Evidence for enhanced functional activity of cervical cord in relapsing multiple sclerosis

Functional MRI (fMRI) was used to assess proprioceptive‐associated cervical cord activity in 24 relapsing multiple sclerosis (MS) patients and 10 controls. Cord and brain conventional and diffusion tensor (DT) MRI were also acquired. fMRI was performed using a block design during a proprioceptive stimulation consisting of a passive flexion‐extension of the right upper limb. Cord lesion number, cross‐sectional area, mean diffusivity (MD) and fractional anisotropy (FA), whole brain and left corticospinal tract lesion volume (LV), gray matter (GM) MD, and normal‐appearing white matter (NAWM) MD and FA were calculated. MS patients had higher average cord fMRI signal changes than controls (3.4% vs. 2.7%, P = 0.03). Compared to controls, MS patients also had a higher average signal change in the anterior section of the right cord at C5 (P = 0.005) and left cord at C5–C6 (P = 0.03), whereas no difference was found in the other cord sections. Cord average signal change correlated significantly with cord FA and brain left corticospinal tract LV, GM‐MD, and NAWM‐FA. This study shows an abnormal pattern of activations in the cervical cord of MS patients following proprioceptive stimulation. Cord fMRI changes might have a role in limiting the clinical consequences of MS associated with irreversible tissue damage. Magn Reson Med 59:1035–1042, 2008. © 2008 Wiley‐Liss, Inc.     

RELN and VLDLR mutations underlie two distinguishable clinico‐radiological phenotypes

Pontocerebellar hypoplasias (PCH) are characterized by lack of development and/or early neurodegeneration of cerebellum and brainstem. We report five patients referred for PCH, showing atypical clinical and magnetic resonance imaging (MRI) features suggestive of defects in the Reelin pathway. We screened for mutations in RELN or VLDLR and compared the phenotype of these patients with that of previously reported patients. All patients had profound cerebellar hypoplasia on MRI with peculiar cerebellar morphology, associated with flattened pons and neocortical abnormalities. Patient 1 had profound motor and intellectual disability with moderate lissencephaly suggestive of RELN mutations and was shown to harbor a splicing homozygous RELN mutation. The four other patients had a milder phenotype consistent with CARMQ1 (cerebellar ataxia and mental retardation with or without quadrupedal locomotion). These patients showed mild simplification or thickening of cortical gyration and had VLDLR mutations. Reelin signaling regulates neuronal migration in the developing mammalian brain. VLDLR is a key component of the Reelin pathway. Our patients had a very small and dysplatic cerebellar vermis that should suggest the involvement of these genes. Moreover, differences in clinical severity, involvement of the cerebellar hemispheres, together with the severity of the neocortical defect, enables RELN‐mutated patients to be distinguished from VLDLR‐mutated patients.     

Proposed norms for the Glasgow hearing-aid benefit profile (Ghabp) questionnaire

Abstract

Objective: To form a normative set of responses to the GHABP questionnaire from a large regional dataset. Design: Participants were asked to rate their hearing disability, handicap, hearing-aid (HA) use, HA benefit, HA satisfaction, and residual (aided) disability on a five-point scale for four situations: quiet conversation, television (TV) listening, noisy conversation, and group conversation. A subset of participants also estimated the time spent in these situations. Study sample: A group of 1574 adults with normal to profound hearing thresholds participated. Results: There was a significant relationship between increasing perceived disability and increasing hearing loss as given by the better-ear audiometric average (BEA). Responses for HA measures did not vary greatly with hearing loss: HA use was reported as high, whereas residual disability, HA benefit, and satisfaction were all reported on average as moderate. Conclusions: The results can be used as a normative dataset with which to evaluate individual responses in the clinic, where the GHABP provides a useful short-form questionnaire to engage the patient. The lack of systematic changes in hearing-aid related responses shows room for improvement in the benefit afforded by amplification.     

