Phenotypic spectrum of myelin protein zero-related neuropathies: a large cohort study from five mutation clusters across Italy.

BACKGROUND: We aimed to investigate the clinical features of a large cohort of patients with myelin protein zero (MPZ)-related neuropathy, focusing on the five main mutation clusters across Italy. METHODS: We retrospectively gathered a minimal data set of clinical information in a series of patients with these frequent mutations recruited among Italian Charcot-Marie-Tooth (CMT) registry centres, including disease onset/severity (CMTES-CMT Examination Score), motor/sensory symptoms and use of orthotics/aids. RESULTS: We collected data from 186 patients: 60 had the p.Ser78Leu variant ('classical' CMT1B; from Eastern Sicily), 42 the p.Pro70Ser (CMT2I; mainly from Lombardy), 38 the p.Thr124Met (CMT2J; from Veneto), 25 the p.Ser44Phe (CMT2I; from Sardinia) and 21 the p.Asp104ThrfsX13 (mild CMT1B; from Apulia) mutation. Disease severity (CMTES) was higher (p<0.001) in late-onset axonal forms (p.Thr124Met=9.2±6.6; p.Ser44Phe=7.8±5.7; p.Pro70Ser=7.6±4.8) compared with p.Ser78Leu (6.1±3.5) patients. Disease progression (ΔCMTES/year) was faster in the p.Pro70Ser cohort (0.8±1.0), followed by p.Ser44Phe (0.7±0.4), p.Thr124Met (0.4±0.5) and p.Ser78Leu (0.2±0.4) patients. Disease severity (CMTES=1.2±1.5), progression (ΔCMTES/year=0.1±0.4) and motor involvement were almost negligible in p.Asp104ThrfsX13 patients, who, however, frequently (78%, p<0.001) complained of neuropathic pain. In the other four clusters, walking difficulties were reported by 69-85% of patients, while orthotic and walking aids use ranged between 40-62% and 16-28%, respectively. CONCLUSIONS: This is the largest MPZ (and late-onset CMT2) cohort ever collected, reporting clinical features and disease progression of 186 patients from five different clusters across Italy. Our findings corroborate the importance of differentiating between 'classical' childhood-onset demyelinating, late-onset axonal and mild MPZ-related neuropathy, characterised by different pathomechanisms, in view of different therapeutic targets.

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.

CIDP, CMT1B, or CMT1B plus CIDP?

Charcot-Marie-Tooth disease type 1 (CMT1) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have distinct clinical and neurophysiological features that result from dysmyelination in CMT1 and macrophage-mediated segmental demyelination in CIDP. CMT1 may occur in genetically isolated cases with atypical presentations that converge phenotypically with CIDP; in rare cases, however, CMT1 may be complicated by superimposed CIDP. We report the case of a patient harboring a de novo heterozygous null mutation of the myelin protein zero (MPZ) gene and affected by subclinical CMT1B who became symptomatic due to superimposed CIDP. Peripheral nerve high-resolution ultrasound (HRUS) aided in establishing the coexistence of CMT1B and CIDP; the diagnosis was further supported by favorable clinical, neurophysiological, and ultrasound responses to immunoglobulin therapy.

Convergent pathological and ultrasound features in hereditary syndromic and non-syndromic minifascicular neuropathy related to DHH.

Minifascicular neuropathy (MN) is a rare, autosomal recessive disease with prominent structural changes of peripheral nerves. So far, it has been observed in females with a 46,XY karyotype and mutations of the Desert Hedgehog (DHH) gene, thus linking MN to gonadal dysgenesis (GD) and disorders of sex development (DSD). However, a 46,XX proband with normal female sex and gender development underwent clinical evaluations, nerve conduction studies and genetic screening for a severe motor-sensory neuropathy with a pathological phenotype that hinted at MN. Indeed, sural nerve biopsy revealed a profound disturbance of perineurium development with a thin and loose structure. High-resolution ultrasound (HRUS) also disclosed diffuse changes of nerve echotexture that visibly correlated with the pathological features. After extensive genetic testing, a novel homozygous DHH null mutation (p.Ser185*) was identified in the proband and in her sister, who was affected by a similar motor-sensory neuropathy, but was eventually found to be a 46,XY patient according to a late diagnosis of DSD with complete GD. DHH should therefore be considered as a possible cause of rare non-syndromic hereditary motor-sensory neuropathies, regardless of DSD. Furthermore, HRUS could effectively smooth the complex diagnostic workup as it demonstrated a high predictive power to detect MN, providing the same detailed correlations to the pathologic features of the nerve biopsy and Dhh-/- mice in both sisters. Hence, HRUS may assume a pivotal role in guiding molecular analysis in individuals with or without DSD.

