The incidence of multiple sclerosis (MS) changes from generation to generation in ethnically different immigrants compared with native-born people. We aimed to determine whether there are ...generational changes in MS phenotypes among North African immigrants in France.
Cohort study with data from a population-based MS registry to compare the clinical characteristics of 80 first (NAG1) and 167 second (NAG2) generation North Africans with MS living in France with 5200 native-born Europeans. Adjusted Cox models were used to test the association between scores of 3 and 6 on the expanded disability status scale (EDSS) and the "origin/generation" variable.
Cox models for EDSS scores 3 and 6 showed a higher risk of score 3 (hazard ratio = 1.738, 95% confidence interval 1.237 to 2.444; P = .002) and 6 (hazard ratio = 2.372, 95% confidence interval 1.626 to 3.462; P<.0001) for NAG1 than Europeans. Being NAG2 was not significantly associated with higher hazards of scores 3 and 6.
We found two different phenotypes among NAG1 and NAG2 MS patients in France. NAG1, but not NAG2, have a higher risk of disability than Europeans. This raises the question of environmental factors in MS expression, and advocates appropriate patient management according to generation in immigrants.
In 2017, a new treatment by nusinersen, an antisense oligonucleotide delivered by repeated intrathecal injections, became available for patients with spinal muscular atrophy (SMA), whereas clinical ...trials had mainly involved children. Since 2020, the oral, selective SMN2-splicing modifier risdiplam has been available with restrictions evolving with time. In this peculiar context of lack of data regarding adult patients, many questions were raised to define the indications of treatment and the appropriate follow-up in this population. To homogenize access to treatment in France, a national multidisciplinary team meeting dedicated to adult SMA patients, named SMA multidisciplinary team meeting, (SMDTs) was created in 2018. Our objective was to analyze the value of SMDTs in the decision-making process in SMA adult patients and to provide guidelines about treatment.
From October 2020 to September 2021, data extracted from the SMDT reports were collected. The primary outcome was the percentage of cases in which recommendations on validating treatment plans were given. The secondary outcomes were type of treatment requested, description of expectations regarding treatment and description of recommendations or follow-up and discontinuation. Data were analyzed using descriptive statistics. Comparisons between the type of treatment requested were performed using Mann-Whitney test or the Student t test for quantitative data and the Fisher's exact test or the χ
test for qualitative data.
Cases of 107 patients were discussed at the SMDTs with a mean age of 35.3 (16-62). Forty-seven were SMA type 2, and 57 SMA type 3. Twelve cases were presented twice. Out of 122 presentations to the SMDTs, most of requests related to the initiation of a treatment (nusinersen (n = 46), risdiplam (n = 54), treatment without mentioning preferred choice (n = 5)) or a switch of treatment (n = 12). Risdiplam requests concerned significantly older patients (p = 0.002), mostly SMA type 2 (p < 0.0001), with greater disease severity in terms of motor and respiratory function compared to requests for nusinersen. In the year prior to presentation to the SMDTs, most of the patients experienced worsening of motor weakness assessed by functional tests as MFM32 or other meaningful scales for the most severe patients. Only 12% of the patients discussed had a stable condition. Only 49/122 patients (40.1%) expressed clear expectations regarding treatment. The treatment requested was approved by the SMDTs in 72 patients (67.2%). The most common reasons to decline treatment were lack of objective data on the disease course prior discussion to the SMDTs or inappropriate patient's expectations. Treatment requests were more likely to be validated by the SMDTs if sufficient pre-therapeutic functional assessment had been performed to assess the natural history (55% vs. 32%) and if the patient had worsening rather than stable motor function (p = 0.029). In patients with approved treatment, a-priori criteria to define a further ineffectiveness of treatment (usually after 14 months of treatment) were proposed for 67/72 patients.
In the context of costly treatments with few controlled studies in adults with SMA, in whom assessment of efficacy can be complex, SMDTs are 'real-world observatories' of great interest to establish national recommendations about indications of treatment and follow-up.
