Genetics of neurodegenerative diseases

This issue contains a number of articles on neurodegenerative diseases, most of them genotypically analyzed with next-generation sequencing. Readers will find articles identifying potential mutations in new genes, articles examining different phenotypes associated with variation in the same gene, and a report showing an unusual phenotype associated with a known mutation in the PRNP gene. Finally, the imaging phenotypes of mutations in 2 different frontotemporal lobar dysfunction (FTLD) genes are compared.

Kohli et al.¹ used whole-exome sequencing (WES) on 11 affected individuals in an extended family with an apparent autosomal dominant pattern of late-onset Alzheimer disease (LOAD). They detected a likely damaging missense change in the tetratricopeptide repeat domain 3 (TTC3) gene in all affected individuals. TTC3 is a regulator of Akt signaling, a key pathway disrupted in LOAD.

Nuytemans et al.² examined the overlap in the genetics of Parkinson disease (PD) and Alzheimer disease (AD) as it relates to variants in the ATP-binding cassette transporter A7 (ABCA7) gene. ABCA7 is involved in clearance of aggregated proteins, and loss-of-function (LOF) variants in ABCA7 are risk factors for AD. They therefore analyzed 396 unrelated patients with PD and 222 controls to search for ABCA7 variants. Indeed, LOF variants were more common in patients with PD, indicating potentially shared pathways in AD and PD.

Mano et al.³ examined 3 patients with apparent autosomal dominant PD and dementia. WES revealed a heterozygous c.314C>T (p.P105L) mutation in PRNP. This mutation is most commonly associated with spastic paraplegia. They then identified 2 additional families with the same mutation and a shared 7.1-Mbp haplotype among all individuals. This suggests the presence of a founder mutation and could also point to shared cis-acting variants (in addition to a valine at codon 129) predisposing to the parkinsonian presentation.

Ameur et al.⁴ examined MRI changes in patients with behavioral variant FTLD. They showed that white matter lesions were more common in progranulin (GRN) mutation carriers than in individuals with C9ORF72 repeat expansions. Many patients had extensive frontal white matter lesions in the absence of noteworthy cardiovascular risk factors.

STUDY FUNDING

No targeted funding reported.

DISCLOSURE

Stefan M. Pulst has served on the editorial boards of Journal of Cerebellum, NeuroMolecular Medicine, Continuum, Experimental Neurology, Neurogenetics, and Nature Clinical Practice Neurology and as Editor-in-Chief of Current Genomics. Dr. Pulst conducts research supported by the NIH, Target ALS, and the National Ataxia Foundation. He has consulted for Ataxion Therapeutics, has received research funding from ISIS Pharmaceuticals, has served on a speakers' bureau for Athena Diagnostics, Inc., and is a stockholder of Progenitor Life Sciences. He has received license fee payments from Cedars-Sinai Medical Center and has given expert testimony for Hall & Evans, LLC. Dr. Pulst has received publishing royalties from Churchill Livingston (The Ataxias), AAN Press (Genetics in Neurology and Molecular Genetic Testing in Neurology, 2nd–5th editions), Academic Press (Genetics of Movement Disorders), and Oxford University Press (Neurogenetics). Dr. Pulst holds patents for Nucleic acids encoding ataxin-2–binding proteins, Nucleic acid encoding Schwannomin-binding proteins and products related thereto, Transgenic mouse expressing a polynucleotide encoding a human ataxin-2 polypeptide, Methods of detecting spinocerebellar ataxia-2 nucleic acids, Nucleic acid encoding spinocerebellar ataxia-2 and products related thereto, Schwannomin-binding proteins, and Compositions and methods for spinocerebellar ataxia. He receives an honorarium from the AAN as the Editor of Neurology: Genetics. Go to Neurology.org/ng for full disclosure forms.