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Neurological involvement is relatively common in Erdheim–Chester disease (ECD), a rare clonal disorder of histiocytic myeloid precursors characterized by multisystem involvement. In ECD patients, neurological symptoms can occur either at onset or during the disease course and may lead to various degrees of neurological disability or affect patients’ life expectancy. The clinical neurological presentation of ECD often consists of cerebellar symptoms, showing either a subacute or progressive course. In this latter case, patients manifest with a slowly progressive cerebellar ataxia, variably associated with other non-specific neurological signs, infratentorial leukoencephalopathy, and cerebellar atrophy, possibly mimicking either adult-onset degenerative or immune-mediated ataxia. In such cases, diagnosis of ECD may be particularly challenging, yet some peculiar features are helpful to address it. Here, we retrospectively describe four novel ECD patients, all manifesting cerebellar symptoms at onset. In two cases, slow disease progression and associated brain MRI features simulated a degenerative cerebellar ataxia. Three patients received a definite diagnosis of histiocytosis, whereas one case lacked histology confirmation, although clinical diagnostic features were strongly suggestive. Our findings regarding existing literature data focused on neurological ECD will be also discussed to highlight those diagnostic clues helpful to address diagnosis.

Myotonic dystrophy type 1 (DM1, MIM #160900), the most common muscular dystrophy among adults, is a multisystem disorder, which affects, besides the skeletal muscle, several other tissues and/or organs, including the gastrointestinal apparatus, with manifestations that frequently affect the quality of life of DM1 patients. So far, only few, mainly retrospective studies evaluated this specific topic in DM1, so we performed a perspective study, enrolling 61 DM1 patients who underwent an extensive diagnostic protocol, including administration of the Gastrointestinal Symptom Rating Scale (GSRS), a validated patient-reported questionnaire about GI symptoms, laboratory tests, liver US scan, and an intestinal permeability assay, in order to characterize frequency and assess correlations regarding specific gastrointestinal manifestations with demographic or other DM1-related features. Our results in our DM1 cohort confirm the high frequency of various gastrointestinal manifestations, with the most frequent being constipation (45.9%). γGT levels were pathologically increased in 65% of DM1 patients and GPT in 29.82%; liver ultrasound studies showed steatosis in 34.4% of patients. Significantly, 91.22% of DM1 patients showed signs of altered intestinal permeability at the specific assay. We documented a gender-related prevalence and severity of gastrointestinal manifestations in DM1 females compared to DM1 males, while males showed higher serum GPT and γGT levels than females. Correlation studies documented a direct correlation between severity of muscle weakness estimated by MIRS score and γGT and alkaline phosphatase levels, suggesting their potential use as biomarkers of muscle disease severity in DM1.

The molecular characterization of Hereditary Spastic Paraplegias (HSP) and inherited cerebellar ataxias (CA) is challenged by their clinical and molecular heterogeneity. The recent application of Next Generation Sequencing (NGS) technologies is increasing the diagnostic rate, which can be influenced by patients’ selection. To assess if a clinical diagnosis of CA/HSP received in a third-level reference center might impact the molecular diagnostic yield, we retrospectively evaluated the molecular diagnostic rate reached in our center on 192 unrelated families (90 HSP and 102 CA) (i) before NGS and (ii) with the use of NGS gene panels. Overall, 46.3% of families received a genetic diagnosis by first-tier individual gene screening: 43.3% HSP and 50% spinocerebellar ataxias (SCA). The diagnostic rate was 56.7% in AD-HSP, 55.5% in AR-HSP, and 21.2% in sporadic HSP. On the other hand, 75% AD-, 52% AR- and 33% sporadic CA were diagnosed. So far, 32 patients (24 CA and 8 HSP) were further assessed by NGS gene panels, and 34.4% were diagnosed, including 29.2% CA and 50% HSP patients. Eleven novel gene variants classified as (likely) pathogenic were identified. Our results support the role of experienced clinicians in the diagnostic assessment and the clinical research of CA and HSP even in the next generation era.

