Alexander M. Rossor

Patterns of temporal lobe atrophy in semantic dementia and Alzheimer's disease.

Volumetric magnetic resonance imaging analyses of 30 subjects were undertaken to quantify the global and temporal lobe atrophy in semantic dementia and Alzheimers disease. Three groups of 10 subjects were studied: semantic dementia patients, Alzheimers disease patients, and control subjects. The temporal lobe structures measured were the amygdala, hippocampus, entorhinal cortex, parahippocampal gyrus, fusiform gyrus, and superior, middle, and inferior temporal gyri. Semantic dementia and Alzheimers disease groups did not differ significantly on global atrophy measures. In semantic dementia, there was asymmetrical temporal lobe atrophy, with greater left‐sided damage. There was an anteroposterior gradient in the distribution of temporal lobe atrophy, with more marked atrophy anteriorly. All left anterior temporal lobe structures were affected in semantic dementia, with the entorhinal cortex, amygdala, middle and inferior temporal gyri, and fusiform gyrus the most severely damaged. Asymmetrical, predominantly anterior hippocampal atrophy was also present. In Alzheimers disease, there was symmetrical atrophy of the entorhinal cortex, hippocampus, and amygdala, with no evidence of an anteroposterior gradient in the distribution of temporal lobe or hippocampal atrophy. These data demonstrate that there is a marked difference in the distribution of temporal lobe atrophy in semantic dementia and Alzheimers disease. In addition, the pattern of atrophy in semantic dementia suggests that semantic memory is subserved by anterior temporal lobe structures, within which the middle and inferior temporal gyri may play a key role. Ann Neurol 2001;49:433–442

Charcot–Marie–Tooth disease: frequency of genetic subtypes and guidelines for genetic testing

Background 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. Methods 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. Results 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. Conclusion 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.

The distal hereditary motor neuropathies

The distal hereditary motor neuropathies (dHMN) comprise a heterogenous group of diseases that share the common feature of a length-dependent predominantly motor neuropathy. Many forms of dHMN have minor sensory abnormalities and/or a significant upper-motor-neuron component, and there is often an overlap with the axonal forms of Charcot–Marie–Tooth disease (CMT2) and with juvenile forms of amyotrophic lateral sclerosis and hereditary spastic paraplegia. Eleven causative genes and four loci have been identified with autosomal dominant, recessive and X-linked patterns of inheritance. Despite advances in the identification of novel gene mutations, 80% of patients with dHMN have a mutation in an as-yet undiscovered gene. The causative genes have implicated proteins with diverse functions such as protein misfolding (HSPB1, HSPB8, BSCL2), RNA metabolism (IGHMBP2, SETX, GARS), axonal transport (HSPB1, DYNC1H1, DCTN1) and cation-channel dysfunction (ATP7A and TRPV4) in motor-nerve disease. This review will summarise the clinical features of the different subtypes of dHMN to help focus genetic testing for the practising clinician. It will also review the neuroscience that underpins our current understanding of how these mutations lead to a motor-specific neuropathy and highlight potential therapeutic strategies. An understanding of the functional consequences of gene mutations will become increasingly important with the advent of next-generation sequencing and the need to determine the pathogenicity of large amounts of individual genetic data.

Mutations in BICD2 Cause Dominant Congenital Spinal Muscular Atrophy and Hereditary Spastic Paraplegia

Dominant congenital spinal muscular atrophy (DCSMA) is a disorder of developing anterior horn cells and shows lower-limb predominance and clinical overlap with hereditary spastic paraplegia (HSP), a lower-limb-predominant disorder of corticospinal motor neurons. We have identified four mutations in bicaudal D homolog 2 (Drosophila) (BICD2) in six kindreds affected by DCSMA, DCSMA with upper motor neuron features, or HSP. BICD2 encodes BICD2, a key adaptor protein that interacts with the dynein-dynactin motor complex, which facilitates trafficking of cellular cargos that are critical to motor neuron development and maintenance. We demonstrate that mutations resulting in amino acid substitutions in two binding regions of BICD2 increase its binding affinity for the cytoplasmic dynein-dynactin complex, which might result in the perturbation of BICD2-dynein-dynactin-mediated trafficking, and impair neurite outgrowth. These findings provide insight into the mechanism underlying both the static and the slowly progressive clinical features and the motor neuron pathology that characterize BICD2-associated diseases, and underscore the importance of the dynein-dynactin transport pathway in the development and survival of both lower and upper motor neurons.

Novel mutations expand the clinical spectrum of DYNC1H1-associated spinal muscular atrophy

Objective: To expand the clinical phenotype of autosomal dominant congenital spinal muscular atrophy with lower extremity predominance (SMA-LED) due to mutations in the dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) gene. Methods: Patients with a phenotype suggestive of a motor, non–length-dependent neuronopathy predominantly affecting the lower limbs were identified at participating neuromuscular centers and referred for targeted sequencing of DYNC1H1. Results: We report a cohort of 30 cases of SMA-LED from 16 families, carrying mutations in the tail and motor domains of DYNC1H1, including 10 novel mutations. These patients are characterized by congenital or childhood-onset lower limb wasting and weakness frequently associated with cognitive impairment. The clinical severity is variable, ranging from generalized arthrogryposis and inability to ambulate to exclusive and mild lower limb weakness. In many individuals with cognitive impairment (9/30 had cognitive impairment) who underwent brain MRI, there was an underlying structural malformation resulting in polymicrogyric appearance. The lower limb muscle MRI shows a distinctive pattern suggestive of denervation characterized by sparing and relative hypertrophy of the adductor longus and semitendinosus muscles at the thigh level, and diffuse involvement with relative sparing of the anterior-medial muscles at the calf level. Proximal muscle histopathology did not always show classic neurogenic features. Conclusion: Our report expands the clinical spectrum of DYNC1H1-related SMA-LED to include generalized arthrogryposis. In addition, we report that the neurogenic peripheral pathology and the CNS neuronal migration defects are often associated, reinforcing the importance of DYNC1H1 in both central and peripheral neuronal functions.

