BACKGROUND AND PURPOSE: Charcot-Marie-Tooth disease type 1 (CMT1) is a group of autosomal dominantly inherited demyelinating sensorimotor neuropathies. Symptoms usually start in the first to second decade and include distal muscle weakness and wasting, sensory disturbances and foot deformities. The most frequent cause is a duplication of PMP22 whilst point mutations in PMP22 and other genes are rare causes. Recently, FBLN5 mutations have been reported in CMT1 families. METHODS: Individuals with FBLN5-associated CMT1 were compiled from clinical and research genetic testing laboratories. Clinical data were extracted from medical records or obtained during patients' visits at our centres or primary care sites. RESULTS: Nineteen CMT1 families containing 38 carriers of three different FBLN5 missense variants were identified and a mutational hotspot at c.1117C>T (p.Arg373Cys) was confirmed. Compared to patients with the common PMP22 duplication, individuals with FBLN5 variants had a later age of diagnosis (third to fifth decade) and less severely reduced motor median nerve conduction velocities (around 31 m/s). The most frequent clinical presentations were prominent sensory disturbances and painful sensations, often as initial symptom and pronounced in the upper limbs, contrasting with rather mild to moderate motor deficits. CONCLUSIONS: Our study confirms the relevance of FBLN5 mutations in CMT1. It is proposed to include FBLN5 in the genetic work-up of individuals suspected with CMT1, particularly when diagnosis is established beyond the first and second decade and comparably moderate motor deficits contrast with early and marked sensory involvement. FBLN5-associated CMT1 has a recognizable clinical phenotype and should be referred to as CMT1H according to the current classification scheme.

• Klíčová slova
• FBLN5, Charcot-Marie-Tooth neuropathy, autosomal dominant, demyelinating neuropathy, inherited peripheral neuropathy,
• MeSH
• Charcotova-Marieova-Toothova nemoc genetika   MeSH
• extracelulární matrix - proteiny genetika   MeSH
• fenotyp MeSH
• genetické testování MeSH
• lidé MeSH
• mutace MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• extracelulární matrix - proteiny MeSH
• FBLN5 protein, human MeSH Prohlížeč

BACKGROUND AND OBJECTIVES: Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy and often presents during childhood. Guidelines for the optimal management of common problems experienced by individuals with CMT do not exist, for either children or adults. We formed the Paediatric CMT Best Practice Guidelines Consortium to develop evidence and consensus-based recommendations for the clinical management of children and adolescents with CMT, with the primary objective of promoting optimal, standardised care globally. METHODS: Development of this clinical practice guideline involved a series of systematic reviews covering 10 clinical questions, modified Delphi methodology involving an international panel of clinicians to generate consensus where evidence did not exist, and application of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to evaluate the body of literature and formulate recommendations. RESULTS: The final guideline includes three evidence-based and 31 consensus-based recommendations. They encompass the management of muscle weakness, balance and mobility impairment, sensory symptoms, muscle cramps, impaired upper limb function, respiratory impairment, maintenance of joint range of motion and non-surgical management of joint deformity. Consensus was not achieved in some management areas, reflecting differences in practice between clinicians and healthcare settings, and highlighting the need for further research. CONCLUSIONS: This clinical practice guideline provides practical and implementable guidance on the management of common clinical problems experienced by children with CMT and advocates for improved access to multidisciplinary care. Successful dissemination and implementation of these recommendations will be critical in ensuring their application across multiple healthcare settings.