De Novo Mutations in the Motor Domain of KIF1A Cause Cognitive Impairment,Spastic Paraparesis,Axonal Neuropathy,and Cerebellar Atrophy

KIF1A is a neuron‐specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic paraparesis or sensory and autonomic neuropathy type‐2. Here, we report 11 heterozygous de novo missense mutations (p.S58L, p.T99M, p.G102D, p.V144F, p.R167C, p.A202P, p.S215R, p.R216P, p.L249Q, p.E253K, and p.R316W) in KIF1A in 14 individuals, including two monozygotic twins. Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases. All these de novo mutations are located in the motor domain (MD) of KIF1A. Structural modeling revealed that they alter conserved residues that are critical for the structure and function of the MD. Transfection studies suggested that at least five of these mutations affect the transport of the MD along axons. Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy. Our findings thus indicate that de novo missense mutations in the MD of KIF1A cause a phenotype that overlaps with, while being more severe, than that associated with recessive mutations in the same gene.     

Biallelic HERC1 mutations in a syndromic form of overgrowth and intellectual disability

We report two Colombian siblings affected by overgrowth, intellectual disability and facial dysmorphism. Exome (via NGS) and Sanger sequencing revealed that biallelic sequence variants in a novel gene (HERC1) might be related to the disease pathogenesis. These results provide useful data for future genotype–phenotype correlations and for a molecular diagnosis of overgrowth.     

Children followed with difficulty: How do they differ?

OBJECTIVE: To determine if very low birthweight children followed with ease differ in any perinatal or sociodemographic characteristics, or outcomes, compared with children followed with more difficulty. METHODOLOGY: Consecutive children of birthweight < 1000 g or with gestational ages < 28 weeks born in 1991 (n = 51) or of birthweight < 1500 g born in 1992 (n = 166) at the Royal Women's Hospital, Melbourne, surviving to 5 years of age, were assessed at 5 years of age, corrected for prematurity. Those who attended on the first mutually agreed appointment without substantial reluctance were considered to have been followed with ease. The remainder were considered to have been followed with difficulty. Outcomes included impairments such as cerebral palsy, blindness, deafness, and low IQ. Children had a disability if they had any of cerebral palsy, blindness, deafness requiring amplification, or an IQ more than 1 SD below the mean. RESULTS: Of the 217 survivors, 204 (94%) were assessed fully at 5 years of age. Of the 204 children assessed, 153 (75%) were followed with ease, and 51 (25%) with difficulty. Of data available in the perinatal period, significantly fewer children followed with more difficulty came from intact families, and more of their mothers had fewer than 12 years of schooling. More children followed with difficulty had a disability (41% compared with 19%), as they predominantly had lower IQ scores (mean difference in IQ - 12.7, 95% confidence interval - 18.0, - 7.4). The association between difficulty of assessment and both higher rates of disability and lower IQ scores remained after adjustment for significant perinatal and sociodemographic variables. CONCLUSIONS: Children followed with difficulty can partly be recognized on several sociodemographic characteristics in the perinatal period, and have substantially worse sensorineural outcomes than those followed with ease. In any longitudinal study, the more incomplete the follow up, the lower will be the rate of adverse sensorineural outcome.     

智力障碍儿童的亚端粒拷贝数变异检测

目的应用多重连接探针扩增技术(MLPA)检测亚端粒拷贝数变异,探讨遗传性智力障碍(ID)的发病机制。方法收集68例G-显带染色体核型分析结果正常的ID患儿,通过MLPA P036筛查亚端粒拷贝数变异。结果 68例患儿中检出亚端粒拷贝数异常者7例(10%),均为缺失突变,其中1例患儿涉及2个亚端粒的缺失变异,另1例患儿涉及4个亚端粒的缺失变异。结论亚端粒拷贝数变异是遗传性ID的重要病因;MLPA可作为研究遗传性ID患儿发病机制的经济、有效的方法。