Neurodegeneration With Brain Iron Accumulation Patients Research Articles

Clinical, neuroimaging and genetic findings in Brazilian patients with neurodegeneration with brain iron accumulation

Neurodegeneration with brain iron accumulation (NBIA) encompasses a clinically and genetically heterogeneous group of rare disorders. Here, we report clinical, neuroimaging and genetic studies in twenty three Brazilian NBIA patients. In thirteen subjects, deleterious variants were detected in known NBIA-causing genes (PANK2, PLA2G6, C9ORF12, WDR45 and FA2H), including previously unreported variants in PANK2 and PLA2G6. Two patients carried rare, likely pathogenic variants in genes not previously associated with NBIA: KMT2A c.11785A > C (p.Ile3929Leu), and TIMM8A c.127T > C (p.Cys43Arg), suggesting an expansion of their associated phenotypes to include NBIA. In eight patients the etiology remains unsolved, suggesting variants undetectable by the adopted methods, or the existence of additional NBIA-causing genes.

Neurodegeneration with Brain Iron Accumulation Disorders and Retinal Neurovascular Structure.

The unique neurovascular structure of the retina has provided an opportunity to observe brain pathology in many neurological disorders. However, such studies on neurodegeneration with brain iron accumulation (NBIA) disorders are lacking. To investigate NBIA's neurological and ophthalmological manifestations. This cross-sectional study was conducted on genetically confirmed NBIA patients and an age-gender-matched control group. The thickness of retinal layers, central choroidal thickness (CCT), and capillary plexus densities were measured by spectral domain-optical coherence tomography (SD-OCT) and OCT angiography, respectively. The patients also underwent funduscopy, electroretinography (ERG), visual evoked potential (VEP), and neurological examination (Pantothenate-Kinase Associated Neurodegeneration-Disease Rating Scale [PKAN-DRS]). The generalized estimating equation model was used to consider inter-eye correlations. Seventy-four patients' and 80 controls' eyes were analyzed. Patients had significantly decreased visual acuity, reduced inner or outer sectors of almost all evaluated layers, increased CCT, and decreased vessel densities, with abnormal VEP and ERG in 32.4% and 45.9%, respectively. There were correlations between visual acuity and temporal peripapillary nerve fiber layer (positive) and between PKAN-DRS score and disease duration (negative), and scotopic b-wave amplitudes (positive). When considering only the PKAN eyes, ONL was among the significantly decreased retinal layers, with no differences in retinal vessel densities. Evidence of pachychoroid was only seen in patients with Kufor Rakeb syndrome. Observing pathologic structural and functional neurovascular changes in NBIA patients may provide an opportunity to elucidate the underlying mechanisms and differential retinal biomarkers in NBIA subtypes in further investigations. © 2023 International Parkinson and Movement Disorder Society.

Olfactory status in neurodegeneration with brain iron accumulation disorders.

Olfactory dysfunction has been suggested as a diagnostic and discriminative biomarker in some neurodegenerative disorders. However, there are few studies regarding the olfactory status in rare diseases including neurodegeneration with brain iron accumulation (NBIA) disorders. Genetically-confirmed NBIA patients were enrolled. Neurological and cognitive examinations were conducted according to the Pantothenate Kinase-Associated Neurodegeneration-Disease Rating Scale (PKAN-DRS) and the Mini-Mental State Examination (MMSE) questionnaire, respectively. Olfaction was assessed in three domains of odor threshold (OT), odor discrimination (OD), odor identification (OI), and total sum (TDI) score by the Sniffin' Sticks test. The olfactory scores were compared to a control group and a normative data set. Thirty-seven patients, including 22 PKAN, 6 Kufor Rakeb syndrome, 4 Mitochondrial membrane Protein-Associated Neurodegeneration (MPAN), 5 cases of other 4 subtypes, and 37 controls were enrolled. The mean PKAN-DRS score was 51.83±24.93. Sixteen patients (55.2%) had normal cognition based on MMSE. NBIA patients had significantly lower olfactory scores compared to the controls in TDI and all three subtests, and 60% of them were hyposmic according to the normative data. Including only the cognitively-normal patients, still, OI and TDI scores were significantly lower compared to the controls. The phospholipase A2-Associated Neurodegeneration (PLAN) and MPAN patients had a significantly lower OI score compared to the cognitively-matched PKAN patients. Olfactory impairment as a common finding in various subtypes of NBIA disorder can potentially be considered a discriminative biomarker. Better OI in PKAN compared to PLAN and MPAN patients may be related to the different underlying pathologies.