• Klíčová slova
• hmsn (Charcot-Marie-Tooth), paediatric neurology, systematic reviews,
• MeSH
• Charcotova-Marieova-Toothova nemoc * diagnóza   terapie   MeSH
• dítě MeSH
• dospělí MeSH
• konsensus MeSH
• lidé MeSH
• mladiství MeSH
• směrnice pro lékařskou praxi jako téma MeSH
• svalová slabost MeSH
• svalové křeče MeSH
• systematický přehled jako téma MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The aim of this study was to evaluate the utility of the Charcot-Marie-Tooth Neuropathy Score (CMTNS) for evaluation of disease severity in young children with Charcot-Marie-Tooth type 1A. Current validated scoring scales for Charcot-Marie-Tooth are the CMTNS and the Neuropathy Impairment Score (NIS). Both work well for adult patients, and usually also for children over 10 years of age. There is no validation of scales for young children. Children with genetically proven Charcot-Marie-Tooth type 1A disease (n = 20, aged 3 to 10 years) were examined clinically, followed by electrophysiologic examination, and were scored under the CMTNS scale. The clinical symptoms were mild; the two most frequent symptoms were difficulty in heel walking and lower limb areflexia. The score was maximally abnormal in four of the nine categories. Categories for sensation, sensory symptoms, and motor symptoms of the arms were normal in all cases. The score was below 8 for all tested children. To conclude, the CMTNS in children aged 10 years and younger has limited sensitivity; out of nine categories, only four are useful. Thus, evaluation of disease severity and progression in young children with Charcot-Marie-Tooth disease remains limited, and there is need for other, effective scoring systems.

• MeSH
• Charcotova-Marieova-Toothova nemoc diagnóza   MeSH
• dítě MeSH
• lidé MeSH
• neurologické vyšetření * MeSH
• předškolní dítě MeSH
• progrese nemoci MeSH
• stupeň závažnosti nemoci MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• hodnotící studie MeSH
• práce podpořená grantem MeSH

BACKGROUND: Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited neuropathy, a debilitating disease without known cure. Among patients with CMT1A, disease manifestation, progression and severity are strikingly variable, which poses major challenges for the development of new therapies. Hence, there is a strong need for sensitive outcome measures such as disease and progression biomarkers, which would add powerful tools to monitor therapeutic effects in CMT1A. METHODS: We established a pan-European and American consortium comprising nine clinical centres including 311 patients with CMT1A in total. From all patients, the CMT neuropathy score and secondary outcome measures were obtained and a skin biopsy collected. In order to assess and validate disease severity and progression biomarkers, we performed qPCR on a set of 16 animal model-derived potential biomarkers in skin biopsy mRNA extracts. RESULTS: In 266 patients with CMT1A, a cluster of eight cutaneous transcripts differentiates disease severity with a sensitivity and specificity of 90% and 76.1%, respectively. In an additional cohort of 45 patients with CMT1A, from whom a second skin biopsy was taken after 2-3 years, the cutaneous mRNA expression of GSTT2, CTSA, PPARG, CDA, ENPP1 and NRG1-Iis changing over time and correlates with disease progression. CONCLUSIONS: In summary, we provide evidence that cutaneous transcripts in patients with CMT1A serve as disease severity and progression biomarkers and, if implemented into clinical trials, they could markedly accelerate the development of a therapy for CMT1A.

• Klíčová slova
• Charcot Marie Tooth disease 1A, biomarker, disease progression, disease severity, skin biopsy,
• MeSH
• biopsie MeSH
• Charcotova-Marieova-Toothova nemoc krev   genetika   terapie   MeSH
• dospělí MeSH
• fosfodiesterasy genetika   MeSH
• genetická transkripce genetika   MeSH
• genetické markery genetika   MeSH
• glutathiontransferasa genetika   MeSH
• glykoproteiny genetika   MeSH
• jaderné proteiny MeSH
• kathepsin A genetika   MeSH
• kůže patologie   MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• lidé středního věku MeSH
• lidé MeSH
• messenger RNA genetika   MeSH
• neuregulin-1 genetika   MeSH
• PPAR gama genetika   MeSH
• prognóza MeSH
• progrese nemoci * MeSH
• pyrofosfatasy genetika   MeSH
• senioři MeSH
• výsledek terapie * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• CDAN1 protein, human MeSH Prohlížeč
• CTSA protein, human MeSH Prohlížeč
• ectonucleotide pyrophosphatase phosphodiesterase 1 MeSH Prohlížeč
• fosfodiesterasy MeSH
• genetické markery MeSH
• glutathiontransferasa MeSH
• glykoproteiny MeSH
• GSTT2 protein, human MeSH Prohlížeč
• jaderné proteiny MeSH
• kathepsin A MeSH
• messenger RNA MeSH
• neuregulin-1 MeSH
• NRG1 protein, human MeSH Prohlížeč
• PPAR gama MeSH
• pyrofosfatasy MeSH

