Charcot–Marie–Tooth disease (CMT) is a clinically and genetically heterogeneous group of diseases with approximately 45 different causative genes described. The aims of this study were to determine the frequency of different genes in a large cohort of patients with CMT and devise guidelines for genetic testing in practice.
The genes known to cause CMT were sequenced in 1607 patients with CMT (425 patients attending an inherited neuropathy clinic and 1182 patients whose DNA was sent to the authors for genetic testing) to determine the proportion of different subtypes in a UK population.
A molecular diagnosis was achieved in 62.6% of patients with CMT attending the inherited neuropathy clinic; in 80.4% of patients with CMT1 (demyelinating CMT) and in 25.2% of those with CMT2 (axonal CMT). Mutations or rearrangements in PMP22, GJB1, MPZ and MFN2 accounted for over 90% of the molecular diagnoses while mutations in all other genes tested were rare.
Four commonly available genes account for over 90% of all CMT molecular diagnoses; a diagnostic algorithm is proposed based on these results for use in clinical practice. Any patient with CMT without a mutation in these four genes or with an unusual phenotype should be considered for referral for an expert opinion to maximise the chance of reaching a molecular diagnosis.
PD-GBA patients were identified by Sanger sequencing of the glucocerebrosidase gene in 220 sporadic PD (PD-S) patients. The G2019S mutation in LRRK2 had previously been excluded. A control group of glucocerebrosidase mutation negative PD-S were selected from the same cohort. Each participant had the following...]]>
Spinocerebellar ataxia syndromes presenting in adulthood have a broad range of causes, and despite extensive investigation remain undiagnosed in up to ~50% cases. Mutations in the mitochondrially encoded MTATP6 gene typically cause infantile-onset Leigh syndrome and, occasionally, have onset later in childhood. The authors report two families with onset of ataxia in adulthood (with pyramidal dysfunction and/or peripheral neuropathy variably present), who are clinically indistinguishable from other spinocerebellar ataxia patients.
Genetic screening study of the MTATP6 gene in 64 pedigrees with unexplained ataxia, and case series of two families who had MTATP6 mutations.
Three pedigrees had mutations in MTATP6, two of which have not been reported previously and are detailed in this report. These families had the m.9185T>C and m.9035T>C mutations, respectively, which have not previously been associated with adult-onset cerebellar syndromes. Other investigations including muscle biopsy and respiratory chain enzyme activity were non-specific or normal.
MTATP6 sequencing should be considered in the workup of undiagnosed ataxia, even if other investigations do not suggest a mitochondrial DNA disorder.
Amyotrophic lateral sclerosis 4 (ALS4), a rare form of autosomal dominant juvenile-onset ALS characterised by slow progression and sparing of bulbar and respiratory muscles,
Slight delays in early development resulted in the patient beginning to walk at 1.5 years. He was prone to falls and had suffered from pes cavus since childhood. At 35 years of age, the patient presented with difficulty walking. One year later he found it difficult to fully extend his fingers and this was exacerbated over the following 3 months. Nerve conduction studies revealed asymmetric demyelinating patterns (median nerve motor conduction velocity: right 29 m/s, left 53 m/s). Subsequently, the patient developed a neurogenic bladder. Intravenous immunoglobulin therapy (20 g/day...]]>
Orthostatic tremor is a rare tremor syndrome triggered exclusively by standing, with pathognomonic neurophysiological features. More recently, it has been suggested that orthostatic tremor can present either in isolation (pure orthostatic tremor) or associated with other movement disorders (orthostatic tremor-plus). The present study aims at expanding the knowledge concerning orthostatic tremor associated with other movement disorders.
A retrospective case review of the clinical and neurophysiological data of patients diagnosed with orthostatic tremor.
Median age of onset was 61 years with a median diagnostic delay of 4.5 years. Orthostatic tremor-plus accounted for eight cases (30.8%). The associated movement disorders were Parkinson's disease (n=1), parkinsonism (n=1), progressive supranuclear palsy (n=1), restless leg syndrome (n=1), multifocal action tremor (n=2), pathological proven dementia with Lewy bodies (n=1) and focal dystonia of the arm (n=1). There were no significant differences between primary orthostatic tremor and orthostatic tremor-plus in demographics, clinical presentation of orthostatic tremor, findings in neurophysiological studies and response to treatment. In the majority of cases (n=18, 72%), there was a progressive and disabling course with refractoriness to medical therapy without significant differences between pure orthostatic tremor and orthostatic tremor-plus.
