Academic literature on the topic 'Hereditary motor neuropathy, HMN'

BackgroundInherited peripheral neuropathies (IPNs) represent a broad group of genetically and clinically heterogeneous disorders, including axonal Charcot-Marie-Tooth type 2 (CMT2) and hereditary motor neuropathy (HMN). Approximately 60%–70% of cases with HMN/CMT2 still remain without a genetic diagnosis. Interestingly, mutations in HMN/CMT2 genes may also be responsible for motor neuron disorders or other neuromuscular diseases, suggesting a broad phenotypic spectrum of clinically and genetically related conditions. Thus, it is of paramount importance to identify novel causative variants in HMN/CMT2 patients to better predict clinical outcome and progression.MethodsWe designed a collaborative study for the identification of variants responsible for HMN/CMT2. We collected 15 HMN/CMT2 families with evidence for autosomal recessive inheritance, who had tested negative for mutations in 94 known IPN genes, who underwent whole-exome sequencing (WES) analyses. Candidate genes identified by WES were sequenced in an additional cohort of 167 familial or sporadic HMN/CMT2 patients using next-generation sequencing (NGS) panel analysis.ResultsBioinformatic analyses led to the identification of novel or very rare variants in genes, which have not been previously associated with HMN/CMT2 (ARHGEF28, KBTBD13, AGRN and GNE); in genes previously associated with HMN/CMT2 but in combination with different clinical phenotypes (VRK1 and PNKP), and in the SIGMAR1 gene, which has been linked to HMN/CMT2 in only a few cases. These findings were further validated by Sanger sequencing, segregation analyses and functional studies.ConclusionsThese results demonstrate the broad spectrum of clinical phenotypes that can be associated with a specific disease gene, as well as the complexity of the pathogenesis of neuromuscular disorders.

AbstractHereditary neuropathy is an umbrella term for a group of nonsyndromic conditions with a prevalence of approximately 1:2,500. In addition to the most frequent form, Charcot–Marie–Tooth's disease (CMT, or hereditary motor and sensory neuropathy), there are additional entities such as hereditary neuropathy with liability to pressure palsies (HNPP), hereditary motor neuropathies (HMNs), and hereditary sensory and autonomic neuropathies (HSANs). With the exception of HNPP, which is almost always caused by defects of the PMP22 gene, all other forms show genetic heterogeneity with altogether close to 100 genes involved. Mutation detection rates vary considerably, reaching up to 80% in demyelinating CMT (CMT1) but are still as low as 10 to 30% in axonal CMT (CMT2), HMN, and HSAN. Based on current information, analysis of only four genes (PMP22, GJB1, MPZ, MFN2) identifies 80 to 90% of CMT-causing mutations that can be detected in all known disease genes. For the remaining patients, parallel analysis of multiple neuropathy genes using next-generation sequencing is now replacing phenotype-oriented multistep gene-by-gene sequencing. Such approaches tend to generate a wealth of genetic information that requires comprehensive evaluation of the pathogenic relevance of identified variants. In this review, we present current classification systems, specific phenotypic clues, and genetic testing algorithms in the different subgroups of hereditary neuropathies.

Although the genetic architecture of amyotrophic lateral sclerosis (ALS) is incompletely understood, recent findings suggest a complex model of inheritance in ALS, which is consistent with a multistep pathogenetic process. Therefore, the aim of our work is to further explore the architecture of ALS using targeted next generation sequencing (NGS) analysis, enriched in motor neuron diseases (MND)-associated genes which are also implicated in axonal hereditary motor neuropathy (HMN), in order to investigate if disease expression, including the progression rate, could be influenced by the combination of multiple rare gene variants. We analyzed 29 genes in an Italian cohort of 83 patients with both familial and sporadic ALS. Overall, we detected 43 rare variants in 17 different genes and found that 43.4% of the ALS patients harbored a variant in at least one of the investigated genes. Of note, 27.9% of the variants were identified in other MND- and HMN-associated genes. Moreover, multiple gene variants were identified in 17% of the patients. The burden of rare variants is associated with reduced survival and with the time to reach King stage 4, i.e., the time to reach the need for percutaneous endoscopic gastrostomy (PEG) positioning or non-invasive mechanical ventilation (NIMV) initiation, independently of known negative prognostic factors. Our data contribute to a better understanding of the molecular basis of ALS supporting the hypothesis that rare variant burden could play a role in the multistep model of disease and could exert a negative prognostic effect. Moreover, we further extend the genetic landscape of ALS to other MND-associated genes traditionally implicated in degenerative diseases of peripheral axons, such as HMN and CMT2.

