervention trials.

Occipital horn syndrome and a mild Menkes phenotype associated with splice site mutations at the MNK locus

We have found mutations in the Menkes disease gene (MNK) which impair, but do not abolish, correct mRNA splicing in patients with less severe clinical phenotypes. In one family, four males aged 2–36 years with a distinctive Menkes variant have a mutation at the +3 position of a splice donor site near the 3′ end of the Menkes coding sequence that is associated with exon skipping and a stable mutant transcript. In an unrelated 15-year-old male with typical occipital horn syndrome, a point mutation at the −2 exonic position of a splice donor site in the middle of the gene causes exon-skipping and activation of a cryptic splice acceptor site. In both mutations, maintenance of some normal splicing is demonstrable by RT-PCR, cDNA sequencing and ribonuclease protection.

Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities

Rett syndrome (RTT) is characterized by specific motor, cognitive, and behavioral deficits. Because several of these abnormalities occur in other disease states associated with alterations in aminergic neurotransmitters, we investigated the contribution of such alterations to RTT pathogenesis. We found that both individuals with RTT and Mecp2-null mice have lower-than-normal levels of aminergic metabolites and content. Deleting Mecp2 from either TH-positive dopaminergic and noradrenergic neurons or PET1-positive serotonergic neurons in mice decreased corresponding neurotransmitter concentration and specific phenotypes, likely through MeCP2 regulation of rate-limiting enzymes involved in aminergic neurotransmitter production. These data support a cell-autonomous, MeCP2-dependent mechanism for the regulation of aminergic neurotransmitter synthesis contributing to unique behavioral phenotypes.

Clinical and genetic heterogeneity in benign hereditary chorea

Background Benign hereditary chorea (BHC) is an autosomal dominant disorder that can be distinguished from Huntington disease by its early onset, stable or only slightly progressive course, and absence of mental deterioration. The variation in clinical features is such that its very existence has been doubted. The authors recently described the localization of a gene responsible for BHC on chromosome 14q in a large Dutch family. Objective To report results of extensive clinical and linkage analyses for this Dutch family and six other families with BHC. Results Three of the seven families had linkage to a region on chromosome 14q13.1-q21.1. HOMOG analysis showed odds of 10 × 1011 in favor of locus heterogeneity. Haplotype analyses for the linked families resulted in a reduction of the critical interval for the BHC gene to 8.4 cM between marker D14S49 and marker D14S278. Clinically, these three families had a homogeneous picture with early-onset chorea, sometimes accompanied by slight ataxia in walking, but without dystonia, myoclonic jerks, or dysarthria. The severity of the choreatic movements tended to abate in adolescence or early adulthood. In the unlinked families, symptoms and signs were more heterogeneous as to age at onset and the occurrence of myoclonic jerks or dystonia. ConclusionsBHC is a clinically and genetically heterogeneous disorder, with one well-defined clinical syndrome mapping to chromosome 14q.

Extrapyramidal involvement in Rett's syndrome

Extrapyramidal dysfunction is poorly characterized in Retts syndrome, a neurodegenerative disorder in girls. We studied the motor and behavioral findings in 32 Retts 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, parkin-sonian 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.

Distinctive Menkes disease variant with occipital horns: Delineation of natural history and clinical phenotype

To delineate further the clinical spectrum of Menkes disease, an X-linked recessive disorder of copper transport, we studied 4 related males, ranging in age from 4-38 years, with a unique phenotype that combines manifestations of classical and mild Menkes disease and occipital horn syndrome (OHS). The propositus, and 18-year-old man, was evaluated following an intracerebral hemorrhage at age 15 years and was noted to have marked hypotonia, motor delay with mental retardation, bladder diverticula, failure to thrive, and diarrhea from infancy; seizures from age 3 years; and abnormal hair (pili torti) and face, cutis laxa, and multiple joint dislocations. Radiographic abnormalities included occipital exostoses, tortuous cerebral blood vessels with multiple branch occlusions, and hammer-shaped clavicles. Biochemical studies demonstrated reduced copper and ceruloplasmin levels in serum, and abnormal plasma catecholamine ratios. We reported previously the molecular defect in this family, a splice-site mutation that predicts formation of approximately 20% of the normal Menkes gene product [Kaler et al., 1994: Nat Genet 18:195-202]. Here, we detail the clinical course and physical features and radiographic findings in these 4 individuals, and compare their phenotype with classical and mild Menkes and OHS. Unusual Menkes disease variants such as this may escape recognition due to anomalies that appear inconsistent with the diagnosis, particularly prolonged survival and later onset of seizures. Males with mental retardation and connective tissue abnormalities should be evaluated for biochemical evidence of defective copper transport.

