Expanding SPTAN1 monoallelic variant associated disorders: From epileptic encephalopathy to pure spastic paraplegia and ataxia.

PURPOSE: Nonerythrocytic αII-spectrin (SPTAN1) variants have been previously associated with intellectual disability and epilepsy. We conducted this study to delineate the phenotypic spectrum of SPTAN1 variants. METHODS: We carried out SPTAN1 gene enrichment analysis in the rare disease component of the 100,000 Genomes Project and screened 100,000 Genomes Project, DECIPHER database, and GeneMatcher to identify individuals with SPTAN1 variants. Functional studies were performed on fibroblasts from 2 patients. RESULTS: Statistically significant enrichment of rare (minor allele frequency < 1 × 10-5) probably damaging SPTAN1 variants was identified in families with hereditary ataxia (HA) or hereditary spastic paraplegia (HSP) (12/1142 cases vs 52/23,847 controls, p = 2.8 × 10-5). We identified 31 individuals carrying SPTAN1 heterozygous variants or deletions. A total of 10 patients presented with pure or complex HSP/HA. The remaining 21 patients had developmental delay and seizures. Irregular αII-spectrin aggregation was noted in fibroblasts derived from 2 patients with p.(Arg19Trp) and p.(Glu2207del) variants. CONCLUSION: We found that SPTAN1 is a genetic cause of neurodevelopmental disorder, which we classified into 3 distinct subgroups. The first comprises developmental epileptic encephalopathy. The second group exhibits milder phenotypes of developmental delay with or without seizures. The final group accounts for patients with pure or complex HSP/HA.

A collaborative genetic carrier screening model for the British Ashkenazi Jewish community.

We present a unique model of a British genetic carrier screening programme for individuals with Ashkenazi Jewish ancestry that exemplifies a partnership between a publicly funded healthcare service (the NHS) and a charity, Jnetics. This model provides affordable access to carrier screening for severe autosomal recessive diseases increased in this community. Prior to the development of this programme, the British healthcare system only provided Tay Sachs' screening for this community, leaving them at higher risk of having a child with a serious autosomal recessive disease. The Jnetics screening programme is promoted through community and social media campaigns, involves educational outreach, a pre-test genetic counselling service by a dedicated NHS-based genetic counsellor, saliva-based DNA testing, comprehensive reporting and, where required, post-test genetic counselling. The charity raises funds to subsidise the screening. In 6 years, the model has been successfully implemented in hospital and community settings and in schools and universities, aiming to reach those pre-conception. In response to the COVID-19 pandemic, the programme adapted by offering genetic screening virtually and has subsequently expanded in its outreach. Furthermore, the screening panel is currently being expanded to include other conditions increased in the Ashkenazi and also the Sephardi and Mizrahi Jewish communities. An example of innovation and accessibility, providing free screening to all students and disadvantaged individuals, the programme aims to provide a model that can potentially be adopted by other genetically at-risk communities.

How to assess tendon reflexes of the lower limb in the elderly.

BACKGROUND: Clinicians frequently experience difficulty in eliciting the reflexes of elderly patients using standard methods due to paratonia/frontal rigidity. If reflexes are incorrectly thought to be absent, important diagnostic errors may be made. Neurologists use alternative methods when technical difficulties require them, but these are not widely used by non-neurologists. METHODS: A neurologist and a medical student both used standard and non-standard techniques to assess reflexes of the lower limb in geriatric inpatients, aged over 65, to determine which method permitted the most confident assessment of the presence of knee and ankle reflexes. RESULTS: 45 patients were assessed. The consultant found that in 20 patients (44%) all three knee reflex methods examined produced similar results. When the methods produced different results, the "superior patellar supine" method was the best single method overall (best or equal best in 19 patients (42%)). For the ankle reflex all four reflex methods examined produced similar results in only 7 patients (16%). When the methods produced different results the "Achilles strike elevated" method was best or equal best in 32 patients (71%) and the "plantar strike" method in 29 patients (64%). If the student had relied on standard methods alone, reflexes would have been incorrectly called absent in 28 limbs (37%) for knee jerks and 52 limbs (84%) for ankle jerks. Supplementing standard methods with alternative methods reduced these error rates to 19% and 21% respectively. CONCLUSIONS: Our findings indicate that a reasonable practical approach is to assess the knee reflex with the standard method and then, if a definite reflex has not been recorded, move on to use the "superior patellar supine" method; and for the ankle reflex begin with the "plantar strike method" and then, if necessary, move on to use the "Achilles strike elevated" method.