BAG3 mutations: another cause of giant axonal neuropathy

Mutations in Bcl‐2 associated athanogene‐3 (BAG3) are a rare cause of myofibrillar myopathy, characterised by rapidly progressive proximal and axial myopathy, cardiomyopathy and respiratory compromise. Neuropathy has been documented neurophysiologically in previously reported cases of BAG3‐associated myofibrillar myopathy and in some cases giant axons were observed on nerve biopsies; however, neuropathy was not thought to be a dominant feature of the disease. In the context of inherited neuropathy, giant axons are typically associated with autosomal recessive giant axonal neuropathy caused by gigaxonin mutations but have also been reported in association with NEFL‐ and SH3TC2‐associated Charcot‐Marie‐Tooth disease. Here, we describe four patients with heterozygous BAG3 mutations with clinical evidence of a sensorimotor neuropathy, with predominantly axonal features on neurophysiology. Three patients presented with a significant neuropathy. Muscle magnetic resonance imaging (MRI) in one patient revealed mild to moderate atrophy without prominent selectivity. Examination of sural nerve biopsies in two patients demonstrated giant axons. This report confirms the association of giant axonal neuropathy with BAG3‐associated myofibrillar myopathy, and highlights that neuropathy may be a significant feature.

A practical approach to the genetic neuropathies

Charcot–Marie–Tooth disease is the commonest inherited neuromuscular disease. It is characterised by degeneration of peripheral sensory and motor nerves and can be classified into axonal and demyelinating forms. This review provides a diagnostic approach to patients with suspected inherited neuropathy and an algorithm for genetic testing that includes recent advances in genetics such as next-generation sequencing. We also discuss important aspects of the long-term management of patients with inherited neuropathy.

Rapidly progressive asymmetrical weakness in Charcot-Marie-Tooth disease type 4J resembles chronic inflammatory demyelinating polyneuropathy

Charcot-Marie-Tooth disease type 4J (CMT4J), a rare form of demyelinating CMT, caused by recessive mutations in the phosphoinositide phosphatase FIG4 gene, is characterised by progressive proximal and distal weakness and evidence of chronic denervation in both proximal and distal muscles. We describe a patient with a previous diagnosis of CMT1 who presented with a two year history of rapidly progressive weakness in a single limb, resembling an acquired inflammatory neuropathy. Nerve conduction studies showed an asymmetrical demyelinating neuropathy with conduction block and temporal dispersion. FIG4 sequencing identified a compound heterozygous I41T/K278YfsX5 genotype. CMT4J secondary to FIG4 mutations should be added to the list of inherited neuropathies that need to be considered in suspected cases of inflammatory demyelinating neuropathy, especially if there is a background history of a more slowly progressive neuropathy.

Recent advances in the genetic neuropathies.

PURPOSE OF REVIEW Charcot-Marie-Tooth disease (CMT) is one of the commonest inherited neuromuscular diseases with a population prevalence of 1 in 2500. This review will cover recent advances in the genetics and pathomechanisms of CMT and how these are leading to the development of rational therapies. RECENT FINDINGS Pathomechanistic and therapeutic target advances in CMT include the identification of the ErbB receptor signalling pathway as a therapeutic target in CMT1A and pharmacological modification of the unfolded protein response in CMT1B. In CMT2D, due to mutations in glycyl-tRNA synthetase, vascular endothelial growth factor-mediated stimulation of the Nrp1 receptor has been identified as a therapeutic target. Preclinical advances have been accompanied by the publication of large natural history cohorts and the identification of a sensitive biomarker of disease (muscle MRI) that is able to detect disease progression in CMT1A over 1 year. SUMMARY Advances in next-generation sequencing technology, cell biology and animal models of CMT are paving the way for rational treatments. The combination of robust natural history data and the identification of sensitive biomarkers mean that we are now entering an exciting therapeutic era in the field of the genetic neuropathies.

A novel p.Glu175X premature stop mutation in the C-terminal end of HSP27 is a cause of CMT2

Mutations in the gene HSPB1, encoding the small heat shock protein 27 (HSP27), are a cause of distal hereditary motor neuropathy (dHMN) and axonal Charcot‐Marie‐Tooth disease (CMT2). dHMN and CMT2 are differentiated by the presence of a sensory neuropathy in the latter although in the case of HSPB1 this division is artificial as CMT2 secondary to HSPB1 mutations is predominantly a motor neuropathy with only minimal sensory involvement. A recent study in mice has suggested that mutations in the C‐terminus result in a motor only phenotype resembling dHMN, whereas mutations at the N‐terminus result in a CMT2‐like phenotype. However, we present a family with a novel mutation in the C‐terminus of HSP27 (p.Glu175X) with a motor predominant distal neuropathy but with definite sensory involvement compatible with CMT2. This case highlights the artificial distinction between patients with motor predominant forms of CMT2 and dHMN and argues against the hypothesis that mutations in the C‐terminus have no sensory involvement.