The gold standard for facioscapulohumeral muscular dystrophy (FSHD) genetic diagnostic procedures was published in 2012. With the increasing complexity of the genetics of FSHD1 and 2, the increase of genetic testing centers, and the start of clinical trials for FSHD, it is crucial to provide an update on our knowledge of the genetic features of the FSHD loci and renew the international consensus on the molecular testing recommendations. To this end, members of the FSHD European Trial Network summarized the evidence presented during the 2022 ENMC meeting on Genetic diagnosis, clinical outcome measures, and biomarkers. The working group additionally invited genetic and clinical experts from the USA, India, Japan, Australia, South‐Africa, and Brazil to provide a global perspective. Six virtual meetings were organized to reach consensus on the minimal requirements for genetic confirmation of FSHD1 and FSHD2. Here, we present the clinical and genetic features of FSHD, specific features of FSHD1 and FSHD2, pros and cons of established and new technologies (Southern blot in combination with either linear or pulsed‐field gel electrophoresis, molecular combing, optical genome mapping, FSHD2 methylation analysis and FSHD2 genotyping), the possibilities and challenges of prenatal testing, including pre‐implantation genetic testing, and the minimal requirements and recommendations for genetic confirmation of FSHD1 and FSHD2. This consensus is expected to contribute to current clinical management and trial‐readiness for FSHD.

SETTING: Neuromyelitis optica (NMO), or Devic's disease, is a rare acute in ammatory disease characterised by demyelination affecting the spinal cord and optic nerves. Although NMO usually occurs in isolation, the association between NMO and active pulmonary tuberculosis (TB) has been suggested by a number of case reports and series. OBJECTIVE: To investigate the possible association between NMO and TB. DESIGN: A retrospective case-control study. We included adult patients admitted to our institution with a nal diagnosis of NMO based on accepted criteria between January 1995 and February 2011. Controls were hospitalbased and consisted of patients admitted with a diagnosis of Guillain-Barré syndrome. RESULTS: Fourteen patients met the inclusion criteria, of whom 11 (79%) had a preceding or simultaneous diagnosis of pulmonary TB (PTB). The diagnosis of PTB preceded the onset of NMO by a median time of 4 weeks (range 0–12). Two of the controls were diagnosed with PTB. The odds ratio for the presence of active PTB in the NMO group vs. the control group was 4.6 (95%CI 1.71–15.49). CONCLUSION: These results indicate an association be- tween NMO and PTB in our population. The most likely mechanism is immune-mediated in ammatory demye- lination of the optic nerves and spinal cord triggered by pulmonary infection with Mycobacterium tuberculosis.

Objective We describe and compare the sociodemographic and clinical features, treatments, and prognoses and survival times of patients with amyotrophic lateral sclerosis (ALS) in Africa. Methodology We conducted a multicentre, hospital-based cohort study in Africa. Patients with ALS diagnosed in the neurology departments of participating hospitals from 2005 to 2017 were included. Subgroup analysis was performed by subcontinent. Survival analyses were conducted using the Cox proportional hazards model. Results Nine centres from eight African countries participated. A total of 185 patients with ALS were included: 114 from Northern Africa, 41 from Western Africa and 30 from Southern Africa. A male predominance (male to female ratio 2.9) was evident. The median age at onset was 53.0 years (IQR 44.5–64.0 years). The onset was bulbar in 22.7%. Only 47 patients (26.3%) received riluzole, mainly in Northern and Western Africa. The median survival from the time of diagnosis was 14.0 months (95% CI 10.7 to 17.2 months). The median survival was longer in Northern Africa (19.0 months, 95% CI 10.8 to 27.2 months) than in Western (4.0 months, 95% CI 0.8 to 7.1 months) and Southern (11.0 months, 95% CI 5.6 to 16.4 months) Africa (Breslow test, p<0.0001). Both subcontinental location and riluzole treatment independently affected survival. Conclusion More African patients with ALS were male and younger and exhibited a lower proportion of bulbar onset compared with patients with ALS from Western nations. Survival was consistent with that in Western registers but far shorter than what would be expected for young patients with ALS. The research improves our understanding of the disease in Africa.

Neuromuscular diseases (NMDs) affect ∼15 million people globally. In high income settings DNA-based diagnosis has transformed care pathways and led to gene-specific therapies. However, most affected families are in low-to-middle income countries (LMICs) with limited access to DNA-based diagnosis. Most (86%) published genetic data is derived from European ancestry. This marked genetic data inequality hampers understanding of genetic diversity and hinders accurate genetic diagnosis in all income settings. We developed a cloud-based transcontinental partnership to build diverse, deeply-phenotyped and genetically characterized cohorts to improve genetic architecture knowledge, and potentially advance diagnosis and clinical management. We connected 18 centres in Brazil, India, South Africa, Turkey, Zambia, Netherlands and the UK. We co-developed a cloud-based data solution and trained 17 international neurology fellows in clinical genomic data interpretation. Single gene and whole exome data were analysed via a bespoke bioinformatics pipeline and reviewed alongside clinical and phenotypic data in global webinars to inform genetic outcome decisions. We recruited 6001 participants in the first 43 months. Initial genetic analyses ‘solved’ or ‘possibly solved’ ∼56% probands overall. In-depth genetic data review of the four commonest clinical categories (limb girdle muscular dystrophy, inherited peripheral neuropathies, congenital myopathy/muscular dystrophies and Duchenne/Becker muscular dystrophy) delivered a ∼59% ‘solved’ and ∼13% ‘possibly solved’ outcome. Almost 29% of disease causing variants were novel, increasing diverse pathogenic variant knowledge. Unsolved participants represent a new discovery cohort. The dataset provides a large resource from under-represented populations for genetic and translational research. In conclusion, we established a remote transcontinental partnership to assess genetic architecture of NMDs across diverse populations. It supported DNA-based diagnosis, potentially enabling genetic counselling, care pathways and eligibility for gene-specific trials. Similar virtual partnerships could be adopted by other areas of global genomic neurological practice to reduce genetic data inequality and benefit patients globally.

Parkinson's disease (PD), defined as a neurodegenerative disorder, is characterized by the loss of dopaminergic neurons in the substantia nigra in the midbrain. Loss-of-function mutations in the parkin gene are a major cause of autosomal recessive, early-onset PD. Parkin has been implicated in the maintenance of healthy mitochondria, although previous studies show conflicting findings regarding mitochondrial abnormalities in fibroblasts from patients harboring parkin-null mutations. The aim of the present study was to determine whether South African PD patients with parkin mutations exhibit evidence for mitochondrial dysfunction. Fibroblasts were cultured from skin biopsies obtained from three patients with homozygous parkin-null mutations, two heterozygous mutation carriers and two wild-type controls. Muscle biopsies were obtained from two of the patients. The muscle fibers showed subtle abnormalities such as slightly swollen mitochondria in focal areas of the fibers and some folding of the sarcolemma. Although no differences in the degree of mitochondrial network branching were found in the fibroblasts, ultrastructural abnormalities were observed including the presence of electron-dense vacuoles. Moreover, decreased ATP levels which are consistent with mitochondrial dysfunction were observed in the patients' fibroblasts compared to controls. Remarkably, these defects did not manifest in one patient, which may be due to possible compensatory mechanisms. These results suggest that parkin-null patients exhibit features of mitochondrial dysfunction. Involvement of mitochondria as a key role player in PD pathogenesis will have important implications for the design of new and more effective therapies.