Abstract Neurodegenerative disorders are a diverse group of disorders that affect specific subsets of neurons. Motor neuron diseases, neurodegenerative disorders of motor neurons, are seen commonly as sporadic cases and less frequently as familial disease forms. The familial forms show genetic and phenotypic heterogeneity. Clinically motor neuron diseases may be seen as rapidly progressive disorders like amyotrophic lateral sclerosis, ALS or slowly progressive disorders like hereditary motor neuropathies, HMN. The only proven causes for motor neuron diseases are gene mutations that lead to motor neuron degeneration in familial disease forms. Only some of these genes have been identified and have contributed greatly to our understanding of the neurobiology of familial and sporadic disease forms. Identification of additional disease causing genes would help enhance our knowledge of the pathophysiological mechanisms underlying all forms of motor neuron disorders, which would lead to early diagnoses, effective prophylaxis and efficient therapies for these disorders. This study aimed to find gene mutations that cause rapid and slowly progressive familial motor neuron disorders in Australian families and to determine their relevance to sporadic forms of motor neuron disease. The familial forms of ALS show reduced disease penetrance, that is, not all gene mutation carriers manifest the disease. This study examines ALS penetrance in a group of Australian families. The most frequently observed mutations in ALS families are cytosolic superoxide dismutase/SOD1 gene mutations. In a collection of ALS families in our centre, families without the common SOD1 gene mutations were genotyped for other ALS genes and loci and studied using genetic linkage and haplotype analyses. Studies in a large Australian ALS family further confirmed genetic heterogeneity in non-SOD familial ALS, all known autosomal dominant ALS genes and chromosomal loci were excluded as cause of disease in this family. Such families can be studied further to identify additional disease genes and loci mapped in other ALS families. These families represent powerful resources for identification of additional ALS genes. Identifying the pathogenic genes in families with reduced disease penetrance may be more relevant to sporadic forms of disease. dHMN is a chronic neurodegenerative disorder predominantly affecting motor neurons. In a large Australian dHMN family, all the known dHMN genes and chromosomal loci were excluded as cause of disease. A genome wide microsatellite screen was performed in this family and genetic linkage was established to a novel 12.98 Mb locus on chromosome 7q34.2-q36. Candidate genes in this large interval will be screened based on their function and expression profile. Identification of a new dHMN locus provides the basis for future identification of a novel gene involved in motor neuron degeneration. Genes in dHMN have been shown to be pathogenic in ALS and Charcot Marie Tooth syndromes. The new locus for dHMN mapped in this project would lead to identification of a novel dHMN gene, which may elucidate the pathogenesis underlying a wide range of neurodegenerative disorders.

Doctor of Philosophy
Abstract Neurodegenerative disorders are a diverse group of disorders that affect specific subsets of neurons. Motor neuron diseases, neurodegenerative disorders of motor neurons, are seen commonly as sporadic cases and less frequently as familial disease forms. The familial forms show genetic and phenotypic heterogeneity. Clinically motor neuron diseases may be seen as rapidly progressive disorders like amyotrophic lateral sclerosis, ALS or slowly progressive disorders like hereditary motor neuropathies, HMN. The only proven causes for motor neuron diseases are gene mutations that lead to motor neuron degeneration in familial disease forms. Only some of these genes have been identified and have contributed greatly to our understanding of the neurobiology of familial and sporadic disease forms. Identification of additional disease causing genes would help enhance our knowledge of the pathophysiological mechanisms underlying all forms of motor neuron disorders, which would lead to early diagnoses, effective prophylaxis and efficient therapies for these disorders. This study aimed to find gene mutations that cause rapid and slowly progressive familial motor neuron disorders in Australian families and to determine their relevance to sporadic forms of motor neuron disease. The familial forms of ALS show reduced disease penetrance, that is, not all gene mutation carriers manifest the disease. This study examines ALS penetrance in a group of Australian families. The most frequently observed mutations in ALS families are cytosolic superoxide dismutase/SOD1 gene mutations. In a collection of ALS families in our centre, families without the common SOD1 gene mutations were genotyped for other ALS genes and loci and studied using genetic linkage and haplotype analyses. Studies in a large Australian ALS family further confirmed genetic heterogeneity in non-SOD familial ALS, all known autosomal dominant ALS genes and chromosomal loci were excluded as cause of disease in this family. Such families can be studied further to identify additional disease genes and loci mapped in other ALS families. These families represent powerful resources for identification of additional ALS genes. Identifying the pathogenic genes in families with reduced disease penetrance may be more relevant to sporadic forms of disease. dHMN is a chronic neurodegenerative disorder predominantly affecting motor neurons. In a large Australian dHMN family, all the known dHMN genes and chromosomal loci were excluded as cause of disease. A genome wide microsatellite screen was performed in this family and genetic linkage was established to a novel 12.98 Mb locus on chromosome 7q34.2-q36. Candidate genes in this large interval will be screened based on their function and expression profile. Identification of a new dHMN locus provides the basis for future identification of a novel gene involved in motor neuron degeneration. Genes in dHMN have been shown to be pathogenic in ALS and Charcot Marie Tooth syndromes. The new locus for dHMN mapped in this project would lead to identification of a novel dHMN gene, which may elucidate the pathogenesis underlying a wide range of neurodegenerative disorders.

