Rare mendelian disorders are being characterized with increasing success owing to the rapid development of tools for defining phenotypic and genetic determinants. The elucidation of disease pathogenesis may simultaneously trigger the identification of pathway-specific treatment targets, but the development of disease-modifying medications is often hampered by the fragmentation of efforts and the low number of available patients. The integration of scattered resources is, therefore, crucial for the success of future scientific accomplishments. Here we report the inception of a central data repository for a group of rare disorders collectively called Neurodegeneration with Brain Iron Accumulation (NBIA).

NBIA has an estimated prevalence of 1–3 / 106 and consists of several genetically-defined entities that clinically often overlap but also have unique features (Table1). The neuropathological hallmarks include iron accumulation associated with neuronal loss and gliosis, which appear as hypointense lesions (iron) with or without hyperintense patches (gliosis) on T2-weighted MRI in most NBIA forms. The “eye of the tiger” sign (a hypointense area with a hyperintense center) in the globus pallidus is seen in Pantothenate Kinase-Associated Neurodegeneration (PKAN) ([1]). Iron in the brain can be assessed by using dual spin-echo and multiple gradient-echo MRI sequences, which allow monitoring an endophenotype of the disease. Biological heterogeneity of NBIA is reflected by the differential appearance of various neuronal inclusions in the genetically defined sub-entities. However, shared functions of the affected genes are also recognized in the maintenance of membrane phospholipids and the regulation of mitochondrial energy metabolism, explaining the degenerative features of neuropathology ([2]). Even though the excess of iron appears pathogenic, molecular causes and consequences of its accumulation remain unknown. An iron-chelating agent, deferiprone, approved for systemic iron-overload disorders, is currently being tested in the largest subgroup of NBIA, PKAN (Table1). This deferiprone trial with the associated biobank and patient registry represent core work packages in TIRCON (Treat Iron-Related Childhood-Onset Neurodegeneration), an international consortium supported by the European Commission´s Seventh Framework Programme.

Table 1 NBIA disorders
Full size table

As a central data repository of TIRCON, the NBIA registry (http://www.tirconregistry.org) manages links to the deferiprone trial database, the NBIA image archive and biobank. The collected information includes demographics, family and patient history, clinical signs, neurological exam, laboratory results, brain iron assessment and volumetry by imaging, treatments and trials. The disease course is captured by standardized scales measuring dystonia severity, quality of life and sleep, functional independence, cognition, motor functioning and activity of daily living. The annually entered information enables a longitudinal reconstruction of the disease course, while genomic, transcriptomic, proteomic and metabolomic data from research on the biobank specimens contribute additional dimensions to the registry.

The technical development of the registry involved significant preparatory works. During an initial phase of six months, existing local databases and their datasets were analysed in order to specify data elements which are harmonized and most useful for the international NBIA registry. For quick and easy data entry by participating clinicians, web-based forms have been created. Management of directly identifying data are restricted to the respective sites, and only patient codes (pseudonyms) will be entered into the registry database. Together with these patient pseudonyms, codes identifying biospecimens, images, and data in the deferiprone trial database are kept in the registry and safeguarded by a sophisticated security and privacy architecture.

The registry’s security and privacy concept builds upon the security architecture of the German mitoNET repository ([3]), which has been successfully running for more than three years. Access rights are strictly role-based, and pseudonyms are kept spatially and organizationally separate from the registry database storing medical/research data. Double coding is used for all pseudonyms, which are additionally secured by encryption. In terms of the US Health Insurance Portability and Accountability Act, protected health information compliant with the “limited data set” definition is stored.

For the use of data and biosamples, agreements have been specified and approved by local ethics committees and data protection authorities. Future research proposals will be reviewed by the TIRCON’s Scientific Steering Committee (SSC). If the proposal is approved, pseudonymous or anonymous data will be released to the future investigator, depending on the proposal and the vote of the SSC. As an additional safeguard, re-identification attempts are prohibited by the data use agreements.

In summary, this registry longitudinally collects multi-dimensional information on NBIA disorders to provide a rich resource for future natural history studies, evaluations of clinical and paraclinical surrogates or potential predictors of the disease, and correlation analyses of clinical subentities with pathogenic mutations, alleles of disease modifying genes, results of “-omics” and environmental factors. It will support the design of placebo-controlled, randomized, double-blind clinical trials, and allow probing which clinical, imaging or laboratory features of the disease may be modified by a treatment modality. The NBIA registry represents a paradigm fostering integration of international resources for the enhancement of scientific synergism and future research activities in a group of rare diseases.