Fabry disease in W162C mutation: a case report of two patients and a review of literature.

BACKGROUND: Fabry disease is a multisystemic disorder characterized by deposition of globotriaosylceramide (Gb3) and its deacylated form in multiple organs, sometimes localized in specific systems such as the nervous or cardiovascular system. As disease-modifying therapies are now available, early diagnosis is paramount to improving life quality and clinical outcomes. Despite the widespread use of non-invasive techniques for assessing organ damage, such as cardiac magnetic resonance imaging (MRI) for patients with cardiac disease, organ biopsy remains the gold standard to assess organ involvement. CASE PRESENTATION: The cases of two patients, father and daughter with a W162C mutation, are described. The father presented with late-onset, cardiac Fabry disease, subsequently developing systolic dysfunction and heart failure. His daughter, while asymptomatic and with normal cardiac assessment (except for slightly reduced native T1 values by cardiac MRI), had already initial myocyte Gb3 deposits on the endomyocardial biopsy, allowing her to start therapy precociously and potentially modifying the course of her disease. A review of the literature concerning the W162C mutation is then provided, showing that it is usually associated to classic, multisystemic Fabry disease rather than the cardiac-restricted form as in these two cases. CONCLUSIONS: Three main points can be concluded from this report. First, the W162C mutation can present with a more variegate phenotype than that predicted on a molecular basis. Second, endomyocardial biopsy was shown in this case to precede non-invasive investigation in determining organ involvement, justifying further studies on this potentially reliable technique, Third, difficulties can arise in the management of asymptomatic female carriers.

Seeding Activity of Skin Misfolded Tau as a Biomarker for Tauopathies.

Background: Tauopathies are a group of age-related neurodegenerative diseases characterized by the accumulation of pathologically phosphorylated tau protein in the brain, leading to prion-like propagation and aggregation. They include Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD). Currently, reliable diagnostic biomarkers that directly reflect the capability of propagation and spreading of misfolded tau aggregates in peripheral tissues and body fluids are lacking. Methods: We utilized the seed-amplification assay (SAA) employing ultrasensitive real-time quaking-induced conversion (RT-QuIC) to assess the prion-like seeding activity of pathological tau in the skin of cadavers with neuropathologically confirmed tauopathies, including AD, PSP, CBD, and PiD, compared to normal controls. Results: We found that the skin prion-SAA demonstrated a significantly higher sensitivity (75-80%) and specificity (95-100%) for detecting tauopathy, depending on the tau substrates used. Moreover, increased tau-seeding activity was also observed in biopsy skin samples from living AD and PSP patients examined. Analysis of the end products of skin-tau SAA confirmed that the increased seeding activity was accompanied by the formation of tau aggregates with different physicochemical properties related to two different tau substrates used. Conclusions: Overall, our study provides proof-of-concept that the skin tau-SAA can differentiate tauopathies from normal controls, suggesting that the seeding activity of misfolded tau in the skin could serve as a diagnostic biomarker for tauopathies.

Corrigendum: Case report: De novo mutation of a-galactosidase A in a female patient with end-stage renal disease: report of a case of late diagnosis of Anderson-Fabry disease.

[This corrects the article DOI: 10.3389/fgene.2023.1122893.].

Skin nerve phosphorylated α-synuclein in the elderly.

To determine the incidence of phosphorylated α-synuclein (p-syn) in skin nerves in very old subjects who are prone to developing incidental Lewy bodies, we prospectively performed skin biopsies on 33 elderly subjects, including 13 (>85 years old) and 20 patients (>70 years) suspected of having an acquired small fiber neuropathy. All subjects underwent neurological examination prior to the biopsy. Two screened female subjects (ages 102 and 98 years) were excluded from the study because they showed evidence of a slight bradykinetic-rigid extrapyramidal disorder on neurological examination and were not considered healthy; both showed p-syn in skin nerves. We did not identify p-syn in skin nerves in the remaining 31 subjects. A PubMed analysis of publications from 2013 to 2023 disclosed 490 healthy subjects tested for skin p-syn; one study reported p-syn in 4 healthy subjects, but the remaining subjects tested negative. Our data underscore the virtual absence of p-syn in skin nerves of healthy controls, including those who are very elderly. These data support skin biopsy as a highly specific tool for identifying an underlying synucleinopathy in patients in vivo.