The distal hereditary motor neuropathies (dHMN) are a clinically and genetically heterogeneous group of disorders that primarily affect motor neurons, without significant sensory involvement. Using genome wide linkage analysis in a large Australian family (CMT54), a form of dHMN was previously mapped by this laboratory, to a 12.98 Mb interval on chromosome 7q34-q36. The axonal neuropathy seen in this family was classified as dHMN1; with autosomal dominant inheritance, early but variable age of onset, and muscle weakness and wasting affecting the lower limbs. In this project, genetic linkage analysis of the chromosome 7q34-q36 disease interval was carried out in the original family (CMT54) and 20 smaller families from an Australian dHMN cohort. Fine mapping in family CMT54, including unaffected individuals suggested a minimum probable candidate interval of 6.92 Mb, flanked by markers D7S615 and D7S2546 within the 12.98 Mb critical disease interval. Of the additional dHMN families, one (family CMT44) achieved suggestive linkage to the chromosome 7q34-q36 disease locus with a LOD score of 2.02. Mutation screening was carried out in family CMT54 at the chromosome 7q34-q36 locus. The 12.9 Mb disease interval contains 89 annotated protein-coding genes, of which 60 lay within the prioritised 6.92 Mb interval. A combination of methods was used to screen these genes for a putative pathogenic mutation. Functional candidate genes were identified via a literature and database search. The coding exons of 35 prioritised candidate genes were sequenced and no pathogenic mutation was identified. Cytogenetic analysis excluded large scale chromosomal abnormalities. Array based comparative genomic hybridisation of the 7q34-q36 interval in patients did not identify any pathogenic duplications or deletions. Next generation sequencing (NGS) techniques were used to identify sequence variants within the remaining genes within the 7q34-q36 interval and elsewhere in the genome. Two NGS based approaches were applied to mutation screening in family CMT54. Initially, the chromosome 7q34-q36 disease interval was analysed in one affected individual using a custom designed DNA capture microarray and 454 GS FLX (Roche) sequencing. Approximately 80% of patient coding exons were captured, sequenced and no pathogenic mutations were identified. The chromosome 7q34-q36 target captured DNA sample was also re-sequenced along with an additional two affected individuals and one unaffected parent using exome capture and Solexa (Illumina) sequencing. Combined, 99.5% of coding exons were sequenced in the chromosome 7q34-q36 interval and all sequence variants that were identified were excluded from a pathogenic role. Sequence variants identified elsewhere in the exome were also excluded from a pathogenic role. Exome sequencing of dHMN family CMT44 did not identify any putative pathogenic mutation at the chromosome 7q34-q36 locus. The exomes of four affected and one unaffected individuals were sequenced. Exome wide analysis identified a potential digenic inheritance in CMT44 of a previously published MFN2 mutation causing a mild CMT2 phenotype and a second mutation causing a dHMN phenotype. Potential candidate mutations for dHMN were identified in two genes, PCDHGA4 and DNAH11. PCDHGA4, was previously shown to function in the brain and spinal cord, and deletion of PCDHG genes in a mouse model causes a severe neurodegenerative phenotype. The gene mutation causing dHMN that maps to chromosome 7q34-q36 remains to be identified. The disease mutation may lie in a coding region not captured by current exome platforms, a non-coding region, or the mutation may cause disease through an alternate mechanism not detected by the methods employed in this thesis. Future studies should concentrate on transcriptome analysis by next-gen RNA sequencing, which may identify unknown transcripts and exons that map to chromosome 7q34-q36 or highlight sequence variants located in regulatory elements. Identification of new gene mutations is critical to further understanding the biochemical and cellular processes underlying dHMN. Although the causative mutation for dHMN on 7q34-q36 was not identified, a significant proportion of the disease interval has been excluded using a combination of traditional and new technologies. The purpose of this thesis is to identify new gene mutations causing dHMN. The genetic and functional data presented here suggest this will be a difficult task; the genetic heterogeneity complicates genetic analysis and the multiple molecular mechanisms implicated to date make it difficult to pinpoint specific candidate genes. The identification of additional genes and genetic modifiers is necessary to increase our understanding of the disease mechanisms causing dHMN and related neuropathies. This will directly aid in the diagnosis and classification of these neurodegenerative diseases and may lead to new therapeutics and treatment strategies.

