Severe brain atrophy after long-term survival seen in siblings with familial amyotrophic lateral sclerosis and a mutation in the optineurin gene: a case series

Abstract

IntroductionPrevious 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.Case presentationThe 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.ConclusionWe conclude that a homozygous deletion-type mutation in the optineurin gene may be associated with widespread multisystem degeneration in amyotrophic lateral sclerosis.

Clinicopathological characteristics of patients with amyotrophic lateral sclerosis resulting in a totally locked-in state (communication Stage V)

“…However, a few patients required TIV over 24 months after the onset, such as our patient 3 with pTDP-43-ir NCI, and three patients reported in the existing literature, showing pTDP-43-ir NCI [ 11 ], basophilic inclusions [ 14 ], and a mutation in OPTN [ 28 ], respectively (Tables 1 and 3 ). These patients showed that patients who required TIV after more than 24 months from disease onset could not necessarily avoid progression to Stage V.…”

“…In contrast, patients with marked cerebral atrophy due to degeneration of the cerebral cortex and white matter have also been reported [ 11 , 17 , 20 ]. Neuroradiologically, a progressive cerebral atrophy has been shown in siblings with ALS who carried a mutation in the gene for optineurin ( OPTN ) [ 28 ]. However, the distribution and characteristics of the cerebral lesions are unclear.…”

Loss of Optineurin In Vivo Results in Elevated Cell Death and Alters Axonal Trafficking Dynamics

“…Many mutations in OPTN have been associated with disease, including some that are predicted to eliminate OPTN’s function [1] , [4] , [21] , [22] , [24] – [28] , [30] , [35] . We chose to study the loss of function of Optn in the zebrafish with the sa0143 (L278X) mutant of optn (number sign in Fig.…”

“…Subsequent groups have implicated many different mutations in OPTN with this disease [2] – [20] . Amyotrophic lateral sclerosis (ALS) is a progressive debilitating condition where the loss of spinal motor neurons leads to paralysis and death, and researchers have also found mutations in OPTN to be associated with various forms of this disease [21] – [35] . More recently, mutations in OPTN have been implicated in the metabolic bone disorder Paget’s disease of bone [36] – [38] .…”

Inducible turnover of optineurin regulates T cell activation

“…Mutations in Optn have been implicated in development of human diseases such as glaucoma (Aung et al, 2003; Ueno et al, 2011), amyotrophic lateral sclerosis and Paget’s disease of the bone (Albagha et al, 2010). At this point, the role of Optn in immune cells is less well understood.…”