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.     

Charcot–Marie–Tooth disease: genetic subtypes in the Sardinian population

Charcot–Marie–Tooth disease (CMT) is characterised by great variability of genetic subtypes. This study aimed to assess the genetic subtypes of CMT disease in the Sardinian population. Genetic screening was performed for CMT cases (CMT1, CMT2, and hereditary neuropathy with susceptibility to pressure palsies [HNPP]). A total of 1,043 subjects (119 index cases) were evaluated. In CMT1 index cases (69/119; 58%), PMP22 duplication at 17p11.2 was the most frequent genetic diagnosis (60/69; 87%), followed by mutations in the GJB1 gene (5/69; 7.2%), in the SH3TC2 gene (3/69; 4.4%) and PMP22 Gly107Val point mutation (1/69; 1.4%). The CMT2 group (24/119; 20.1%) comprised 10/24 (41.6%) patients carrying MPZ gene Ser44Phe mutation, 6/24 (25%) with mutations in MFN2 and HSPB1, and 1/24 (4.2%) in GJB1 and LRSAM1. In the HNPP group (26/119; 21.9%), the majority of patients reported the PMP22 deletion (25/26; 96.2%). Further studies are needed to comprehend the overall picture of the disease in Mediterranean area.     

Clinical spectrum and frequency of Charcot–Marie–Tooth disease in Italy: Data from the National CMT Registry

Background and purpose

Data are reported from the Italian CMT Registry.

Methods

The Italian CMT Registry is a dual registry where the patient registers and chooses a reference center where the attending clinician collects a minimal dataset of information and administers the Charcot–Marie–Tooth (CMT) Examination/Neuropathy Score. Entered data are encrypted.

Results

Overall, 1012 patients had registered (535 females) and 711 had received a genetic diagnosis. Demyelinating CMT (65.3%) was more common than axonal CMT2 (24.6%) and intermediate CMT (9.0%). The PMP22 duplication was the most frequent mutation (45.2%), followed by variants in GJB1 and MPZ (both ~10%) and MFN2 (3.3%) genes. A relatively high mutation rate in some “rare” genes (HSPB1 1.6%, NEFL 1.5%, SH3TC2 1.5%) and the presence of multiple mutation clusters across Italy was observed. CMT4A was the most disabling type, followed by CMT4C and CMT1E. Disease progression rate differed depending on the CMT subtype. Foot deformities and walking difficulties were the main features. Shoe inserts and orthotic aids were used by almost one-half of all patients. Scoliosis was present in 20% of patients, especially in CMT4C. Recessive forms had more frequently walking delay, walking support need and wheelchair use. Hip dysplasia occurred in early-onset CMT.

Conclusions

The Italian CMT Registry has proven to be a powerful data source to collect information about epidemiology and genetic distribution, clinical features and disease progression of CMT in Italy and is a useful tool for recruiting patients in forthcoming clinical trials.     

GJB1/Connexin 32 whole gene deletions in patients with X-linked Charcot–Marie–Tooth disease

The X-linked form of Charcot–Marie–Tooth disease (CMTX) is the second most common form of this genetically heterogeneous inherited peripheral neuropathy. CMT1X is caused by mutations in the GJB1 gene. Most of the mutations causative for CMT1X are missense mutations. In addition, a few disease causative nonsense mutations and frameshift deletions that lead to truncated forms of the protein have also been reported to be associated with CMT1X. Previously, there have been reports of patients with deletions of the coding sequence of GJB1; however, the size and breakpoints of these deletions were not assessed. Here, we report five patients with deletions that range in size from 12.2 to 48.3 kb and that completely eliminate the entire coding sequence of the GJB1 gene, resulting in a null allele for this locus. Analyses of the breakpoints of these deletions showed that they are nonrecurrent and that they can be generated by different mechanisms. In addition to PMP22, GJB1 is the second CMT gene for which both point mutations and genomic rearrangements can cause a neuropathy phenotype, stressing the importance of CMT as a genomic disorder.     

