Fahr Disease Clinical Trial
Official title:
A Randomized, Placebo-controlled, Double-blind Trial to Study the Effects of Etidronate on Ectopic CALCIfication in FAhr's Disease or Syndrome
Fahr's disease or syndrome are neurodegenerative diseases in which patients present with bilateral vessel associated calcifications in the basal ganglia. The clinical penetration of Fahr's disease or syndrome is incomplete and heterogeneous comprising of neuropsychiatric signs, cognitive decline, movement disorders, and various other signs (migraine, speech disorders, pain, seizures). The symptoms start between 30 and 50 years and are (slowly) progressive. Symptomatic patients have an increased risk for dependence in activities of daily living and impaired quality of life. Currently, disease-modifying therapies are not available for patients with Fahr's disease or syndrome. However, in a small case series it was shown that alendronate was effective in the clinical treatment of several patients with Fahr's disease or syndrome. Now the time has come to investigate the effectiveness of treatment with bisphosphonates in patients with Fahr's disease or syndrome in a randomized controlled trial.
Fahr's disease, scientifically known as primary familial brain calcification (PFBC), is a neurodegenerative disease in which all patients present with bilateral vessel associated calcifications in the basal ganglia in the absence of other secondary causes of brain calcifications. When a secondary cause is identified, the term Fahr's syndrome is often used. Dominantly-inherited PFBC is associated with mutations in four genes; solute carrier family 20 member 2 (SLC20A2), xenotropic and polytropic retrovirus receptor 1 (XPR1), platelet-derived growth factor b (PDGFB) and platelet-derived growth factor receptor b (PDGFRB). Recessively inherited PFBC is associated with mutations in two genes; myogenesis-regulating glycosidase (MYORG) and junctional adhesion molecule 2 (JAM2). Mutations in the known genes account for half of patients, suggesting genetic heterogeneity, with new genes yet to be discovered. The estimated minimal prevalence in studies with PFBC diagnosed with genetic and imaging studies is 2.1 to 6.6 per 1,000 suggesting that PFBC is actually not a rare disorder and is underdiagnosed. The clinical penetration of Fahr's disease or syndrome is incomplete and heterogeneous comprising of neuropsychiatric signs (depression, anxiety, psychosis), cognitive decline, movement disorders (ataxia, dystonia, Parkinsonism) and various other signs (migraine, speech disorders, pain, seizures). The symptoms start between 30 and 50 years and are (slowly) progressive. Symptomatic patients have an increased risk for dependence in activities of daily living and impaired quality of life. Histology shows small vessel and capillary calcifications, vascular insufficiency and blood-brain barrier damage. Neural pathology has been described and there are indications that calcifications could interfere with neural circuitry. It is not known how mutations in different genes lead to a common pathology. Yet PFBC belongs to a group of genetic diseases that due to different types of faulty phosphor metabolism leads to a shortage of inorganic pyrophosphate (PPi). PPi is the strongest inhibitor of ectopic calcification in the body. PPi can be replaced by etidronate, a stable molecular homologue of PPi and a well known bisphosphonate that has been used widely. Presently, the rare genetic diseases Pseudoxanthoma Elasticum (PXE), Generalized Arterial Calcification of Infancy (GACI) and Arterial Calcification due to Cluster of Designation 73 (CD73) deficiency (ACDC) are successfully treated with this medication. In PFBC, it was shown that due to mutations in the SLC20A2 gene the Pi Transporter 2 (PiT2) is compromised. The PiT2 transporter plays an important role in the maintenance of Pi homeostasis which is essential for adenosine triphosphate synthesis. Another mutation, XPR1 is responsible for phosphate efflux and mutations here lead to calcium deposition in endothelial cells. Recently, it was shown that mutations in the PDGFB and PDGFRB genes cause osteoblast like cells to mediate in the calcification process, as was also shown in PXE, GACI and ACDC patients. Currently, disease-modifying therapies are not available for patients with Fahr's disease or syndrome. However, in a small case series it was shown that alendronate was effective in the clinical treatment of several patients with Fahr's disease or syndrome. Now the time has come to investigate the effectiveness of treatment with bisphosphonates in patients with Fahr's disease or syndrome in a randomized controlled trial. ;