Sporadic hereditary neuropathies misdiagnosed as chronic inflammatory demyelinating polyradiculoneuropathy: Pitfalls and red flags.

Hereditary neuropathies may be misdiagnosed with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). A correct diagnosis is crucial for avoiding unnecessary therapies and access genetic counseling. We report on nine patients (seven men, mean age 49.2 ± 16.1) diagnosed with and treated as CIDP, in whom mutations or variants of unknown significance (VUS) in genes associated with hereditary neuropathies were reported. All underwent neurological and neurophysiological examination, eight also cerebrospinal fluid (CSF) analysis. In 4/9, nerve ultrasound and/or MR-neurography were performed. All the patients complained of progressive upper or lower limbs sensory-motor symptoms, with heterogeneous disease duration (1-34 years, mean 8.6 ± 10.8). Neurophysiology showed demyelinating signs in seven patients, mixed findings with predominant axonal damage in two patients. Neuroimaging disclosed diffuse abnormalities at proximal and distal segments. Molecular screening showed PMP22 duplication in two patients, mutations in the MPZ, EGR2, and GJB1 genes were reported in each of the remaining patients. The two patients with mixed neurophysiological findings had p.Val30Met mutation in the transthyretin gene. Two patients had VUS in the MARS and HSPB1 genes. Four patients had partial response to immunomodulant therapies, and CSF and neurophysiological features suggesting an inflammatory condition concomitant with the hereditary neuropathy. Hereditary neuropathy may be misdiagnosed with CIDP. The most common pitfalls are CSF (high protein levels and oligoclonal bands), incorrect interpretation of neurophysiology, and transient benefit from therapies. Neuroimaging may be helpful in cases with atypical presentations or when severe axonal damage complicate the neurophysiological interpretation.

Charcot-Marie-Tooth disease: experience from a large Italian tertiary neuromuscular center.

INTRODUCTION: Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disease. Thanks to the advances of the latest generation sequencing, more than 80 causative genes have been reported to date. METHODS: In this retrospective, observational study, we have analyzed clinical, electrophysiological, and genetic data of CMT patients in care at Neuromuscular Center of Messina University Hospital, Messina, Italy, for at least 22 years (from 1994 to 2016). Our center is the only reference center for genetic neuropathies in Sicily and in the southern part of Calabria. RESULTS: We reviewed the clinical records of 566 patients with the aim to evaluate how many patients received a genetic diagnosis and the distribution of the genetic subtypes. About 352/566 (62.19%) received a genetic diagnosis. The most frequent genetic diagnoses were CMT1A/PMP22 duplication (51.13%), followed by HNPP/PMP22 deletion (15.05%), CMT1B/MPZ mutation (10.22%), CMTX/GJB1 mutation (9.37%), and CMT2F/HSPB1 (4%). Other rare mutations included MFN2 mutation (n. 8 pts), BSCL2 mutation (n.8 pts), PMP22 point mutation (n.7 pts), GDAP1 mutation (n.4 pts), GARSmutation (n. 2 pts), TRPV4 mutation (n. 2 pts), LITAF mutation (n.1 pt), and NEFL mutation (n. 1 pt). CONCLUSIONS: Our study provides further data on frequency of CMT genes, subtypes in a wide Mediterranean area and contributes to help clinicians in addressing the genetic testing workup.

Nerve size correlates with clinical severity in Charcot-Marie-Tooth disease 1A.

INTRODUCTION: Nerve cross-sectional area (CSA) is larger than normal in Charcot-Marie-Tooth disease 1A (CMT1A), although to a variable extent. We explored whether CSA is correlated with CMT clinical severity measured with neuropathy score version 2 (CMTNS2) and its examination subscore (CMTES2) in CMT1A. METHODS: We assessed 56 patients with CMT1A (42 families). They underwent nerve conduction study (NCS) and nerve high-resolution ultrasound (HRUS) of the left median, ulnar, and fibular nerves. RESULTS: Univariate analysis showed NCS and HRUS variables to be significantly correlated with CMTNS2 and CMTES2 and with each other. Multivariate analysis showed that ulnar motor nerve conduction velocity (ß: -0.19) and fibular compound muscle action potential amplitude (-1.50) significantly influenced CMTNS2 and that median forearm CSA significantly influenced CMTNS2 (ß: 5.29) and CMTES2 (4.28). DISCUSSION: Nerve size is significantly associated with clinical scores in CMT1A, which suggests that it might represent a potential biomarker of CMT damage and progression.

