Amyotrophic Lateral Sclerosis and Frontotemporal Dementia via the TBK1 Gene

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a selective loss of motor neurons in the motor cortex, brain steam, and spinal cord (Tandan and Bradley. 1985. PubMed ID: 4051456). The dysfunction and loss of these neurons results in rapid progressive muscle weakness, atrophy and ultimately paralysis of limb, bulbar and respiratory muscles. The mean age of onset of symptoms is about 55 years of age; most cases begin between 40 and 70 years of age. The annual incidence of ALS is 1-2 per 100,000 (Cleveland and Rothstein. 2001. PubMed ID: 11715057).

The most common symptoms include twitching and cramping of muscles of the hands and feet, loss of motor control in the hands and arms, weakness and fatigue, tripping and falling. Symptoms usually begin with asymmetric involvement of the muscles. As the disease progresses, symptoms may include difficulty in talking, breathing and swallowing, shortness of breath, and paralysis.

Cognitive impairment was not been initially associated with ALS. However, frontotemporal dementia (FTD) has been reported in several cases. Dementia now has been documented in patients with ALS from different ethnic groups and affects both males and females (Wikström et al. 1982. PubMed ID: 7125994; Lipton et al. 2004. PubMed ID: 15351890; Mitsuyama and Inoue. 2009. PubMed ID: 19780984).

About 10% of ALS cases are familial (Emery and Holloway. 1982. PubMed ID: 7180680). In most of these families, ALS is inherited in an autosomal dominant manner (AD-ALS) and shows age-dependent penetrance. In rare families, the disease is transmitted in an autosomal recessive or dominant X-linked pattern.

About 90% of patients with ALS are sporadic cases (SALS) with no known affected relatives. It is unclear how many of the apparently sporadic cases are inherited with low penetrance. The clinical presentations of familial ALS (FALS) and sporadic ALS (SALS) are similar. However, the onset of symptoms in FALS is usually earlier compared to that of SALS (Kinsley et al. 1993. PubMed ID: 20301623).

Autosomal Dominant ALS (AD-ALS) is a clinically and genetically heterogeneous disorder that affects all ethnic groups. Several genes have been implicated in the disease. They include C9orf72, SOD1, FUS, TARDBP, ANG, OPTN, VCP, VAPB, PFN1, MATR3, CHCHD10, ANG, and TBK1.

Pathogenic variants in the TBK1 gene have been implicated in ALS, FTD and ALS/FTD (Cirulli et al. 2015. PubMed ID: 25700176; Le Ber. 2015. PubMed ID: 26476236; van der Zee. 2017. PubMed ID: 28008748). Over 100 pathogenic variants have been reported to date. About half of the variants are missense; the other half is predicted to be truncating. Variants have been reported in both sporadic and familial cases (Freischmidt et al. 2017. PubMed ID: 27892983).

The TBK1 gene encodes TANK Binding Kinase 1, which is involved in several cellular processes including oncogenesis and immunological autophagy (Clément et al. 2008. PubMed ID: 19160540; Pilli et al. 2012. PubMed ID: 22921120).

Pathogenic variants in the TBK1 gene were detected in about 3.6% of ALS-FTD cases, 1.3% of ALS cases, and 0.4% of FTD cases (van der Zee et al. 2017. PubMed ID: 28008748).

This test provides full coverage of all coding exons of the TBK1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.