Table 1
Clinical trial database search results, June 2021. Results of clinical trials database search for NBIA disorders. All interventional trials, completed and active, found on ClinicalTrials.gov or the EU Clinical Trials Register are listed. * Status is as reported on clinical trials database in August 2021 and may not represent actual trial enrolment status.
| NBIA | DATABASE REF. | STATUS* | LOCATION |
|---|---|---|---|
| Pilot Study: Iron-chelating treatment in patients with Neurodegeneration with Brain Iron Accumulation (NBIA) | NCT00907283 2008-005206-39 | Ongoing | Italy |
| PKAN | |||
| CoA-Z in Pantothenate Kinase-associated Neurodegeneration (PKAN) | NCT04182763 | Recruiting | North America |
| A study for efficacy of pantethine in the treatment of pantothenate kinase-associated neurodegeneration | ChiCTR1900021076 | Completed | China |
| Stimulation of the Globus pallidus internus in patients with NBIA (formerly Hallervorden-Spatz-Syndrome): prospective analysis of international therapeutic outcomes and development of a therapeutic algorithm | DRKS00003106 | Recruiting | Worldwide |
| Compassionate Use of Deferiprone in Patients With PKAN | NCT02635841 | Available | – |
| Efficacy and Safety Study of Fosmetpantotenate (RE-024) in PKAN Participants | NCT03041116 2016-001955-29 | Terminated | Europe, USA |
| Long-term Safety and Efficacy Study of Deferiprone in Patients with Pantothenate Kinase-Associated Neurodegeneration (TIRCON-EXT) | NCT02174848 2014-001427-79 | Completed | Germany, UK |
| A randomized, double-blind, placebo-controlled trial of deferiprone in patients with pantothenate kinase-associated neurodegeneration (TIRCON) | ISRCTN72904618 NCT01741532 2012-000845-11 | Completed | Europe, USA |
| Phase II trial to assess safety and efficacy of Iron chelating agent Deferiprone in patients with Pantothenate Kinase-Associated Neurodegeneration | 2008-003059-56 | Completed | Italy |
| PLAN | |||
| A Study to Assess Efficacy and Safety of RT001 in Subjects With Infantile Neuroaxonal Dystrophy | NCT03570931 | Active, not recruiting | USA |
| Desipramine in Infantile Neuroaxonal Dystrophy (INAD) | NCT03726996 | Terminated | USA |
| Aceruloplasminemia | |||
| Clinical Curative Effect Evaluation Study of Treatment of Oral Deferiprone Tablets in Aceruloplasminaemia Patients | NCT04184453 | Recruiting | China |
Table 2
Summary of reported NBIA genes. Genes tabulated in order of estimated prevalence, from most commonly identified to least commonly identified NBIA subtypes [124]. Abbreviations: aNAD, atypical neuroaxonal dystrophy; BG, basal ganglia; BPAN, β-propeller protein–associated neurodegeneration; CoA, coenzyme A; CoPAN, CoA synthase protein–associated neurodegeneration; ER, endoplasmic reticulum; FAHN, fatty acid hydroxylase–associated neurodegeneration; GP, globus pallidus; INAD, Infantile Neuroaxonal Dystrophy; MIM, Mendelian Inheritance in Man; MPAN, mitochondrial membrane protein–associated neurodegeneration; MRI, magnetic resonance imaging; NBIA, neurodegeneration with brain iron accumulation; PKAN, pantothenate kinase–associated neurodegeneration; PLAN, phospholipase A2-associated neurodegeneration; 4’-PPT, 4’-phosphopantetheine; RCT, randomized controlled trial; SN, substantia nigra. ‡Mineralization in the brain has specific patterns on brain MRI with iron (Fe3+) accumulation appearing hypointense on T2-weighted images and isointense on T1-weighted images.
