Titin founder mutation is a common cause of myofibrillar myopathy with early respiratory failure.

OBJECTIVE: Titin gene (TTN) mutations have been described in eight families with hereditary myopathy with early respiratory failure (HMERF). Some of the original patients had features resembling myofibrillar myopathy (MFM), arguing that TTN mutations could be a much more common cause of inherited muscle disease, especially in presence of early respiratory involvement. METHODS: We studied 127 undiagnosed patients with clinical presentation compatible with MFM. Sanger sequencing for the two previously described TTN mutations in HMERF (p.C30071R in the 119th fibronectin-3 (FN3) domain, and p.R32450W in the kinase domain) was performed in all patients. Patients with mutations had detailed review of their clinical records, muscle MRI findings and muscle pathology. RESULTS: We identified five new families with the p.C30071R mutation who were clinically similar to previously reported cases, and muscle pathology demonstrated diagnostic features of MFM. Two further families had novel variants in the 119th FN3 domain (p.P30091L and p.N30145K). No patients were identified with mutations at position p.32450. CONCLUSIONS: Mutations in TTN are a cause of MFM, and titinopathy is more common than previously thought. The finding of the p.C30071R mutation in 3.9% of our study population is likely due to a British founder effect. The occurrence of novel FN3 domain variants, although still of uncertain pathogenicity, suggests that other mutations in this domain may cause MFM, and that the disease is likely to be globally distributed. We suggest that HMERF due to mutations in the TTN gene be nosologically classified as MFM-titinopathy.

Insights from a Pan India Sero-Epidemiological survey (Phenome-India Cohort) for SARS-CoV2.

To understand the spread of SARS-CoV2, in August and September 2020, the Council of Scientific and Industrial Research (India) conducted a serosurvey across its constituent laboratories and centers across India. Of 10,427 volunteers, 1058 (10.14%) tested positive for SARS-CoV2 anti-nucleocapsid (anti-NC) antibodies, 95% of which had surrogate neutralization activity. Three-fourth of these recalled no symptoms. Repeat serology tests at 3 (n = 607) and 6 (n = 175) months showed stable anti-NC antibodies but declining neutralization activity. Local seropositivity was higher in densely populated cities and was inversely correlated with a 30-day change in regional test positivity rates (TPRs). Regional seropositivity above 10% was associated with declining TPR. Personal factors associated with higher odds of seropositivity were high-exposure work (odds ratio, 95% confidence interval, p value: 2.23, 1.92-2.59, <0.0001), use of public transport (1.79, 1.43-2.24, <0.0001), not smoking (1.52, 1.16-1.99, 0.0257), non-vegetarian diet (1.67, 1.41-1.99, <0.0001), and B blood group (1.36, 1.15-1.61, 0.001).

Neurology research and teaching in Malawi.

In this article, British neurologists share their experiences of neurology in Malawi--as educators and researchers. Malawi is a resource-poor country in Central Africa. The spectrum of neurological illnesses is varied and primarily related to HIV and neuroinfections. Structured overseas training programmes for residents can lead to academic exchange with mutual benefit. New links can be established which can then be used to launch international health initiatives. Such visits can also lead to the development of institutional links, the fostering of which can have a role in the achievement of the global health agenda.

Idiopathic intracranial hypertension in otolaryngology.

Idiopathic intracranial hypertension (IIH) is defined as increased intracranial pressure in the absence of intracranial mass or obstructive hydrocephalus. Over 80% of patients are overweight women. IIH is usually encountered in the neurology and ophthalmology practise as headaches, visual disturbance and papilloedema are the characteristic features of this syndrome. Patients with IIH also experience tinnitus, hearing loss, balance disturbance, cerebrospinal fluid (CSF) otorrhoea or rhinorrhoea and in some cases these otorhinological symptoms can be presenting features of this syndrome. IIH is also associated with obstructive sleep apnoea. Otolaryngologists should be familiar with this important condition as it can manifest a variety of symptoms that are more frequently seen in their clinics. Sometimes otolaryngologists may be involved in the surgical management of this condition, such as repair of CSF rhinorrhoea or otorrhoea or endoscopic optic nerve decompression. The aim of this review article is to familiarise the otolaryngologists with the important features of this unusual syndrome which may remain unrecognised in the otolaryngology practice.

Acute hemiparesis in Sturge-Weber syndrome.

A young woman, known to have Sturge-Weber syndrome, was admitted with headache and left hemiparesis. Neuroimaging showed chronic occlusion of the venous sinuses without evidence of acute thrombus formation, or a recent vascular event.

First case of compound heterozygosity in Na,K-ATPase gene ATP1A2 in familial hemiplegic migraine.

Familial hemiplegic migraine (FHM) is a rare autosomal-dominant subtype of migraine with aura, associated with hemiparesis during the aura. Here we describe a unique FHM family in which two novel allelic missense mutations in the Na,K-ATPase gene ATP1A2 segregate in the proband with hemiplegic migraine. Both mutations show reduced penetrance in family members of the proband. Cellular survival assays revealed Na,K-ATPase dysfunction for both ATP1A2 mutants, indicating that both mutations are disease causative. This is the first case of compound heterozygosity for any of the known FHM genes.

A presenilin 1 mutation (Arg278Ser) associated with early onset Alzheimer's disease and spastic paraparesis.

Early onset familial Alzheimer's disease (EOFAD) has been associated with mutations in three genes, of which presenilin 1 (PSEN1) mutations are the most frequent. Several families with an association of progressive dementia and spastic paraplegia caused by PSEN1 mutations have been described. Here we described a novel PSEN1 mutation that was associated with dementia and spastic paraplegia in a family with 5 affected individuals in three generations. The proband was a 44-year-old woman who presented with 5 years history of progressive difficulties in walking, cognition and visuospatial impairment. Her maternal grandmother, mother and two maternal aunts also had similar neurological presentation. Molecular genetic analysis showed a missense mutation predicted to substitute an arginine residue for a serine residue at position 278 in the PSEN1 polypeptide (Arg278Ser). The novel PSEN1 mutation identified in this patient adds to the diverse list of existing mutations causing EOFAD associated with spastic paraparesis.