Congenital Hypomyelination (CH) is the most severe demyelinating form of Hereditary Motor and Sensory Neuropathies and manifests at birth in human. Some subtypes of CH are due to dommant mutations in the gene coding for PO glycoprotein, which fiinctions as a homophilic adhesion protein, responsible for compaction of opposing myelin lamellae. By homologous recombination in ES cells, we have generated a mouse containing a nonsense mutation m the intracellular portion of PO (Q215X) that, in the heterozygous state, is associated with CH neuropathy in humans.

Hereditary Motor and Sensory Neuropathy-Russe (HMSNR) is a rare recessive form of Charcot-Marie-Tooth disease (CMT) that has been identified in the European Gypsy (Roma) population. Clinically, HMSNR manifests with typical CMT symptoms, while no associated features have been detected. Distinct neuropathological features of HMSNR include the presence of numerous clusters of thinly myelinated fibres originating from regenerative activity. HMSNR has been previously mapped to chromosome 10q using a large Bulgarian Gypsy kindred. Subsequent identification of related chromosome 10q haplotypes in Spanish and Romanian Gypsy families suggested a founder mutation in the Gypsy population as the cause of HMSNR. This thesis describes the refined mapping of the HMSNR gene by generating a high-density physical-genetic map of the HMSNR region containing 20 microsatellite markers and 229 SNPs and insertion/deletions which allowed meticulous mapping of recombination breakpoints resulting in a reduction of the HMSNR gene region from 1 Mb to just 63.8 kb. Analysis of positional candidates by direct sequencing included 14 known genes, 7 predicted genes and 42 expressed sequence tags (ESTs) nonoverlapping with the genes. 78 putative HMSNR mutations were identified, two of which exhibit complete segregation with the HMSNR phenotype. Both are located in the so-called testis-specific part of unexpected candidate gene hexokinase 1 (HK1), in a rare alternative untranslated 5’ exon of HK1 and in the adjacent downstream intron. Expression analysis of transcripts containing the alternative exon suggests that the exon is not confined to testis but may be expressed in the nervous system. It remains to be speculated how a gene that functions in the fundamental process of energy generation might be involved in a neuropathy. Further investigations are likely to expand the knowledge about the importance of HK1 in the peripheral nervous system and may elucidate new roles of HK1

Peripheral neuropathy associated with agenesis of the corpus callosum (ACCPN or HMSN/ACC) is a severe polyneuropathy affecting both the peripheral nervous system and the central nervous system. It is transmitted as an autosomal recessive trait and is particularly frequent in the French Canadian population of Quebec (Canada). The disease was linked to chromosome 15 in 1996 by Dr. Rouleau's team.
We genotyped polymorphic markers in the ACCPN candidate region on chromosome 15 in over 67 patients and 200 control individuals. Observation of affected haplotypes confirmed the presence of a founder effect in the French Canadian population. Recombination analysis reduced the candidate interval to approximately 2 cM between markers D15S1040 and ACTC on chromosome 15. Linkage disequilibrium analysis suggested the gene resides nearest marker D15S1232. A physical map of the newly refined candidate region was constructed using YAC, BAC and PAC clones. These clones were used to confirm the position of candidate ESTs and genes as being either within or outside the ACCPN candidate region.
The connexin 36 gene, which was confirmed to reside within the region, was excluded as the gene responsible for ACCPN using SSCP analysis. The SLC12A6 gene was also confirmed to reside within the candidate interval and was tested for mutations using SSCP, dHPLC and sequence analyses. We found a total of four disease-specific mutations in SLC12A6, all of which are expected to truncate the KCC3 protein (the protein produced by the SLC12A6 gene). Two of the four mutations were identified in the French Canadian population; 80 French Canadian ACCPN patients are homozygous for the c.2436delG in exon 18 and one French Canadian patient is a compound heterozygote, having the c.2436delG mutation as well as the 1584_1585delCTinsG mutation in exon 11. Two additional mutations were identified in one Turkish and one Italian family in exons 22 and 15 respectively. The effects of the c.2436delG mutation on KCC3 function was studied in X. laevis oocytes and the truncated protein is not functional. Finally, collaborators at Vanderbilt University disrupted the slc12a6 gene in the mouse and found a phenotype similar to the human disease.
Identification of SLC12A6 as the gene mutated in ACCPN will allow for accurate molecular diagnosis as well as carrier testing in the French Canadian population. It is also the first step in understanding the molecular mechanism leading to the disease.

