Sural nerve biopsy in peripheral neuropathies: 30-year experience from a single center.

INTRODUCTION: Nerve biopsy has been widely used to investigate patients with peripheral neuropathy, and in many centers, it is still a useful diagnostic tool in this setting. In this study, we reviewed the histopathological spectrum of the nerve biopsies performed in our center in a 30-year period and we analyzed their relevance in the clinical setting. MATERIALS AND METHODS: Retrospective analysis of the retrieved data was done for cases of nerve biopsies performed in our institute between 1988 and 2018. Surgical technique and histopathological analysis were done accordingly to standard protocol. RESULTS: Complete clinical and pathological data were available only for 717 cases. The procedure was generally safe, with only 0.3% superimposed infection. Main pathological results were "unspecific" axonal polyneuropathy (49.8%), vasculitis neuropathy (9.3%), acquired demyelinating neuropathy (8.9%), and Charcot-Marie-Tooth (8.2%). Considering clinical-neurophysiological suspicion of vasculitis, nerve biopsy confirmed the diagnosis in 60.9% of cases. DISCUSSION: In conclusion, for inherited neuropathies, we do not recommend this invasive procedure, but we strongly suggest a genetic test. Conversely, in vasculitic neuropathies or in dysimmune neuropathies not clearly confirmed by neurophysiological examination, nerve biopsy continues to represent a useful and irreplaceable tool.

Primary multifocal lymphoma of peripheral nervous system: case report and review of the literature.

INTRODUCTION: Primary lymphomas of peripheral nerves are extremely rare, and only a few cases have been reported. METHODS: We describe the clinical, neurophysiological, radiological, and pathological findings in a 61-year-old woman affected by primary multifocal lymphoma of the peripheral nervous system without systemic involvement. RESULTS: Fascicular left femoral nerve biopsy was decisive for the diagnosis of diffuse large B-cell non-Hodgkin lymphoma. Magnetic resonance imaging, fluorine-18 fluorodeoxyglucose positron emission tomography computed tomography, and nerve ultrasound contributed to the diagnosis. CONCLUSIONS: Primary lymphoma of peripheral nerves (PLPNs) is a rare but potentially treatable condition, which is frequently misdiagnosed. In the literature, there are very few descriptions of PLPNs, most of which are mononeuropathies. The possibility of a neuropathy associated with lymphoma should be considered in patients with poor response to treatment and severe pain symptoms.

Clinical, neurophysiological and pathological findings of HNPP patients with 17p12 deletion: a single-centre experience.

BACKGROUND: Classic clinical manifestations of HNPP are characterized by recurrent painless mononeuropathies, but a minority of patients present with an atypical clinical pattern, including CMT-like neuropathy, acute or chronic inflammatory demyelinating neuropathy-like polyneuropathy, and carpal tunnel syndrome. Electrophysiological examination plays a central role in the diagnosis of HNPP, disclosing a non-uniform conduction slowing, more pronounced at entrapment sites. PATIENTS AND METHODS: We report clinical, electrophysiological and pathological findings from 73 patients with HNPP, coming from 53 unrelated families, followed at our Institute of Neurology over a 20-year period. RESULTS: Typical presentation with recurrent multiple mononeuropathies was observed in 28/64 (44%) patients. In the remaining 36/64 (56%), we observed an atypical clinical presentation, characterized by generalized weakness and cramps, chronic ulnar neuropathy, carpal tunnel syndrome, chronic sensory polyneuropathy, Guillain-Barrè-like presentation, and CMT-like presentation. Nine patients were asymptomatic for neuropathic symptoms. Nerve conduction studies showed in all cases a sensori-motor demyelinating polyneuropathy with conduction abnormalities preferentially localized at common entrapment sites. When performed, sural nerve biopsy disclosed the focal thickening of the myelin sheath in all patients. CONCLUSIONS: About half of the patients with HNPP from our cohort showed an atypical clinical presentation. Neurophysiological examination represents the main tool for a proper diagnosis.

Ultrasound evaluation in transthyretin-related amyloid neuropathy.

INTRODUCTION: Familial amyloid polyneuropathy is a rare condition caused by mutations of the transthyretin gene (TTR). We assessed the pattern of nerve ultrasound (US) abnormalities in patients with TTR-related neuropathy. METHODS: Seven patients with TTR-related neuropathy (TTR-N) and 5 asymptomatic TTR-mutation carriers (TTR-C) underwent neurological examination, nerve conduction studies, and US evaluation. RESULTS: Multifocal US abnormalities were identified in 6 of 7 TTR-N patients. A single patient with only a mild sensory polyneuropathy had normal nerves on US evaluation. In the TTR-C, we only detected an enlarged ulnar nerve at the elbow. Interestingly, disease severity correlated with number of nerves affected on US evaluation. CONCLUSIONS: No specific pattern of US abnormalities was identified in this cohort. However, in TTR-related amyloid neuropathy, US may be a helpful tool in monitoring disease progression, and/or clinical response to pharmacological treatment.

Cerebellar degeneration associated with mGluR1 autoantibodies as a paraneoplastic manifestation of prostate adenocarcinoma.

Subacute cerebellar degeneration associated with metabotropic glutamate receptor type 1 (mGluR1) autoantibodies is an uncommon syndrome known to be part of the spectrum of paraneoplastic cerebellar degenerations associated with neuronal autoantibodies. We describe a patient with prostate adenocarcinoma who developed a subacute cerebellar ataxia. Autoantibodies specific to mGluR1 were detected in patient's serum and cerebrospinal fluid (CSF). Immunohistochemistry analyses of patient's prostate adenocarcinoma revealed abundant mGluR1 expression in luminal acinar epithelial cells and binding of patient's IgGs to tumoral mGluR1. These findings suggest that cerebellar degeneration associated with mGluR1 antibodies can be a paraneoplastic accompaniment of prostate adenocarcinoma.