Objective: Segmental demyelination is the pathological hallmark of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but other elementary lesions are frequently observed, configuring a series of different pathological pictures. In this article, we review the pathological findings of a large series of sural nerve biopsies from our cohort of CIDP patients. Patients and Methods: Patients with CIDP who underwent nerve biopsy were retrospectively selected from those referred to the Institute of Neurology of the “Università Cattolica del Sacro Cuore” in Rome, Italy, from 1982 to February 2020. Sural nerve biopsy was performed according to standard protocols. Results: Sural nerve biopsy was performed in 43/130 CIDP patients. Demyelinating abnormalities and axonal loss were found in 67.4% and 83.7% of biopsies, respectively. Conversely, onion bulbs and inflammatory infiltrates were rare (18.6% and 4.7%, respectively). In three cases, we observed normal pathological findings. Conclusions: A pathognomonic pathological finding of CIDP cannot be established, but we confirm the utility of nerve biopsy in this setting to confirm the diagnosis (also in atypical phenotypes) and to elucidate pathogenic mechanisms.

Hereditary spastic paraplegia (HSP) refers to a group of genetically heterogeneous neurodegenerative motor neuron disorders characterized by progressive age-dependent loss of corticospinal motor tract function, lower limb spasticity, and weakness. Recent clinical use of next generation sequencing (NGS) methodologies suggests that they facilitate the diagnostic approach to HSP, but the power of NGS as a first-tier diagnostic procedure is unclear. The larger-than-expected genetic heterogeneity—there are over 80 potential disease-associated genes—and frequent overlap with other clinical conditions affecting the motor system make a molecular diagnosis in HSP cumbersome and time consuming. In a single-center, cross-sectional study, spanning 4 years, 239 subjects with a clinical diagnosis of HSP underwent molecular screening of a large set of genes, using two different customized NGS panels. The latest version of our targeted sequencing panel (SpastiSure3.0) comprises 118 genes known to be associated with HSP. Using an in-house validated bioinformatics pipeline and several in silico tools to predict mutation pathogenicity, we obtained a positive diagnostic yield of 29% (70/239), whereas variants of unknown significance (VUS) were found in 86 patients (36%), and 83 cases remained unsolved. This study is among the largest screenings of consecutive HSP index cases enrolled in real-life clinical-diagnostic settings. Its results corroborate NGS as a modern, first-step procedure for molecular diagnosis of HSP. It also disclosed a significant number of new mutations in ultra-rare genes, expanding the clinical spectrum, and genetic landscape of HSP, at least in Italy.

Coinfections with human immunodeficiency virus (HIV) and infectious agents have been recognized since the early 90s. In the central nervous system (CNS) of HIV+ patients, parasitic protozoans like Toxoplasma gondii have been described as responsible for the space occupying lesions (SOL) developed. However, the involvement of Trypanosoma cruzi is also described but appears to be less frequent in acquired immunodeficiency syndrome (AIDS) and transplant recipients, associated with necrotizing myocarditis and neurological symptoms related to the occurrence of necrotizing pseudotumoral encephalitis (NPE) and meningoencephalitis (NME). The present work aims to present a Venezuelan case of NME associated with the coinfection of HIV and a T. cruzi-like trypanosomatid as well as its evolution and diagnosis by histopathological techniques, electron microscopy, and PCR methods using formalin-fixed- (FF-) and paraffin-embedded- (PE-) tissues. Postmortem cytological studies of leptomeninges imprints reveal the presence of trypomastigotes of Trypanosoma sp. Histopathological and electron microscopy studies allowed us to identify an amastigote stage and to reject the involvement of other opportunistic microorganisms as the etiological agent of the SOL. The definitive confirmation of T. cruzi as the etiological agent was achieved by PCR suggesting that the NME by T. cruzi was due to a reactivation of Chagas’ disease.