Currently only 25-30% of patients with axonal forms of Charcot-Marie-Tooth disease (CMT) receive a genetic diagnosis. We aimed to identify the causative gene of CMT type 2 in 8 non-related French ...families with a distinct clinical phenotype. We collected clinical, electrophysiological, and laboratory findings and performed genetic analyses in four different French laboratories. Seventy-two patients with autosomal dominant inheritance were identified. The disease usually started in the fourth decade and the clinical picture was dominated by sensory ataxia (80%), neuropathic pain (38%), and length-dependent sensory loss to all modalities. Electrophysiological studies showed a primarily axonal neuropathy, with possible isolated sensory involvement in milder phenotypes. Disease severity varied greatly but the clinical course was generally mild. We identified 2 novel variants in LRSAM1 gene: a deletion of 4 amino acids, p.(Gln698_Gln701del), was found in 7 families and a duplication of a neighboring region of 10 amino acids, p.(Pro702_Gln711dup), in the remaining family. A common haplotype of ~450 kb suggesting a founder effect was noted around LRSAM1 in 4 families carrying the first variant. LRSAM1 gene encodes for an E3 ubiquitin ligase important for neural functioning. Our results confirm the localization of variants in its catalytic C-terminal RING domain and broaden the phenotypic spectrum of LRSAM1-related neuropathies, including painful and predominantly sensory ataxic forms.
Cerebrospinal fluid (CSF) collections extending longitudinally at the anterior aspect of the spinal dura have been reported in association with various conditions and under multiple names. The aim of ...this study was to report cases associated with brachial amyotrophy (BA) and examine its relationship with other clinical variants.
We conducted a retrospective cohort study including patients who presented with a motor deficit of the upper limbs and an anterior interdural CSF collection on spinal MRI. We performed a systematic review of the literature to include cases revealed by BA.
Seven patients presenting with BA and a confirmed dural dissection on spinal MRI were included. All patients were male with a slowly progressing history of asymmetrical and proximal motor deficit of the upper limbs. Chronic denervation affecting mostly C5 and C6 roots was found on electroneuromyography. Spinal MRI demonstrated an anterior CSF collection dissecting the interdural space and exerting a traction on cervical motor roots. Dynamic computed tomography myelogram localized the dural defect every time it was performed (4/7 cases), and surgical closure was possible for 3 patients, leading to resolution of the collection. Literature review yielded 18 other published cases of spinal dural dissections revealed by BA, including 4 in association with spontaneous intracranial hypotension and 4 others in association with superficial siderosis.
We propose a unifying diagnosis termed "spinal anterior dural dissection" (SADD) to encompass spinal dural CSF collections revealed by BA (SADD-BA), spontaneous intracranial hypotension (SADD-SIH), or superficial siderosis (SADD-SS).
Background and purpose
This study was undertaken to assess skin biopsy as a marker of disease onset and severity in hereditary transthyretin amyloidosis with polyneuropathy (ATTRv‐PN), a treatable ...disease.
Methods
In this single center retrospective study, skin Congo red staining and intraepidermal nerve fiber density (IENFD) were evaluated in symptomatic ATTRv‐PN patients and asymptomatic TTR gene mutation carriers between 2012 and 2019. Non‐ATTRv subjects with suspected small fiber neuropathy who underwent skin biopsy during the same timespan were used as controls.
Results
One hundred eighty‐three symptomatic ATTRv‐PN patients, 36 asymptomatic carriers, and 537 non‐ATTRv patients were included. Skin biopsy demonstrated amyloid depositions in 80% of the 183 symptomatic cases. Skin amyloid deposits were found in 75% of early stage ATTRv‐PN patients, and in 14% of asymptomatic carriers. All 183 symptomatic and 34 of 36 asymptomatic patients displayed decreased ankle IENFD with a proximal–distal gradient distribution, and reduced IEFND correlated with disease severity and duration.
Conclusions
Our study demonstrates skin amyloid deposits are a marker of ATTRv‐PN disease onset, and decreased IENFD a marker of disease progression. These results are of major importance for the early identification of ATTRv‐PN patients in need of disease‐modifying treatments.
Skin biopsy provides useful information in hereditary transthyretin amyloidosis with polyneuropathy. Amyloid deposition in skin is a biomarker of disease onset in paucisymptomatic subjects, especially in early onset Val30Met. Small nerve fiber reduction, which often precedes disease onset, correlates with disease severity.