Biomarkers of neurodegeneration in isolated and antidepressant-related rapid eye movement sleep behavior disorder.

BACKGROUND AND PURPOSE: This study compared the features of isolated rapid eye movement (REM) sleep behavior disorder (iRBD) and antidepressant-related REM sleep behaviour disorder (RBD) with the aim of highlighting markers that might distinguish the two entities. METHODS: The observational cohort study included RBD patients with and without antidepressant use (antiD+ and antiD- patients, respectively), without cognitive impairment and parkinsonism. Clinical features of RBD, subtle motor and non-motor symptoms of parkinsonism, sleep architecture, REM atonia index, dopamine transporter-single photon emission computed tomography (DAT-SPECT) and skin biopsies for the intraneuronal alpha-synuclein (α-syn), were evaluated in the baseline work-up. RESULTS: Thirty-nine patients, 10 antiD+ and 29 antiD-, were included. AntiD+ patients (more frequently female) reported more psychiatric symptoms, less violent dream enactment, and less frequent hyposmia. Dermal α-syn was detected in 93.1% of antiD- versus 30% of antiD+ patients (p = 0.00024). No differences appeared in other motor and non-motor symptoms, Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III score, DAT-SPECT, or polysomnographic features. CONCLUSIONS: Patients with antidepressant-related RBD have clinical and neuropathological features suggesting a lower risk of evolution than those with iRBD.

Progressive Ataxia and Palatal Tremor Is Not Associated with IgLON5 Antibodies: Results From Two Cases.

Progressive ataxia and palatal tremor (PAPT) and anti-IgLON5 disease share possible clinical presentations. Furthermore, both have been associated to a tauopathy mainly affecting the brainstem. Nonetheless, anti-IgLON5 antibodies have never been tested in PAPT. We report on two PAPT cases without evidence of anti-IgLON5 antibodies in both CSF and serum. Despite common clinical and pathological characteristics, PAPT and IgLON5 disease are two distinct entities.

Case report: De novo mutation of a-galactosidase A in a female patient with end-stage renal disease: report of a case of late diagnosis of Anderson-Fabry disease.

Background: Anderson-Fabry disease (AFD) is an X-linked disease that results from reduced activity of the enzyme galactosidase alpha (GLA). When the GLA gene sequence is altered by mutations that alter the normal DNA sequence, variants of the alpha-galactosidase A enzyme are produced, which may or may not function. These mutations are responsible for Fabry disease, and to date, over 800 different mutations of the gene have been described in patients with Anderson-Fabry disease. In this case, we report the case of a woman who is the sole family member with this type of mutation. Case presentation: We report a case of a 52-year-old woman with end-stage chronic kidney disease in dialysis treatment. The patient's alpha-galactosidase activity was 6.6 nmol/ml/h in whole blood, and lyso-GB3 levels were 11.45 nmol/L (normal range < 2.3 nmol/L). Alpha-galactosidase A gene sequence analysis revealed a pathogenic variant of c.947dupT in exon 6, leading to the p. I317NfsTer16 amino acid substitution. The genetic analysis did not detect the same mutation in any of the other screened family members. Conclusion: The international Fabry disease genotype-phenotype database (dbFGP) reports a pathogenic variant c.947dupT in exon 6 that is probably associated with a classical phenotype of Fabry disease. In this case report, we report the case of a woman who is the sole family member with this type of pathogenic variant. Similar situations have not been described in the literature for this pathogenic variant, and it represents an important case of inter- and intrafamilial variability in patients with Fabry disease. The literature shows that de novo pathogenic variants are frequently found in the context of Fabry disease.

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. Clinical data were retrospectively collected. If available, lower limb skin biopsy samples were evaluated for somatic epidermal and autonomic subepidermal structure innervation and compared to healthy controls (HCs). RESULTS: Forty patients, median age at onset 54 years (interquartile range [IQR] 49-61) and disease duration 10 years (IQR 6-16), were enrolled. Mild-to-moderate positive symptoms (median Neuropathic Pain Symptom Inventory score 12.1/50, IQR 5.5-22.3) and relevant autonomic disturbances (median Composite Autonomic Symptom Score 31 37.0/100, IQR 17.7-44.3) were frequently reported and showed scarce correlation with disease duration. A non-length-dependent impairment in nociception was evident in both clinical and paraclinical investigations. An extreme somatic denervation was observed in all patients at both proximal (fibers/mm, RFC1 cases 0.0 vs. HCs 20.5, p < 0.0001) and distal sites (fibers/mm, RFC1 cases 0.0 vs. HCs 13.1, p < 0.0001); instead only a slight decrease was observed in cholinergic and adrenergic innervation of autonomic structures. CONCLUSIONS: RFC1 disease is characterized by a severe and widespread somatic SFN. Skin denervation may potentially represent the earliest feature and drive towards the suspicion of this disorder.

