Moreno Ferrarini

Giant axon and neurofilament accumulation in Charcot–Marie–Tooth disease type 2E

The axonal type 2 Charcot–Marie–Tooth disease (CMT2) is phenotypically poorly characterized. Here the authors report a family with a Pro22Ser mutation in the neurofilament-light gene (NF-L; CMT2E) manifesting electrophysiologically as the demyelinating type 1 CMT (CMT1) and pathologically as an axonopathy with giant axons and accumulation of disorganized NF. NF-L should be investigated in CMT2 as well as in CMT1 not associated with the usual genes PMP22, Cx32, and P0.

Two novel mutations in dynamin-2 cause axonal Charcot-Marie-Tooth disease.

Background: Recently, mutations affecting different domains of dynamin-2 (DNM2) were associated alternatively with autosomal dominant centronuclear myopathy or dominant intermediate (demyelinating and axonal) Charcot–Marie–Tooth disease (CMT) type B. Objective: To assess the etiologic role of DNM2 in CMT. Methods: We performed a mutational screening of DNM2 exons 13 through 16 encoding the pleckstrin homology domain in a large series of CMT patients with a broad range of nerve conduction velocities and without mutations in more common genes. Results: We identified two novel DNM2 mutations that cosegregated with purely axonal CMT in two pedigrees without clinical evidence of primary myopathy. Conclusion: Patients with axonal Charcot–Marie–Tooth disease type 2 neuropathy without mutations in more common genes should undergo investigation for DNM2 pleckstrin homology.

Variable presentations of TTR-related familial amyloid polyneuropathy in seventeen patients

Autosomal‐dominant transthyretin (TTR)‐related amyloidosis usually manifests in the second to fourth decade with a length‐dependent axonal neuropathy with prominent involvement of the small fibers and multi‐organ systemic failure. We retrospectively analyzed seventeen probands, including thirteen apparently isolated cases, carrying eight mutations of TTR gene (age of onset = 60.4 ± 13.5 years). Thirteen patients were initially un/misdiagnosed; interval from onset to definite diagnosis was 3.3 ± 2.3 years. Inaugural syndromes were a length‐dependent motor‐sensory neuropathy in seven cases, a sensory neuropathy in four, an isolated carpal tunnel syndrome in three, a pure dysautonomia in two, and a painful neuropathy in one. Atypical presentations included demyelinating nerve conduction changes with increased cerebrospinal fluid proteins resembling chronic inflammatory demyelinating polyradiculoneuropathy and a predominantly motor involvement resembling a motor neuron disorder. Misleading findings also included amyloid‐negative abdominal fat aspirate/biopsy, biclonal gammopathy, and hepatitis C virus (HCV) seropositivity. Sural nerve biopsy detected amyloid deposits in thirteen of fifteen patients, including one case with a previous negative biopsy. TTR‐immunohistochemistry was necessary to complete the diagnosis of primary amyloidosis light chain in a patient with biclonal gammopathy. A recurrent p.Phe64Leu mutation manifested in the seventh decade with painful motor‐sensory polyneuropathy, dysautonomia, bulbar palsies, and fasciculations. TTR should be tested in a wide clinical spectrum of cryptogenetic, progressive, and motor‐sensory neuropathies even manifesting with a very late onset.

A novel HSPB1 mutation in an Italian patient with CMT2/dHMN phenotype.

Mutations in the gene encoding 27-kDa small heat-shock protein B1 (HSPB1) have been reported in association with Charcot-Marie-Tooth disease type 2F or dHMN type II. We describe an Italian patient with wasting and weakness of distal muscles, involving primarily and mostly the lower limbs and later the upper limbs, in which a novel mutation of HSPB1, T180I, was detected. Electrophysiological evaluation disclosed a pure motor axonal neuropathy. Sural nerve biopsy showed a mild reduction of myelinated fibre density. All these findings suggested a CMT2/dHMN phenotype.