Long-Term Neuroradiological and Clinical Evaluation of NBIA Patients Treated with a Deferiprone Based Iron-Chelation Therapy.

Neurodegeneration with brain iron accumulation (NBIA) comprises various rare clinical entities with brain iron overload as a common feature. Magnetic resonance imaging (MRI) allows diagnosis of this condition, and genetic molecular testing can confirm the diagnosis to better understand the intracellular damage mechanism involved. NBIA groups disorders include: pantothenate kinase-associated neurodegeneration (PKAN), mutations in the gene encoding pantothenate kinase 2 (PANK2); neuroferritinopathy, mutations in the calcium-independent phospholipase A2 gene (PLA2G6); aceruloplasminemia; and other subtypes with no specific clinical or MRI specific patterns identified. There is no causal therapy, and only symptom treatments are available for this condition. Promising strategies include the use of deferiprone (DFP), an orally administered bidentate iron chelator with the ability to pass through the blood–brain barrier. This is a prospective study analysis with a mean follow-up time of 5.5 ± 2.3 years (min–max: 2.4–9.6 years) to define DFP (15 mg/kg bid)’s efficacy and safety in the continuous treatment of 10 NBIA patients through clinical and neuroradiological evaluation. Our results show the progressive decrease in the cerebral accumulation of iron evaluated by MRI and a substantial stability of the overall clinical neurological picture without a significant correlation between clinical and radiological findings. Complete ferrochelation throughout the day appears to be of fundamental importance considering that oxidative damage is generated, above, all by non-transferrin-bound iron (NTBI); thus, we hypothesize that a (TID) administration regimen of DFP might better apply its chelating properties over 24 h with the aim to also obtain clinical improvement beyond the neuroradiological improvement.

Treat Iron-Related Childhood-Onset Neurodegeneration (TIRCON)-An International Network on Care and Research for Patients With Neurodegeneration With Brain Iron Accumulation (NBIA).

In order to improve clinical care, coordinate research activities and raise awareness for the ultra-orphan Neurodegeneration with Brain Iron Accumulation (NBIA) disorders, a group of NBIA clinicians and researchers, industry partners and patient advocacies from six European countries, Canada and the US joined forces in 2010 to set-up the collaborative initiative TIRCON (Treat Iron-Related Childhood-Onset Neurodegeneration). As a research project, TIRCON received funding in the 7th Framework Programme (FP7) of the European Union (EU) from 2011 to 2015. After successful and timely completion of the initial FP7 project, funding and donations from industry and patient organizations have sustained the further development of TIRCON's dedicated clinical research infrastructure and its governance architecture, as well as the ongoing efforts undertaken in the NBIA community to establish a network of care. From the beginning, the University Hospital of the Ludwig-Maximilians-University in Munich, Germany has been coordinating the TIRCON initiative. It consists of 8 work packages, of which the first double-blind, placebo-controlled, randomized, multi-site clinical trial in NBIA (deferiprone in PKAN, completed) and a global patient registry and biobank, currently comprising baseline and follow-up data of > 400 NBIA patients have gained particular importance. Here we describe TIRCON's history with all the challenges and achievements in diagnosing and treating NBIA. Today, TIRCON lays the ground for future clinical care and research. In these times, it may also serve as a good example of well-directed governmental funding and fruitful international scientific collaboration.

Anesthesia in patients with NBIA : Neurodegeneration with brain iron accumulation

Neurodegeneration with brain iron accumulation (NBIA) forms agroup of rare hereditary diseases with rapid neurodegenerative progression due to an abnormal accumulation of iron in the basal ganglia. This causes extrapyramidal symptoms as well as dystonia and mental retardation. The most common form of NBIA is pantothenate kinase-associated neurodegeneration (PKAN, formerly Hallervorden-Spatz syndrome). There are multiple anesthesiological challenges with great implications for the clinical routine, particularly regarding the preparation for general anesthesia and the premedication visits. As with other orphan diseases, the available recommendations are mainly based on case reports. This article gives ashort overview of complications associated with NBIA pertaining to general anesthesia. This includes anesthesia-relevant clinical symptoms and perioperative management. The published literature and case reports (available on PubMed) were reviewed to extract aset of recommendations. So far only afew reports have included the anesthesia management of NBIA patients. Most of them refer to PKAN as the predominant type (50% of cases). Recommendations were found on www.orphananesthesia.eu and consensus guidelines on PKAN in general. In particular, dystonia-related restrictions in the maxillofacial area can complicate airway management and cause difficulties with respect to intubation. Furthermore, local or regional anesthesia as the sole anesthesia technique is not eligible/viable due to the reduced compliance of the patient. Special attention should be paid to atimely premedication visit and evaluation to ensure sufficient time to safely plan and prepare the anesthetic procedure. The handling of NBIA patients requires good preparation, including an interdisciplinary team and customized time management. In principle, both general anesthesia as abalanced method and total intravenous anesthesia (TIVA) seem to be possible/viable options. The main focus is on airway management. Even after brief sedation in the context of diagnostic measures, the patient should be monitored for longer than usual.