Charcot-Marie-Tooth 2F: phenotypic presentation of the Arg136Leu HSP27 mutation in a multigenerational family.

Mutations in the small heat-shock protein HSP27 gene are associated with distal hereditary motor neuropathy and with the axonal form of Charcot-Marie-Tooth disease type 2. We present the clinical and electrophysiological data on a multigenerational family with the p.Arg136Leu HSP27 mutation. Atypical features such as deafness and pyramidal signs were present in our cases adding new data to the large spectrum of HSP27-related phenotype.

Parental mosaicism of a novel PMP22 mutation with a minimal neuropathic phenotype.

Genetic germinal and somatic mosaicisms of dominant Charcot-Marie-Tooth disease (CMT) mutations are rarely reported and/or recognized. We describe a novel heterozygous p.Trp39Cys missense mutation in the extracellular domain of the peripheral myelin protein 22 (PMP22) associated with an early-onset demyelinating CMT type 1 E (CMT1E) in two siblings born from asymptomatic non-consanguineous parents. The 29-year-old mother, harboring approximately 20% of the mutant PMP22 allele in blood, had minor signs of distal polyneuropathy (pes cavus, decreased ankle jerk reflexes and vibration sense in legs) and slight reduction of sural nerve action potentials (SNAPs). Authors suggest that mutations of CMT-related genes which originate in post-zygotic stages may be associated with mild phenotypes of peripheral neuropathy.

Unusual features of central nervous system involvement in CMTX associated with a novel mutation of GJB1 gene.

In this study, we report a novel connexin 32 (CX32) mutation associated with cognitive impairment and a differential degree of peripheral nerve involvement. We present clinical, electrophysiological, and neuroimaging data on a family with X-linked Charcot-Marie-Tooth disease caused by a 41A>G mutation of the gap junction protein beta 1 (GJB1) gene. The proband and her sister presented with a severe neuropathy with subclinical cognitive impairment; the proband's brother showed severe cognitive impairment and a mild neuropathy. This family report confirms that Charcot-Marie-Tooth type X is a clinically heterogeneous group, with great variability of phenotypes, possible severe involvement in females and clinical signs of cognitive impairment. Thus, this novel mutation should be added to the group of CX32 mutations with a central nervous system phenotype.

Autonomic nervous system involvement in a new CMT2B family.

We describe the first Italian family affected by CMT2B carrying a Val162Met substitution in the RAB7 gene. The clinical and electrophysiological features of our family are similar to those of previously reported families with RAB7 mutations, also for the higher occurrence of ulcers in males. However, in this family we evaluated the autonomic nervous system, never investigated in CMT2B, by means of skin biopsy and sudomotor and cardiovascular tests. Our findings provide both pathological and functional evidence of autonomic nervous system involvement in CMT2B and expand the phenotypic characterization of CMT2B disease.

Inherited demyelinating neuropathies with micromutations of peripheral myelin protein 22 gene.