Hereditary transthyretin amyloidosis is a life-threatening autosomal dominant systemic disease due to pathogenic
variants (ATTRv), mostly affecting the peripheral nerves and heart. The disease is ...characterised by a combination of symptoms, organ involvement and histological amyloid deposition. The available disease-modifying ATTRv treatments (DMTs) are more effective if initiated early. Pathological nerve conduction studies (NCS) results are the cornerstone of large-fibre polyneuropathy diagnosis, but this anomaly occurs late in the disease. We investigated the utility of a multimodal neurological and cardiac evaluation for detecting early disease onset in ATTRv carriers.
We retrospectively analysed a cohort of ATTRv carriers with normal NCS results regardless of symptoms. Multimodal denervation and infiltration evaluations included a clinical questionnaire (Lauria and New York Heart Association (NYHA)) and examination, intra-epidermal nerve fibre density assessment, autonomic assessment based on heart rate variability, Sudoscan, meta-iodo-benzyl-guanidine scintigraphy, cardiac biomarkers, echocardiography, MRI and searches for amyloidosis on skin biopsy and bone scintigraphy.
We included 130 ATTRv carriers (40.8% men, age: 43.6±13.5 years), with 18 amyloidogenic
gene mutations, the majority of which was the late-onset Val30Met variant (42.3%). Amyloidosis was detected in 16.9% of mutation carriers, including 9 (6.9%) with overt disease (Lauria>2 or NYHA>1) and 13 asymptomatic carriers (10%) with organ involvement (small-fibre neuropathy or cardiomyopathy). Most of these patients received DMT. Abnormal test results of unknown significance were obtained for 105 carriers (80.8%). Investigations were normal in only three carriers (2.3%).
Multimodal neurological and cardiac investigation of TTRv carriers is crucial for the early detection of ATTRv amyloidosis and initiation of DMT.
ABSTRACT
Introduction
Many patients treated with intravenous immunoglobulin (IVIg) are >60 years of age. Tolerability has yet to be demonstrated in this age group.
Methods
This is a retrospective ...study of adverse reactions among consecutive patients treated with IVIg for neurological disorders. Risk factors were recorded. Correlation and relative risks were calculated for age, risk factors, IVIg course, daily dose, concentration, preparation, and duration of treatment. An infusion and monitoring protocol was applied.
Results
Two hundred forty‐four patients were reviewed, including 62% who were ≥60 years of age (total dose 1.8 ± 0.4 g/kg body weight, daily dose 30.3 ± 2.0 g). Sixty‐nine percent received sugar‐stabilized IVIg. Forty‐nine percent presented with >1 risk factor. Adverse reactions occurred in 35% and led to treatment discontinuation in 5%, with a similar incidence among age groups. In patients ≥60 years old, sucrose‐free IVIg administration was an independent predictor of adverse reactions, including renal failure.
Conclusion
In the elderly, IVIg infusions are safe. Adverse reactions mainly depend on IVIg preparation and administration. Renal failure is not uncommon with sugar‐free IVIg. Muscle Nerve 53: 683–689, 2016
Abstract
Neurological immune-related adverse events are complications of programmed-cell death 1 or programmed-cell death 1 ligand immunotherapies that can be life threatening and often lead to ...anticancer immunotherapy withdrawal. Scant clinical data are available that integrate the clinical presentation, therapeutic management and long-term outcome. All consecutive adult patients treated by programmed-cell death 1 or programmed-cell death 1 ligand immunotherapies, given alone or in combination with other treatment, who experienced a neurological immune-related adverse event with a severity grade ≥2 in Paris Saclay-University hospitals were investigated from June 2014 to February 2019. The frequency of neurological immune-related adverse events was calculated from the prospective Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie cohort. Forty patients presenting with 51 distinct neurological immune-related adverse events were included. The prevalence of grade ≥2 neurological immune-related adverse events was estimated to be 1.22% in the Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie cohort. Among 40 patients with neurological immune-related adverse events, 65% received programmed-cell death 1 or programmed-cell death 1 ligand monotherapy and 35% received a combination of programmed-cell death 1 plus anti-CTLA4 (Common Terminology Criteria for Adverse Events). Clinical neurological presentations were peripheral (48%), central (35%), or mixed (18%). The severity of neurological immune-related adverse events was grade 2 for 14 (35%) and ≥grade 3 for 26 patients (65%). The mortality rate related to neurological immune-related adverse events was 8%. Corticosteroid treatment led to neurological recovery in 74%. Long-term follow-up highlighted that 53% of patients experienced long-term neurological sequelae. Five patients were rechallenged by programmed-cell death 1 monotherapy without recurrence of their neurological immune-related adverse event(s). Neurological immune-related adverse events induced by programmed-cell death 1 or programmed-cell death 1 ligand are rare but are severe with a mortality rate of 8% and long-term sequelae for 53% of patients. Corticosteroids should be started when neurological immunological complications are identified to avoid long-term sequelae.
