Amyotrophic Lateral Sclerosis / Motor Neuron Disease via the ANXA11 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). 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).

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; Lipton et al. 2004; Mitsuyama and Inoue 2009).

About 10% of ALS cases are familial (Emery and Holloway 1982). In most of these families, ALS is inherited in an autosomal dominant manner (AD-ALS) and is 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 and Siddique 2015).

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, TBK1 and ANG.

Recently, whole exome sequencing studies by an international consortium of researchers revealed heterozygous pathogenic variants in the ANXA11 gene in both familial and sporadic ALS patients. A total of six different variants, all missense, have been reported. One of these, p.Asp40Gly, was detected in four apparently unrelated families from the United Kingdom and Italy. All patients with the p.Asp40Gly variant shared a common founder haplotype.

Evidence for pathogenicity included co-segregation of the variants with ALS in families with a history of the disease. In-vitro expression studies indicated altered binding properties of the mutated ANXA11 proteins. In addition, pathological postmortem examinations showed aggregation of the mutated protein in the affected tissues of patients with the p.Asp40Gly variant (Smith et al. 2017).

Based on the available data, all patients with the p.Asp40Gly variant presented with a late-onset classic form of ALS, with no dementia. First symptoms included difficulty in speaking and swallowing, indicating a bulbar-onset disease.

The ANXA11 gene encodes Annexin A11, a calcium-dependent phospholipid-binding protein that is involved in intracellular vesicle trafficking (Lecona et al. 2003; Smith et al. 2017).

Pathogenic variants in the ANXA11 gene were detected in about 1% of familial Amyotrophic Lateral Sclerosis cases, and 1.7% of sporadic cases (Smith et al. 2017).

This test provides full coverage of all coding exons of the ANXA11 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.