CMT1X phenotypes represent loss of GJB1 gene function.

OBJECTIVE: To investigate possible genotype-phenotype correlations and to evaluate the natural history of patients with Charcot-Marie-Tooth disease type 1X (CMT1X). BACKGROUND: CMT1X is caused by over 260 distinct mutations in the gap junction beta 1 (GJB1) gene, located on the X chromosome, which encodes the gap junction protein connexin 32 (Cx32). The natural history of CMT1X is poorly understood, and it remains unknown whether particular mutations cause more severe neuropathies through abnormal gain-of-function mechanisms. METHODS: We evaluated 73 male patients with CMT1X, who each have 1 of 28 different GJB1 mutations predicted to affect nearly all domains of Cx32. Disability was evaluated quantitatively by the CMT Neuropathy Score (CMTNS) as well as by the CMT Symptom Score (CMTSS) and the CMT Examination Score (CMTES), which are both based on the CMTNS. Patients were also evaluated by neurophysiology. RESULTS: In all patients, disability increased with age, and the degree of disability was comparable with that observed in patients with a documented GJB1 deletion. Disability correlated with a loss of motor units as assessed by motor unit number estimates. CONCLUSIONS: Taken together, these data suggest that most GJB1 mutations cause neuropathy by a loss of normal connexin 32 function. Therefore, treatment of male patients with Charcot-Marie-Tooth disease type 1X may prove amenable to gene replacement strategies.

Reliability and validity of the CMT neuropathy score as a measure of disability.

OBJECTIVE: To determine the validity and reliability of the Charcot-Marie-Tooth disease (CMT) neuropathy score (CMTNS) in patients with inherited neuropathy. BACKGROUND: Natural history studies and potential treatment trials for patients with various forms of CMT are limited by the lack of quantitative methodologies to monitor disease progression. Most cases of CMT can be considered length-dependent axonal neuropathies because disability for even the demyelinating forms correlates with length-dependent axonal degeneration. The total neuropathy score (TNS) is a validated composite measure of disability in length-dependent axonal neuropathies but is weighted toward predominantly sensory neuropathies. Thus, the authors have devised a CMTNS, modified from the TNS, to provide a single measure to quantify CMT disability. METHODS: The authors measured inter- and intrainvestigator reliability of the CMTNS and performed a validation of the score with the Neuropathy Impairment Score (NIS), patient self-assessment scores, an ambulation index, and other measures of disability. RESULTS: Inter- and intrainvestigator reliability was more than 95% in the 60 patients evaluated. Patients could be divided into mild (CMTNS, < or =10), moderate (CMTNS, 11 to 20), and severe (CMTNS, > or =21) categories and demonstrated excellent correlations among all measures of disability. CONCLUSION: The Charcot-Marie-Tooth disease (CMT) neuropathy score is a validated measure of length-dependent axonal and demyelinating CMT disability and can be investigated as an end point for longitudinal studies and clinical trials of CMT.

Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth disease type 1A (CMT1A), the most frequent form of CMT, is caused by a 1.5 Mb duplication on the short arm of chromosome 17. Patients with CMT1A typically have slowed nerve conduction velocities (NCVs), reduced compound motor and sensory nerve action potentials (CMAPs and SNAPs), distal weakness, sensory loss and decreased reflexes. In order to understand further the molecular pathogenesis of CMT1A, as well as to determine which features correlate with neurological dysfunction and might thus be amenable to treatment, we evaluated the clinical and electrophysiological phenotype in 42 patients with CMT1A. In these patients, muscle weakness, CMAP amplitudes and motor unit number estimates correlated with clinical disability, while motor NCV did not. In addition, loss of joint position sense and reduction in SNAP amplitudes also correlated with clinical disability, while sensory NCV did not. Taken together, these data strongly support the hypothesis that neurological dysfunction and clinical disability in CMT1A are caused by loss or damage to large calibre motor and sensory axons. Therapeutic approaches to ameliorate disability in CMT1A, as in amyotrophic lateral sclerosis and other neurodegenerative diseases, should thus be directed towards preventing axonal degeneration and/or promoting axonal regeneration.

Explicit memory in pregnant women.

OBJECTIVE: The study was conducted to systematically investigate previous anecdotal reports of memory decline during pregnancy. STUDY DESIGN: We used a longitudinal design to investigate memory in women throughout pregnancy and in the postpartum period. Closely matched, nonpregnant women were similarly studied at equivalent intervals. We also assessed degree of depression and anxiety. RESULTS: There was a significant time-by-group interaction (P < .01) for both immediate and delayed recall of paragraph length material. Contrasts showed a significant decline in memory for the pregnant group from the second to the third trimester (P < .01). No significant changes in memory were noted for the control group. The pregnant women scored higher on both depression and anxiety scales; however, somatic rather than cognitive items accounted for the elevated scores. Fluctuations in mood and memory did not coincide. CONCLUSION: There is a pregnancy-related decline in memory, which is limited to the third trimester. The decline is not attributable to depression, anxiety, sleep deprivation, or other physical changes associated with pregnancy.

Psychosocial dimensions of learning disabilities: external validation and relationship with age and academic functioning.