The ryanodine receptor RyR1 is the main sarcoplasmic reticulum Ca
channel in skeletal muscle and acts as a connecting link between electrical stimulation and Ca
-dependent muscle contraction. ...Abnormal RyR1 activity compromises normal muscle function and results in various human disorders including malignant hyperthermia, central core disease, and centronuclear myopathy. However, RYR1 is one of the largest genes of the human genome and accumulates numerous missense variants of uncertain significance (VUS), precluding an efficient molecular diagnosis for many patients and families. Here we describe a recurrent RYR1 mutation previously classified as VUS, and we provide clinical, histological, and genetic data supporting its pathogenicity. The heterozygous c.12083C>T (p.Ser4028Leu) mutation was found in thirteen patients from nine unrelated congenital myopathy families with consistent clinical presentation, and either segregated with the disease in the dominant families or occurred de novo. The affected individuals essentially manifested neonatal or infancy-onset hypotonia, delayed motor milestones, and a benign disease course differing from classical RYR1-related muscle disorders. Muscle biopsies showed unspecific histological and ultrastructural findings, while RYR1-typical cores and internal nuclei were seen only in single patients. In conclusion, our data evidence the causality of the RYR1 c.12083C>T (p.Ser4028Leu) mutation in the development of an atypical congenital myopathy with gradually improving motor function over the first decades of life, and may direct molecular diagnosis for patients with comparable clinical presentation and unspecific histopathological features on the muscle biopsy.
At the end of 2019, sculptures of emaciated lions were installed beneath the White Cliffs of Dover and along the Thames in London by British artist Jason deCaires Taylor: they were part of a series ...called “Pride of Brexit”, and, in the words of the sculptor, were to be understood as “a monument to one of the most unpatriotic events Britain has ever seen”. The lions that crouch across the Thames and Westminster have been graffitied with pro-Brexit slogans such as “Take back control” or “Brexit...
A rapidly expanding field, the study of the interactions between missions and sciences, and most notably missions and anthropology, has opened up new ways of examining the scholarly work of ...missionaries and their extra-apostolic activities. Historians of missions are drawn to archival materials that had been previously overlooked, such as the contributions of missionaries to scientific journals, or their correspondence with figures that worked outside of missionary circles. This article focuses on one such correspondence between the social anthropologist James George Frazer and the Revd John Roscoe, who worked for the Church Missionary Society in Uganda between 1889 and 1911. Not only was Roscoe a mine of information on Central African tribes for Frazer, he was also, after he retired from the CMS, a keen student of anthropology who devoted the second part of his life to anthropological ventures: he wrote the first ethnological account on the Baganda, contributed to enriching the Cambridge Museum of Archaeology and Anthropology's collections of Central African relics and artefacts, helped set up training courses in anthropology for prospective missionaries and led an anthropological expedition. His work, and his long correspondence with Frazer, bears the mark of the renowned anthropologist's theories on totemism, a notion that was at the core of the international anthropological scene in the late-Victorian and Edwardian period.
Background
Treatments may become redundant in older patients with multiple sclerosis (MS). Our aim was to explore whether stopping treatments might be possible in patients aged over 50 with disease ...inactivity.
Methods
Patients over 50 were included from the population-based MS Lorraine registry if they had a relapsing–remitting course at onset and had experienced no relapse for ≥ 3 years. Patients who stopped treatments were defined as “stoppers”, and the others as “stayers”. The outcomes were the time to first relapse, to first disability progression, and to the occurrence of EDSS score of 6, assessed by multivariate analysis using a propensity score.
Results
132 stoppers and 366 stayers had a median follow-up of 7 years. There was no difference in Log-rank tests for the times to first relapse (
p
= 0.61) and to first disability progression (
p
= 0.22). In Cox models, stopping treatments was not associated with an increased risk of relapse (adjusted Hazard ratio (aHR) = 0.92 0.72–1.16;
p
= 0.47) or of an increase in EDSS score (aHR = 0.89 0.71–1.13;
p
= 0.34). However, stopping was associated with a higher risk of occurrence of EDSS score of 6 (aHR = 3.29 2.22–4.86;
p
< 0.0001), with a significant difference for the time to occurrence of EDSS score of 6 (
p
= 0.003).
Conclusion
Our study suggests that stopping injectable disease-modifying treatments, in patients over 50 with disease inactivity, is not associated with an increased risk of relapse or EDSS progression, but there might be a higher risk of reaching EDSS 6. These results have to be confirmed by interventional studies.
Neuromyotonia: a skin-deep problem Maurier, François; Michaud, Maud; Reviron, Roxane ...
