Lessons of the month 3: Spontaneous resolution of frontotemporal brain sagging syndrome.

We present a case of a man with headache and progressive behavioural disturbance. His cognitive decline progressed over a few months such that he was unable to hold a conversation or carry out any daily tasks such as washing and dressing. He had some upper motor neurone signs in his limbs and features of brainstem dysfunction including dysarthria and ocular abnormalities. His brain magnetic resonance imaging showed signs of brain 'sagging'. He was thought to have frontotemporal brain sagging syndrome. Prior to any treatment, he began to improve. Over the course of a week he became markedly better, was back to normal within 3 months and remains so 7 months later. We propose that resolution of spontaneous intracranial hypotension led to resolution of frontotemporal brain sagging syndrome. We believe this is the first case described where this has occurred without any intervention. It is important to recognise this condition as a potentially reversible cause of dementia.

Single-copy expression of an amyotrophic lateral sclerosis-linked TDP-43 mutation (M337V) in BAC transgenic mice leads to altered stress granule dynamics and progressive motor dysfunction.

Mutations in the gene encoding the RNA-binding protein TDP-43 cause amyotrophic lateral sclerosis (ALS), clinically and pathologically indistinguishable from the majority of 'sporadic' cases of ALS, establishing altered TDP-43 function and distribution as a primary mechanism of neurodegeneration. Transgenic mouse models in which TDP-43 is overexpressed only partially recapitulate the key cellular pathology of human ALS, but may also lead to non-specific toxicity. To avoid the potentially confounding effects of overexpression, and to maintain regulated spatio-temporal and cell-specific expression, we generated mice in which an 80 kb genomic fragment containing the intact human TDP-43 locus (either TDP-43WT or TDP-43M337V) and its regulatory regions was integrated into the Rosa26 (Gt(ROSA26)Sor) locus in a single copy. At 3 months of age, TDP-43M337V mice are phenotypically normal but by around 6 months develop progressive motor function deficits associated with loss of neuromuscular junction integrity, leading to a reduced lifespan. RNA sequencing shows that widespread mis-splicing is absent prior to the development of a motor phenotype, though differential expression analysis reveals a distinct transcriptional profile in pre-symptomatic TDP-43M337V spinal cords. Despite the presence of clear motor abnormalities, there was no evidence of TDP-43 cytoplasmic aggregation in vivo at any timepoint. In primary embryonic spinal motor neurons and in embryonic stem cell (ESC)-derived motor neurons, mutant TDP-43 undergoes cytoplasmic mislocalisation, and is associated with altered stress granule assembly and dynamics. Overall, this mouse model provides evidence that ALS may arise through acquired TDP-43 toxicity associated with defective stress granule function. The normal phenotype until 6 months of age can facilitate the study of early pathways underlying ALS.

Autosomal dominant inheritance of rapidly progressive amyotrophic lateral sclerosis due to a truncation mutation in the fused in sarcoma (FUS) gene.

Mutations in the gene encoding the RNA-binding protein fused in sarcoma (FUS) account for 4 - 5% of familial cases of amyotrophic lateral sclerosis (ALS). We describe the identification and in vitro cellular characterization of a genetic mutation in a family in which the index case, and subsequently her two children, each developed rapidly progressive ALS at a young age and died within a year of onset. Exome capture and sequencing revealed a mutation in the FUS gene consisting of a 2-bp deletion, c.1509_1510delAG, resulting in a predicted truncated protein, p.G504Wfs * 12, lacking the nuclear localization signal. Expression of this mutation in HEK293 and NSC-34 cells demonstrated severe cytoplasmic mislocalization of mutant FUS, and colocalization with stress granules when compared to wild-type, R521C and P525L mutant FUS. This study provides further evidence of a broad correlation between clinical severity of FUS-related ALS and mislocalization of the protein to the cytoplasm.

Progressive epidural lipomatosis with steroid use in severe refractory asthma.

BACKGROUND: Long-term immunosuppression with oral corticosteroids is frequently used to treat inflammatory diseases of the lung and is advocated in the management of some patients with asthma. METHODS: The authors describe the case of a 35-year-old man with severe refractory asthma who developed a slowly progressive thoracic spinal cord syndrome. RESULTS: Spinal imaging demonstrated the presence of spinal epidural lipomatosis, a rare complication of prolonged corticosteroid therapy, which is characterized by overgrowth of fat in the epidural space and neuronal compression. CONCLUSIONS: Spinal epidural lipomatosis should be considered in patients receiving long-term corticosteroid therapy who develop symptoms and signs suggestive of spinal cord compression.