This study was designed to assess the following in a group of 152 children with learning disabilities between the ages of 7 and 13 years: (a) the relationships between age and psychosocial functioning: (b) the relationships among psychosocial functioning, cognitive abilities, and academic achievement; and (c) the external validity of statistically derived psychosocial subtypes. Participants were assigned to one of seven psychosocial subtypes on the basis of a profile-matching algorithm. Overall, the findings suggested no increase in psychopathology with advancing age. In addition, clear relationships were found between academic achievement patterns and personality subtypes. Finally, the subtypes could be distinguished on the basis of a behavior problem checklist not used for the construction of the subtypes.

Psychosocial functioning of children with learning disabilities at three age levels.

In this study, the relationship between age and patterns of psychosocial functioning was investigated in a sample of 728 children with learning disabilities (LD). In the first part of the study, Young (7-8 years), Middle (9-10 years), and Old (11-13 years) children were subtyped by cluster analysis applied to scores on the Personality Inventory for Children (PIC). The subtypes that emerged at each age level were similar to those found in our previous research, and were comparable at each age level. In the second part of the study, children were classified within a PIC-based psychosocial typology developed in previous studies. When the subtypes were broken down by age category, the mean PIC profiles of Young, Middle, and Old children did not differ substantially in shape or elevation, and the proportions of Young, Middle, and Old children in each subtype were comparable. These results suggest that patterns of psychosocial functioning of children with LD are stable across ages 7-13 years and, overall, do not show increased psychopathology with increased age.

Psychosocial functioning of children: relations between personality subtypes and academic achievement.

Five hundred children from ages 6 to 12 who had been referred for neuropsychological assessment were clustered into six subtypes using a k-means technique applied to 10 PIC scales. Five of the six subtypes were virtually identical to subtypes identified in previous research (viz., normal, somatic concern, mild anxiety, externalized psychopathology, and internalized psychopathology). A sixth subtype (conduct disorder) was also found. Wide Range Achievement Test (WRAT) Reading and Spelling scores discriminated between normal, somatic concern, and conduct disorder subtypes on the one hand vs. the more disturbed externalized and internalized psychopathology subtypes on the other; the latter groups scored higher on these measures. The internalized psychopathology subtype also showed large discrepancies between reading vs. arithmetic and spelling vs. arithmetic. The results support the view that psychosocial functioning is related to assets and deficits in cognitive/academic functioning in children, and that particular patterns of such assets and deficits are related to particular forms of psychopathology.

Lateralizing value of transient hypofrontality during Wada's test.

Five of 22 subjects who underwent Wada's test in our institution over last year developed transient hypofrontality, always following the injection of the side contralateral to seizure focus (as defined by prior ictal recordings). This event may have lateralizing value and could well be because of pharmacological ablation of contralateral frontal-lobe combined with compromised ipsilateral frontal-lobe causing transient hypofrontality.

Event-related potentials in complex partial seizures.

Both early (N1 and P2) and late (N2 and P3) event-related potentials (ERP) were obtained in 16 patients with complex partial seizures, 12 with left hemispheric ictal focus and 4 with right, to see if they help in lateralizing the seizure focus, and also to determine if they correlate with behavioral (MMPI, Bear-Fedio), attentional (Trails A and B), cognitive (WAIS-R, Boston Naming, Warrington Word and Face recognition) and mental speed (Stroop color naming and reading) tasks. Early waves were more often lateralized than late waves but both were often falsely lateralizing. Early waves were better correlated with behavioral tasks whereas late waves were better with those measuring mental speed, attention and cognition. These data tentatively discourage the utility of ERP in preoperative lateralization of seizure focus but argue for their potential value in psychophysiological correlations.

Psychosocial functioning of learning-disabled children: relations between WISC Verbal IQ-Performance IQ discrepancies and personality subtypes.

A total of 132 children with learning disabilities (LD) between the ages of 6 and 12 years were divided equally into 3 groups on the basis of the difference between WISC VIQ-PIQ scores (viz., VIQ greater than PIQ, VIQ = PIQ, and VIQ less than PIQ). The mean Personality Inventory for Children (PIC) profiles for the VIQ = PIQ and VIQ less than PIQ groups were normal; however, the VIQ greater than PIQ group showed pathological elevations on some PIC scales. Group average linkage cluster analysis using 10 PIC scales revealed 6 psychosocial subtypes. Within these subtypes, children with VIQ greater than PIQ were found at lower than expected frequencies in normal and mildly disturbed subtypes, but at higher than expected frequencies in seriously disturbed subtypes. These results support the notion that patterns of cognitive performance are related to patterns of psychosocial functioning in children with LD.

Psychosocial functioning of learning-disabled children: replicability of statistically derived subtypes.

The PIC scores of 132 learning-disabled children between the ages of 6 and 12 years were investigated using Q-factor analysis, four hierarchical-agglomerative clustering techniques, and one iterative partitioning clustering technique. Results revealed excellent correspondence between the subtypes derived by all grouping methods in terms of both misclassifications and mean PIC profile similarity of the subtypes across techniques. The mean PIC profile of one subtype indicated normal psychosocial adjustment; a second subtype exhibited evidence of significant internalized psychopathology; a third subtype had a mean PIC profile suggestive of externalized psychosocial maladjustment. These subtypes were virtually identical to three subtypes reported by Porter and Rourke (1985) in another study of learning-disabled children. The results indicate that learning-disabled children comprise a heterogeneous population in terms of psychosocial functioning and that subtypes of learning-disabled children with similar patterns of socioemotional adjustment can be recovered reliably from this population across samples and statistical grouping techniques.