One of the largest series on orthostatic tremor is presented and the second only focused on additional movement disorders. A progressive course was found, with increasing disability associated with orthostatic tremor. Dementia with Lewy bodies and task specific arm dystonia are reported for the first time as associated movement disorders.
The prevalence and outcome of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in patients with solid organ transplantation is unknown, and there are no guidelines for the evaluation and treatment of such patients.
An 8 year long monocentric prospective study was conducted in which, in a population of 1557 solid organ transplant recipients, the characteristics of 10 consecutive patients (0.6%) who developed a syndrome that fulfilled the clinical, biological and electrophysiological criteria for definite CIDP were investigated.
Five patients had liver transplantation, three had kidney transplantation, one had heart transplantation and one had lung transplantation. The mean interval between transplantation and CIDP was 10 months. Six patients developed CIDP after immunosuppressive therapy dosage was decreased and were treated with intravenous immunoglobulin (IVIG) and increased dosage of immunosuppressive therapy. Four patients were treated with IVIG only. Neuropathy improved in all cases, and CIDP had a monophasic course in all patients, with no relapse observed over a mean follow-up of 5 years.
CIDP in solid organ transplant recipients is rare, appears in the first year after transplantation, has a monophasic course and is responsive to IVIG treatment. CIDP being treatable, it should be systematically considered in solid organ transplant recipients who develop a rapidly disabling sensorimotor polyneuropathy.
30 years ago very high multiple sclerosis (MS) prevalence rates were recorded in northern Scotland. A prevalence study was repeated in Aberdeen, Orkney and Shetland to see if prevalence rates had changed, assess which factors affect prevalence and record disability status.
Hospital, general practice and laboratory records were searched to identify prevalent MS patients (alive and registered with a participating general practice on 24 September 2009). Records were reviewed to confirm diagnoses applying Poser definite and probable and McDonald diagnostic criteria. Disability status (Expanded Disability Status Scale) was recorded from records and questionnaires. Rates were standardised to the Scottish population.
590 patients were found (Aberdeen 442, Orkney 82, Shetland 66). Mean age and disease duration were 53 and 19.4 years, respectively. The standardised prevalence rates for Poser probable/definite MS per 100 000 were: combined area 248 (95% CI 229 to 269), Orkney 402 (95% CI 319 to 500), Shetland 295 (95% CI 229 to 375) and Aberdeen 229 (95% CI 208 to 250). McDonald diagnostic criteria gave a lower prevalence (202, 95% CI 198 to 206). Prevalence was highest in women (2.55:1, 95% CI 2.26 to 2.89) with about 1 in 170 women in Orkney affected. Prevalence was lowest in the most deprived socioeconomic group. 45% had significant disability (Expanded Disability Status Scale ≥6).
The prevalence of MS has increased in the overall area, most markedly in Orkney, then Shetland, over the past 30 years. This increase could be due to a number of factors, but rising incidence as reflected by a rising sex ratio, influenced by gene–environment interaction, is the most likely. Orkney has the highest prevalence rate recorded worldwide.
MOOD ATROPHY OF MEDIAL TEMPORAL LOBES ON MRI IN "PROBABLE" ALZHEIMER'S DISEASE AND NORMAL AGEING: DIAGNOSTIC VALUE AND NEUROPSYCHOLOGICAL CORRELATES
Authors: Scheltens P, Leys D, Barkhof F, et al
Published: 1992;55:967–72
Philip Scheltens and Laura A van de Pol of the Alzheimer Centre and Department of Neurology, VU University Medical Centre, Amsterdam, ask after 20 years of visual rating of medial temporal lobe atrophy on MRI in dementia, what have we learnt?
In the last decades of the previous century, interest in diagnosing Alzheimer's disease (AD) was rising. At the same time, MRI was being discovered as an exciting, non-invasive, high resolution method to study brain changes in vivo. Autopsy studies had shown that the medial temporal lobe structures, including the hippocampus, were the structures affected earliest and most severely in AD.