STUDY DESIGN: Matched pair study. INTRODUCTION: Differences in hand-muscle strength/dexterity between dominant (DH) and non-dominant (NDH) hand in Charcot-Marie-Tooth disease (CMT) are not well understood. PURPOSE OF THE STUDY: To compare muscle strength/dexterity between DH and NDH and to correlate manual dexterity, strength and sensory function. PATIENTS AND METHODS: Thirty CMT patients were studied using functional muscle testing (FMT) and strength (dynamometry), dexterity (the Nine Hole Peg Test [NHPT]), and Jebsen-Taylor Hand Function [JTT]), and sensory function (the Nottingham Sensory Assessment [NSA]). RESULTS: Scores were worse for DH than NDH on FMT (p = 0.043) and NHPT (p = 0.014) but not on JTT (p = 0.098), handgrip strength (p = 0.710) or tripod pinch (p = 0.645). NSA did not correlate significantly with any tests (p's0.05). CONCLUSIONS: In CMT disease, DH appears more impaired than NDH in terms of function and dexterity. Greater muscle weakness in DH may also emerge as CMT progresses. LEVEL OF EVIDENCE: 3b.

• Klíčová slova
• Charcot-Marie-Tooth disease, Hand strength, Hereditary motor and sensory neuropathy, Manual dexterity, Sensory function,
• MeSH
• Charcotova-Marieova-Toothova nemoc patofyziologie   MeSH
• dospělí MeSH
• funkční lateralita fyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• motorické dovednosti fyziologie   MeSH
• neurologické vyšetření MeSH
• senioři MeSH
• síla ruky fyziologie   MeSH
• svalová síla - dynamometr MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Biallelic SBF2 mutations cause Charcot-Marie-Tooth disease type 4B2 (CMT4B2), a sensorimotor neuropathy with autosomal recessive inheritance and association with glaucoma. Since the discovery of the gene mutation, only few additional patients have been reported. We identified seven CMT4B2 families with nine different SBF2 mutations. Revisiting genetic and clinical data from our cohort and the literature, SBF2 variants were private mutations, including exon-deletion and de novo variants. The neuropathy typically started in the first decade after normal early motor development, was predominantly motor and had a rather moderate course. Electrophysiology and nerve biopsies indicated demyelination and excess myelin outfoldings constituted a characteristic feature. While neuropathy was >90% penetrant at age 10 years, glaucoma was absent in ~40% of cases but sometimes developed with age. Consequently, SBF2 mutation analysis should not be restricted to individuals with coincident neuropathy and glaucoma, and CMT4B2 patients without glaucoma should be followed for increased intraocular pressure. The presence of exon-deletion and de novo mutations demands comprehensive mutation scanning and family studies to ensure appropriate diagnostic approaches and genetic counseling.

• Klíčová slova
• SBF2, CMT4B2, Charcot-Marie-Tooth neuropathy, autosomal recessive, de novo mutation, glaucoma,
• MeSH
• biopsie MeSH
• Charcotova-Marieova-Toothova nemoc diagnóza   genetika   MeSH
• dítě MeSH
• dospělí MeSH
• fenotyp * MeSH
• genetická predispozice k nemoci * MeSH
• genetické asociační studie * metody   MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutace * MeSH
• nereceptorové tyrosinfosfatasy genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• nereceptorové tyrosinfosfatasy MeSH
• SBF2 protein, human MeSH Prohlížeč

In a large pedigree with the autosomal dominant form of Charcot-Marie-Tooth neuropathy type I (CMT 1) segregating in four generations, genetic linkage was studied between this disease and three genetic markers from the centromere region of chromosome 1: Duffy blood group (Fy), salivary and pancreatic isoamylases (AMY 1, AMY 2), and DNA polymorphism at the antithrombin III locus, detected with the probe pAT3c. The lod-scores found do not support linkage between CMT 1 and both Fy and AT 3, since they are negative for all recombination frequencies. Very close linkage could have been excluded. For the AMY polymorphism, the pedigree was not linkage-informative. In agreement with the data from literature, these results support the notion of genetic heterogeneity of CMT 1: in the pedigree under study, the responsible locus is probably not in the centromeric region of the chromosome 1, where it was shown to map to in several other pedigrees. Thus, there seem to exist at least two loci responsible for this type of CMT disease.

