We report the development of an international registry for Neurodegeneration with Brain Iron Accumulation (NBIA), in the context of TIRCON (Treat Iron-Related Childhood-Onset Neurodegeneration), an EU-FP7 – funded project. This registry aims to combine scattered resources, integrate clinical and scientific knowledge, and generate a rich source for future research studies. This paper describes the content, architecture and future utility of the registry with the intent to capture as many NBIA patients as possible and to offer comprehensive information to the international scientific community.
KeywordsRare diseases Neurodegeneration Iron Registry Consortium NBIA TIRCON
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).
Classic form: Early onset – rapid progression
Pantothenate kinase-associated neurodegeneration (PKAN)
Gait abnormality, dystonia, dysarthria, corticospinal involvement, pigmentary retinopathy
“Eye-of-the-tiger” sign in the GP
Mitochondrial membrane protein-associated neurodegeneration (MPAN)
Speech and gait difficulties, progressive spastic paraparesis, dystonia, optic atrophy, axonal motor neuropathy, cognitive decline
Increased iron in GP and SN; “Eye of the tiger” sign very rare
Fatty-acid hydroxylase-associated neurodegeneration (FAHN)
Onset with focal dystonia and gait impairment, ataxia, dysarthria, spastic quadriparesis, nystagmus, visual loss, no or mild cognitive impairment and seizures in late stages; overlaps with some HSP syndromes and phenotypes of leukodystrophies
Abnormal iron in GP and SN, optic, cerebellar and brainstem atrophy, confluent subcortical and periventricular hyperintensity, thinning of the CC
PLA2G6-associated neurodegeneration (PLAN) –Infantile neuroaxonal dystrophy (INAD)
Severe psychomotor regression, hypotonia, peripheral motor neuropathy, hyperreflexia, tetraparesis, ataxia, gait abnormalities
Cerebellar atrophy, abnormal iron in GP and other nuclei
Atypical form: Later onset – slower progression
Atypical pantothenate kinase-associated neurodegeneration (PKAN)
Speech abnormalities, depression, impulsivity, aggression, emotional instability
Eye-of-the-tiger sign or variants of it in the GP or other signs of increased iron and gliosis in the GP
Atypical mitochondrial membrane protein-associated neurodegeneration (MPAN)
Psychiatric features, parkinsonism, dystonia-parkinsonism, motor axonal neuropathy, mild gait difficulty, optic atrophy, cognitive decline
Increased iron in GP and SN
HuntingtonÂ´s disease-like presentation: adult-onset chorea or dystonia, orofacial action dystonia, cognitive decline
Abnormal iron and later cystic changes in the basal ganglia
Diabetes mellitus, retinal degeneration, blepharospasm, facial and neck dystonia, chorea, tremor, dysarthria, ataxia – typically adult onset
Pathological iron in both the brain and viscera; in the brain: GP, striatum, thalami, dentate nuclei
In the viscera: liver
PLA2G6-associated neurodegeneration (PLAN) –neuroaxonal dystrophy (NAD)
Progressive dystonia, dysarthria, language delay, corticospinal signs, psychiatric features and social difficulties or similar to but later onset version of INAD
Cerebellar and optic nerve atrophy
Iron may or may not be increased
Other NBIA form
Juvenile onset parkinsonism, corticospinal signs, supranuclear gate palsy and cognitive decline, facial-faucial-finger myoclonus, visual hallucinations, oculogyric crisis
Generalized brain atrophy, increased iron in the caudate and lenticular nuclei, but increased iron is not always present
Hypogonadism, diabetes, alopecia, hearing loss, mental retardation, progressive generalized and focal dystonia, dysarthria, cognitive decline
Increased iron in GP, SN and other nuclei; white matter abnormalities
Static Encephalopathy with Neurodegeneration in Adulthood (SENDA)
Childhood onset cognitive impairment without progression; in adult age sudden onset progressive dystonia-parkinsonism and corticospinal signs.
Increased iron in the GP and SN; on T1W MRI, hyperintensity with central band of hypointensity in the SN; cerebral and cerebellar atrophy
As a central data repository of TIRCON, the NBIA registry () 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 (), 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.