Deterioration of cognitive functioning is a debilitating symptom in many neurodegenerative diseases, such as Huntington's disease (HD). To date, there are no effective treatments for the cognitive problems associated with HD. Cognitive assessment outcomes will have a central role in the efforts to develop treatments to delay onset or slow the progression of the disease. The TRACK-HD study was designed to build a rational basis for the selection of cognitive outcomes for HD clinical trials.
There were a total of 349 participants, including controls (n=116), premanifest HD (n=117) and early HD (n=116). A standardised cognitive assessment battery (including nine cognitive tests comprising 12 outcome measures) was administered at baseline, and at 12 and 24 months, and consisted of a combination of paper and pencil and computerised tasks selected to be sensitive to cortical-striatal damage or HD. Each cognitive outcome was analysed separately using a generalised least squares regression model. Results are expressed as effect sizes to permit comparisons between tasks.
10 of the 12 cognitive outcomes showed evidence of deterioration in the early HD group, relative to controls, over 24 months, with greatest sensitivity in Symbol Digit, Circle Tracing direct and indirect, and Stroop word reading. In contrast, there was very little evidence of deterioration in the premanifest HD group relative to controls.
The findings describe tests that are sensitive to longitudinal cognitive change in HD and elucidate important considerations for selecting cognitive outcomes for clinical trials of compounds aimed at ameliorating cognitive decline in HD.
Patients with encephalitis associated with antibodies against N-methyl-D-aspartate-receptor antibody (NMDAR-ab) encephalitis frequently show psychotic symptoms, amnesia, seizures and movement disorders. While brain MRI in NMDAR-ab encephalitis is often normal, abnormalities of cerebral glucose metabolism have been demonstrated by positron emission tomography (PET) with 18F-fluorodeoxyglucose(FDG) in a few usually isolated case reports. However, a common pattern of FDG-PET abnormalities has not been reported.
The authors retrospectively identified six patients with NMDAR-ab encephalitis in two large German centres who underwent at least one whole-body FDG-PET for tumour screening between January 2007 and July 2010. They analysed the pattern of cerebral uptake derived from whole-body PET data for characteristic changes of glucose metabolism compared with controls, and the changes of this pattern during the course of the disease.
Groupwise analysis revealed that patients with NMDAR-ab encephalitis showed relative frontal and temporal glucose hypermetabolism associated with occipital hypometabolism. Cross-sectional analysis of the group demonstrated that the extent of these changes is positively associated with clinical disease severity. Longitudinal analysis of two cases showed normalisation of the pattern of cerebral glucose metabolism with recovery.
A characteristic change in cerebral glucose metabolism during NMDAR-ab encephalitis is an increased frontotemporal-to-occipital gradient. This pattern correlates with disease severity. Similar changes have been observed in psychosis induced by NMDAR antagonists. Thus, this pattern might be a consequence of impaired NMDAR function.
The management of anticoagulation (AC) therapy in patients with central nervous system (CNS) haemorrhage remains challenging. This study examines the potential factors associated with spinal haematoma among patients who develop CNS haemorrhage while on AC therapy.
Based on a systematic review using MEDLINE and EMBASE, two reviewers screened publications and extracted data on all CNS-haemorrhage cases. First, all cases were grouped into brain, posterior fossa and spinal haemorrhage. Second, the spinal-haemorrhage group was subdivided into those patients experiencing complete neurological recovery, incomplete recovery, no recovery and death. Finally, axonal survival and inflammatory response after spinal cord injury (SCI) due to trauma and spinal haemorrhage were examined using postmortem spinal cord tissue.
Data were extracted from 72 publications including 553 patients. There were significant differences among the CNS groups regarding patient characteristics and management, while their outcomes were comparable. Outcomes among the spinal-haemorrhage subgroups were not associated with patient characteristics and management. Postmortem examination of spinal cord showed that axonal survival and inflammatory response in a spinal-haemorrhage case were similar to a case of traumatic SCI.