• MeSH
• antithrombin III genetika   MeSH
• Charcotova-Marieova-Toothova nemoc diagnóza   genetika   MeSH
• dominantní geny MeSH
• genetická vazba * MeSH
• isoamylasa genetika   MeSH
• krevní skupiny - systém Duffy genetika   MeSH
• lidé MeSH
• lidské chromozomy, pár 1 * MeSH
• rodokmen MeSH
• spinální svalová atrofie genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• Názvy látek
• antithrombin III MeSH
• isoamylasa MeSH
• krevní skupiny - systém Duffy MeSH

We report a 24-year-old male with an unusual combination of two inherited neuromuscular disorders--Charcot-Marie-Tooth (CMT) disease type 1A and Duchenne muscular dystrophy (DMD). A phenotypic presentation of this patient included features of both these disorders. Nerve conduction studies revealed demyelinating peripheral neuropathy. Electromyography showed a profound myogenic pattern. The serum creatine kinase level was highly elevated. Muscle biopsy revealed a dystrophic picture with deficient dystrophin immunostaining. CMT1A duplication on chromosome 17p11.2 was found. The frame-shift mutation c.3609-3612delTAAAinsCTT (p.K1204LfsX11) was detected in the dystrophin gene by analysing mRNA isolated from the muscle tissue. The patient inherited both these mutations from his mother. The combination of CMT1A and DMD has not been reported as yet.

• MeSH
• Charcotova-Marieova-Toothova nemoc komplikace   diagnóza   genetika   MeSH
• dospělí MeSH
• Duchennova muskulární dystrofie komplikace   diagnóza   genetika   MeSH
• lidé MeSH
• rodokmen MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

• MeSH
• amyotrofická laterální skleróza diagnóza   MeSH
• Charcotova-Marieova-Toothova nemoc diagnóza   MeSH
• dítě MeSH
• dospělí MeSH
• elektrická stimulace MeSH
• elektromyografie * MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• nervové vedení MeSH
• senioři MeSH
• svalová atrofie diagnóza   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH

The association of GNB4 with Charcot-Marie-Tooth (CMT) has recently been described in a publication by Soong et al. (Soong, et al., 2013). Here we present a patient with CMT in whom whole exome sequencing identified the mutation p.Lys57Glu in the GNB4 gene (NM_021629.3:c.169A>G). The patient, now 41 years old, is a sporadic case in the family. At the age of 35 he presented with severe disability (CMT neuropathy score 29), profound muscle atrophies, pes cavus and scoliosis. Previously, the patient was tested for PMP22 duplications/deletions and later also with 64 CMT gene panel, with no causal variant found. Subsequently, whole exome sequencing was performed. The p.Lys57Glu in the GNB4 gene was identified as the most probable causal variant, the mutation is not present in the patient's parents, neither in his unaffected sister, therefore we assume that the mutation arose de novo. Taken together, these findings support the causal and pathogenic character of the variant. Our report provides important evidence that GNB4 should become an established CMT gene and our findings confirm the original publication by Soong et al. (2013).

• Klíčová slova
• Charcot–Marie–Tooth disease, De novo, GNB4, Whole exome sequencing,
• MeSH
• Charcotova-Marieova-Toothova nemoc genetika   patologie   patofyziologie   MeSH
• dospělí MeSH
• lidé MeSH
• mutace MeSH
• proteiny vázající GTP - beta-podjednotky genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• GNB4 protein, human MeSH Prohlížeč
• proteiny vázající GTP - beta-podjednotky MeSH