Treatment of Ectopic Calcification in Fahr's Disease or Syndrome

• Status: Not yet recruiting
• Trial end date: 2025-09-01
• Target enrollment: 0
• Participant gender: All

Summary

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: UMC Utrecht
• Collaborator: Netherlands Brain Foundation
• Treatments: Etidronic Acid

Criteria

Inclusion Criteria:

1. Age of 18 years or over

2. Clinical diagnosis of Fahr's disease or syndrome. No international accepted diagnostic criteria for Fahr's disease or syndrome exist yet. It is diagnosed mostly based on the clinical presentation. For the present study the following criteria are used:

1. Clinical symptoms consistent with a clinical diagnosis of Fahr's disease or syndrome.

2. Bilateral calcifications of the basal ganglia as seen on the computed tomography (CT) scan of the head. To rule out basal ganglia calcifications due to aging, a CT based calcification score will be used as proposed by Nicolas et al. Calcification is graded from 0 (no calcification) to 5 (serious and confluent) in specific locations of the brain; lenticular, caudate, thalamus nuclei, subcortical white matter, cortex, cerebellar hemispheres, vermis, midbrain, pons, and medulla. The total calcification score (ranging from 0 to 80) is obtained by adding all location-specific points, where a score higher than the age-specific threshold points at Fahr's disease or syndrome.46

Furthermore, the next criteria are supportive for the clinical diagnosis of PFBC:

3. Frequently, the family history is consistent with autosomal dominant inheritance. A positive family history with at least one relative in the first or second degree with symptoms of PFBC is supportive for the clinical diagnosis of PFBC.

4. The presence of a (likely) pathogenic mutation in one of the PFBC-related genes is supportive for the clinical diagnosis of PFBC. Mutations in up to now 4 known genes are associated with an autosomal dominant pattern of inheritance: solute carrier family 20 member 2 (SLC20A2) (OMIM#213600), xenotropic and polytropic retrovirus receptor 1 (XPR1) (OMIM#616413), platelet-derived growth factor b (PDGFB) (OMIM#615483), and platelet-derived growth factor receptor b (PDGFRB) (OMIM#615007). Autosomal recessively inherited PFBC is associated with mutations in two genes: myogenesis-regulating glycosidase (MYORG) (OMIM#618317) and junctional adhesion molecule 2 (JAM2) (OMIM#618824).

Exclusion Criteria:

1. Unable or unwilling to sign an informed consent.

2. Severe renal impairment (estimated creatinine clearance/estimated glomerular filtration rate of < 30 ml/min/1.73m2 calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation).

3. Contraindication to receiving oral medication.

4. Known abnormality of the esophagus that would interfere with the passage of the drug.

5. Known sensitivity to etidronate.

6. Pregnancy, women with an active pregnancy wish < 1 year, or women who are breastfeeding at the time of inclusion.

7. Any other medical or social condition that, in the opinion of the Principal Investigator, might put the subject at risk of harm during the study or might adversely affect the interpretation of the study data.

8. Use of bisphosphonate during last 5 years.

9. Hypocalcemia (calcium <2,20 mmol/L)*.

10. 25-hydroxy (25-OH) vitamin D deficiency <35 nmol/L)*.

• After correcting the hypocalcemia or vitamin D deficiency, a participant is again suitable for participation in the CALCIFADE trial, as long as the participant meets the inclusion criteria.