Self-reported outcomes and quality of life of patients with non-dystrophic myotonia: The French IMPACT 2022 survey.

International audienceNon-dystrophic myotonias (NDM) are disabling genetic diseases that impact quality of life. To reduce the impact of NDM, patients develop coping strategies such as lifestyle adaptation and avoiding key triggers. To understand how myotonia affects patients’ lives, the IMPACT survey, an online questionnaire on patient-reported outcomes, was developed based on international IMPACT questionnaire. The French IMPACT 2022 survey was completed by 47 NDM French patients. Besides muscle stiffness (98%), patients reported muscle pain (83%), falls (70%) and anxiety (77%). These issues negatively impacted abilities to work/study (49%), daily life at home (49%) and overall mobility outside (49%). Most patients (96%) reported ongoing pharmacological treatment (mexiletine, 91%) associated with improvement in muscle stiffness (100%) and reduction in falls (94%), muscle pain (87%) and anxiety (80%). Patients were moderately satisfied (19.1%), satisfied (42.6%) and very satisfied (29.8%) with the current management; 32% rated their quality of life positively (≥ 8 on 10-point scale). In conclusion, this French survey confirms the impact of myotonia on daily life and quality of life. The improvement in patient-reported outcomes in treated participants highlights the importance of managing myotonia with effective treatments. More work should be initiated to assess the importance of NDM symptom management and patients’ adherence and compliance to treatment

Different Genetic Signatures of Small-Cell Lung Cancer Characterize Anti-GABABR and Anti-Hu Paraneoplastic Neurological Syndromes

Objective: Small-cell lung cancer (SCLC) is the malignancy most frequently associated with paraneoplastic neurological syndromes (PNS) and can trigger different antibody responses against intracellular (Hu) or neuronal surface (GABABR) antigens. Our aim was to clarify whether the genomic and transcriptomic features of SCLC are different in patients with anti-GABABR or anti-Hu PNS compared with SCLC without PNS. Methods: A total of 76 SCLC tumor samples were collected: 34 anti-Hu, 14 anti-GABABR, and 28 SCLC without PNS. The study consisted of 4 steps: (1) pathological confirmation; (2) next generation sequencing using a panel of 98 genes, including those encoding the autoantibodies targets ELAVL1-4, GABBR1-2, and KCTD16; (3) genome-wide copy number variation (CNV); and (4) whole-transcriptome RNA sequencing. Results: CNV analysis revealed that patients with anti-GABABR PNS commonly have a gain in chromosome 5q, which contains KCTD16, whereas anti-Hu and control patients often harbor a loss. No significantly different number of mutations regarding any onconeural genes was observed. Conversely, the transcriptomic profile of SCLC was different, and the differentially expressed genes allowed effective clustering of the samples into 3 groups, reflecting the antibody-based classification, with an overexpression of KCTD16 specific to anti-GABABR PNS. Pathway analysis revealed that tumors of patients with anti-GABABR encephalitis were enriched in B-cell signatures, as opposed to those of patients with anti-Hu, in which T-cell- and interferon-γ-related signatures were overexpressed. Interpretation: SCLC genetic and transcriptomic features differentiate anti-GABABR, anti-Hu, and non-PNS tumors. The role of KCTD16 appears to be pivotal in the tumor immune tolerance breakdown of anti-GABABR PNS. ANN NEUROL 2023

SORD-related peripheral neuropathy in a French and Swiss cohort: Clinical features, genetic analyses, and sorbitol dosages.

Biallelic variants in SORD have been reported as one of the main recessive causes for hereditary peripheral neuropathies such as Charcot-Marie-Tooth disease type 2 (CMT2) and distal hereditary motor neuropathy (dHMN) resulting in lower limb (LL) weakness and muscular atrophy. In this study, phenotype and genotype landscapes of SORD-related peripheral neuropathies were described in a French and Swiss cohort. Serum sorbitol dosages were used to classify SORD variants. Patients followed at neuromuscular reference centres in France and Switzerland were ascertained. Sanger sequencing and next generation sequencing were performed to sequence SORD, and mass spectrometry was used to measure patients' serum sorbitol. Thirty patients had SORD peripheral neuropathy associating LL weakness with muscular atrophy, foot deformities (87%), and sometimes proximal LL weakness (20%) or distal upper limb weakness (50%). Eighteen had dHMN, nine had CMT2, and three had intermediate CMT. Most of them had a mild or moderate disease severity. Sixteen carried a homozygous c.757delG (p.Ala253Glnfs*27) variant, and 11 carried compound heterozygous variants, among which four variants were not yet reported: c.403C > G, c.379G > A, c.68_100 + 1dup, and c.850dup. Two unrelated patients with different origins carried a homozygous c.458C > A variant, and one patient carried a new homozygous c.786 + 5G > A variant. Mean serum sorbitol levels were 17.01 mg/L ± 8.9 SD for patients carrying SORD variants. This SORD-inherited peripheral neuropathy cohort of 30 patients showed homogeneous clinical presentation and systematically elevated sorbitol levels (22-fold) compared to controls, with both diagnostic and potential therapeutic implications