Juvenile myasthenia gravis in Norway: HLA-DRB1*04:04 is positively associated with prepubertal onset.

BACKGROUND: Juvenile myasthenia gravis (MG) is a rare autoantibody mediated autoimmune disorder targeting the neuromuscular endplate. The clinical hallmark is muscle weakness and fatigability. Disease aetiology is complex, including both genetic and environmental factors. The involvement of genes in the human leukocyte antigen (HLA) is well established in adult MG. However, HLA associations in European juvenile MG have not been studied. This case-control study aimed to investigate and characterize genetic risk factors in prepubertal and postpubertal onset juvenile MG. METHODOLOGY/PRINCIPAL FINDINGS: A population based Norwegian cohort of 43 juvenile MG patients (17 with prepubertal onset, 26 with postpubertal onset) and 368 controls were included. Next generation sequencing of five HLA loci (HLA-A, -B, -C, -DRB1 and -DQB1) was performed, and a positive association was seen with HLA-B*08 (OR (95% CI) = 3.27 (2.00-5.36), Pc = 0.00003) and HLA-DRB1*04:04 (OR (95% CI) = 2.65 (1.57-4.24), Pc = 0.03). Stratified in postpubertal and prepubertal onset, HLA-DRB1*04:04 was only positively associated with the latter (P = 0.01). The HLA-B*08 allele (12.9% in the controls), previously described associated with early onset adult MG, was most frequently observed in postpubertal onset MG (40.4%, P = 0.0002) but also increased among prepubertal onset MG (23.5%, P = 0.05). CONCLUSION: This study provides novel information about HLA susceptibility alleles in Norwegian juvenile MG where HLA-DRB1*04:04 was associated with prepubertal onset.

Juvenile myasthenia gravis in Norway: Clinical characteristics, treatment, and long-term outcome in a nationwide population-based cohort.

BACKGROUND: This study aimed to characterize juvenile myasthenia gravis in a national population-based cohort in Norway, and to evaluate long-term outcome and potential differences correlated with prepubertal versus postpubertal disease onset. PATIENTS AND METHODS: Patients with onset of myasthenia gravis aged ≤18 years were identified through multiple strategies. Retrospective clinical data were collected by means of medical charts. All patients had an updated clinical examination. Cases were divided into prepubertal and postpubertal onset using age 12 years as the cut off. RESULTS: In total, 75 patients were identified of whom 63 were included in the study: 21 in the prepubertal and 42 in the postpubertal onset group. There was a female preponderance in both groups. In total, 59% presented with ocular symptoms, but the great majority of patients in both groups generalized during the two first years of the disease. Myasthenic crisis was more frequent in the prepubertal onset group. All patients were initially treated with pyridostigmine, 26 with steroids, and 17 with other immunosuppressive treatment. The postpubertal cases were more often treated with immunosuppressive therapy. Fifty patients (79%) underwent thymectomy. The general outcome was favourable: 57% became asymptomatic and only four subjects failed to attain clinical improvement. One-third had at least one additional autoimmune disease. CONCLUSION: Despite frequent symptom generalization and a subgroup of prepubertal onset with severe disease, the long-term outcome was good, especially in the thymectomized prepubertal onset group. Polyautoimmunity occurred in both groups in one-third.

Juvenile myasthenia gravis in Norway: A nationwide epidemiological study.

BACKGROUND: The aim of this study was to assess the incidence rate and prevalence of autoimmune myasthenia gravis (MG) among children in Norway. METHODS: This retrospective population-based study was performed in Norway from January 2012 to December 2013. Cases of juvenile MG (JMG) with onset < 18 years were identified through searches in coding systems of electronic patient records at the 15 main hospitals in Norway from 1989 to 2013. In addition, the acetylcholine receptor antibody database at Haukeland University Hospital and the clinical nationwide MG database at Oslo University Hospital were searched for cases of JMG. Diagnosis and age at onset were verified through medical records. Incidence and prevalence rates were calculated using the Norwegian population as reference. RESULTS: In total 63 unique JMG cases were identified. This corresponds to an average annual incidence rate of 1.6 per million. Incidence rate was stable over the study period. Prevalence of JMG was 3.6-13.8 per million. Females constituted the majority of JMG cases (55 vs 8 males). The risk of JMG was higher among females both in the postpubertal and prepubertal group (p < 0.001 and p = 0.02, respectively). CONCLUSION: This study confirms the rarity of JMG in Norway, especially among males, and shows a stable incidence rate over the last 25 years.