Inflammatory demyelinating CNS disorder in a case of X-linked Charcot–Marie–Tooth disease: positive response to natalizumab

Journal of Neurology -     

Inheritance of Charcot–Marie–Tooth disease 1A with rare nonrecurrent genomic rearrangement

Rare copy number variations by the nonrecurrent rearrangements involving PMP22 have been recently suggested to be associated with CMT1A peripheral neuropathy. As a mechanism of the nonrecurrent rearrangement, replication-based fork stalling template switching (FoSTeS) by microhomology-mediated break-induced replication (MMBIR) has been proposed. We found three Korean CMT1A families with putative nonrecurrent duplication. The duplications were identified by microsatellite typing and applying a CGH microarray. The breakpoint sequences in two families suggested an Alu–Alu-mediated rearrangement with the FoSTeS by the MMBIR, and a two-step rearrangement of the replication-based FoSTeS/MMBIR and meiosis-based recombination. The two-step mechanism has still not been reported. Segregation analysis of 17p12 microsatellite markers and breakpoint junction analysis suggested that the nonrecurrent rearrangements are stably inherited without alteration of junction sequence; however, they may allow some alteration of the genomic contents in duplication across generations by recombination event. It might be the first study on the pedigree analysis of the large CMT1A families with nonrecurrent rearrangements. It seems that the exact mechanism of the nonrecurrent rearrangements in the CMT1A may have a far more complex process than has been expected.     

Anti-βubulin antibodies have no diagnostic value in patients with chronic inflammatory demyelinating polyneuropathy

High-titre anti--tubulin antibodies were recently reported to occur in over 50% of sera from patients with chronic inflammatory demyelinating polyneuropathy (CIDP). It was concluded that these antibodies may help to distinguish CIDP from other neuropathies and that they are diagnostically useful. To verify these findings, we studied sera of 43 CIDP patients, only 3 of whom had anti--tubulin antibodies. The differences between the results obtained cannot fully be explained by differences between patients or antigens but may be explained by the use of different techniques (Western blot versus ELISA). We used Western blot, which is less sensitive but far more specific, to detect these antibodies. The findings of our study did not confirm the high frequency of selective high-titre anti--tubulin antibodies in CIDP patients. Therefore we conclude that binding to -tubulin by Western blot cannot serve as a marker of CIDP.Presented in part at the 4th annual meeting of the European Neurological Society Barcelona, June 1994 and at the 4th congress of the International Society of Neuroimmunology, Amsterdam, October 1994     

Association of miR-149 polymorphism with onset age and severity in Charcot–Marie–Tooth disease type 1A

Charcot–Marie–Tooth disease type 1A (CMT1A) is caused by 1.5-fold increased dosage of the PMP22; however, onset age and severity vary considerably among patients. The exact reason behind these phenotypic heterogeneities has rarely been discovered yet. Because miRNAs are the key regulators of gene expression, we speculated that variants of miRNAs might be the genetic modifiers for CMT1A. This study noticed a common single nucleotide polymorphism (n.86T > C, rs2292832) in the miR-149 which was predicted to target several CMT causing genes including PMP22. The rs2292832 was located near the 3′ end of the precursor microRNA of the miR-149. We performed an association study between the rs2292832 polymorphism and clinical phenotypes of CMT1A in subjects consisting of 176 unrelated Korean CMT1A patients and 176 controls. From this study, we observed that rs2292832 was closely associated to the onset age and severity of CMT1A. Particularly, the TC and CC genotypes were significantly associated with late onset and mild symptom. Therefore, we suggest that the rs2292832 variant in the miR-149 is a potential candidate as a genetic modifier which affects the phenotypic heterogeneity of CMT1A. This study may provide the first evidence that polymorphism in the miR gene is associated with the CMT1A phenotype.     

The role of the prefrontal cortex in the development of muscle fatigue in Charcot–Marie–Tooth 1A patients

This study aimed at comparing both peripheral and central mechanisms of muscle fatigue between Charcot–Marie–Tooth 1A patients and healthy individuals during a fatiguing voluntary task by simultaneous electromyographic and electroencephalographic recordings. Six Charcot–Marie–Tooth 1A patients (3 females, 40 ± 11 years) and 6-matched healthy individuals performed four blocks of sub-maximal isometric knee extensions. At the beginning of the session and after each block, electrically-evoked maximal single-twitch, maximal voluntary contraction and surface-electromyography of the vastus lateralis muscle were measured. The movement-related-cortical potentials were averaged in early (block 1–2) and late (block 3–4) stages of fatigue. The effect of fatigue was demonstrated at peripheral level by the decline of maximal voluntary contraction, maximal twitch and surface electromyography amplitude and at central level by the larger amplitude of movement-related-cortical-potentials during late than early stage of fatiguing sub-maximal contractions. Charcot–Marie–Tooth 1A patients showed lower motor cortex activity during motor planning, with earlier onset and larger prefrontal cortex activity during the late stage of the fatiguing task than healthy controls. These data demonstrate the key role of the prefrontal cortex in the development of fatigue in Charcot–Marie–Tooth 1A patients, which may be activated as a compensatory mechanism for the low motor cortex activation, thus reflecting high awareness of movement complexity.     