Neurodegenerative diseases are becoming increasingly prevalent due to the ageing population, and are among the major contributors to disability and disease worldwide. The identification of the gene defects responsible for many of these conditions has played a major role in our understanding of the pathogenic processes involved, and provided opportunity to develop targeted treatment strategies. Cholinergic neurotransmission supports a wide range of physiological and behavioural processes and its dysfunction of cholinergic signalling has been associated with a number of disorders, including myasthenias, cardiovascular disease(1), attention-deficit hyperactivity disorder (ADHD) (2), Alzheimer’s disease (ADi), schizophrenia, addiction(3), and depression(4). SLC5A7 encodes the Na+/Cl- dependent, high-affinity choline transporter (CHT) which represents the rate limiting step in acetylcholine (Ach) synthesis and is critical for normal cholinergic signalling. The work in this thesis details two new inherited disorders, caused by distinct pathogenic disease mechanisms, associated with novel SLC5A7 mutations. Chapter three documents the discovery of two autosomal-dominantly acting SLC5A7/CHT mutations associated with adult onset motor neurone disorders. Initially we identified a frameshift mutation that results in premature truncation of the transporter protein in a large Welsh kindred affected with distal hereditary motor neuropathy type VII (dHMN-VII), in which neurodegeneration and muscle paresis is largely restricted to the distal limb muscles and vocal cords. The mutation responsible results in the dominant-negative interference of the mutant molecule with function of the wild type choline transporter, resulting in significantly reduced (although not completely abolished) transporter activity. This finding is further evidenced by the discovery of a second dHMN family associated with a distinct frameshift SLC5A7 mutation indicative of a similar dominant-negative disease mechanism. Together these findings corroborate a dominant-negative disease mechanism arising from C-terminal truncating SLC5A7 mutations associated with dHMN, and provide further insight into the role of aberrant choline transporter function in neurological disease. Chapter four describes N-terminal missense mutations located in the transmembrane spanning region of SLC5A7/CHT, associated with a severe infantile neuromuscular disorder characterised by predominantly central hypotonia and developmental delay. The phenotypic effects of these mutations are likely to result from the near abolition of CHT-mediated choline transport in homozygous individuals, and are in keeping with those observed in CHT knock-out mouse models(5). The development of a mouse model of the human motor neurone disease arising from SLC5A7 frameshift mutations should allow for further investigation of the mechanism by which truncated CHT leads to the dHMN phenotype. Chapter 5 details treatment hypotheses for dHMN, as well as the generation of a patient-specific knock-in mouse model carrying an Slc5a7 mutation orthologous to that identified in dHMN-VII families in chapter 3, and results from preliminary neurological phenotyping of the mouse model. This model will be crucially important for the exploration of treatment options in dHMN-VII motor neurone disease as a prelude to clinical trials in humans.