Plaçais et al. report a large case-series of 40 patients presenting with 51 neurological adverse events of immune checkpoint inhibitors, wherein corticosteroid therapy was associated with a 74% rate of neurological recovery. Neurological adverse events were severe, as 7.5% of the included patients died and 53% kept long-term neurological sequelae.
Graphical Abstract
Graphical Abstract
Abstract Background Homocystinuria caused by cystathionine beta synthase (CBS) deficiency is most often diagnosed in childhood and has a variable expressivity. The most frequent abnormalities include ...intellectual disability, ectopia lentis, myopia, skeletal abnormalities or thromboembolism. Objective To report a case of homocystinuria unraveled by cerebral venous thrombosis (CVT). Observation A 17 year old female was admitted in our department of neurology for subacute headache and presented seizures in the emergency room. Cerebral imaging revealed CVT. Severe hyperhomocysteinemia was found and led to the diagnosis of homocystinuria due to composite heterozygous mutations in the CBS gene. Further investigations disclosed lens subluxation in association with myopia, mild scoliosis and osteopenia. The patient was treated by heparin followed by warfarin, vitamin therapy and dietary methionine restriction. Total homocysteine and methionine levels became normal in a few weeks and the patient had a complete recovery. Conclusion In patients with CVT, plasma total homocysteine measurement as part of the etiologic work up may reveal severe hyperhomocysteinemia due to CBS or remethylation defects that require specific treatment and management including perhaps protein-restricted diet and/or vitamin therapy for life.
Vingt pour cent des polyneuropathies inflammatoires démyélinisantes chroniques (PIDC) sont résistantes au traitement conventionnel (TC) et 40 % sont dépendantes. Cependant aucune recommandation sur ...l’utilisation des traitements de 2nde ligne (TNC) n’existe.
Décrire et comparer des patients atteints de PIDC ou forme frontière (CANOMAD, NMMBC) sévère traités par TNC ou TC seul. Comparer les répondeurs (R) et non-répondeurs (NR) au TNC.
Étude rétrospective monocentrique incluant les PIDC sévères (ONLS ≥6 ou sous-score ≥4 au nadir) hospitalisées entre 2014 et 2018. Vingt-deux patients ont été inclus dans le groupe « TNC » (rituximab, cyclophosphamide, leur association, greffe de cellules souches) et 51 dans le groupe « TC seul ». Les scores MRC, ONLS, mRS ont été évalués après TC dans les 2 groupes et après TNC. La réponse au TNC est définie par delta ONLS ≥−1 ou le sevrage en TC à 12 mois.
Les patients « TNC » étaient moins répondeurs et plus dépendants au TC. Au terme du suivi (131 mois), l’évolution est plus favorable après TNC qu’après TC seul : delta MRC +30 vs +13 (p0,083), delta ONLS −2,6 vs −1 (p0,038), delta mRS −1,2 vs −0,2 (p0,018).
Le TNC permet d’obtenir une réponse chez 17 patients (77,3 %) et de diminuer les TC de 83 %. Les R avaient plus souvent une PIDC qu’une forme frontière, des délais diagnostique et à l’instauration du TNC plus courts.
Dans cette série de neuropathies inflammatoires démyélinisantes sévères, les TNC ont permis d’obtenir chez des patients résistants et/ou dépendants aux TC, une réponse clinique importante, supérieure à celle obtenue après TC, et de diminuer significativement les posologies de ces traitements de 1ère intention. Cette réponse survient de façon précoce (dès 6 mois) et durable.
Il semble licite de proposer un TNC à des patients présentant une PIDC invalidante, résistante/dépendante aux TC, d’autant que les délais d’évolution de maladie et depuis le TC sont courts.
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