In search of a diagnosis: deploying genomics at scale
A substantial number of children have a disease identified as “rare” without having any kind of causative diagnosis (autism is not a causative diagnosis!). In a UK pilot study, 2,183 proband children were referred for exome sequencing with additional sequencing of family members if warranted. The overall diagnostic yield was surprisingly high, about 25% overall. Of the approximately half of probands who had neurological or sensory disorder, an explanatory diagnosis was reached in almost 40% of the cases. Two thoughts: 1) the day is rapidly coming when the family of any special need child will be offered exome sequencing; 2) as the experience base grows, the diagnostic yield will increase. 100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care — Preliminary Report
In search of a diagnosis: thinkers needed
A piece highlighting the disappearance of the thinking internist, as every specialty gets more compartmentalized and time-pressured. Apart from at a few centers (Mayo, Cleveland Clinic), patients with unusual symptoms end-up on long diagnostic odysseys, wandering from specialist to specialist without anyone to pull the clinical picture together in a coherent manner – at great expense of time, money, and discouragement. While we wait for a sufficiently competent AI, the authors argue that we need a new specialty – consultative medicine. But in my opinion, the bigger problem will be how to compensate that specialty in a way that is attractive to the brightest – it’s hard to compete with the payday of procedure-driven specialties. What we are seeing is a symptom of an incentive system that rewards “doing” much more than thinking and planning. Consultative Medicine — An Emerging Specialty for Patients with Perplexing Conditions
Durability of gene therapy: hemophilia A (Spark)
Are gene therapies durable? We are beginning to accumulate data that suggests they are, at least at the few years’ mark demonstrated by Spark in their treatment for hemophilia A. They are about 2 years behind Biomarin, which showed the same for their gene therapy in early 2020. Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A
Durability of cell therapy: Epidermolysis bullosa
Are non-hematopoietic genetically modified cell therapies durable? There are so few examples that it is very early to tell, but a case report from Germany shows promise. It describes a child with a genetic deficiency in a laminin essential for the cohesion of the epidermis who had horrific bullous disease (essentially delamination of the skin, leaving a state equivalent to a catastrophic burn). The authors explanted skin, cultured keratinocytes, transduced them with a proper copy of the defective gene, and transplanted them back into the child at multiple skin sites. Five years later, the child is alive and doing well, and the transplanted areas of the skin are reasonably normal both grossly and histologically. Transgenic Epidermal Cultures for Junctional Epidermolysis Bullosa — 5-Year Outcomes
Getting Covid is very protective… as long as you don’t die or get long-Covid
A brief letter to the editor from authors in Qatar describing their experience with Covid during the country’s second wave (alpha/beta variants), using its national health record database. They identified 1300 reinfections (i.e. disease in people who had been infected in the first wave): 0.3% were severe (i.e. hospitalized) and there were no deaths. For those infected for the first time (~6,000 records) the rate of severe infection was 3% and 0.1% died. Severity of SARS-CoV-2 Reinfections as Compared with Primary Infections (free access)
The New England Journal of Medicine is a premier weekly medical journal covering many topics of interest to the health sector. In this monthly series we offer an opinionated perspective on selected highlights that might be of interest to our clients and others.