Mutations in the 3' untranslated region of FUS causing FUS overexpression are associated with amyotrophic lateral sclerosis.

Mutations in the gene encoding fused-in-sarcoma (FUS) have been identified in a subset of patients with sporadic and familial amyotrophic lateral sclerosis (ALS). Variants in the 3' untranslated region (3'UTR) of FUS have also been reported in ALS patients, but their pathogenic role has not been assessed. We sequenced the whole 3'UTR of FUS in 420 ALS patients who were negative for mutations in the currently known ALS genes and in 480 ethnically matched controls. We detected four 3'UTR variants (c.*48 G>A, c.*59 G>A, c.*108 C>T and c.*110 G>A) in four sporadic and in one familial ALS patients compared with none in controls (P = 0.02).We investigated whether these variants impaired FUS expression in primary fibroblast cultures from three patients harbouring the c.*59 G>A, c.*108 C>T and c.*110 G>A variants, respectively. The pattern of FUS expression was also investigated in fibroblasts from one ALS patient with FUS R521C mutation, in two ALS patients without mutations in the known ALS genes and in four control individuals. By immunostaining and immunoblotting, large amounts of FUS were observed in both the cytoplasm and nuclei of mutant 3'UTR FUS fibroblasts. In FUS R521C mutant fibroblasts, we observed a slight increase of FUS in the cytoplasm associated with a remarkable loss of detection in nuclei. Our findings show that mutations in 3'UTR of FUS are overrepresented in ALS patients and result into translation de-regulation of FUS. Overexpression and mislocalization of wild-type FUS likely contribute to ALS pathogenesis in these cases.

TTR-related amyloid neuropathy: clinical, electrophysiological and pathological findings in 15 unrelated patients.

Familial amyloid polyneuropathy (FAP) is a rare condition caused by mutations of the transthyretin (TTR) gene and it is generally characterized by a length-dependent polyneuropathy affecting prevalently the small fibers. We reviewed clinical, electrophysiological and pathological findings of 15 unrelated patients with genetically confirmed TTR-FAP. All patients presented a progressive sensory-motor polyneuropathy. Pathological findings were negative for amyloid deposits in about half of the cases. Sequence analysis of TTR gene revealed the presence of three different mutations (p.Val30Met, p.Phe64Leu, and p.Ala120Ser). The p.Val30Met was the most frequently identified mutation and it often occurred in apparently sporadic cases. Conversely, the p.Phe64Leu generally presented in a high percentage of familial cases in patients coming from Southern Italy. Clinicians should consider, to avoid misdiagnosis, the screening for TTR mutations in patients presenting with progressive axonal polyneuropathy of undetermined etiology, including apparently sporadic cases with pathological examinations negative for amyloid deposition.

Uncommon pathological findings in sural nerve biopsy from a patient with Churg-Strauss related multiple mononeuropathy.

We describe a patient with severe multiple mononeuropathy associated with hypereosinophilia, asthma and pulmonary non cavitating micronodules. Sural nerve biopsy revealed marked perineural thickening and microfasciculation with inflammatory infiltrates in the perinerium and in the epinerium. The patient markedly improved with steroid therapy. Our final diagnosis was Churg-Strauss related multiple mononeuropathy. Thus, we report a case of Churg-Strauss related multiple mononeuropathy with uncommon pathological findings on sural nerve and we underline the importance of clinical evaluation for this diagnosis.

Classification of familial amyotrophic lateral sclerosis by family history: effects on frequency of genes mutation.

OBJECTIVE: To classify familial amyotrophic lateral sclerosis (FALS) on the base of family history, and to determine whether frequency of mutations in major amyotrophic lateral sclerosis (ALS) genes varies in different FALS categories. METHODS: Included in the study are 53 FALS families. Patients were classified as definite, probable and possible FALS, according to recently proposed criteria. Seven ALS-associated genes, including SOD1, TARDBP, FUS, ANG, ATXN2, OPTN and C9ORF72, were analysed. RESULTS: Thirteen patients (24.5%) were included in the definite group. The great majority of our FALS cases (40/53, 75.5%) were families with only two affected relatives; of these, 31 (58.5%) were included in the probable, and 9 (17%) in the possible FALS categories. The percentage of mutations was 61.5% in definite, 41.9% in probable and 11.1% in possible FALS. With respect to probable FALS, if cases with parent-to-child transmission of the disease were considered separately, the mutational load increased to 61.5%, as observed in definite FALS. CONCLUSIONS: Our findings provide evidence that frequency of mutations in currently known ALS genes varies widely among different FALS categories. Families with only two affected relatives have heterogeneous genetic components, the chance to detect mutations being higher in cases with parent-to-child transmission.

P525L FUS mutation is consistently associated with a severe form of juvenile amyotrophic lateral sclerosis.

Some FUS mutations have been observed in patients with the juvenile form of Amyotrophic Lateral Sclerosis starting before 25 years. We report an 11-year-old girl affected by sporadic juvenile ALS with a rapid course resulting in tracheostomy after 14 months from the onset. Sequencing FUS gene revealed a de novo P525L mutation. Our findings, together with literature data, indicate that this mutation is consistently associated with a specific phenotype characterized by juvenile onset, severe course and high proportion of de novo mutations in sporadic cases.