A somatic and germline mosaic mutation in MPZ/P0 mimics recessive inheritance of CMT1B

Objective: To identify the molecular basis of a demyelinating Charcot–Marie–Tooth disease type 1 (CMT1) with presumed autosomal recessive inheritance. Background: CMT1, an inherited motor and sensory neuropathy with low nerve conduction velocities, is caused by dominantly inherited mutations in the genes of the peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ/P0), and early growth response 2 transcription factor (EGR2/Krox-20). Patients and methods: Two young sisters born of clinically and electrophysiologically healthy parents had a severe CMT1 neuropathy of presumed autosomal recessive inheritance. The older sister underwent a nerve biopsy. The authors analyzed PMP22, MPZ/P0, and EGR2/Krox-20 by automated direct nucleotide sequencing. For rapid mutation detection, they determined the restriction-fragment-length polymorphisms for TaqI in the fluorescein-labeled target DNA sequence amplified by PCR. Results: Nerve biopsy disclosed a demyelinating and remyelinating neuropathy with onion bulb formations. Both sisters had a novel heterozygous G308→A transition of MPZ/P0 without any mutation of PMP22 or EGR2/Krox-20. The G308→A transition was a nonconservative mutation that changed a glycine into a glutamate at the amino acid residue 74 in the extracellular domain of the mature MPZ/P0. None of 50 healthy controls had the mutation. The healthy mother had a low amount of the mutation in blood (≅ 20%) as well as in skin, buccal epithelium, and hairs (30%). Because the healthy mother carried clones of somatic mutant cells and had transmitted the G308→A transition to the affected daughters, she also harbored germline mutant cells. Conclusion: In hereditary demyelinating neuropathies, somatic and germline mosaicism of dominant mutations in the myelin protein genes may mimic autosomal recessive inheritance.

Vascular endothelial growth factor helps differentiate neuropathies in rare plasma cell dyscrasias.

POEMS syndrome and amyloidosis are rare plasma cell diseases that share common features, including polyneuropathy. The aim of this study was to investigate serum vascular endothelial growth factor (sVEGF) in patients with amyloidosis and to evaluate changes in response to treatment. Twenty‐five patients [17 primary light‐chain amyloidosis (AL‐A), 7 transthyretin amyloidosis (TTR‐A), 1 senile wild‐type TTR‐A] were studied. sVEGF was analyzed by ELISA. Sera from 8 myeloma and 7 POEMS patients were also evaluated. The median sVEGF level was 420 pg/ml in AL‐A and 179 pg/ml in TTR‐A patients; this was significantly lower than in POEMS syndrome (median 2580 pg/ml, P = 0.0002 and 0.001, respectively). sVEGF of AL‐A patients showed no changes in response to treatment. sVEGF was not increased in amyloid patients regardless of neuropathy, and did not mirror the course of the disease. sVEGF should be tested in patients with overlapping and atypical clinical features. Muscle Nerve, 2011

Inter-nerves and intra-nerve conduction heterogeneity in CMTX with Arg(15)Gln mutation

OBJECTIVE In X-linked Charcot-Marie-Tooth disease (CMTX), electrophysiological and histopathological studies have suggested either a demyelinating or an axonal polyneuropathy. We report a CMTX family with a striking heterogeneity of nerve conductions between and within nerves. METHODS Two men and one woman have been studied by conduction velocities, sural nerve biopsy with morphometry (one man) and DNA analysis. RESULTS In both men motor conduction velocities were slowed in the demyelinating range, conduction velocity differences among nerves in the same subject varied from 13 to 24 m/s, and distal median compound muscle action potential (CMAP) amplitudes were 3-5 times reduced compared to ulnar CMAPs. Abnormal area reduction or excessive temporal dispersion of proximal CMAP was present in at least two nerves in all patients. Sural nerve biopsy showed reduction of large myelinated fibres, cluster formations, occasional onion bulbs. Teased fibres study revealed short internodes for fibre diameter, enlarged Ranvier nodes but no evidence of segmental demyelination and remyelination. DNA analysis showed an Arg(15)Gln mutation in connexin32 gene in all patients. CONCLUSIONS In this family conduction slowing and segmental conduction abnormalities, in absence of morphological evidence of de-remyelination, may be related to short internodes, widened Ranvier nodes and the specific effect of the mutation. The occurrence in some CMTX patients of a non uniform involvement between and within nerves, as in acquired demyelinating neuropathies, should be kept in mind to avoid misdiagnoses.

