A case of ALS-FTD in a large FALS pedigree with a K17I ANG mutation.

Please be advised that this information was generated on 2016-09-24 and may be subject to change. Approximately 90% of amyotrophic lateral sclerosis (ALS) cases are sporadic (SALS), but 10% are familial (FALS). Mutations in SOD1, Alsin, Dyn-actin, SETX, DJ-1, VAPB, and TDP-43 1 have been reported (table e-1 on the Neurology ® Web site at www.neurology.org). After the identification of sequence variation VEGF in patients with ALS, mutations in another angiogenic gene (ANG) were identified in SALS and FALS. 2,3 Studies in other populations have identified ANG mutations in patients with ALS, but also in healthy controls. This suggests that not all mutations are pathogenic. Methods. A total of 39 unrelated FALS patients, negative for SOD1 mutations, were screened for ANG mutations. This study was approved by the local ethics committee and participants provided informed consent. DNA was isolated from venous blood and ANG mutation analysis was performed as described in appendix e-1. A total of 275 unrelated , healthy controls were taken from a prospective population-based study on ALS in The Netherlands and were also screened. 5 PMut predict the impact of an amino acid substitution on the structure and function of the protein. Results. We identified one mutation in one patient (122 AϾT) (figure, A), leading to an amino acid substitution of lysine to isoleucine (K17I) (figure, B). PMut analysis predicted this mutation to be pathogenic. Sequence alignments of ANG in different species demonstrated high conservation (figure, C). Analysis of this pedigree revealed an autosomal dominant inheritance of the mutation (male to male transmission) (figure, D). DNA was available from 44 out of 62 family members (five affected individuals). All affected family members carried the K17I mutation. Ten carriers were identified, but all were under 50 years of age (except one who was 75 years old without symptoms or signs of ALS). The K17I mutation was not found in 275 control samples. Cases III-3, III-4, and IV-1 all presented with progressive upper and lower motor neuron loss of limbs. Case III-1 rapidly developed weakness in both arms with atrophy, fasciculations, and dyspnea, but no upper motor neuron signs. The patient died after 6 months from onset. Case III-2 initially presented with parkinsonism (bradykinesia, diminished pos-tural reflexes, cogwheel rigidity [right arm], shuffling , short-stepped gait, and decreased spontaneous eye blink rate). There was no autonomic dysfunction and eye movements were intact. Dopaminergic treatment had little effect. After 5 years, …