The peripheral myelin protein 22 gene (PMP22) encodes an intrinsic membrane protein of compact myelin. Duplication or deletion of PMP22 causes the most common autosomal dominant neuropathies, Charcot-Marie-Tooth disease type 1A or hereditary neuropathy with liability to pressure palsies. Charcot-Marie-Tooth disease type 1A is a hypertrophic de-remyelinating neuropathy manifesting with peroneal muscular atrophy and uniform, marked, slowing of nerve conduction velocities. Hereditary neuropathy with liability to pressure palsies is a recurrent focal neuropathy with sausage-like myelin thickening (tomacula) and non-uniform nerve conduction velocity changes. Missense or nonsense mutations also cause more severe Charcot-Marie-Tooth disease type 1A forms of infancy or hereditary neuropathy with liability to pressure palsies, but they are presumably very rare. We performed a mutational scanning of PMP22 in 229 index patients (46 familial, 183 isolated) referred for suspected inherited neuropathy. The series included 125 cases with hereditary neuropathy with liability to pressure palsies (mean age 42.5 years), 47 cases with Charcot-Marie-Tooth disease type 1A (motor nerve conduction velocities at median nerve below 38 m/s) (mean age 40.7 years) and 57 cases with Charcot-Marie-Tooth with unknown nerve conduction velocities (mean age 43 years). Preliminary molecular studies ruled out PMP22 duplication or deletion or mutations in a comprehensive panel of Charcot-Marie-Tooth genes. Mutational scanning of PMP22 was done by denaturing high performance liquid chromatography and automated nucleotide sequencing. To investigate the molecular basis of phenotype-to-genotype correlations, we performed a transcriptional analysis of PMP22 using reverse-transcriptase polymerase chain reaction and quantitative real-time polymerase chain reaction in two phenotypically divergent nerve biopsies. Ten patients harboured eight micromutations of PMP22 including four novel changes. In six familial and three sporadic cases, detected mutations caused premature or delayed stop codons and were associated with hereditary neuropathy with liability to pressure palsies; the related pathological pictures ranged from classical tomaculous neuropathy to a mild demyelinating neuropathy with atypical non-tomaculous myelin thickenings. In a single family a c.179-2A> G mutation affecting the splice acceptor site of intron 2 cosegregated with a Charcot-Marie-Tooth disease type 1A-like syndrome and a peculiar pathological picture of demyelinating neuropathy without Charcot-Marie-Tooth disease type 1A-like classical onion bulbs or tomacula. Transcriptional analysis of a novel c.174_178 + 7delAAACGGTGAGGC deletion involving exon 2 and intron 2 demonstrated an unstable mutant transcript leading to a p.Asn59GlyfsX12 change; the mutation represented a null allele and caused a typical tomaculous hereditary neuropathy with liability to pressure palsies. The Charcot-Marie-Tooth disease type 1-like c.179-2A > G allele led to a stable transcript with an in-frame deletion of exon 3 (p.Glu60_Ala106del); the predicted shorter protein could exert variable molecular effects. In conclusion, micromutations of PMP22 cause a clinical and pathological continuum of demyelinating neuropathies that may include atypical phenotypes.

Neuropathic pain in Charcot-Marie-Tooth disease: A clinical and laser-evoked potential study.

BACKGROUND: Pain, either nociceptive or neuropathic (NP), is a common symptom in Charcot-Marie-Tooth (CMT) disease. METHODS: We investigated small fibers involvement and its correlation with pain in different CMT subtypes through a systematic clinical and neurophysiological study. We enrolled 50 patients: 19 with duplication of PMP22 (CMT1A), 11 with mutation of MPZ (CMT1B, CMT2I/J, or CMTDID), 12 with mutation of GJB1 (CMTX1), and 8 with mutation of MFN2 (CMT2A and CMT2A2B). Pain was rated with the 11-point Numerical Rating Scale and characterized through Neuropathic Pain Symptoms Inventory. Laser-evoked potentials (LEPs) were recorded after right foot and hand stimulation and N2-P2 complex amplitude and latency were compared with those of 41 controls. RESULTS: Overall pain prevalence was 36%. NP was present in 14.6% of patients, with a length-dependent distribution in 85.7% of cases, and it was significantly more frequent in CMT1A (p < 0.001). Aδ fibers involvement greatly varies between CMT subtypes, reflecting differences in molecular pathology and pathophysiologic mechanisms. Prolonged N2 latency from foot stimulation was noted in 11 CMT1A patients, 5 of which report NP. MPZ-CMTs displayed different neurophysiological phenotypes and a very low prevalence of NP. LEPs were normal in all but one CMTX1 patients, although lower limbs N2-P2 amplitude was significantly reduced in males (p = 0.043). MFN2-CMTs were NP free and LEPs recordings were all normal. NP strictly correlated with LEPs alterations (p = 0.017). CONCLUSIONS: NP prevalence varies among CMTs subtypes and is mainly related to Aδ fibers impairment. SIGNIFICANCE: Neuropathic pain is a frequent finding in Charcot-Marie Tooth disease and is related to Aδ fibers impairment. Patients at higher risk are those belonging to certain genetic subtypes (i.e. CMT1A and CMT2J) or with laser-evoked potentials abnormalities. While managing this disease, clinicians should be aware of this symptom in order to offer best treatment options to their patients.

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.

Déjerine-Sottas syndrome with a silent nucleotide change of myelin protein zero gene.

