Neurodegeneration caused by intronic expansions of C9ORF72 is a clinically heterogeneous but pathologically distinct disease

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• 作者：Dr Johnathan Cooper-Knock^a ; ^{j.cooper-knock@sheffield.ac.uk} ; J Robin Highley^a ; Judith Hartley^a ; Antonio Milano^b ; Stephen Sawcer^c ; Alistair Compston^c ; Antonina Frolov^d ; Gavin Charlesworth^d ; Nicholas Wood^d ; Oliver Bandmann^a ; Christopher J McDermott^a ; Janine Kirby^a ; Paul Ince^a ; Pamela Shaw^a
• 刊名：The Lancet
• 出版年：2013
• 出版时间：27 February, 2013
• 年：2013
• 卷：381
• 期：supp_S1
• 页码：S32
• 全文大小：53 K

文摘

Background

Crossover between neurodegenerative diseases is described but poorly understood. Hexanucleotide repeat expansions of C9ORF72 are a major cause of motorneuron disease (MND)/frontotemporal dementia but we and others have observed clinical heterogeneity within C9ORF72-positive probands and their families, including a high incidence of parkinsonism. We aimed to determine whether C9ORF72 expansions are an upstream cause of clinically and pathologically distinct neurodegenerative diseases. This would have significant implications for neurodegeneration research.

Methods

In cohorts of patients with clinical parkinsonism (n=518), multiple sclerosis (MS) (n=215), and MND (n=563) we screened DNA for the C9ORF72 expansion, reviewed clinical histories, and undertook pathological evaluation of brain tissue where available.

Findings

We identified the C9ORF72 expansion in one patient with clinical parkinsonism (0¡¤2 % ), 23 patients with MND (13¡¤7 % ), and none of the patients with MS. The C9ORF72 positive parkinsonian patient had a family history of MND and displayed pathology consistent with MND with C9ORF72 expansion in addition to ¦Á-synucleinopathy. Two further patients with MND were identified with ¦Á-synucleinopathy: one with the C9ORF72 expansion, the other without. Of five MND patients who initially presented with MS, four (80 % ) were positive for the C9ORF72 expansion. C9ORF72-MND is more rapidly progressive in the presence of preceding MS. Pathological examination of MND patients with C9ORF72 expansions revealed p62 positive, TDP-43 negative neuronal cytoplasmic inclusions in frontal cortex, hippocampus, and substantia nigra, which were relatively absent in MND patients without C9ORF72 expansions.

Interpretation

C9ORF72 expansions are not a major cause of either classic Parkinson's disease with ¦Á-synucleinopathy or MS. MS appears to increase the penetrance of the C9ORF72 expansion and exaggerate the severity. We suggest that p62 positive, TDP-43 negative neuronal cytoplasmic inclusions within the substantia nigra account for the association between C9ORF72 expansions and parkinsonism. Moreover we suggest that the distribution of these inclusions determines the clinical heterogeneity of C9ORF72 disease.

Funding

UK Medical Research Council.