Marie Tooth Disease Type Research Articles

Clinical Phenotype in an Early-Onset French Pediatric Population: Charcot-Marie-Tooth's Disease Type 2A.

Charcot-Marie-Tooth's disease type 2A (MCT2A), induced by mutation of the mitofusin 2 (MFN2) gene represents the main cause of MCT2. The aim of this study is to provide details of the clinical and electromyographic phenotype of MCT2A in a pediatric population. We conducted a French multicenter retrospective study, including all children with a genetic diagnosis of MCT2A. Thirteen MCT2A children were included with a beginning of symptoms before the age of 10 years ("early-onset group"). We report two new mutations: c.1070 A → T (p.Lys357.Met) and c.280 C → G (p.Arg94Gly). The evolution of the disease is marked by a fast worsening for three patients with loss of motor autonomy, while the evolution is relatively stable for eight patients. The group of early-onset MCT2A seems more heterogeneous than previously described, with a nonconstant severe phenotype.

In-silico and Molecular Analysis of RTN4 as novel therapeutic option for axonal regeneration

To find interactions of the ligand with axonali nhibitors, and to check the optimum interactions of existing drugs as inhibitors for the protein that hinders the growth of injured neurons. The study was conducted at Kongju National University, Korea from May 2016 to March 2017. It consisted of two parts. Molecular analysis and bioinformatics analysis. The study comprised a family of six with Charcot-Marie-Tooth phenotypes, recommended by a neurologist for molecular analysis on the clinical symptoms to find the mutations responsible for the disease. Blood samples were collected from each family member and total deoxyribonucleic acid was extracted and it was analysed for Reticulon 4 gene by sequencing the coding and intronic regions. However, a missense mutation was found on exon 2 of the gene in the proband and the whole family was subsequently analysed. Bioinformatics analysis and docking studies were carried out to investigate the potential behaviour of Reticulon 4 as therapeutic agent. Sequencing analysis was performed to find the pathoegenic variant responsible for Charcot-Marie-Tooth type 1. After checking pathogenicity of the mutation, Reticulon 4 gene was found to be not involved in Charcot- Marie-Tooth disease type 1. Reticulon 4 gene was not found to be involved in causing Charcot-Marie-Tooth disease type 1.

Clinical characteristics and MTMR13/SBF2 gene mutation analysis of a Charcot - Marie-Tooth disease type 4B2 Chinese family

Clinical characteristics and MTMR13/SBF2 gene mutation analysis of a Charcot - Marie-Tooth disease type 4B2 Chinese family

Clinical progression in Charcot–Marie-Tooth disease type 1A duplication: clinico-electrophysiological and MRI longitudinal study of a family

Long-term follow-up studies in Charcot-Marie-Tooth disease type 1 duplication (CMT1A) are scanty. Here we describe a longitudinal study in a CMT1A pedigree. Our CMT1A pedigree comprised 11 examined patients, ages between 13 and 83 (median, 36) years, serially evaluated for up to 26 years. In all 11 patients we carried out electrophysiological evaluation, and in three of them magnetic resonance imaging (MRI) of lower-limb musculature. The 54-year-old proband patient, yearly examined as of age 28, developed at age 48 gradual and progressive distal lower-leg weakness ascending to thigh musculature. His serial electrophysiological studies showed diffuse slowing of motor conduction velocity, absence or severe attenuation of distal compound muscle action potentials, and spontaneous muscle activity in the tibialis anterior and rectus femoris. Two MRI studies of lower limbs, at ages 51 and 54, showed extensive fatty atrophy of lower-leg musculature, and progressive and distally accentuated fatty atrophy of anterior and posterior femoral muscles. An outstanding finding in the first MRI was the presence of marked edema of anterior femoral musculature, which to a great degree was replaced by fatty atrophy in the second study. Muscle edema was also noted in lower-leg and posterior femoral musculature. There was minimal fatty atrophy of the gluteus maximus, the remaining pelvic muscles being preserved. The other ten patients showed mild or moderate phenotype, which remained quiescent over the period of observation. Electrophysiological studies disclosed diffuse and uniform slowing of nerve conduction velocities; in no case was spontaneous muscle activity recorded. MRI showed the CMT1A characteristic pattern of distally accentuated fatty atrophy involving foot and lower-leg musculature with preservation of thigh musculature. We conclude that a small proportion of patients with CMT1A develop a late progression of disease manifested with accentuated distal leg weakness ascending to involve thigh musculature, and that long-term follow-up is essential for its detection.