Systemic Biomarkers Show Elevated Oxidative Stress and Chronic Inflammation in Two Disorders of Neurodegeneration with Brain Iron Accumulation (NBIA)

Background: Neurodegeneration with Brain Iron Accumulation (NBIA) is a group of rare genetic disorders characterized by progressive degenerative motor symptoms and the accumulation of iron in the basal ganglia. Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a form of NBIA caused by a mutation in the PANK2 gene leading to a deficiency in pantothenate kinase. Phospholipase A2G6-Associated Neurodegeneration (PLAN) is caused by a mutation in the PLA2G6 gene resulting in impaired phospholipase activity. Current understanding of systemic changes in NBIA disorders is limited, leaving no clear diagnostic biomarkers. Monitoring the systemic changes could identify candidate biomarkers for assessing disease severity and evaluating the efficacy of new therapies.Previous studies of Parkinson's disease (PD) have found a systemic burden of increased oxidative stress and chronic inflammation accompanies the neurological symptoms of the disease. Similarly, abnormal systemic iron regulation associated with brain iron accumulation as well as damage associated with neuromuscular degeneration could lead to increased oxidative stress and a state of chronic inflammation in NBIA. Our initial investigation of a patient with PLAN1, revealed elevated levels of systemic oxidative stress. We investigated a group of PKAN patients as well as continued our investigation of a patient with PLAN to evaluate the possibility of abnormal iron trafficking, increased oxidative stress and chronic inflammation in NBIA. Our aim was to expand our investigation of circulating levels of inflammatory cytokines, oxidative stress markers and iron regulatory and metabolic proteins in NBIA patients to include a group of patients with PKAN.Methods: Plasma samples from 15 PKAN patients were collected at the UCSF Benioff Children's Hospital in Oakland, California. Similarly, a plasma sample from a patient with PLAN was collected in Campbell River, British Columbia. Plasma samples from a matched group of 15 healthy controls were also collected at the University of Victoria. All patients provided informed consent to the study.The pro-inflammatory cytokines IL-6 and TNFα as well as the anti-inflammatory cytokine IL-10 were measured by ELISA. Total levels of the lipid peroxidation product malondialdehyde (MDA) were measured using N-Methyl-Phenyl-Indole (NMPI). Free, acutely generated, MDA not bound to proteins, was measured by removing plasma proteins via a 10KD spin filtration then measuring the MDA content of resulting filtrate using NMPI.Results: The levels of MDA and Free MDA were significantly elevated in PKAN patients at baseline in comparison to controls (p = 0.05, p = 0.03). IL-6 and TNFα were slightly, but not significantly elevated at baseline compared to controls. We previously demonstrated, similar elevations of oxidative stress in our case study of an NBIA patient with PLAN1. Additionally, all three inflammatory cytokines measured for this study expansion in PLAN were higher than average levels observed in the PKAN and control groups (S ee Table 1). Further analysis of systemic biomarkers in NBIA including proteomic analysis of 30 systemic blood proteins, including iron trafficking proteins is ongoing.Conclusions: We expand previous findings of elevated levels of systemic oxidative stress in other neurodegenerative diseases such as PD to include NBIA patients with PKAN and PLAN. We provide novel evidence of elevated levels of Free MDA; representative of an acute oxidative stress burden in NBIA in addition to the previously noted elevation in total MDA levels. We provide preliminary signs that of an accompanying inflammatory burden in NBIA, but a larger sample group may be needed to determine its significance.