Fabry Disease Nephropathy: Histological Changes With Nonclassical Mutations and Genetic Variants of Unknown Significance.

RATIONALE & OBJECTIVE: Fabry disease (FD) is an X-linked genetic disorder that causes lysosomal storage of glycosphingolipids, primarily globotriaosylceramide (Gb3) and its derivative globotriaosylsphingosine (lyso-Gb3), with multiorgan dysfunction including chronic kidney disease. Affected individuals may be carriers of gene variants that are of uncertain significance (GVUS). We describe kidney pathology at the early stages of FD-related kidney disease to gain insights into its association with GVUS and sex. STUDY DESIGN: Single-center, case series. SETTING & PARTICIPANTS: Thirty-five consecutively biopsied patients (aged 48.1±15.4 years, 22 females) from among 64 patients with genetically diagnosed FD. Biopsies were retrospectively screened using the International Study Group of Fabry Nephropathy Scoring System. OBSERVATIONS: Genetic mutation type, p.N215S and D313Y, sex, age, estimated glomerular filtration rate (eGFR), plasma lyso-Gb3 (pLyso-Gb3) levels, and histological parameters, including Gb3 deposits were recorded. Genetic analyses showed mostly missense mutations, p.N215S variant in 15, and the "benign polymorphism" D313Y in 4 of the biopsied patients. Morphological lesions were similar for men and women except for interstitial fibrosis and arteriolar hyalinosis being more common in men. Early in their clinical course, patients with normal/mild albuminuria had podocyte, tubular, and peritubular capillary vacuoles/inclusions, and evidence of chronicity, i.e., glomerulosclerosis, interstitial fibrosis, tubular atrophy. These findings appeared to be associated with pLyso-Gb3, eGFR, and age. LIMITATIONS: Retrospective design and inclusion of outpatients partially based on family pedigree. CONCLUSIONS: In early stages of kidney disease in the setting of FD, numerous histological abnormalities are present. These observations suggest that kidney biopsies early in FD may reveal activity of kidney involvement that may inform clinical management.

Pathology vs pathogenesis: Rationale and pitfalls in the clinicopathology model of neurodegeneration.

In neurodegenerative disorders, the term pathology is often implicitly referred to as pathogenesis. Pathology has been conceived as a window into the pathogenesis of neurodegenerative disorders. This clinicopathologic framework posits that what can be identified and quantified in postmortem brain tissue can explain both premortem clinical manifestations and the cause of death, a forensic approach to understanding neurodegeneration. As the century-old clinicopathology framework has yielded little correlation between pathology and clinical features or neuronal loss, the relationship between proteins and degeneration is ripe for revisitation. There are indeed two synchronous consequences of protein aggregation in neurodegeneration: the loss of the soluble/normal proteins on one; the accrual of the insoluble/abnormal fraction of these proteins on the other. The omission of the first part in the protein aggregation process is an artifact of the early autopsy studies: soluble, normal proteins have disappeared, with only the remaining insoluble fraction amenable to quantification. We here review the collective evidence from human data suggesting that protein aggregates, known collectively as pathology, are the consequence of many biological, toxic, and infectious exposures, but may not explain alone the cause or pathogenesis of neurodegenerative disorders.

Recurrent Painful Ophthalmoplegic Neuropathy: A case report with atypical features and a review of the literature.

