by Rhys Doshi L6C
Neuroferritinopathy is a severe neurological disorder, which is triggered when there is a gradual accumulation of iron in the brain [1]. Neurodegeneration with brain iron accumulation (NBIA) refers to a group of rare diseases that share clinical characteristics associated with excessive iron accumulation in the basal ganglia as well as progressive neurological deficits, such as chorea, dystonia, parkinsonism and cognitive impairment. Neuroferritinopathy is a form of NBIA caused by mutations in the ferritin light chain (FTL1) gene on chromosome 19q13.3.The build-up of iron can be caused by several factors, including increased blood-brain barrier permeability, inflammation, redistribution of iron within the brain and changes in iron homoeostasis [2].
The most common initial clinical manifestations of Neuroferritinopathy are chorea and dystonia, and only six patients have been described who initially presented with tremors [3]. A 27-year-old woman visited a movement disorders clinic in Korea regarding severe voice and mild hand tremors. She reported first experiencing a mild voice tremor at 13 years of age. Her voice tremor began to progressively worsen in her early 20s, and had since experienced hand tremors most commonly when holding a cup or spoon. She was the second child of two siblings, and her birth, perinatal, and developmental histories were not remarkable. Her father also experienced severe hand tremors that began in his 30s and died of suspected parkinsonism in his mid-40s. Although her speech volume was almost normal, she spoke with a severe voice tremor without breaks in speech. When sitting on a chair, she exhibited mild cervical dystonia that caused a slight turning of her head leftward and a continuous mild head tremor. When her arms and hands were extended or positioned under the nose, she showed mild dystonic hyperextension of both fingers and fine postural tremor with her left fingers.[4] This woman was a neuroferritinopathy patient who exhibited early prominent voice tremors and carried an insertional mutation in the FTL1 gene.
Initial discovery of Neuroferritinopathy (which affects roughly 100 patients worldwide) came when a surprising number of individuals diagnosed found to live in the Lake District, Cumbria, experienced similar symptoms with a series of incorrect diagnoses. Professor John Burn, a clinical geneticist at Newcastle Hospitals NHS Foundation Trust, conducted research into the ancestry of the families affected, and uncovered an interesting link to them all - they all shared genetic commonality. All cases were bound to share the same ancestor traced back to the 18th Century,
Professor Burn suggested that they all shared common ancestry with Christian Fletcher from Cockermouth, Cumbria [5].
For the new randomised placebo-controlled trial (DefINe), led by the University of Cambridge, an existing drug, deferiprone, will be given to 40 patients taking the medicine for a year. Deferiprone is used to remove excess iron from the body in patients with thalassemia, sickle cell disease or anaemia who have blood transfusions. Deferiprone is an iron chelator, combining with iron in the blood.
The combination of iron and deferiprone is then removed from the body by the kidneys[ 6]. This makes it an ideal candidate for treating Neuroferritinopathy. The trial is being funded by LifeArc, a non-profit medical research organisation that has contributed £750 000, and Lipomed, a Swiss life sciences company, that has offered a generic form of deferiprone. During the trial, patients will undergo a very sensitive type of MRI to monitor the brain’s iron levels [7].
Professor Patrick Chinnery, lead of DefINe trial, said, “If successful, the trial will open the possibility of using a similar approach for other neurodegenerative conditions linked to the iron build-up in the brain, including Parkinson’s disease.” [8] If successful, the evidence collected will form the basis of an application for licensing in the UK under ‘Exceptional Circumstances’, which is only used for rare conditions where the total number of people affected is low. The result of this would lead to the drug being able to benefit all people with the condition more quickly[5].
(1) https://medlineplus.gov/genetics/condition/neuroferritinopathy/ 16/04/2024 (2) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5672917/# 16/04/2024 (3) https://pubmed.ncbi.nlm.nih.gov/27022507/ 16/04/2024
(4) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987522/#b1-jmd-19038 16/04/2024
(5) https://www.cam.ac.uk/research/news/clinical-trial-underway-to-treat-ultra-rare -genetic-disease-with-possible-link-to-leader-of-mutiny 16/04/2024 (6) https://www.mayoclinic.org/drugs-supplements/deferiprone-oral-route 16/04/2024
(7) https://www.msn.com/en-gb/health/other/drug-trial-offers-hope-for-genetic-dis order-first-discovered-in-cumbria/ar-BB1kgy3I 16/04/2024