On the complexity of clinical and molecular bases of neurodegeneration with brain iron accumulation

Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited heterogeneous neurodegenerative rare disorders. These patients present with dystonia, spasticity, parkinsonism and neuropsychiatric disturbances, along with brain magnetic resonance imaging (MRI) evidence of iron accumulation. In sum, they are devastating disorders and to date, there is no specific treatment. Ten NBIA genes are accepted: PANK2, PLA2G6, C19orf12, COASY, FA2H, ATP13A2, WDR45, FTL, CP, and DCAF17; and nonetheless, a relevant percentage of patients remain without genetic diagnosis, suggesting that other novel NBIA genes remain to be discovered. Overlapping complex clinical pictures render an accurate differential diagnosis difficult. Little is known about the pathophysiology of NBIAs. The reported NBIA genes take part in a variety of pathways: CoA synthesis, lipid and iron metabolism, autophagy, and membrane remodeling. The next-generation sequencing revolution has achieved relevant advances in genetics of Mendelian diseases and provide new genes for NBIAs, which are investigated according to 2 main strategies: genes involved in disorders with similar phenotype and genes that play a role in a pathway of interest. To achieve an effective therapy for NBIA patients, a better understanding of the biological process underlying disease is crucial, moving toward a new age of precision medicine.

Transcranial Sonography in Mitochondrial Membrane Protein-Associated Neurodegeneration

IntroductionAlthough the nature of basal ganglia hyperechogenicity in transcranial sonography (TCS) examinations remains unclear, many studies have shown associations between hyperechogenicity and iron accumulation. The role of iron in basal ganglia hyperechogenicity raises interest in the use of TCS in forms of neurodegeneration with brain iron accumulation (NBIA). Here we analyzed TCS and magnetic resonance imaging (MRI) findings among patients affected by one type of NBIA, mitochondrial membrane protein-associated neurodegeneration (MPAN).MethodsInvestigations using MRI and TCS were performed on 13 patients exhibiting a C19orf12 gene mutation.ResultsThe use of T2/T2* MRI revealed hypointense lesions restricted to the globus pallidus and substantia nigra. Using TCS examination, 12 patients exhibited bilateral hyperechogenicity of the lenticular nucleus, while no patients showed substantia nigra hyperechogenicity.ConclusionInvestigations with TCS revealed a distinctive hyperechogenicity pattern of the basal ganglia in MPAN patients, which might be useful for differential diagnostics. The variable TCS imaging findings in NBIA patients may result from the presence of different iron content, iron binding partners, such as ferritin and neuromelanin, as well as structural changes, such as gliosis.

Clinical Heterogeneity of Atypical Pantothenate Kinase-Associated Neurodegeneration in Koreans.

ObjectiveNeurodegeneration with brain iron accumulation (NBIA) represents a group of inherited movement disorders characterized by iron accumulation in the basal ganglia. Recent advances have included the identification of new causative genes and highlighted the wide phenotypic variation between and within the specific NBIA subtypes. This study aimed to investigate the current status of NBIA in Korea.MethodsWe collected genetically confirmed NBIA patients from twelve nationwide referral hospitals and from a review of the literature. We conducted a study to describe the phenotypic and genotypic characteristics of Korean adults with atypical pantothenate kinase-associated neurodegeneration (PKAN).ResultsFour subtypes of NBIA including PKAN (n = 30), PLA2G6-related neurodegeneration (n = 2), beta-propeller protein-associated neurodegeneration (n = 1), and aceruloplasminemia (n = 1) have been identified in the Korean population. The clinical features of fifteen adults with atypical PKAN included early focal limb dystonia, parkinsonism-predominant feature, oromandibular dystonia, and isolated freezing of gait (FOG). Patients with a higher age of onset tended to present with parkinsonism and FOG. The p.R440P and p.D378G mutations are two major mutations that represent approximately 50% of the mutated alleles. Although there were no specific genotype-phenotype correlations, most patients carrying the p.D378G mutation had a late-onset, atypical form of PKAN.ConclusionsWe found considerable phenotypic heterogeneity in Korean adults with atypical PKAN. The age of onset may influence the presentation of extrapyramidal symptoms.

PP15.15 – 2688: NBIA Alliance – The impact of the international NBIA patient advocacy on NBIA research and vice versa