INTRODUCTION: Recurrent Painful Ophthalmoplegic Neuropathy, previously known as Ophthalmoplegic Migraine, is a poorly characterized disorder mainly because there are few cases described. We report a new case of Recurrent Painful Ophthalmoplegic Neuropathy and a review of the literature to contribute to increasing the knowledge of the clinical features of this disorder. CASE REPORT AND REVIEW OF LITERATURE: A 45-year-old woman presented with adult-onset recurrent attacks of abducens and oculomotor palsy associated with diplopia followed by headache. Most notably, pain always presented many days after oculomotor impairment, a feature never described in the literature. A diagnosis of possible Recurrent Painful Ophthalmoplegic Neuropathy was made after excluding other possible mimicking disorders. Symptoms usually resolved gradually with corticosteroid therapy, albeit without a clear-cut benefit.Clinical data collected from 1989 to 2022 showed that adult onset in Recurrent Painful Ophthalmoplegic Neuropathy is not uncommon. While III cranial nerve palsy is typical, VI and IV nerve palsy have also been described. PATHOPHYSIOLOGY AND DIAGNOSIS: Several hypotheses have been proposed, including nerve compression, ischemia or inflammation/demyelination, but none has been completely accepted.Diagnosis remains of exclusion; magnetic resonance imaging and blood exams are key in differential diagnosis. CONCLUSIONS: Our case gives us the possibility to expand the clinical features of Recurrent Painful Ophthalmoplegic Neuropathy, also contributing to updating the pathophysiological hypotheses.

Coexistence of SCN4A and CLCN1 mutations in a family with atypical myotonic features: A clinical and functional study.

Non-dystrophic myotonias include several entities with possible clinical overlap, i.e. myotonia congenita caused by CLCN1 gene mutations, as well as paramyotonia congenita and sodium channel myotonia caused by SCN4A gene mutations. Herein, we describe the clinical features of five relatives affected by clinical and neurophysiological myotonia, with an aspecific and mixed phenotype. Next-generation sequencing identified the novel p.K1302R variant in SCN4A and the p.H838P variant in CLCN1. Segregation of the two mutations with the disease was confirmed by genotyping affected and non-affected family members. Patch-clamp experiments showed that sodium currents generated by p.K1302R and WT hNav1.4 were very similar. Mutant channel showed a small negative shift (5 mV) in the voltage-dependence of activation, which increased the likelihood of the channel to open at more negative voltages. The p.H838P mutation caused a reduction in chloride current density and a small voltage-dependence shift towards less negative potentials, in agreement with its position into the CBS2 domain of the C-terminus. Our results demonstrated that the mild functional alterations induced by p.K1302R and p.H838P in combination may be responsible for the mixed myotonic phenotypes. The K1302R mutant was sensitive to mexiletine and lamotrigine, suggesting that both drugs might be useful for the K1302R carriers.

Phosphorylated α-synuclein in skin Schwann cells: a new biomarker for multiple system atrophy.

Multiple system atrophy (MSA) is characterized by accumulation of phosphorylated α-synuclein (p-syn) as glial cytoplasmic inclusions in the brain and a specific biomarker for this disorder is urgently needed. We aimed at investigating if p-syn can also be detected in skin Remak non-myelinating Schwann cells (RSCs) as Schwann cell cytoplasmic inclusions (SCCi) and may represent a reliable clinical biomarker for MSA. This cross-sectional diagnostic study evaluated skin p-syn in 96 patients: 46 with probable MSA (29 with parkinsonism type MSA and 17 with cerebellar type MSA), 34 with Parkinson's disease (PD) and 16 with dementia with Lewy bodies (DLB). We also included 50 healthy control subjects. Patients were recruited from five different medical centres. P-syn aggregates in skin sections were stained by immunofluorescence, followed by analyses with confocal microscopy and immuno-electron microscopy. All analyses were performed in a blinded fashion. Overall, p-syn aggregates were found in 78% of MSA patients and 100% of patients with PD/DLB, whereas they could not be detected in controls. As for neuronal aggregates 78% of MSA patients were positive for p-syn in somatic neurons, whereas all PD/DLB patients were positive in autonomic neurons. When analysing the presence of p-syn in RSCs, 74% of MSA patients were positive, whereas no such SCCi could be observed in PD/DLB patients. Analyses by immuno-electron microscopy confirmed that SCCi were only found in cases with MSA and thus absent in those with PD/DLB. In conclusion, our findings demonstrate that (i) fibrillar p-syn in RSCs is a pathological hallmark of MSA and may be used as a specific and sensitive disease biomarker; (ii) in Lewy body synucleinopathies (PD/DLB) only neurons contain p-syn deposits; and (iii) the cell-specific deposition of p-syn in the skin thus mirrors that of the brain in many aspects and suggests that non-myelinated glial cells are also involved in the MSA pathogenesis.

Late-onset Fabry disease due to a new (p.Pro380Leu) pathogenic variant of GLA Gene.

