Rett spent more than two decades as a disorder with a known gene and nothing to do about it. This review runs the full distance: MECP2 as a regulator of transcription, the multisystem picture clinicians actually manage day to day, and a pipeline that has gone from empty to crowded in a handful of years. The therapeutic section is the reason to read it, covering gene transfer, approaches that aim to reactivate the silent X allele, and the disease-modifying candidates now in or approaching trials.
What makes Rett unusual as a gene therapy target is that dose cuts both ways. Too little MECP2 causes Rett; too much causes MECP2 duplication syndrome. A straightforward add-back strategy therefore has a therapeutic window in a way that most loss-of-function disorders do not, which is precisely why reactivating the patient's own silenced copy is being pursued so hard. For clinical services the consequence is immediate and unglamorous: families will start asking about trials, and eligibility runs through a confirmed variant, a documented phenotype and being findable in the first place.
Protein restriction is the treatment, and muscle is the thing it quietly costs. Loss of muscle mass in children managed for intoxication-type disorders is common enough here to argue for routine assessment rather than incidental notice, which puts it in the same category as bone health: a long-term consequence of successful management.
A stocktake across inherited metabolic disease of what has reached approval, what is in trials and what remains preclinical. Worth it for the distinction between disorders where a single corrected tissue is enough and those where the target organ, usually brain, keeps the delivery problem unsolved.
The cohort here is the one every diagnostic service accumulates and none has a protocol for: patients who have had genome sequencing and still have no answer. Proteomic profiling is layered onto the existing genomic data, looking for protein-level evidence, an absent or reduced product, that lifts a candidate variant out of uncertainty. Functional support is what converts uncertain significance into a classification. Whether it can be delivered broadly rather than one bespoke assay per gene is the open question, and item 06 puts a price on the answer.
What the UDN did that ordinary diagnostic pathways do not, set out as the strategies that actually produced diagnoses: reanalysis, deeper phenotyping, multi-omic testing, functional modelling and patient matchmaking. The useful reading is as a checklist for the cases sitting unresolved after first-tier testing, most of which will never see a network like this one.
Functional testing is what resolves variants of uncertain significance, and almost nowhere is it funded as a routine step. This puts a cost and an outcome against adding it to the undiagnosed pathway. Whether RNA and other functional assays earn a place is a reimbursement question before it is a laboratory one, and this is the form of evidence payers ask for.
Joint guidance on when prenatal sequencing is indicated, what should be reported and how uncertainty is handled when the decision window is measured in days. Prenatal is where turnaround time, uncertain findings and counselling capacity collide hardest, and recommendations written to be used globally have to survive settings with very different service structures.
Observational cohorts generate actionable findings in participants who were never patients, under consent written for research rather than care. This sets out what a cohort owes those participants and what infrastructure returning a result actually requires: confirmation in an accredited laboratory, a route into clinical services, and someone to do the counselling.
Sequencing after stillbirth creates an expectation of an explanation that the service around it is rarely built to carry. Consent has to be taken at the worst possible moment, tissue quality constrains what can be tested, and the result, positive or negative, lands in a conversation about recurrence risk. The workforce question is the honest one.
A first-in-indication dose escalation in a BH4 synthesis defect, a population small enough that a phase 1/2 read-out carries real weight. Sepiapterin enters the pathway upstream of tetrahydrobiopterin itself, which is the reason to look at the pharmacodynamic data rather than just the safety table.
Enzyme replacement stops at the blood-brain barrier, which is why cell-derived vesicles keep being proposed as carriers for the neuronopathic forms. The evidence here is largely preclinical, and reading it that way is the point: a plausible delivery route is not yet a therapy.
