Clinicopathologic study on an ALS family with a heterozygous E478G optineurin mutation.
ABSTRACT We investigated a family manifesting amyotrophic lateral sclerosis (ALS) with a heterozygous E478G mutation in the optineurin (OPTN) gene. Clinically, slow deterioration of motor function, mood and personality changes, temporal lobe atrophy on neuroimaging, and bizarre finger deformity were noted. Neuropathologically, TAR DNA-binding protein 43 (TDP-43)-positive neuronal intracytoplasmic inclusions were observed in the spinal and medullary motor neurons. In these cells, the immunoreactivity of nuclear TDP-43 was reduced. Consecutive sections revealed that the inclusions were also reactive with anti-ubiquitin and anti-p62 antibodies, but noticeably negative for OPTN. In addition, TDP-43/p62-positive glial cytoplasmic inclusions (GCIs) were scattered throughout the spinal cord and the medullary motor nuclei. Furthermore, Golgi fragmentation was identified in 70% of the anterior horn cells (AHCs). The presence of AHCs with preserved nuclear TDP-43 and a fragmented Golgi apparatus, which are unrecognizable in sporadic ALS, indicates that patients with the E4787G OPTN mutation would manifest Golgi fragmentation before loss of nuclear TDP-43. In the neocortex, GCIs were sparsely scattered among the primary motor and temporal cortices, but no neuronal TDP-43-positive inclusions were detected. In the amygdala and the ambient gyrus, argyrophilic grains and ballooned neurons were seen. The thorough neuropathologic investigations performed in this work demonstrated that OPTN-positive inclusion bodies, if any, were not prominent. We postulate that optineurinopathy is closely linked with TDP-proteinopathy and speculate that this heterozygous E478G mutation would cause ALS by acting through a dominant-negative mechanism.
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ABSTRACT: Amyotrophic lateral sclerosis (ALS) is increasingly recognized to be a syndromic disorder in which the degeneration of motor neurons is frequently accompanied by a range of syndromes reflective of frontotemporal dysfunction, including a behavioural or cognitive syndrome, a dysexecutive syndrome or a frontotemporal dementia. Both sporadic and familial variants of ALS can be affected. The anatomic substrate of each is a frontotemporal lobar degeneration (FTLD) characterized by superficial linear spongiosus, atrophy and neuronal loss, and both astrocytic and neuronal deposition of TDP-43 as pathological inclusions. Largely unrecognized however is the extent of alterations in tau protein metabolism, particularly in cognitively impaired patients (ALSci). This includes hyper-phosphorylation (pThr(175)) and tau phosphatase resistance, increased fibril formation ex vivo of tau isolated from ALSci and tau immunoreactive aggregates in neurons, dystrophic neurites and astrocytes. In this article, we will review the contemporary clinical, genetic and neuropathological characteristics of the frontotemporal syndromes of ALS and propose that as opposed to being a FTLD in which TDP-43 is the primary disease protein (FTLD-TDP) and that the frontotemporal syndromes of ALS represent a hybrid of both TDP-43 and tau pathology.Journal of Molecular Neuroscience 08/2011; 45(3):648-55. DOI:10.1007/s12031-011-9609-0 · 2.76 Impact Factor
- Acta Neuropathologica 11/2011; 123(2):289-92. DOI:10.1007/s00401-011-0915-y · 9.78 Impact Factor
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ABSTRACT: Previous studies have shown widespread multisystem degeneration in patients with sporadic amyotrophic lateral sclerosis who develop a total locked-in state and survive under mechanical ventilation for a prolonged period of time. However, the disease progressions reported in these studies were several years after disease onset. There have been no reports of long-term follow-up with brain imaging of patients with familial amyotrophic lateral sclerosis at an advanced stage of the disease. We report the cases of siblings with amyotrophic lateral sclerosis with homozygous deletions of the exon 5 mutation of the gene encoding optineurin, in whom brain computed tomography scans were followed up for more than 20 years. The patients were a Japanese brother and sister. The elder sister was 33 years of age at the onset of disease, which began with muscle weakness of her left lower limb. Two years later she required mechanical ventilation. She became bedridden at the age of 34, and died at the age of 57. A computed tomography scan of her brain at the age of 36 revealed no abnormality. Atrophy of her brain gradually progressed. Ten years after the onset of mechanical ventilation, atrophy of her whole brain, including the cerebral cortex, brain stem and cerebellum, markedly progressed. Her younger brother was 36 years of age at the onset of disease, which presented as muscle weakness of his left upper limb. One year later, he showed dysphagia and dysarthria, and tracheostomy ventilation was performed. He became bedridden at the age of 37 and died at the age of 55. There were no abnormal intracranial findings on brain computed tomography scans obtained at the age of 37 years. At the age of 48 years, computed tomography scans showed marked brain atrophy with ventricular dilatation. Subsequently, atrophy of the whole brain rapidly progressed as in his elder sister. We conclude that a homozygous deletion-type mutation in the optineurin gene may be associated with widespread multisystem degeneration in amyotrophic lateral sclerosis.Journal of Medical Case Reports 12/2011; 5(1):573. DOI:10.1186/1752-1947-5-573