The results of this study suggest that the management of patients with spinal haemorrhage considerably differ from individuals with an intracranial haemorrhage during AC. However, survival and neurological recovery appear to be comparable among the CNS groups. The studied factors failed to discriminate the patient subgroups according to survival and neurological recovery. Finally, the neuropathology result reinforces the possibility that the mechanism of SCI may not be relevant for axonal survival and inflammatory response within the spinal cord.
The aim of this study was to investigate whether axonal excitability indices are associated with survival in patients with amyotrophic lateral sclerosis (ALS). Previous nerve excitability studies suggested increased persistent sodium currents in motor axons of patients with ALS, which lead to axonal hyperexcitability and potentially enhance neuronal death.
112 patients with sporadic ALS were followed up until endpoint (death or tracheostomy). Multivariate analyses were performed using the Cox proportional hazard model. Threshold tracking was used to measure multiple axonal excitability indices in median motor axons, such as strength–duration time constant (SDTC; a measure of nodal persistent sodium current). Latent addition was also used to estimate the magnitude of persistent sodium currents.
The overall median tracheostomy-free survival from onset was 37 months. Prolonged SDTC was strongly associated with shorter survival (adjusted HR 4.07; 95% CI 1.7 to 9.8; p=0.0018) compared with older onset age (>60 years; HR=1.80) and bulbar onset (HR=1.80). Estimated median survival was 34 months in the longer SDTC group and 51 months in the shorter SDTC group. This index was highly statistically significant even after multiple testing adjustments with age and site of onset (bulbar or limb). Latent addition study results were consistent with these findings.
Axonal persistent sodium currents, estimated by SDTC and latent addition, are strong and independent predictors for shorter survival in patients with ALS. Membrane hyperexcitability is possibly associated with motor neuronal death, and modulation of excessive sodium currents could be a novel therapeutic option for ALS.
In the isolated population of Sardinia, a Mediterranean island, ~25% of ALS cases carry either a p.A382T mutation of the TARDBP gene or a GGGGCC hexanucleotide repeat expansion in the first intron of the C9ORF72 gene.
To describe the co-presence of two genetic mutations in two Sardinian ALS patients.
We identified two index ALS cases carrying both the p.A382T missense mutation of TARDBP gene and the hexanucleotide repeat expansion of C9ORF72 gene.
The index case of Family A had bulbar ALS and frontemporal dementia (FTD) at 43. His father, who carried the hexanucleotide repeat expansion of C9ORF72 gene, had spinal ALS and FTD at 64 and his mother, who carried the TARDBP gene p.A382T missense mutation, had spinal ALS and FTD at 69. The index case of Family B developed spinal ALS without FTD at 35 and had a rapid course to respiratory failure. His parents are healthy at 62 and 63. The two patients share the known founder risk haplotypes across both the C9ORF72 9p21 locus and the TARDBP 1p36.22 locus.
Our data show that in rare neurodegenerative causing genes can co-exist within the same individuals and are associated with a more severe disease course.
HTS was operationalised thus: following introductions and initial pleasantries, HTS was adjudged to be present (HTS+) if the patient turned her/his head away from the interlocutor and towards the accompanying person(s) when first invited to describe symptoms (eg, ‘Tell me...]]>
MOOD DISORDER AS A SPECIFIC COMPLICATION OF STROKE
Authors: Folstein MF, Maiberger R, McHugh PR
Year published: 1977
Dr Alan J Carson, University of Edinburgh, discusses the realisation that depression after stroke was not simply a reaction to disability
Appraising the impact of Folstein et al's
FUNCTIONAL ABILITIES AFTER STROKE: MEASUREMENT, NATURAL HISTORY AND PROGNOSIS
Author(s): Wade DT, Hewer RL
Published: 1987
A quarter of a century later, three findings are still valid and psychometric issues are still active
In 1987, we published a paper asking three questions concerning recovery after stroke:
How quickly and how much do people recover? Can we predict the extent of recovery? What is a good (simple, cheap) way of measuring recovery?
Surprisingly, the answers remain valid, and the issues raised in the paper remain active even though this paper was published nearly 25 years ago and despite very many more studies on the same questions. What are the key features still relevant?
This paper justified and supported the extensive use of the Barthel Activities of Daily Living (ADL) Index as a measure of dependence in personal activities of daily living. There is still no better measure; specifically, the Barthel ADL Index is not inferior to the widely...]]>