A novel mutation of aprataxin associated with ataxia ocular apraxia type 1: phenotypical and genotypical characterization.

Ataxia oculomotor apraxia type 1 (AOA1) is the most common form of autosomal recessive ataxia in Japan, and the second in Portugal after Friedreich ataxia. AOA1 is typically characterized by early-onset cerebellar ataxia, oculomotor apraxia, hypoalbuminemia, hypercholesterolemia and late axonal sensori-motor neuropathy. AOA1 is associated with the aprataxin gene (APTX) encoding a protein involved in DNA repair. We characterized a novel homozygous missense mutation of APTX in a 34 year-old female patient born from consanguineous parents. The mutation, a Val230Gly caused by a c.689 T>G substitution, involved the histidine-triad (HIT) domain of the protein, affected a phylogenetically conserved amino acid and was absent in the control population. We described the clinical and neurophysiological features, the findings at structural and functional brain imaging, and the pathological picture of the sural nerve biopsy. The report emphasized the genetical and phenotypical heterogeneity of AOA1 by demonstrating atypical features such as absence of oculomotor apraxia and signs of pyramidal involvement. Expression studies by Western blotting on fibroblasts demonstrated that the homozygous Val230Gly mutation was associated with decreased levels of APTX indicating a loss-of-function mechanism.

Two novel Italian CADASIL families from Central Italy with mutation CGC-TGC at codon 1006 in the exon 19 Notch3 gene.

Here we describe clinical, neuropsychological and neuroradiological findings in 6 subjects belonging to two unrelated Italian cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) kindreds from the same geographic area who shared a common Arg1006Cys mutation. Subjects from Family A were virtually asymptomatic, and yet showed MRI pathological findings and a cluster of sub-clinical neuropsychological defects mainly centred on the visuospatial domain; patients from Family B had presented several clinically relevant episodes and showed a general cognitive impairment compatible with the clinical picture of vascular dementia. The present clinical observations are consistent with the hypothesis of a geographical clustering for CADASIL, and highlight that sub-clinical cognitive impairment may help to identify this syndrome in families presenting with only migraine.

Mutational and haplotype map of NOTCH3 in a cohort of Italian patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of familial vascular dementia, is caused by mutations of the NOTCH3 gene. Approximately two hundred pathogenic mutations have been reported within five exons (exons 3, 4, 6, 11 and 19) which accounted for 78% of known mutations in worldwide series. We reported twenty-one NOTCH3 pathogenic mutations (including five novel ones) identified in 53 index Italian patients. Exons 4 (28%), 7 (21%) and 19 (24%) were the most frequently involved. To dissect genetic heterogeneity, we analyzed five haplotyped tagging single nucleotide polymorphisms (rs1044009, rs4809030, rs10426042, rs10423702 and rs3815188) in 95 patients, 39 unaffected pedigree members and 50 healthy controls. SNPs were analyzed using the Illumina VeraCode Universal Capture Beads technology by Allele Specific Primer Extension (ASPE). We identified ten different haplotypes named H1-H10; H1 was the most common haplotype in patients and controls and it was associated with at least twelve out of the twenty-one mutations. Detected mutations were not associated to specific haplotypes while genotyping was compatible with a possible founder effect for the novel p.S396C mutation which clustered in a restricted geographical area of northeast Italy. The results added on to the genetic heterogeneity of CADASIL and emphasized difficulties in designing algorithms for molecular diagnosis.