Interrater agreement in the assessment of motor manifestations of Huntington's disease

With prospects improving for experimental therapeutics aimed at postponing the onset of illness in preclinical carriers of the Huntingtons disease (HD) gene, we assessed agreement among experienced clinicians with respect to the motor manifestations of HD, a relevant outcome measure for preventive trials in this population. Seventy‐five clinicians experienced in the evaluation of patients with early HD and six non‐clinicians were shown a videotape compiled from the film archives of the United States–Venezuela Collaborative HD Research Project. Observers were asked to rate a 2–3‐minute segment of the motor examination for each of 17 at‐risk subjects. The rating scale ranged from 0 (normal) to 4 (unequivocal extrapyramidal movement disorder characteristic of HD). As measured by a weighted κ statistic, there was substantial agreement among the 75 clinicians in the judgment of unequivocal motor abnormalities comparing scale ratings of 4 with ratings that were not 4 (weighted κ = 0.67; standard error (SE) = 0.09). Agreement among the non‐clinicians was only fair (weighted κ = 0.28; SE = 0.10). Even under the artificial conditions of a videotape study, experienced clinicians show substantial agreement about the signs that constitute the motor manifestations of illness in subjects at risk for HD. We expect these findings to translate to a similar level of interobserver agreement in the clinical trial setting involving experienced investigators examining live patients.

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.

Child neurology training via the research pathway: outcome study.

This article describes a residency training track that was developed by the American Board of Psychiatry and Neurology to promote the career development of child neurologists who wanted to become researchers. In this pathway, 1 year of research in the basic neurosciences replaces 1 year of pediatrics or internal medicine. Since 1992, 38 residents from more than 20 training programs have been accepted into this pathway. Of the 28 who have completed residency training, 22 are in academic positions as faculty or fellows, and 6 are working in nonacademic hospital settings. Of these 22, 6 describe their research as basic, and 12 describe their research as being both basic and clinical; 15 have been successful in obtaining external funding. Thus far, these trainees have published more than 125 articles in peer-reviewed journals. Although small in scope, this training track has met its objective of producing clinician-scientists. ( J Child Neurol 2004;19:142—144).

Loss of MeCP2 Causes Urological Dysfunction and Contributes to Death by Kidney Failure in Mouse Models of Rett Syndrome

Rett Syndrome (RTT) is a neurodevelopmental disorder characterized by loss of acquired skills during development, autonomic dysfunction, and an increased risk for premature lethality. Clinical experience identified a subset of individuals with RTT that present with urological dysfunction including individuals with frequent urinary tract infections, kidney stones, and urine retention requiring frequent catheterization for bladder voiding. To determine if urologic dysfunction is a feature of RTT, we queried the Rett Syndrome Natural History Study, a repository of clinical data from over 1000 individuals with RTT and found multiple instances of urological dysfunction. We then evaluated urological function in a mouse model of RTT and found an abnormal pattern of micturition. Both male and female mice possessing Mecp2 mutations show a decrease in urine output per micturition event. Furthermore, we identified signs of kidney failure secondary to urethral obstruction. Although genetic strain background significantly affects both survival and penetrance of the urethral obstruction phenotype, survival and penetrance of urethral obstruction do not directly correlate. We have identified an additional phenotype caused by loss of MeCP2, urological dysfunction. Furthermore, we urge caution in the interpretation of survival data as an endpoint in preclinical studies, especially where causes of mortality are poorly characterized.