Graham Warner

BACKGROUND: Although a molecular diagnosis is possible in most patients having Charcot-Marie-Tooth disease (CMT), recessively inherited and axonal neuropathies still present a diagnostic challenge. OBJECTIVE: To determine the cause of axonal CMT type 2 in 3 siblings. DESIGN: Case report. SETTING: Academic research. PARTICIPANTS: Three siblings who subsequently developed profound cerebellar ataxia. MAIN OUTCOME MEASURES: Muscle biopsy specimen molecular genetic analysis of the POLG1 (polymerase gamma-1) gene, as well as screening of control subjects for POLG1 sequence variants. RESULTS: Cytochrome c oxidase deficient fibers and multiple deletions of mitochondrial DNA were detected in skeletal muscle. Three compound heterozygous substitutions were detected in POLG1. CONCLUSION: Even in the absence of classic features of mitochondrial disease, POLG1 should be considered in patients having axonal CMT that may be associated with tremor or ataxia.

AIMS: This study set out to establish a novel procedure for the measurement of human nerve growth factor (NGF) messenger ribonucleic acid (mRNA) and to use this method to measure NGF expression in skin biopsies from control subjects and from patients with early neuropathies. NGF mRNA levels were related to functional measures of the competence of NGF-responsive nerves. METHODS: mRNA levels were measured by competitive reverse transcription with polymerase chain reaction amplification (cRT-PCR). Functional correlates of this observation were assessed by indices of thermal sensitivity--mediated by C-fibres, whose phenotype is regulated by NGF. RESULTS: NGF mRNA was increased in skin biopsies from 19 diabetic patients (5.12+/-3.88 (SD)) compared with samples from eight controls (1.57+/-0.95; P=0.001). Diabetic patients showed significantly (P < 0.001) diminished detection of cool and warm stimuli compared to age matched control group (n=24), but there were no differences in detection of heat as pain, or correlation with NGF mRNA levels. CONCLUSIONS: These findings suggest abnormally increased expression of NGF in diabetic neuropathy, which may represent a compensatory mechanism for impaired phenotype in NGF-responsive neurones.

