Lack of unique neuropathology in amyotrophic lateral sclerosis associated with p.K54E angiogenin (ANG) mutation.

J Kirby,E F Goodall,C J Mcdermott,J R Highley,P G Ince,J A Hartley,L Cox,H C Hollinger,C Hewitt,M Fox,P J Shaw

doi:10.1111/nan.12007

J Kirby, E F Goodall + Show 9 more

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https://doi.org/10.1111/nan.12007

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Abstract

AimsFive to 10% of cases of amyotrophic lateral sclerosis are familial, with the most common genetic causes being mutations in the C9ORF72, SOD1, TARDBP and FUS genes. Mutations in the angiogenin gene, ANG, have been identified in both familial and sporadic patients in several populations within Europe and North America. The aim of this study was to establish the incidence of ANG mutations in a large cohort of 517 patients from Northern England and establish the neuropathology associated with these cases.MethodsThe single exon ANG gene was amplified, sequenced and analysed for mutations. Pathological examination of brain, spinal cord and skeletal muscle included conventional histology and immunohistochemistry.ResultsMutation screening identified a single sporadic amyotrophic lateral sclerosis case with a p.K54E mutation, which is absent from 278 neurologically normal control samples. The clinical presentation was of limb onset amyotrophic lateral sclerosis, with rapid disease progression and no evidence of cognitive impairment. Neuropathological examination established the presence of characteristic ubiquitinated and TDP-43-positive neuronal and glial inclusions, but no abnormality in the distribution of angiogenin protein.DiscussionThere is only one previous report describing the neuropathology in a single case with a p.K17I ANG mutation which highlighted the presence of eosinophilic neuronal intranuclear inclusions in the hippocampus. The absence of this feature in the present case indicates that patients with ANG mutations do not always have pathological changes distinguishable from those of sporadic amyotrophic lateral sclerosis.

Highlights

Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease characterized by degeneration of motor neurones in the cerebral cortex, brainstem and spinal cord
To date 20 different mutations have been identified in ALS patients (Table 1), with angiogenin gene (ANG) mutations accounting for 1.2–2.6% of familial ALS (FALS) cases and 0.35–0.8% of sporadic ALS (SALS) cases
IHC for TDP-43 revealed both normal nuclear labelling and neuronal and glial cytoplasmic inclusions of similar morphology and distribution to Mutation screening of the ANG gene in a large cohort of ALS patients from Northern England identified a single mutation in a SALS case: c.232A>G that results in p.K54E amino acid change

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease characterized by degeneration of motor neurones in the cerebral cortex, brainstem and spinal cord. It results in progressive muscular weakness, wasting and paralysis that typically causes death within 3–5 years of onset [1]. An association between the angiogenin gene (ANG), located on chromosome 14q11.2, and ALS was originally demonstrated by Greenway and colleagues. They identified that the G allele of the synonymous rs11701 single nucleotide polymorphism (SNP) was overrepresented in Scottish and Irish ALS cases compared with controls [8]. To date 20 different mutations have been identified in ALS patients (Table 1), with ANG mutations accounting for 1.2–2.6% of familial ALS (FALS) cases and 0.35–0.8% of sporadic ALS (SALS) cases

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