Charcot-Marie-Tooth disease type 1B (CMT1B) and Déjerine-Sottas syndrome type B (DSSB) are caused by missense or frameshift mutations of myelin protein zero (MPZ) gene. We identified an apparently silent synonymous c.411C>T transition in MPZ exon 3 (p.Gly137Gly) which segregated with DSS in a two-generation pedigree. Retro-transcriptional analysis of MPZ in the proband's archive sural nerve biopsy identified an r.410_448del mutant transcript which resulted from an activated cryptic splice site in exon 3 and led to an in-frame partial deletion of exon 3 (p.Gly137_Lys149del). Quantitative real-time polymerase chain reaction (QRT-PCR) compared with two unrelated CMT1B nerves carrying a frameshift c.306delA mutation (p.Asp104ThrfsX13) indicated that the r.410_448del was stable differing from the p.Asp104ThrfsX13-associated transcript which was subjected to nonsense-mediated decay. The report highlighted the possible pathogenic role of synonymous MPZ mutations and difficulties in interpreting results from routine mutational screenings.

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.

Rare among Rare: Phenotypes of Uncommon CMT Genotypes.

(1) Background: Charcot-Marie-Tooth disease (CMT) is the most frequent form of inherited chronic motor and sensory polyneuropathy. Over 100 CMT causative genes have been identified. Previous reports found PMP22, GJB1, MPZ, and MFN2 as the most frequently involved genes. Other genes, such as BSCL2, MORC2, HINT1, LITAF, GARS, and autosomal dominant GDAP1 are responsible for only a minority of CMT cases. (2) Methods: we present here our records of CMT patients harboring a mutation in one of these rare genes (BSCL2, MORC2, HINT1, LITAF, GARS, autosomal dominant GDAP1). We studied 17 patients from 8 unrelated families. All subjects underwent neurologic evaluation and genetic testing by next-generation sequencing on an Ion Torrent PGM (Thermo Fischer) with a 44-gene custom panel. (3) Results: the following variants were found: BSCL2 c.263A > G p.Asn88Ser (eight subjects), MORC2 c.1503A > T p.Gln501His (one subject), HINT1 c.110G > C p.Arg37Pro (one subject), LITAF c.404C > G p.Pro135Arg (two subjects), GARS c.1660G > A p.Asp554Asn (three subjects), GDAP1 c.374G > A p.Arg125Gln (two subjects). (4) Expanding the spectrum of CMT phenotypes is of high relevance, especially for less common variants that have a higher risk of remaining undiagnosed. The necessity of reaching a genetic definition for most patients is great, potentially making them eligible for future experimentations.

Aberrant Splicing in GJB1 and the Relevance of 5' UTR in CMTX1 Pathogenesis.

The second most common form of Charcot-Marie-Tooth disease (CMT) follows an X-linked dominant inheritance pattern (CMTX1), referring to mutations in the gap junction protein beta 1 gene (GJB1) that affect connexin 32 protein (Cx32) and its ability to form gap junctions in the myelin sheath of peripheral nerves. Despite the advances of next-generation sequencing (NGS), attention has only recently also focused on noncoding regions. We describe two unrelated families with a c.-17+1G>T transversion in the 5' untranslated region (UTR) of GJB1 that cosegregates with typical features of CMTX1. As suggested by in silico analysis, the mutation affects the regulatory sequence that controls the proper splicing of the intron in the corresponding mRNA. The retention of the intron is also associated with reduced levels of the transcript and the loss of immunofluorescent staining for Cx32 in the nerve biopsy, thus supporting the hypothesis of mRNA instability as a pathogenic mechanism in these families. Therefore, our report corroborates the role of 5' UTR of GJB1 in the pathogenesis of CMTX1 and emphasizes the need to include this region in routine GJB1 screening, as well as in NGS panels.

Inherited motor-sensory neuropathy with upper limb predominance associated with the tropomyosin-receptor kinase fused gene.

The Tropomyosin-receptor kinase fused gene (TFG) encodes TFG which is expressed in spinal motor neurons, dorsal root ganglia and cranial nerve nuclei, and plays a role in the dynamics of the endoplasmic reticulum. Two dominant missense TFG mutations have previously been reported in limited geographical areas (Far East, Iran, China) in association with hereditary motor sensory neuropathy with proximal involvement (HMSN-P) of the four limbs, or with Charcot-Marie-Tooth disease type 2 (CMT2). The 60-year-old female proband belonging to a three-generation Italian family presented with an atypical neuropathy characterized by diffuse painful cramps and prominent motor-sensory impairment of the distal upper limbs. Her sural nerve biopsy showed chronic axonal neuropathy without active degeneration or regeneration. Targeted next-generation sequencing of a panel with 98 genes associated with inherited peripheral neuropathies/neuromuscular disorders identified three candidate genes: TFG, DHTKD1 and DCTN2. In the family, the disease co-segregated with the TFG p.(Gly269Val) variant. TFG should be considered in genetic testing of patients with heterogeneous inherited neuropathy, independently of their ethnic origin.