Fabry disease is a rare X-linked lysosomal storage disorder due to pathogenic variants of the galactosidase alpha (GLA) gene, leading to a deficiency of alpha-galactosidase A. The inadequate enzymatic activity leads to progressive glycosphingolipids accumulation within tissues and subsequent multi-systemic dysfunction, with predominant involvement of heart, kidney, and nervous system. Two subtypes are recognized: the classic type and the late-onset type. We here describe the clinical characteristics of a patient with late-onset Fabry disease carrying a not previously identified GLA gene variant. This 50-year-old man came to hospital because of an acute ischemic stroke. He also complained of acroparesthesia and had angiokeratomas in the nape and the back. Blood alpha-galactosidase A activity was low, plasmatic lyso-Gb3 level was borderline, cardiac MRI showed cardiac fibrosis, brain MRI documented cerebrovascular disease, and skin biopsy revealed small fiber neuropathy without globotriaosylceramide-3 skin deposits. Genetic study by means of targeted next-generation sequencing analysis disclosed a missense substitution c.1139C>T (p.Pro380Leu) in the GLA gene. We suggest that this novel variant should be considered as pathogenic and associated with a late-onset variant of Fabry disease with a predominant neurological phenotype.

A Second Case With the V374A KCND3 Pathogenic Variant in an Italian Patient With Early-Onset Spinocerebellar Ataxia.

Background and Objectives: To date, approximately 20 heterozygous mainly loss-of-function variants in KCND3 have been associated with spinocerebellar ataxia (SCA) type 19 and 22, a clinically heterogeneous group of neurodegenerative disorders. We aimed at reporting the second patients with the V374A KCND3 mutation from an independent family, confirming its pathogenic role. Methods: We describe the clinical history of a patient with SCA and conducted genetic investigations including mitochondrial DNA analysis and exome sequencing. Results: This male patient was reported to have unstable gait with tremors at the lower limbs and dysarthric speech since childhood. A neurologic examination also showed dysarthria, nystagmus, action tremor, dysmetria, and weak deep tendon reflexes. He had marked cerebellar atrophy at brain MRI, more evident at vermis. Molecular analysis, including exome sequencing and an in silico panel analysis of genes associated with SCA, revealed the c.1121T>C [p.V374A] mutation in KCND3. Discussion: This report consolidates the pathogenicity of the V374A KCND3 mutation and suggests that the ataxic paroxysmal exacerbations are not a key phenotypic feature of this mutation.

The Effect of Curcumin on Idiopathic Parkinson Disease: A Clinical and Skin Biopsy Study.

There are currently no standardized therapies for Parkinson disease (PD). Curcumin shows anti-amyloidogenic properties in vitro and may be a promising treatment for PD. We evaluated the effects of curcumin supplementation on clinical scales and misfolded, phosphorylated α-synuclein (p-syn) accumulation in skin biopsies in 19 PD patients who received curcumin supplementation for 12 months and 14 PD patients to treated with curcumin. The patients underwent autonomic (COMPASS-31), motor (MDS-UPDRS and H&Y) and nonmotor (NMSS) questionnaires and skin biopsies to evaluate clinical involvement and p-syn load in skin nerves at the beginning and the end of study. Curcumin and curcuminoid levels were assayed in plasma and CSF. Supplemented patients showed detectable CSF curcuminoid levels that were lower than those in plasma. They showed a decrease of COMPASS-31 and NMSS scores, and a slight p-syn load decrease versus untreated patients who displayed a worsening of these parameters despite increased levodopa doses. Multiple regression models showed a significant effect of curcumin supplementation in decreasing the worsening of the clinical parameters and p-syn load at after curcumin treatment. These data suggest that curcumin can cross the blood-brain barrier, that it is effective in ameliorating clinical parameters and that it shows a tendency to decrease skin p-syn accumulation in PD patients.

Cannabis-Based Products in a Neurological Setting: A Clinical and Pharmacokinetic Survey.

