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 ()-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.

Conduction slowing, conduction block and temporal dispersion in demyelinating, dysmyelinating and axonal neuropathies: Electrophysiology meets pathology.

Nerve conduction studies are usually the first diagnostic step in peripheral nerve disorders and their results are the basis for planning further investigations. However, there are some commonplaces in the interpretation of electrodiagnostic findings in peripheral neuropathies that, although useful in the everyday practice, may be misleading: (1) conduction block and abnormal temporal dispersion are distinctive features of acquired demyelinating disorders; (2) hereditary neuropathies are characterized by uniform slowing of conduction velocity; (3) axonal neuropathies are simply diagnosed by reduced amplitude of motor and sensory nerve action potentials with normal or slightly slow conduction velocity. In this review, we reappraise the occurrence of uniform and non-uniform conduction velocity slowing, conduction block and temporal dispersion in demyelinating, dysmyelinating and axonal neuropathies attempting, with a translational approach, a correlation between electrophysiological and pathological features as derived from sensory nerve biopsy in patients and animal models.

Leprosy Neuropathy in a Non-Endemic Area: A Clinical and Pathological Study.

The extent of nerve involvement in leprosy is highly variable in distribution and clinical presentation. Mononeuropathies, multiple mononeuropathies, and polyneuropathies can present both in the context of a cutaneous and/or systemic picture and in the form of pure neuritic leprosy (PNL). The differential diagnosis of leprosy neuropathy remains challenging because it is a very rare condition and, especially in Western countries, is often overlooked.

Daytime sleepiness and sleep quality in Charcot-Marie-Tooth disease.

Background: Sleep abnormalities have been reported in Charcot-Marie-Tooth disease (CMT), but data are scanty. We investigated their presence and correlation in a large CMT patients' series.

Methods: Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI) were administered to CMT patients of the Italian registry and controls.

Clinical and pathology characterization of small nerve fiber neuro(no)pathy in cerebellar ataxia with neuropathy and vestibular areflexia syndrome.

Background And Purpose: Biallelic mutation/expansion of the gene RFC1 has been described in association with a spectrum of manifestations ranging from isolated sensory neuro(no)pathy to a complex presentation as cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS). Our aim was to define the frequency and characteristics of small fiber neuropathy (SFN) in RFC1 disease at different stages.

Methods: RFC1 cases were screened for SFN using the Neuropathic Pain Symptom Inventory and Composite Autonomic Symptom Score 31 questionnaires.

Peripheral neuropathy as clinical onset of monoclonal IgM/k-related amyloidosis.

Aim: Neuropathy is a frequent complication of Waldenström's macroglobulinemia (WM), the most common being a demyelinating polyneuropathy with anti-myelin associated glycoprotein (MAG) antibodies, but also cryoglobulins, vasculitis, neurolymphomatosis, and amyloidosis. We describe a patient with IgM/kappa WM who presented with a severe, not length-dependent, peripheral neuropathy as clinical onset of IgM/kappa-related amyloidosis.

Methods: A 69-year-old woman came to our attention for weight loss, gait imbalance and sensory loss at upper limbs.

Frequency, entity and determinants of fatigue in Charcot-Marie-Tooth disease.

Background And Purpose: Fatigue, a disabling symptom in many neuromuscular disorders, has been reported also in Charcot-Marie-Tooth disease (CMT). The presence of fatigue and its correlations in CMT was investigated.

Methods: The Modified Fatigue Impact Scale (MFIS) was administered to CMT patients from the Italian Registry and a control group.

GRN-/- iPSC-derived cortical neurons recapitulate the pathological findings of both frontotemporal lobar degeneration and neuronal ceroidolipofuscinosis.

Heterozygous mutations in the gene coding for progranulin (GRN) cause frontotemporal lobar degeneration (FTLD) while homozygous mutations are linked to neuronal ceroidolipofuscinosis (NCL). While both FTLD/NCL pathological hallmarks were mostly investigated in heterozygous GRN+/- brain tissue or induced pluripotent stem cell (iPSC)-derived neurons, data from homozygous GRN-/- condition are scarce, being limited to a postmortem brain tissue from a single case. Indeed, homozygous GRN-/- is an extremely rare condition reported in very few cases.