SUMMARY Plasma concentrations of protein C, protein S and antithrombin III were measured in 33 unselected children with a history of cryptogenic stroke (group 1), four children with previously ascertained low plasma concentrations of protein C following stroke (group 2) and 42 healthy children underging minor surgery (group 3). Protein S and antithrombin III were normal in all patients. Low concentrations of protein C were found in two patients in group 1 and in six healthy children in group 3. Low protein C concentrations returned to normal over many months in three of the four patients in group 2. Prophylactic antithrombotic therapy and/or termination of pregnancy had been carried out unneccessarily in two families in whom inherited protein C deficiency was not confirmed. The suggestion that heterozygous protein C deficiency contributes to the risk of arterial stroke was not supported by this study. RÉSUMÉ Déficience en protéinc C ct accident vasculo‐cérébral précoce Les concentrations plasmatiques de la protéine C, la proteinc S et L'antithrombine III ont été mesurées chez 33 enfants non sélectionnés présentant une histoire d'accident vasculo‐cérébral cryptogénétique (groupe 1), quatre enfants chez qui une concentration plasmatique basse de protéine C avait été trouvée aprés un accident vasculo‐cérébral (groupe 2) et 42 enfants en bonne santé hospitalisés pour un acte chirurgical mineur (groupe 3). La protéine S et L'antithrombine III étaient à des taux normaux chez tous les enfants. Des faibles concentrations de protéine C ont été trouvées chez deux patients du groupe 1 et six sujets du groupe 3. Les concentrations basses de protéines C ne redevinrent normales qu'aprés de nombreux mois chez trois des enfants du groupe 2. Un traitement prophylactique antithrombique et/ou une interruption de grossesse ont été pratiqués inutilemenl dans deux families chez qui une déficience héréditaire de protéine C ne fut pas confirmée. L'étude ne confirme done pas l'hypothése scion laquclle une déficience hétérozygote en protéine C contribue au risque d'accidents artérials cérébraux. ZUSAMMENFASSUNG Protein C Mangel undfrüher Schlaganfall Bei 33 nicht ausgewählten Kindern mit der Anamnese eines kryptogenen Schlaganfalls (Gruppe I), vier Kindern mit einer zuvor bestätigten niedrigen Plasniakonzentration von Protein C nach einem Schlaganfall (Gruppe 2) und 42 gesunden Kindern, die kleine chirurgische Fingriffe hatten (Gruppe 3), wurden die Plasmakonzentrationen von Protein C, Protein S und Antithrombin III gemessen. Protein S und Antithrombim III waren bei alien Patienten normal. Niedrige Konzentrationen von Protein C wurden bei zwei Patienten der Gruppe 1 und bei sechs gesunden Kindern der Gruppe 3 gefunden. Die niedrigen Protein C Konzentrationen bei drei der vier Patienten aus Gruppe 2 haben sich im Verlauf mehrerer Monate normalisiert. Bei zwei Familien. bei denen ein vererbter Protein C Mangel nicht bestätigt wurde, sind die prophylaktische antithrombotische Therapie und/oder die Beendigung der Schwangerschaft unnötigerweise durchgefürt worden. Die Vermutung, daß der heterozygote Protein C Mangel zum Risiko des arteriellen Schlaganfalls beiträgt, wurde in dieser Studie nich bestätigt. RUSUMEN Deficiencia de proteina C e ictus precoz Se midio las concentraciones plasmáticas de la proteína C, la proteína S y la antitrombina III en 33 niños no seleccionados con una historia de ictus criptogénico (grupo 1), cuatro niños con concentraciones plasmáticas bajas de proteína C post‐ictus previamente determinadas (grupo 2) y 42 niños sanos sujetos a una cirugl'a menor (grupo 3). La proteína S y la antitrombina III eran normales en todos los pacientes: Concentraciones bajas de proteîna C se hallaron en dos pacientes del grupo 1 y en seis niños sanos del grupo 3. Las concentraciones bajas de proteína C se normalizaron después de muchos meses en tres de los cuatro pacientes del grupo 2. La terapeutica antitrombótica profiláctica y/o la termination de embarazo se realizaron de forma innecesaria en dos familias, en las que la deficiencia hereditaria de proteina C no fue confirmada. La sugerencia de que la deficiencia en proteína C heterizigótica contribuye al riesgo de un ictus arterial no fue corroborada por este estudio.

BACKGROUND: White matter disconnection of language-specific brain regions associates with worse aphasia recovery. Despite a loss of direct connections, many stroke survivors may maintain indirect connections between brain regions. OBJECTIVE: To determine (1) whether preserved direct connections between language-specific brain regions relate to better poststroke naming treatment outcomes compared to no direct connections and (2) whether for individuals with a loss of direct connections, preserved indirect connections are associated with better treatment outcomes compared to individuals with no connections. METHODS: We computed structural whole-brain connectomes from 69 individuals with chronic left-hemisphere stroke and aphasia who completed a 3-week-long language treatment that was supplemented by either anodal transcranial direct current stimulation (A-tDCS) or sham stimulation (S-tDCS). We determined differences in naming improvement between individuals with direct, indirect, and no connections using 1-way analyses of covariance and multivariable linear regressions. RESULTS: = .039, respectively). Participants with direct connections between the inferior frontal gyrus pars opercularis and middle temporal gyrus who received S-tDCS and participants with indirect connections who received A-tDCS significantly improved in naming accuracy. CONCLUSIONS: Poststroke preservation of indirect white matter connections is associated with better treated naming improvement in aphasia even when direct connections are damaged. This mechanistic information can be used to stratify and predict treated naming recovery in individuals with aphasia.