Background and Aim: Limited data are available in clinical settings on the pharmacokinetics of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). We investigated the use of cannabis-based products in neurological practice, monitoring patients' steady-state cannabinoids (CBs) plasma concentrations matched with different preparations. Methods: This was a prospective, single-center, observational study. Patients underwent venous blood withdrawal before the CBs' morning dose and then 2.5 h post-dosing. Spasticity or pain were patient self-assessed by the Numeric Rating Scale (NRS) before the morning CB's administration and 2.5 h post-dosing. Results: Thirty-three patients were enrolled. Main indications for CBs were spasticity and chronic pain. Sixteen patients were treated with oromucosal spray formulation Sativex® and 17 with oil-based solutions. Both CBs trough plasma concentrations were ≤ limit of detection (0.1 ng/ml) in 45% of patients. Intrasubject CB's plasma levels significantly increased over baseline values in patients treated with Bediol® oil (p < 0.05) and Sativex® (p < 0.01). Post-dosing CB's bioavailability did not significantly differ between oral oil and oromucosal spray. NRS scores decreased (p < 0.01), matching the increase (p < 0.01) in CB's plasma concentrations. Conclusion: This is the first study investigating CB's plasma concentrations of oral and oromucosal preparations in real-world neurological practice. Findings of similar bioavailability for both CBD and THC after galenic oil compared with oromucosal spray dosing may be clinically relevant and deserve additional research in larger cohorts.

Presence of Skin α-Synuclein Deposits Discriminates Parkinson's Disease from Progressive Supranuclear Palsy and Corticobasal Syndrome.

BACKGROUND: Previous studies reported skin phosphorylated α-synuclein (p-syn) deposits in Parkinson's disease (PD) patients but not in patients with parkinsonism due to tauopathies, although data on the latter are limited. OBJECTIVE: We aimed to assess the presence of skin p-syn deposits in patients with clinical diagnosis of parkinsonism usually due to tauopathy and PD. METHODS: We consecutively recruited 26 patients, 18 fulfilling clinical diagnostic criteria of progressive supranuclear palsy (PSP) and 8 of corticobasal syndrome (CBS), 26 patients with PD, and 26 healthy controls (HC). All subjects underwent skin biopsy to study p-syn deposits in skin nerves by immunofluorescence. RESULTS: Skin p-syn deposits were present in only two of the PSP/CBS patients and none of the HC. Conversely, all PD patients showed p-syn deposition (p < 0.001, Chi-square). The two p-syn positive patients were diagnosed with PSP and CBS, respectively. Although clinical and MRI findings supported these diagnoses, both patients had some atypical features more typical of synucleinopathies. CONCLUSION: The detection of skin p-syn deposits may help in the differential diagnosis of parkinsonism. Indeed, in this study, all PD patients and only two out of 26 with a clinical diagnosis of PSP/CBS had skin p-syn deposits. Furthermore, these two patients showed clinical features that could suggest an atypical synucleinopathy presentation or a mixed pathology.

Paraneoplastic vs. non-paraneoplastic anti-Hu associated dysmotility: a case series and literature review.

OBJECTIVES: This work aimed to report the demographic and clinical characteristics of two new cases with non-paraneoplastic anti-Hu-associated gut motility impairment, and perform a thorough revision covering anti-Hu-associated paraneoplastic (PGID) and non-paraneoplastic (nPGID) gastrointestinal dysmotility. BACKGROUND: Several case series have clearly established a relationship between certain type of cancers, the development of circulating anti-Hu antibodies, and the concomitant usually severe gastrointestinal dysmotility; in contrast, a few studies focused on anti-Hu-associated nPGID. METHODS: We searched for studies regarding anti-Hu-associated gastrointestinal manifestations and extracted data concerning clinical characteristics of patients, including specific demographic, oncological, neurological, gastrointestinal, histological, and treatment response features. RESULTS: Forty-nine articles with a total of 59 cases of anti-Hu-associated gastrointestinal dysmotility were analyzed. The patients' age at symptom onset significantly differed between PGID and nPGID (median 61 vs 31 years, p < 0.001). Most cancers (95%) in PGID were detected within 24 months from the beginning of gastrointestinal symptoms. The impairment of gastrointestinal motility was generalized (i.e., involving the whole gut) in 59.3% of patients, with no significant differences between PGID vs nPGID group. nPGID patients showed a better response to immunomodulatory/immunosuppressive treatment and a longer life expectancy. CONCLUSIONS: Anti-Hu-associated gastrointestinal dysmotility covers a wide clinical spectrum. Patients with otherwise unexplained gastrointestinal dysmotility, especially when associated with other neurological symptoms, should be tested for anti-Hu antibodies regardless age of onset and disease duration. Compared to PGID, nPGID occurs in younger patients with a long duration of disease.