Clinico-pathological features in amyotrophic lateral sclerosis with expansions in C9ORF72

Abstract

Intronic expansion of the GGGGCC hexanucleotide repeat within the C9ORF72 gene causes frontotemporal dementia and amyotrophic lateral sclerosis/motor neuron disease in both familial and sporadic cases. Initial reports indicate that this variant within the frontotemporal dementia/amyotrophic lateral sclerosis spectrum is associated with transactive response DNA binding protein (TDP-43) proteinopathy. The amyotrophic lateral sclerosis/motor neuron disease phenotype is not yet well characterized. We report the clinical and pathological phenotypes associated with pathogenic C9ORF72 mutations in a cohort of 563 cases from Northern England, including 63 with a family history of amyotrophic lateral sclerosis. One hundred and fifty-eight cases from the cohort (21 familial, 137 sporadic) were post-mortem brain and spinal cord donors. We screened DNA for the C9ORF72 mutation, reviewed clinical case histories and undertook pathological evaluation of brain and spinal cord. Control DNA samples (n = 361) from the same population were also screened. The C9ORF72 intronic expansion was present in 62 cases [11% of the cohort; 27/63 (43%) familial, 35/500 (7%) cases with sporadic amyotrophic lateral sclerosis/motor neuron disease]. Disease duration was significantly shorter in cases with C9ORF72-related amyotrophic lateral sclerosis (30.5 months) compared with non-C9ORF72 amyotrophic lateral sclerosis/motor neuron disease (36.3 months, P< 0.05). C9ORF72 cases included both limb and bulbar onset disease and all cases showed combined upper and lower motor neuron degeneration (amyotrophic lateral sclerosis). Thus, clinically, C9ORF72 cases show the features of a relatively rapidly progressive, but otherwise typical, variant of amyotrophic lateral sclerosis associated with both familial and sporadic presentations. Dementia was present in the patient or a close family member in 22/62 cases with C9ORF72 mutation (35%) based on diagnoses established from retrospective clinical case note review that may underestimate significant cognitive changes in late disease. All the C9ORF72 mutation cases showed classical amyotrophic lateral sclerosis pathology with TDP-43 inclusions in spinal motor neurons. Neuronal cytoplasmic inclusions and glial inclusions positive for p62 immunostaining in non-motor regions were strongly over-represented in the C9ORF72 cases. Extra-motor pathology in the frontal cortex (P < 0.0005) and the hippocampal CA4 subfield neurons (P < 0.0005) discriminated C9ORF72 cases strongly from the rest of the cohort. Inclusions in CA4 neurons were not present in non-C9ORF72 cases, indicating that this pathology predicts mutation status.

C9orf72-related disorders: expanding the clinical and genetic spectrum of neurodegenerative diseases

“…Microscopic evaluation unveils neuronal degeneration and loss with variable degrees of gliosis and superficial laminar spongiosis (depending on disease stage), but rarely with Pick bodies and with relative paucity of amyloid plaques and neurofibrillary tangles. Myelin loss in the corticospinal tracts with moderate to severe degeneration of the motor system is also described in cases of FTD even without clinical features of motor neuron disease 9,19 . Marked loss of lower motor neurons in cranial nerve motor nuclei in the brainstem (mainly in the medulla) and in the anterior horns of the spinal cord with marked microglial reaction is observed in all levels of the pyramidal tract in cases with associated ALS phenotype 19 .…”

“…Schematic representation of the main pathophysiological mechanisms involved with motor neuron disease, (1) including protein misfolding, (2) altered RNA processing (mainly disturbed mRNA splicing), (3) defects in axonal transport, (4) abnormal accumulation of reactive oxygen species, (5) mitochondrial dysfunctions, (6) microglial neuroinflammatory mechanisms, (7) direct excitotoxicity by astrocytes, (8) disturbances of autophagy, (9) proteosome abnormalities and (10) ion channel defects. more different mechanisms of neurodegeneration 11,19,20 . An extensive number of genes located in different chromosome regions and related to distinct patophysiological mechanisms have been linked to clinical and neuropathological findings of FTD and ALS (Tables 1 and 2) 4,11,14,20,21 .…”

“…However, asymptomatic patients have also been described in cases with the repeats in the pathogenic interval. Symptomatic patients are described in cases with more than 30 repeats, generally with 250 to 1,600 repeats, and more symptomatic in cases with more than 400 repeats 16,19 .…”

“…The finding of TDP-43 (TAR/transactive response DNA-binding protein 43) positive cytoplasmic inclusions in spinal motor neurons and eventually in glial cells, commonly associated with cytoplasmic neuronal ubiquitin-positive and Tau-negative inclusions in the cortex and spinal cord 19,31,32 . The absence of FUS and Ubiquilin 2 positive inclusions differentiate C9orf72 spectrum from other genetic forms of FTD-ALS disorders 14 .…”

First-in-class thyrotropin-releasing hormone (TRH)-based compound binds to a pharmacologically distinct TRH receptor subtype in human brain and is effective in neurodegenerative models

“…conditions in which hippocampal pathology has been shown to play a role, such as in AD (Palop and Mucke, 2009), and C9orf72-related motor neuron disease and frontotemporal lobe dementia (Al-Sarraj et al, 2011;Cooper-Knock et al, 2012), as well as possibly chronic traumatic encephalopathy (CTE) (McKee et al, 2013).…”