Seipin/BSCL2 mutation screening in sporadic adult-onset upper motor neuron syndromes

Sirs,The ability to distinguish between sporadic presentationsof hereditary spastic paraparesis (HSP) and primary lateralsclerosis (PLS) is important in terms of prognostication andgenetic counseling, but clinical differentiation is problem-atic [6]. Primary lateral scherosis is a sporadic disorder ofprogressive spino-bulbar spasticity and may be part of theclinical spectrum of amyotrophic lateral sclerosis (ALS)[10]. Hereditary spastic paraparesis is a clinically andgenetically heterogeneous group of disorders characterizedby a slowly progressive spastic paraparesis [8, 12].To date, 15 genes and more than 20 additional loci havebeen identified for autosomal dominant (AD), autosomalrecessive and X-linked forms of HSP [5, 7]. The spastingene (SPG4) mutation is the most frequent cause of ADHSP (around 40% of families) and is also frequent insporadic HSP (13%), but not in PLS [3]. We recently foundpathogenic paraplegin gene (SPG7) mutations 11% ofpatients with sporadic HSP [4]. The role of other HSP genesin sporadic upper motor neuron (UMN) syndromes islargely unknown. Two known mutations (c.263G [A/p.N88Sand c.269C[T/p.S90L) in exon 3 of the seipin/BSCL2 gene(SPG17) can cause a range of AD (mixed) upper and lowermotor neuron disorders, including Silver syndrome (HSPwith amyotrophy of the hands), variants of Charcot–Marie-tooth disease type 2, distal hereditary motor neuropathy typeV(dHMNV),butalsopureandcomplicatedformsofHSP[1,13, 14]. Because of incomplete penetrance, the seipin/BSCL2 mutation can manifest as a sporadic disease [14].To investigate whether these two seipin/BSCL2 muta-tions are present in patients with sporadic HSP and PLS,we screened exon 3 of the seipin/BSCL2 gene in 86 Dutchpatients with a sporadic adult-onset UMN syndrome.Inclusion criteria were a gradually progressive UMN syn-drome, adult-onset, disease duration [6 months and anegative family history. Exclusion criteria were lowermotor neuron loss meeting the revised El Escorial criteriafor clinically definite, clinically probable or probable lab-oratory-supported ALS [2] and evidence of other causes ofa UMN syndrome based on a battery of laboratory inves-tigations, including serum biochemistry (including thyroid-stimulating hormone, angiotensin converting enzyme,vitamin B12, folate and vitamin E), analysis of very longchain fatty acids in plasma, serology (syphilis, borreliosis,human T cell lymphotrophic virus type 1 and humanimmunodeficiency virus) and bile alcohol analysis in urine,and cerebral and spinal magnetic resonance imaging(MRI). The presence of the SPG4 and SPG7 mutations wasexcluded in all patients. The study was approved by themedical ethics review board of the University MedicalCenter in Utrecht, and written informed consent wasobtained from all patients.Mutation screening of the seipin/BSCL2 gene was per-formed using automated forward and reverse directsequencing of exon 3. The BSCL2 exon 3 was amplified byPCR using intronic primers (primer sequences available onrequest), and the PCR products were loaded on an Applied

Hand involvement in children with Charcot–Marie-Tooth disease type 1A

Charcot–Marie-Tooth disease type 1A (CMT1A), a demyelinating neuropathy characterised by progressive length-dependent muscle weakness and atrophy, is thought to affect the foot and leg first followed some time later by hand weakness and dysfunction. We aimed to characterise hand strength, function and disease-related symptoms in children with CMT1A. Intrinsic and extrinsic hand strength was measured by hand-held dynamometry, function by nine-hole peg test, and disease-related symptoms by interview and examination in 84 affected children aged 2–16 years. Hand weakness and dysfunction was present from the earliest stages of the disease. While hand strength and function measures tended to increase with age throughout childhood, at no point did they reach normal values. Day-to-day hand problems such as poor handwriting, weakness, pain and sensory symptoms also worsened with age. The hand is affected at all ages in children with CMT1A, but may be under-recognised in its early stages, potentially delaying therapy.