Non-syndromic patients with infantile spasms and malformations of cortical development: absence of seizures in siblings

Background: Parents of children with infantile spasms undergoing epilepsy surgery typically inquire about the risk of other children for a similar affliction. Here, we determined whether non-syndromic patients with infantile spasms and malformation of cortical development (MCD) have a family history of seizures, particularly in siblings.Patients and methods: We selected 29 children with intractable infantile/epileptic spasms who underwent surgery (mean age at surgery: 4.4±3.8 years; 12 males, 17 females; age range 0.8-14.9 years). A pathological diagnosis of MCD was confirmed in all the patients. Family (including parents, and siblings) history of seizures was acquired in all patients through neurology chart review/telephonic interview.Results: Pathological diagnosis of migration disorder (16) and cortical dysplasia (9) was made in these patients. Diagnosis of hemimegalencephaly, dysembryoplastic neuroepithelial tumor (DNET), lissencephaly type1 and porencephaly was also confirmed in 4 different patients. None of the siblings in any family (total number of siblings in the group = 30) were affected by infantile spasms or other types of seizures. The maternal aunt of one patient and mother of another patient had a history of childhood seizures for short durations.Conclusions: Our retrospective study showed that patients with infantile spasms with MCD who underwent resective surgery have low sibling recurrence risk for seizures. Our study suggests that de novo mutations and non-genetic or epigenetic factors are major causes of infantile spasms due to MCD.

Sibling recurrence risk in Dupuytren’s disease

Dupuytren’s disease is a complex condition, with both genetic and environmental factors contributing to its aetiology. We aimed to quantify the extent to which genetic factors predispose to the disease, through the calculation of sibling recurrence risk (ls), and to calculate the proportion of heritability accounted for by currently known genetic loci. From 174 siblings of patients with surgically confirmed disease, 100 were randomly selected. Controls were recruited from patients attending an ophthalmology outpatient clinic for eye conditions unrelated to diabetes. There were no statistically significant differences in baseline characteristics between the case and control groups. In siblings, 47% had Dupuytren’s disease, compared with 10% of controls, giving a ls of 4.5. Currently known loci that predispose to Dupuytren’s disease account for 12.1% of the total heritability of the disease. Dupuytren’s disease was significantly more common in siblings than in controls. These results accurately quantify the magnitude of the genetic predisposition to Dupuytren’s disease.

Genetics of type 1 diabetes mellitus

Type 1 diabetes, previously known as insulin-dependent diabetes mellitus, is a common chronic T-cell-mediated disease in which there is selective autoimmune destruction of the insulin-producing β‎ cells of the pancreas. Although the mechanisms underlying this process are not fully understood, type 1 diabetes occurs as a result of complex interactions between multiple genes (reviewed in references 1–3) and environmental influences, which may both promote and protect against disease. Type 1 diabetes clusters in some families, but with no distinct pattern of inheritance. The concordance rates in monozygotic twins for type 1 diabetes can reach 50%, compared to 6% for dizygotic twins. The sibling recurrence risk ratio (λ‎s) (risk to siblings ÷ risk to general population) value for type 1 diabetes is 15 (6.0 ÷ 0.4 or 6% ÷ 0.4%), and twin studies suggest that 80% to 85% of familial aggregation is accounted for by genes. Type 1 diabetes has been noted to coexist with other autoimmune diseases—notably, Graves’ disease and coeliac disease—in certain families, implying the involvement of common autoimmune pathways. Improved understanding of the so-called ‘allelic architecture’ (the identity of disease-associated gene variants, their frequencies, and size of the risk conferred by each variant) and biological pathways involved in type 1 diabetes is expected to facilitate the identification of new therapeutic targets for the development of new treatments. DNA biomarkers could also assist risk prediction at a population level. This is clinically relevant since individuals can survive with only 20% intact β‎-cell mass, and the time to reach this level of destruction can be considerably delayed in some individuals, offering a window of opportunity for intervention therapy. Furthermore, clinical trials should be improved by only focusing on those patients at highest risk of developing type 1 diabetes. Early prediction, improved treatments, and, ultimately, prevention of type 1 diabetes are major goals because incidence rates are increasing. A recent study by the EURODIAB Study Group, involving 20 population-based registries across 17 European countries, has assessed incidence trends in children diagnosed with type 1 diabetes under the age of 15 between 1989 and 2003: an overall increase of 3.9% per year was reported, and, in the under 5 age group, an increase of 5.4% per year was observed (4).