Genetic testing practices for Charcot–Marie–Tooth type 1A disease

Introduction: Charcot–Marie–Tooth disease type 1A (CMT1A) is caused by a PMP22 gene duplication. CMT1A has a robust electrical phenotype that can be used to direct genetic testing. We compared specialty CMT center CMT1A diagnosis rates to those of outside physicians. Methods: Charts were reviewed for 102 patients with CMT1A seen at a specialty CMT clinic between 2001 and 2009. Nerve conduction studies, family history, date of genetic testing, and type of genetic testing (single gene vs. panel) were collected. Results: Although the specialty clinic ordered more PMP22 duplication testing alone beginning at an earlier year, thereby reducing costs, both the specialty clinic and outside physicians began the decade doing panel testing and ended the decade looking at only PMP22. Conclusions: Specialty centers adapt earlier to changes in testing practice than non‐specialty centers. As the landscape of genetic testing changes, the algorithms for testing will also likely change. Muscle Nerve 49:478–482, 2014     

Pain and small fiber function in charcot–marie–tooth disease type 1A

Introduction: Charcot–Marie–Tooth (CMT) disease type 1A is the most common form of CMT. The main clinical features are distal weakness, sensory loss, and skeletal deformities. Although pain is a frequent complaint, small fiber involvement in CMT1A has not been studied extensively. Methods: We assessed pain and small fiber involvement in 49 CMT1A patients using a variety of pain scales, pain questionnaires, and thermal thresholds. Results: Forty‐three of 49 patients (88%) complained of pain. The pain was localized to the feet in 61% of patients. Only 18% of patients had neuropathic pain. Cold and warm detection thresholds were elevated in 53% and 12% of patients, respectively. Conclusions: Our findings confirm that CMT1A patients have significant pain, which is more likely to be multifactorial in origin and suggests that a proportion of patients have small fiber dysfunction affecting mainly thinly myelinated Aδ fibers. Muscle Nerve 50 : 366–371, 2014     

Peripheral myelin protein 22: Facts and hypotheses

Mutations affecting the peripheral myelin protein 22 (PMP22) gene are associated with inherited motor and sensory neuropathies in mouse (Trembler and Trembler-J) and human (Charcot-Marie-Tooth disease type 1A and Dejerine-Sottas syndrome). Although genetic studies have established a critical role of PMP22 in the formation and/or maintenance of myelin in the peripheral nervous system, the biological function of PMP22 in myelin and in non-myelin forming cells remains largely enigmatic. In this Mini Review, we will summarize the current knowledge about PMP22 and discuss its hypothetical function(s) in a broad context. © 1995 Wiley-Liss, Inc.     

Phenotology of disease-linked proteins

Are there analogous sequence positions in families of related proteins where disease‐linked mutations occur with unusually high frequency? We attempt to answer this question by examining sequence alignments for G‐protein coupled receptors (GPCRs) and voltage‐gated potassium channels that have a significant number of missense mutations linked to some form of human disease. When the disease‐linked mutations are mapped onto the sequences for each family, there are a large number of aligned sites at which disease‐linked mutations occur in more than one protein. The statistical significance of the aligned sites is judged by analysis of artificially‐generated random datasets. There are a modest number of aligned sites that are statistically significant—we refer to these as “phenotologous” sequence positions. Phenotologous sites represent aligned positions at which mutations linked to disease phenotypes occur with high frequency within a family of proteins. The most interesting of these sites are those which are not conserved—such sites are apparently critical in defining structural or functional differences between related proteins. Phenotology may be used to make experimentally testable predictions regarding medical genetics, the molecular basis of disease, and protein structure–function relationships. Hum Mutat 25:90–97, 2005. © 2004 Wiley‐Liss, Inc.     

Mutational analysis and genotype/phenotype correlation in Turkish Charcot-Marie-Tooth Type 1 and HNPP patients

The major Charcot- Marie-Tooth Type 1 (CMT1) locus, CMT1A, and Hereditary neuropathy with liability to pressure palsies (HNPP) cosegregate with a 1.5-Mb duplication and a 1.5-Mb deletion, respectively, in band 17p11.2. Point mutations in peripheral myelin gene 22 (PMP22), myelin protein zero (MPZ), and connexin 32 (Cx32) have been reported in CMT1, and in PMP22 in HNPP patients without deletion. We have screened 54 CMT1 patients, of variable clinical severity, and 25 HNPP patients from Turkey, with no duplication or deletion, for mutations in the PMP22 and Cx32 genes. A novel frameshift mutation affecting the second extracellular domain of PMP22 was found in an HNPP patient, while a point mutation in the second transmembrane domain of the protein was detected in a CMT1 patient. Two point mutations affecting different domains of Cx32 were identified in two CMTX patients. Another patient was found to carry a polymorphism in a non-conserved codon of the Cx32 gene. The clinical phenotypes of the patients correlate well with the effect of the mutation on the protein.     