O controle postural na doença de Charcot-Marie-Tooth (CMT) está subsidiado em estudos com adultos, nos quais deformidades distais, desequilíbrios musculares e aspectos maturacionais estão bem documentados. Para infância e adolescência, o controle postural permanece por ser explorado e pode contribuir para elucidar como um sistema neuromuscular imaturo lida com a doença em curso. Neste contexto, foi proposto um estudo de desenho transversal (Estudo 1) composto por crianças e adolescentes com CMT (encaminhados ao Ambulatório CMT-Infantil do Centro de Reabilitação do HCFMRP-USP; Grupo CMT) e seus pares saudáveis (Grupo Controle), e outro longitudinal (Estudo 2), composto exclusivamente de crianças e adolescentes com CMT. O Estudo 1 caracterizou a oscilação postural e explorou sua interação com variáveis musculoesqueléticas, a partir da comparação do Grupo CMT e Grupo Controle, sendo composto por 53 participantes de ambos os sexos, idade entre 6 e 18 anos, sendo 24 saudáveis e 29 com CMT. Foram coletados dados de massa, estatura, base de apoio, Índice Postural do Pé (IPP), amplitudes passivas de movimento, força muscular isométrica de membros inferiores, medidas de desempenho (teste de caminhada dos 6 min -T6, teste dos 10 m - T10, salto horizontal - SH) e de equilíbrio (estabilometria, Escala de Equilíbrio Pediátrica - EEP). A força muscular isométrica dos grupos musculares inversores, eversores, dorsiflexores, flexores plantares, flexores e extensores de joelho e extensores de quadril foi medida bilateralmente com um dinamômetro manual (Lafayette, modelo 01163). Para avaliação estabilométrica foi usada uma plataforma de força (Bertec, modelo FP 4060-08), com frequência de amostragem de 100 Hz, tempo de registro de 30 s por tentativa. As 4 condições de teste (olhos abertos/superfície rígida; olhos abertos/superfície deformável; olhos fechados/superfície rígida; olhos fechados/superfície deformável) foram repetidas aleatoriamente por 3 vezes, intervaladas por 30 s, perfazendo 12 tentativas. Foram extraídas a área da elipse de confiança, velocidade (total, mediolateral e anteroposterior), frequência (total, mediolateral e anteroposterior) e o Quociente de Romberg (QRv) por meio do programa MATLAB (R2014a), usando um filtro digital Butterworth passa-baixa de 4a ordem, com frequência de corte de 7 Hz. O programa SPSS (versão 17) foi usado para análise estatística (nível de significância de 5%). No aspecto musculoesquelético (amplitude de dorsiflexão, ângulo poplíteo e força muscular da maioria dos grupos testados) e nos testes de desempenho (T10, T6 e SH), os resultados mostraram que o grupo CMT exibiu valores inferiores ao Controle (p<0,05). Quanto ao controle postural, comparações intragrupo das condições de teste no grupo CMT evidenciaram incremento na área e velocidades do centro de pressão (CP), mas não nas frequências, conforme a complexidade da tarefa. Nas comparações intergrupos, tanto a EEP quanto a estabilometria evidenciaram menor equilíbrio no grupo CMT quando comparado ao Controle (aumento da área de confiança da elipse e das velocidades, associadas a um decréscimo da frequência do CP) (p<0,05). As interações mais relevantes entre fatores musculoesqueléticos e equilíbrio sugerem melhor controle postural para indivíduos com pés são planos e amplitudes de dorsiflexão reduzidas. O Estudo 2 buscou detectar alterações no controle postural nos participantes que foram seguidos por 6 e 12 meses consecutivos, sendo 22 com CMT de ambos os sexos, idade entre 6 e 18 anos. Registros da oscilação postural, das variáveis musculoesqueléticas e de desempenho foram analisados em intervalos de 6 meses (AV1, AV2 e AV3). Os programas SPSS (versão 17) e R Core Team (2016) foram usados para análise estatística. O teste de Wilcoxon foi usado para comparar variáveis estabilométricas do seguimento semestral e anual e para uma análise complementar, considerando os subgrupos de 6 a 9 anos (n=8) e de 10 a 17 anos (n=9). O comportamento das variáveis musculoesqueléticas foi analisado com o modelo linear de efeitos mistos. O teste t de Student para amostras pareadas foi usado para analisar T10, T6 e SH. O IPP e EEP foram analisados com o teste exato de Fisher. Os resultados mostraram que não houve mudanças significativas na estabilometria entre AV1 e AV2 ou AV1 e AV3. Nas comparações entre AV1 e AV2, houve aumento significativo no ângulo poplíteo, na força dos grupos musculares eversores de tornozelo e extensores de quadril, no SH e a força muscular dos extensores de joelho sofreu decréscimo (p<0,05). Nas comparações entre AV1 e AV3, houve aumento significativo da força muscular dos grupos inversores, eversores, dorsiflexores e extensores de joelho (p<0,05). A análise complementar do seguimento anual identificou reduções significativas na amplitude de dorsiflexão, velocidade mediolateral (condições olhos abertos/superfície rígida e olhos fechados/superfície rígida) e velocidade total (condições olhos abertos/superfície rígida e olhos fechados/superfície rígida) no subgrupo de crianças (n=8) (p<0,05). No subgrupo de adolescentes (n=9), houve aumento significativo da força muscular de inversores, dorsiflexores e extensores de joelho (p<0,05) enquanto a estabilometria permaneceu inalterada. Em suma, os resultados do Estudo 1 e 2 permitem concluir que o controle postural ii deficitário de crianças e adolescentes com CMT é mensurável com base nas variáveis estabilométricas extraídas da análise global; é expresso por grandes e rápidas oscilações do CP, nas quais a frequência não distingue as condições de teste quando comparadas aos seus pares saudáveis. A velocidade do CP parece refletir as mudanças na estabilidade postural quando crianças e adolescentes são analisados como subgrupos distintos. Além disso, seguimentos anuais parecem ser suficientes para detectar mudanças no controle postural, nas variáveis musculoesqueléticas e de desempenho.