BMJ case reports,
04/2022, Letnik:
15, Številka:
4
Journal Article
Recenzirano
A 45-year-old woman was evaluated for right-sided hemicorporal scar-like skin lesions on her arm and thoracic and inguinal areas that appeared shortly after reduction mammoplasty. Five years later, ...she developed spontaneous cramps and involuntary abnormal, painful, twitching movements in the same areas. With time, the cramps worsened and disabled the patient. The use of her right arm triggered contractures of muscles and abnormal movements. A diagnosis of neuromyotonia (NMT) was established on the basis of clinical findings and on electromyographic findings of a burst of high-frequency motor unit potentials recorded in the right triceps in the area of skin lesions. The results of medullary, encephalic MRI as well as a comprehensive metabolic panel were normal. She was positive for antinuclear antibodies without specificity. Neither antineural antibodies nor antivoltage-gated potassium channel complex antibodies (specifically, leucine-rich glioma inactivated protein 1 and contactin-associated protein-like-2) were detected. Her skin lesions were diagnosed as morphea. Two combined strategies of treatment were initiated: antiepileptic drugs for NMT and corticosteroids and methotrexate for morphea. NMT is a rare, debilitating neurological complication of morphea.
CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M IgM paraprotein, cold agglutinins, and disialosyl antibodies) is a rare syndrome characterized by chronic neuropathy with sensory ...ataxia, ocular, and/or bulbar motor weakness in the presence of a monoclonal IgM reacting against gangliosides containing disialosyl epitopes. Data regarding associated hematologic malignancies and effective therapies in CANOMAD are scarce. We conducted a French multicenter retrospective study that included 45 patients with serum IgM antibodies reacting against disialosyl epitopes in the context of evocating neurologic symptoms. The main clinical features were sensitive symptoms (ataxia, paresthesia, hypoesthesia; n = 45, 100%), motor weakness (n = 18, 40%), ophthalmoplegia (n = 20, 45%), and bulbar symptoms (n = 6, 13%). Forty-five percent of the cohort had moderate to severe disability (modified Rankin score, 3-5). Cold agglutinins were identified in 15 (34%) patients. Electrophysiologic studies showed a demyelinating or axonal pattern in, respectively, 60% and 27% of cases. All patients had serum monoclonal IgM gammopathy (median, 2.6 g/L; range, 0.1-40 g/L). Overt hematologic malignancies were diagnosed in 16 patients (36%), with the most frequent being Waldenström macroglobulinemia (n = 9, 20%). Forty-one patients (91%) required treatment of CANOMAD. Intravenous immunoglobulins (IVIg) and rituximab-based regimens were the most effective therapies with, respectively, 53% and 52% of partial or better clinical responses. Corticosteroids and immunosuppressive drugs were largely ineffective. Although more studies are warranted to better define the optimal therapeutic sequence, IVIg should be proposed as the standard of care for first-line treatment and rituximab-based regimens for second-line treatment. These compiled data argue for CANOMAD to be included in neurologic monoclonal gammopathy of clinical significance.
Mutations in the
FIG4
gene have been identified in various diseases, including amyotrophic lateral sclerosis, Parkinson’s disease, and Charcot–Marie–Tooth 4 J (CMT4J), with a wide range of phenotypic ...manifestations. We present eight cases of CMT4J patients carrying the p.Ile41Thr mutation of
FIG4
. The patients were categorized according to their phenotype. Six patients had a pure CMT; whereas, two patients had a CMT associated with parkinsonism. Three patients had an early onset and exhibited more severe forms of the disease. Three others experienced symptoms in their teenage years and had milder forms. Two patients had a late onset in adulthood. Four patients showed electrophysiological evidence of conduction blocks, typically associated with acquired neuropathies. Consequently, two of them received intravenous immunoglobulin treatment without a significant objective response. Interestingly, two heterozygous patients with the same mutations exhibited contrasting phenotypes, one having a severe early-onset form and the other experiencing a slow disease progression starting at the age of 49. Notably, although 7 out of 8 patients in this study were compound heterozygous for the p.Ile41Thr mutation, only one individual was found to be homozygous for this genetic variant and exhibited an early-onset, severe form of the disease. Additionally, one patient who developed the disease in his youth was also diagnosed with hereditary neuropathy with pressure palsies. Our findings provide insights into the CMT4J subtype by reporting on eight heterogeneous patient cases and highlight the potential for misdiagnosis when conduction blocks or asymmetrical nerve conduction study results are observed in patients with
FIG4
mutations.
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