Can low grade PMP be divided into prognostically distinct subgroups based on histological features? A retrospective study and the importance of using the appropriate classification

Introduction

The pathological classification of PMP of appendiceal origin has prognostic and treatment implications. Our goals were to? Classify low grade mucinous carcinoma peritonei (LGMCP) into prognostically distinct subgroups based on histological features.? Compare the reproducibility of the WHO and the PSOGI classifications for both PMP and the appendiceal primary tumor.

Anticipation in a unique family with Charcot‐Marie‐Tooth syndrome and deafness: Delineation of the clinical features and review of the literature

Charcot‐Marie‐Tooth disease (CMT) is a clinically and genetically heterogeneous group of polyneuropathies characterized by degeneration of peripheral nerves, resulting in distal muscle atrophy, sensory loss, and deformities of hands and feet. We have studied 34 individuals in a large 84‐member four‐generation central Illinois family with autosomal dominant Charcot‐Marie‐Tooth and deafness. Nerve conduction velocities are consistent with type 1 CMT. Audiological evaluation revealed both auditory neuropathy and cochlear involvement in affected individuals. There is increasing clinical severity and younger age of onset of CMT and deafness with each progressive generation, suggestive of anticipation (P < 0.05). The proband, a female diagnosed at birth with hypotonia, bilateral vocal cord palsy, swallowing incoordination, and hearing impairment, died at age 18 months. Another individual died at the age of 3 months from hypotonia later attributed to CMT. Genetic analysis indicated that affected individuals in this family do not have the common 1.4 Mb duplication associated with type 1A CMT; however, all affected individuals have a unique G to C transversion at position 248 in coding exon 3 of the peripheral myelin PMP22 gene located on chromosome 17p11.2‐p12. This mutation is predicted to cause an Ala67Pro substitution in the second transmembrane domain of PMP22, consistent with the molecular cause of the CMT phenotype. However, it does not explain the cochlear component of the deafness, the clinical observation of anticipation, and other features in this family. © 2002 Wiley‐Liss, Inc.     

类物质的吡唑啉酮类衍生物柱前衍生化方法及其在海洋生物的糖类物质组分分析中的应用

糖类物质作为细胞组成中最为重要的物质之一,是蛋白质、脂肪代谢的必要物质,也是是人体必需的营养元素之一。但人们对糖类化物质在生物体内的功能作用的研究却很滞后,这主要是因为糖类物质种类烦多、结构较为复杂且具有多种异构体,存在微观的不均一性。通常情况下,单糖和寡糖仅在基团-CHOH的构型排列上会有所不同,通过常规的方法对其分离鉴定比较困难,为此,常采用衍生化的方法处理,将糖类物质组分转变成为带有发色基团的分子,然后再进行紫外检测和荧光检测。糖类物质在海洋生物中广泛存在,衍生化方法是对海洋生物中糖类物质进行分析的重要手段。     

Clinical,electrophysiological, and molecular findings in early onset hereditary neuropathy with liability to pressure palsy

Introduction: The first episode of hereditary neuropathy with liability to pressure palsy (HNPP) in childhood is rare. Methods: We analyzed retrospectively the data of 7 patients with a deletion in PMP22 and onset of symptoms before age 18 years. Direct sequencing of the LITAF (lipopolysaccharide‐induced tumor necrosis factor) gene was performed in patients and family members. Results: Clinical presentations varied from mononeuropathies to brachial plexopathy, with recurrent episodes in 4 patients. Electrophysiological abnormalities characteristic for HNNP were found in most subjects. Analysis of the LITAF gene revealed an Ile92Val polymorphism in 6 of 7 (86%) probands and 5 of 7 (83%) family members, over 4 times greater frequency than in the general population. Conclusions: Clinical suspicion of HNPP even when nerve conduction study results do not fulfill HNPP criteria should indicate genetic testing. In our patients, early‐onset HNPP was associated frequently with isoleucine92valine LITAF polymorphism. Muscle Nerve 50: 914–918, 2014