Postural control in Charcot-Marie-Tooth disease (CMT) is supported in studies with adults, in which distal deformities, muscular imbalances and maturational aspects are well documented. For childhood and adolescence, standing balance remains to be explored and may contribute to elucidate how an immature neuromuscular system deals with the ongoing disease. In this context, a crosssectional study (Study 1) composed of children and adolescents with CMT (referred to the CMTInfantile Ambulatory of the HCFMRP-USP Rehabilitation Center, CMT Group) and their healthy peers (Control Group), and another longitudinal (Study 2), composed exclusively of children and adolescents with CMT were proposed. Study 1 characterized the postural oscillations and explored its interaction with musculoskeletal variables from the comparison of the CMT Group and Control Group, being composed of 53 participants of both sexes, age between 6 and 18 years, being 24 healthy and 29 with CMT. Mass, height, base of support, foot postural index (PPI), passive amplitudes of movement, isometric muscle strength of lower limbs, performance measures (6-min walk test -T6, 10- T10, horizontal jump - SH) and balance (stabilometry, Pediatric Balance Scale - EEP) were collected. The isometric muscle strength of the inversion, dorsiflexion, plantarflexion, knee extension, knee flexion and hip extension was measured bilaterally with a manual dynamometer (Lafayette, model 01163). Stabilometric evaluationused a force platform (Bertec, model FP 4060-08), with sampling frequency of 100 Hz, recording time of 30 s per trial. The 4 test conditions (open eyes / hard surface, open eyes / deformable surface, closed eyes / hard surface, closed eyes / deformable surface) were randomly repeated 3 times, intervals for 30 s, making 12 trials. The confidence ellipse area, velocity (total, mediolateral and anteroposterior), frequency (total, mediolateral and anteroposterior) and the Romberg Quotient (QRv) were extracted using MATLAB program (R2014a), adopting a 4th order Butterworth digital low-pass filter and a cut-off frequency of 7 Hz. Statistical analysis used the SPSS program (version 17) and it was adopted level of significance of 5%. In the musculoskeletal aspect (amplitude of dorsiflexion, popliteal angle and muscular strength of most of the groups tested) and performance tests (T10, T6 and SH), CMT group showed values lower than Control (p <0.05). For balance, intragroup comparisons of the test conditions in the CMT group evidenced an increased area and velocities of the pressure center (CP), but not the frequencies, according to the complexity of the task. In the intergroup comparisons, EEP and stabilometry showed less postural control in the CMT group when compared to the Control (increased confidence ellipse area and velocities associated with a decrease in CP frequency) (p <0.05). The most relevant interactions between musculoskeletal and oscillations of CP suggest better postural control for subjects the flat feet and reduced dorsiflexion amplitudes. Study 2 comprised 22 participants with CMT of both sexes, aged between 6 and 18 years and it sought to detect changes in postural oscillations in CMT with 6 and 12 consecutive months of follow-up. Postural oscillations, musculoskeletal and performance variables were analyzed at 6-month intervals (AV1, AV2 and AV3). SPSS (version 17) and R Core Team (2016) programs were used for statistical analysis. The Wilcoxon test was used to compare stabilometric variables of the bi-annual and annual follow-up and to a complementary analysis, considering the subgroups of 6 to 9 years (n = 8) and 10 to 17 years (n = 9). The linear mixed effects model analyzed the musculoskeletal variables. Student\'s t-test for paired samples was used to analyze T10, T6 and SH. The Fisher\'s exact test analyzed the IPP and EEP. The results showed no significant changes in the stabilometry between AV1 and AV2 or AV1 and AV3. Comparisons between AV1 and AV2 showed significant increase in the popliteal angle strength of the ankle evertors and hip extensors SH while the muscle strength of knee extensors decreased (p <0.05). Comparisons between AV1 and AV3, showed a significant increase in the muscular strength for inversion, eversion, dorsiflexion and knee extension groups (p <0.05). The complementary analysis of the annual follow-up identified significant reductions in dorsiflexion amplitude, mediolateral velocity (open eyes / rigid surface and closed eyes / rigid surface) and total velocity (open eyes / rigid surface and closed eyes / rigid surfaces) in the subgroup of children (n = 8) (p <0.05). Subgroup of adolescents (n = 9) showed a significant increase in the muscular strength of inverters, dorsiflexors and knee extensors (p <0.05) while the stabilometry remained unchanged. In summary, the results of Study 1 and 2 allow us to conclude that the poor postural control of children and adolescents with CMT is measurable based on the stabilometric variables extracted from the global analysis; is iv expressed by large and rapid CP oscillations, in which frequency does not distinguish the test conditions when compared to their healthy counterparts. The velocity of CP seems to reflect changes in postural stability when children and adolescents are analyzed as distinct subgroups. In addition, annual follow-up appears to be sufficient to detect changes in postural control, musculoskeletal and performance variables.