| NBIA DISORDER MIM NUMBER | GENE INHERITANCE MIM | CELLULAR LOCALIZATION | PROTEIN FUNCTION | MAIN CLINICAL FEATURES OR PHENOTYPES | LOCATION OF MRI MINERALIZATION‡ | OTHER MRI FINDINGS | NEUROPATHOLOGY | TRIALED THERAPIES |
|---|---|---|---|---|---|---|---|---|
| BPAN #300894 | WDR45 XLD *300526 | Autophagosome | Scaffolding protein for assembly of multiprotein complexes | Early childhood onset epilepsy, developmental delay, ataxia, and stereotypies followed by progression with dystonia and parkinsonism in young adulthood | GP, SN | SN has thin, hypointense band surrounded by a ‘halo’ of hyperintensity on T1 | GP and SN: iron, gliosis, neuronal loss and spheroids, tau | |
| PKAN #234200 | PANK2 AR *606157 | Mitochondria | Essential regulatory enzyme in CoA biosynthesis | Dystonia, parkinsonism, retinal degeneration Classical: Onset in childhood, non-ambulant by age 10 Atypical: Later onset, more varied progression | GP, can also affect SN and STN | ‘Eye of the tiger’ sign in GP: T2 hypointensity with central hyperintensity | GP: iron, gliosis, neuronal loss, and spheroids | Deferiprone (oral iron chelation) – RCT completed Fosmetpantotenate (4’-PPA precursor) – RCT completed Oral pantethine (licensed for hyperlipidemia) single-arm, open-label trial completed 4’-PPT – RCT recruiting |
| PLAN #610217 | PLA2G6 AR *603604 | Mitochondria, cytosol, ER | Enzyme that catalyzes release of fatty acids from phospholipids | INAD: Regression in early infancy, strabismus, nystagmus, axial hypotonia and peripheral spasticity with dystonia and progressive tetraparesis. Possible seizures. aNAD: Onset in childhood, similar phenotype to INAD but slower progressing Dystonia-parkinsonism: Adult-onset | GP, SN (may not be present in early disease) | Cerebellar atrophy and claval hypertrophy in INAD and aNAD | Widespread axonal spheroids, Lewy bodies, neurofibrillary tangles, and tau pathology | Deuterated polyunsaturated fatty acid (RT001) open-label trial completed Oral desipramine (tricyclic antidepressant) open-label trial in terminated |
| MPAN #614298 | C19orf12 AR/AD *614297 | Mitochondria, ER, mitochondria associated membrane | Unknown | Childhood dystonia, pyramidal signs, neuropsychiatric features, cognitive decline | GP, SN | T2-hyperintense streaking between GP interna and externa, cerebellar and cortical atrophy | GP: iron, gliosis, neuronal loss, and spheroids Widespread Lewy bodies SN neuron loss | |
| Aceruloplasminemia #604290 | CP AR *117700 | Plasma membrane | Peroxidation of ferrous transferrin to ferric transferrin | Adult-onset chorea, tremor, and dystonia. Retinal degeneration, diabetes mellitus, and anemia also occur with systemic iron deposition. | BG, thalamus, dentate, red nucleus | Prominent white matter T2 hyperintensity, cerebellar atrophy | Spheroid bodies in astrocytes and neurons | Deferiprone (oral iron chelation) in open-label trial recruiting |
| FAHN #612319 | FA2H AR *611026 | ER | Catalyzes the synthesis of 2-hydroxysphingolipids | Childhood dystonia and spasticity | GP, SN | Prominent white matter T2 hyperintensity, pontocerebellar atrophy | Unknown | |
| Kufor-Rakeb syndrome #606693 | ATP13A2 AR *610513 | Mitochondria, lysosome | ATPase that transports inorganic cations and other substrates across cell membranes | Juvenile onset parkinsonism, dystonia, supranuclear gaze palsy | GP, putamen | Cerebral, cerebellar and brainstem atrophy. | Unknown | |
| Neuroferritinopathy #606159 | FTL AD *134790 | Cytosol | Subunit of the intracellular iron storage protein ferritin | Adult-onset chorea, tremor, dystonia. May have respiratory chain complex assay defects. | GP, putamen, caudate nucleus, thalamus, dentate | BG necrosis, mild cerebral and cerebellar atrophy. | Basal ganglia cavitation and numerous iron-positive inclusions in GP and putamen | |
| Woodhouse-Sakati syndrome #241080 | DCAF17 AR *612515 | Nucleolus | Nucleolar protein with possible substrate receptor for CUL4-DDB1 E3 ubiquitin-protein ligase complex | Dystonia, hypogonadism, diabetes mellitus, alopecia | GP | Prominent white matter T2 hyperintensity, cerebellar atrophy | Unknown | |
| CoPAN #615643 | COASY AR *609855 | Mitochondria | Enzyme in CoA biosynthesis | Childhood onset motor impairment, dystonia, spasticity | GP, SN | GP calcification | Unknown |
Figure 1
Overview of the cellular localization of causative genes, implicated pathways, and therapeutic development in monogenic NBIA disorders. Schematic diagram indicating proposed cellular localization of proteins encoded by NBIA-associated genes and their implicated pathways: CoA biosynthesis (turquoise), iron homeostasis (red), lipid metabolism (blue), autophagy (green), and unknown mechanism (grey). Agents in a pink box indicates treatments trialed or in development. B5, vitamin B5 (pantothenate); CoA, coenzyme A.