Familial aggregation of amyotrophic lateral sclerosis

Abstract

Objective To assess the relative risk of amyotrophic lateral sclerosis (ALS) in families of ALS patients. Methods We conducted a cohort study based on the Swedish Multi-Generation Register (MGR) in 1961-2005. Among 6,671 probands (first ALS case in the family), 1,909 full siblings, 13,947 children, and 5,405 spouses were identified (exposed group). Other persons in MGR, who were siblings, children, or spouses to persons without ALS, served as the reference group. Relative risks of ALS among the exposed group, compared to the reference group, were calculated from Poisson regression models. Concurrence of ALS within twins was assessed in 86,441 twin pairs registered in the Swedish Twin Register. Results Nine cases of ALS were noted among the siblings and 37 cases among the children of the probands, giving a 17-fold risk among the siblings (95% confidence interval [CI], 8.1-30.4) and a 9-fold risk among the children (95% CI, 6.2-12.0), compared to the reference group. Siblings and children had a higher excess risk if the proband was diagnosed at younger age, and the excess risks decreased with increasing age at diagnosis of the proband (p < 0.001). Spouses had no significantly increased risk (p = 0.27). Two cases were identified among the co-twins of ALS probands, giving a relative risk of 32 (95% CI, 5.2-102.6). Interpretation The siblings and children of ALS patients have an around 10-fold risk of ALS compared to the reference group. The excess risks vary with both age and kinship, indicating a major genetic role in familial ALS.

The Role of Immune and Inflammatory Mechanisms in ALS

“…Having even a single relative with ALS increases risk of disease for an individual [49]. The genes implicated in sporadic ALS (sALS) include TDP-43 [48], FUS [50] and the SMN gene [51].…”

The Neurogenomics View of Neurological Diseases

“…A potential clue to the molecular bases of sporadic neurological diseases may be the clinical observation that siblings and relatives of a patient with a neurological disease are at an increased risk of developing the same disease; this phenomenon has been observed with regard to Parkinson disease (PD) 12 and amyotrophic lateral sclerosis. 13 These clinical observations suggest the involvement of genetic factors in these diseases ( Figure 1). Until recently, it has been difficult to elucidate the genetic factors underlying sporadic neurological diseases.…”

Measuring the progression of upper motor neuron disease using diffusion MRI and its correlation with Clinical phenotype

“…It is now found that approximately 10% of ALS is inherited, which is referred to as familial ALS (fALS) (Camu, Khoris et al 1999). In all patients, ALS is thought to arise from a combination of genetic susceptibility (Renton, Chio et al 2014, Marangi and Traynor 25 Alruwaili thesis 2016 2015), and environmental exposure (Fang, Kamel et al 2009), and may be due to a multi-stage process (Al-Chalabi, Calvo et al 2014). Causative genes have been identified in fALS, with some of these genetic mutations also found in patients with sporadic ALS (sALS) (Lattante, Conte et al 2012).…”

“…Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive death of upper and lower motor neurons. ALS is thought to arise from a combination of genetic susceptibility and environmental exposure (Fang, Kamel et al 2009, Sutedja, Veldink et al 2009). Patients with ALS develop weakness of the limbs, the bulbar muscles and the diaphragm ).…”