Some causes of focal peripheral nerve damage are self-evident, such as involvement at sites of trauma, tissue necrosis, infiltration by tumour, or damage by radiotherapy. Focal compressive and entrapment neuropathies are particularly valuable to identify in civilian practice, since recovery may follow relief of the compression. Leprosy is a common global cause of focal neuropathy, which involves prominent loss of pain sensation with secondary acromutilation, and requires early antibiotic treatment. Mononeuritis multiplex due to vasculitis requires prompt diagnosis and immunosuppressive treatment to limit the severity and extent of peripheral nerve damage. Various other medical conditions, both inherited and acquired, can present with focal neuropathy rather than polyneuropathy, the most common of which are diabetes mellitus and hereditary liability to pressure palsies. A purely motor focal presentation should raise the question of multifocal motor neuropathy with conduction block, which usually responds well to high-dose intravenous immunoglobulin infusions.

The role of electromyography (EMG) and nerve conduction studies in disorders of single nerve, root, and plexus lesions are discussed. The motor and sensory anatomy underpinning diagnosis is described and a scheme presented showing the key muscles to be examined using EMG to differentiate nerve, plexus, and root lesions. The main causes of mononeuritis multiplex, of either axonal degeneration or demyelinative pathology, are covered, including diabetic neuropathy, vasculitic neuropathy, multifocal motor neuropathy with block, and the Lewis–Sumner syndrome. The confirmatory role of EMG and nerve conduction studies in the investigation of cervical and lumbar radiculopathies is highlighted as is the use of transcranial magnetic stimulation to differentiate cervical radiculopathy with myelopathy from amyotrophic lateral sclerosis. The neurophysiological hallmarks of traumatic cervical plexus lesions, including obstetric causes, inherited and acquired brachial neuritis, hereditary liability to pressure palsies, the cervical rib syndrome, and radiation plexopathy are also covered.

Muscle stiffness as a nonspecific term means limited muscle mobility. Muscle and joint pain may be described as stiffness. Painful, sustained muscle cramps are usually associated with muscle stiffness. A careful history is paramount. Exercise-induced muscle cramps are usually myopathic (metabolic or mitochondrial myopathy) while resting, and nocturnal cramps are neurogenic [neuropathy, motor neuron disease (MND), etc.]. Metabolic cramps are electrically silent. Focal or generalized stiffness is typically seen in stiff person syndrome (SPS). Upper motor neuron (UMN) lesions are associated with spasticity and stiffness [hereditary spastic paraplegia (HSP), primary lateral sclerosis (PLS), myelopathies, etc.]. Painful cramps and fasciculation are important clues to peripheral nerve hyperexcitability disorder, which may also present with neuromyotonia. Not unusually, no cause is found for muscle cramps and stiffness. Symptomatic treatment frequently helps.

Distal arm weakness may be caused by involvement of the intrinsic hand muscles (interossi, thenar and hypothenar muscles, lumbricals) or extrinsic hand muscles (long finger flexors and extensors). ALS is typical for the former type, and IBM is typical for the latter type. Incoordination of skilled finger movement due to cerebellar disease is associated with normal strength. Poor mobility due to joints pain and swelling should not be confused with muscle weakness. Mononeuropathies such as ulnar, radial, median, and AIN,lesions usually cause differential loss of function. Myasthenia sometimes causes weakness of the wrist and finger extensors. A small but distinct group of distal hereditary myopathies should always be borne in mind. Progressive sensorimotor neuropathies are usually associated with sensory symptoms. Multifocal motor neuropathy can be a diagnostic challenge.

In this chapter, the inability of electromyography (EMG) to be able to further progress the diagnosis of myopathy on its own—requiring muscle biopsy and other modalities such as genetics to complete this process—is emphasized. The role of EMG particularly in the era of genetics is discussed. Findings in neurogenic abnormality are next described and the important hereditary conditions such as spinal muscular atrophy (SMA), distal SMA, Brown–Vialetto–Van Laere syndrome, segmental anterior horn cell disease, conditions with progressive bulbar palsy, SMARD1, and pontocerebellar hypoplasia with spinal muscle are discussed in detail. The differential diagnosis of 5q SMA type 1 is specifically outlined. Acquired forms of anterior horn disease, including Hirayama disease, poliomyelitis and enteropathic motor neuropathy, Hopkins syndrome, tumours, and vascular lesions are covered. There is discussion of the use of physiological tests to monitor progress in SMA, with tests including compound muscle action potential amplitude and motor unit number estimation. Finally, the important correlation between muscle biopsy and EMG is highlighted.

Distal arm weakness may be caused by involvement of the intrinsic hand muscles (interossi, thenar and hypothenar muscles, lumbricals) or extrinsic hands muscles (long fingers flexors and extensors). Amyotrophic lateral sclerosis (ALS) is typical of the former type, and inclusion body myositis (IBM) is typical for the later type. Incoordination of skilled finger movement due to cerebellar disease is associated with normal strength. Poor mobility due to joint pain and swelling should not be confused with muscle weakness. Mononeuropathies such as ulnar, radial, median, and anterior interosseus nerve lesions usually cause differential loss of function. Myasthenia gravis sometimes causes weakness of the wrist and finger extensors. A small but distinct group of distal hereditary myopathies should always be kept in mind. Progressive sensorimotor neuropathies are usually associated with sensory symptoms. Multifocal motor neuropathy can be a challenging diagnosis.