Anxiety and depression in Charcot-Marie-Tooth disease: data from the Italian CMT national registry.

Background: There is little information about neuropsychiatric comorbidities in Charcot-Marie-Tooth disease (CMT). We assessed frequency of anxiety, depression, and general distress in CMT.

Methods: We administered online the Hospital Anxiety-Depression Scale (HADS) to CMT patients of the Italian registry and controls.

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).

Progressive brachial plexus enlargement in hereditary transthyretin amyloidosis.

Axonal polyneuropathy is the main feature of hereditary transthyretin amyloidosis (ATTRv). Nerve morphological abnormalities have been reported, but longitudinal changes have never been assessed. We performed a prospective widespread nerve ultrasound evaluation and nerve cross-sectional area (CSA) was compared with baseline data in both ATTRv patients and pre-symptomatic carriers.

A 58-year-old man with B-cell chronic lymphocytic leukemia and multiple strokes.

A 58-year-old male with B-cell chronic lymphocytic leukemia presented with fever, chest pain, and acute-onset neurological deficits suggestive of multiple strokes (A). Brain autopsy revealed softening areas in the brain parenchyma (B, C) corresponding to extensive necrosis (D) caused by neuroinvasion by Aspergillus hyphae (E, F) necrosis (D) caused by neuroinvasion by Aspergillus hyphae (E, F).

RFC1 AAGGG repeat expansion masquerading as Chronic Idiopathic Axonal Polyneuropathy.

Background: A biallelic intronic AAGGG repeat expansion in the Replication Factor C subunit 1 (RFC1) gene has been recently associated with Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome, a disorder often presenting as a slowly evolving sensory neuropathy at the onset. "Chronic Idiopathic Axonal Polyneuropathy" (CIAP) is a common indolent axonal neuropathy of adulthood which remains without an identifiable cause despite thorough investigations.

Methods: We screened 234 probands diagnosed with CIAP for a pathogenic biallelic RFC1 AAGGG repeat expansion.

Alpha-synuclein seeds in olfactory mucosa and cerebrospinal fluid of patients with dementia with Lewy bodies.

In patients with suspected dementia with Lewy bodies, the detection of the disease-associated α-synuclein in easily accessible tissues amenable to be collected using minimally invasive procedures remains a major diagnostic challenge. This approach has the potential to take advantage of modern molecular assays for the diagnosis of α-synucleinopathy and, in turn, to optimize the recruitment and selection of patients in clinical trials, using drugs directed at counteracting α-synuclein aggregation. In this study, we explored the diagnostic accuracy of α-synuclein real-time quaking-induced conversion assay by testing olfactory mucosa and CSF in patients with a clinical diagnosis of probable ( = 32) or prodromal ( = 5) dementia with Lewy bodies or mixed degenerative dementia (dementia with Lewy bodies/Alzheimer's disease) ( = 6).

Mechanisms of Nerve Damage in Neuropathies Associated with Hematological Diseases: Lesson from Nerve Biopsies.

Despite the introduction of non-invasive techniques in the study of peripheral neuropathies, sural nerve biopsy remains the gold standard for the diagnosis of several neuropathies, including vasculitic neuropathy and neurolymphomatosis. Besides its diagnostic role, sural nerve biopsy has helped to shed light on the pathogenic mechanisms of different neuropathies. In the present review, we discuss how pathological findings helped understand the mechanisms of polyneuropathies complicating hematological diseases.

Aberrant Splicing in 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 () 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.

hATTR Pathology: Nerve Biopsy Results from Italian Referral Centers.

Pathological evidence of amyloid on nerve biopsy has been the gold standard for diagnosis in hereditary transthyretin amyloidosis polyneuropathy (hATTR-PN) for a long time. In this article, we reviewed the pathological findings of a large series of sural nerve biopsies from a cohort of hATTR-PN patients, collected by different Italian referral centers. We reviewed clinical and pathological data from hATTR-PN patients, diagnosed and followed in five Italian referral centers for peripheral neuropathies.

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.

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.