Amyotrophic Lateral Sclerosis, Susceptibility To, 24
A number sign (#) is used with this entry because of evidence that susceptibility to amyotrophic lateral sclerosis-24 (ALS24) is conferred by heterozygous mutation in the NEK1 gene (604588) on chromosome 4q33.
For a phenotypic description and a discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400).
Clinical FeaturesBrenner et al. (2016) reported 3 patients with amyotrophic lateral sclerosis with truncating mutations in the NEK1 gene. The first patient presented at age 54 with upper and lower motor neuron signs in the left arm. Symptoms spread to the leg and right side, and within 2 years bulbar signs had developed. The patient was alive at the time of the report. The second patient presented at age 59 with dysphagia, and within 2 years had developed dysarthria, myatrophic paresis of the left arm, and respiratory insufficiency, while the lower extremities were not affected. Hyperreflexia was present in the atrophic limb. The patient died at the age of 63. The patient's mother had died of ALS at the age of 62 after a 5-year disease progression with onset in the hands and progression to tetraparesis. Late in the disease she developed bulbar symptoms and had a gastrostoma. The third patient presented at the age of 75 years with asymmetric amyotrophic paresis of the first dorsal interosseous muscle of the left hand. Within 18 months the disease had progressed to an asymmetric amyotrophic tetraparesis with asymmetric hyperreflexia without spasticity in all limbs, early pseudobulbar dysarthria, dysphagia, and mild respiratory insufficiency. She was still alive 18 months after disease onset. This patient had an affected uncle who died of ALS at the age of 70; detailed medical history was not available. Cognitive impairment was either not clinically evident or absent upon testing in all patients, but the third patient showed atypical hippocampal/temporal frontal lobe functions, such as nonverbal memory, as well as severe hippocampal atrophy and atrophy of caudate and thalamus seen on MRI.
Molecular GeneticsTo identify potential loss-of-function variants in the NEK1 gene in familial ALS, Brenner et al. (2016) analyzed whole-exome sequence data from 265 familial ALS patients and 827 control individuals. They identified 3 patients with NEK1 truncating mutations: a 1-bp deletion (c.42_42delA, Ser14SerfsTer45) and 2 nonsense mutations (S1036X, 604588.0005 and R812X, 604588.0006). One potential loss-of-function mutation was found in the control group (allele frequency = 0.06%), in agreement with the high frequency of similar NEK1 mutations in the ExAC database (allele frequency = 0.05%). Additionally, the S1036X mutation was found in a brother of a proband, who was without symptoms of ALS 4 years after the death of the proband and 9 years after onset of symptoms in the proband. These findings suggested a reduced penetrance of heterozygous NEK1 loss-of-function mutations.
Kenna et al. (2016) conducted whole-exome analyses of 1,022 index familial ALS cases and 7,315 controls. They also performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function variants in NEK1 and familial ALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 arg261-to-his (R261H; 604588.0007) variant as a candidate risk factor. Replication analyses of sporadic ALS cases and independent control cohorts confirmed significant disease association for both the R261H (10,589 samples analyzed) and NEK1 loss-of-function variants (3,362 samples analyzed). In total, NEK1 risk variants were observed in nearly 3% of ALS cases.