Myasthenia gravis and chronic inflammatory demyelinating polyneuropathy in the same patient – a case report

Purpose: To investigate the clinical character, diagnosis and treatment of chronic inflammatory demyelinating polyneuropathy accompanying myasthenia gravis so as to improve the understanding of such diseases.

Materials and methods: A case of chronic inflammatory demyelinating polyneuropathy combined with myasthenia gravis were analyzed retrospectively with review of the literature.

Results: This man was presented with chronic progressive sensory symptoms, flaccid tetraparesis, areflexia and protein-cell dissociation of cerebrospinal fluid. Nerve conduction study was indicative of demyelinating neuropathy. He was suspected as chronic inflammatory demyelinating polyneuropathy and treated with high-dose glucocorticoids. However, his condition worsened. Four months later, he was admitted and was diagnosed as combination of chronic inflammatory demyelinating polyneuropathy and myasthenia gravis. Good clinical results were observed after he was treated with pyridostigmine bromide, prednisone and mycophenolate mofetil.

Conclusions: This case warns clinicians to be aware of these two diseases presenting in the same patient, and the possible implications on treatment choices. A common immunological abnormality might exist in this rare association, but it still remains unknown.     

Altered cerebrospinal fluid index of prealbumin, fibrinogen, and haptoglobin in patients with Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy

Zhang H‐L, Zhang X‐M, Mao X‐J, Deng H, Li H‐F, Press R, Fredrikson S, Zhu J. Altered cerebrospinal fluid index of prealbumin, fibrinogen, and haptoglobin in patients with Guillain–Barré syndrome and chronic inflammatory demyelinating polyneuropathy.
Acta Neurol Scand: 2012: 125: 129–135.
© 2011 John Wiley & Sons A/S. Objectives – Guillain–Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) are autoimmune diseases of the peripheral nervous system. A clinical hallmark of GBS and CIDP is the albumino‐cytologic dissociation in the cerebrospinal fluid (CSF). Changes in the CSF levels of proteins other than albumin in patients with GBS and CIDP are not as well studied. If altered, aberrant levels of CSF proteins may render it possible to establish useful biomarkers for GBS and CIDP. Materials and methods – Enzyme‐linked immunosorbent assay (ELISA) was used to measure the levels of prealbumin, fibrinogen, haptoglobin, apolipoprotein E, apolipoprotein A4 in both CSF and plasma samples from 19 patients with GBS and eight with CIDP, 24 controls with multiple sclerosis (MS) as well as 20 patients with other non‐inflammatory neurological disorders (OND). Results – The levels of prealbumin in both the plasma and the CSF were elevated in patients with GBS and MS compared with the controls. The higher levels of fibrinogen were seen in the CSF of patients with GBS and CIDP, but not in the plasma. The levels of CSF prealbumin and fibrinogen, measured by the CSF index of these proteins, were lower in patients with GBS and that of fibrinogen in patients with CIDP compared with controls with OND. Haptoglobin levels in the CSF rather than in the plasma were higher in patients with GBS and CIDP than in controls. The CSF haptoglobin index was higher in patients with CIDP and MS, but not in those with GBS. No correlation was found between levels of CSF proteins and clinical parameters in patients with GBS and CIDP. Conclusions – Our data provide preliminary evidence that GBS is associated with low CSF index levels of prealbumin and fibrinogen, but normal levels of haptoglobin, whereas CIDP is associated with normal CSF index levels of prealbumin, low fibrinogen, and high levels of haptoglobin. Further studies are needed to identify the underlying mechanisms behind these CSF protein alterations and to clarify whether prealbumin, fibrinogen, and haptoglobin can serve as useful biomarkers for GBS and CIDP.     

Genotype–phenotype correlation and frequency of distribution in a cohort of Chinese Charcot–Marie–Tooth patients associated with GDAP1 mutations

Journal of Neurology - Mutations in ganglioside-induced differentiation-associated-protein 1 (GDAP1) have been associated with both subtypes of Charcot–Marie–Tooth (CMT) disease,...