Objective Neurodegeneration with Brain Iron Accumulation (NBIA) is a group of very rare and mostly hereditary neurological movement disorders characterized by high iron levels in the basal ganglia and a progressive degeneration of the nervous system. Currently, there is no cure or proven therapy for any of the NBIA forms. Given the lack of treatment options, the international consortium TIRCON (Treat–Iron–Related–Childhood–Onset–Neurodegeneration), funded by the EU under FP7, is dedicated to the investigation of NBIA. 13 partners from eight countries are conducting a clinical therapy study and set up a patient registry/biobank in order to improve the infrastructure for NBIA research and care. We present the latest development, goals, recent and upcoming activities of the NBIA lay advocacy, thus demonstrating the rising impact of the growing NBIA Alliance and its member groups in interrelationship to the TIRCON consortium and to further NBIA research groups. Methods The lay advocacy groups, NBIA Disorders Association (NBIADA, USA) and Hoffnungsbaum e.V. (HoBa, Germany), are full partners in TIRCON. Based upon their experience in such collaborative projects, NBIADA and HoBa have been promoting the creation of further patient groups worldwide. The NBIA Alliance, launched under the patronage of TIRCON in 2012, is the only international umbrella association for NBIA lay advocacy groups. Currently, eight NBIA patient organizations are involved in the Alliance. The groups share the common goals of helping families cope with NBIA disorders, promoting improved health care in NBIA, and supporting research to find more effective treatments for these disorders. Results Current efforts include developing a strategic plan to support these common goals and expand the Alliance to other countries. Conclusion We will underline the mutual empowerment of the NBIA patients' movement and the NBIA research and care community.

Efficacy and safety of deferiprone for the treatment of pantothenate kinase-associated neurodegeneration (PKAN) and neurodegeneration with brain iron accumulation (NBIA): Results from a four years follow-up

To evaluate the long-term effect of Deferiprone (DFP) in reducing brain iron overload and improving neurological manifestations in patients with NBIA. 6 NBIA patients (5 with genetically confirmed PKAN), received DFP solution at 15mg/kg po bid. They were assessed by UPDRS/III and UDRS scales and blinded video rating, performed at baseline and every six months. All patients underwent brain MRI at baseline and during follow up. Quantitative assessment of brain iron was performed with T2* relaxometry, using a gradient multi-echo T2* sequence. After 48 months of treatment clinical rating scales and blinded video rating indicated a stabilization in motor symptoms in 5/6 Pts. In the same subjects MRI evaluation showed reduced hypointensity in the globus pallidus (GP); quantitative assessment confirmed a significant increment in the T2* value, and hence reduction of the iron content of the GP. The data from our 4-years follow-up study confirm the safety of DFP as a chelator agent for iron accumulation. The clinical stabilization observed in 5/6 of our patients suggests that DFP may be a reasonable therapeutic option for the treatment of the neurological manifestations linked with iron accumulation and neurodegeneration, especially in adult patients at early stage of the disease. (Clinicaltrials.gov identifier: NTC00907283).

Hereditary Spastic Paraplegia Type 43 (SPG43) is Caused by Mutation inC19orf12

We report here the genetic basis for a form of progressive hereditary spastic paraplegia (SPG43) previously described in two Malian sisters. Exome sequencing revealed a homozygous missense variant (c.187G>C; p.Ala63Pro) in C19orf12, a gene recently implicated in neurodegeneration with brain iron accumulation (NBIA). The same mutation was subsequently also found in a Brazilian family with features of NBIA, and we identified another NBIA patient with a three-nucleotide deletion (c.197_199del; p.Gly66del). Haplotype analysis revealed that the p.Ala63Pro mutations have a common origin, but MRI scans showed no brain iron deposition in the Malian SPG43 subjects. Heterologous expression of these SPG43 and NBIA variants resulted in similar alterations in the subcellular distribution of C19orf12. The SPG43 and NBIA variants reported here as well as the most common C19orf12 missense mutation reported in NBIA patients are found within a highly conserved, extended hydrophobic domain in C19orf12, underscoring the functional importance of this domain.

PANK2 and C19orf12 mutations are common causes of neurodegeneration with brain iron accumulation

Neurodegeneration with brain iron accumulation (NBIA) constitutes a group of neurodegenerative disorders with pronounced iron deposition in the basal ganglia. PANK2 mutations are the most common cause of these disorders. C19orf12 was recently reported as another causative gene. We present phenotypic data and results of screening of PANK2 and C19orf12 in 11 unrelated Iranian NBIA patients. Phenotypic data were obtained by neurologic examination, magnetic resonance imaging, and interviews. Mutation screening of PANK2 and C19orf12 was performed by sequencing. PANK2 and C19orf12 mutations were found in 7 and 4 patients, respectively. Phenotypic comparisons suggest that C19orf12 mutations as compared with PANK2 mutations result in a milder disease course. Mutations in both PANK2 and C19orf12 contributed significantly to NBIA in the Iranian patients. To the best of our knowledge, this is the first genetic analysis reported on a cohort of NBIA patients from the Middle East.

An international registry for neurodegeneration with brain iron accumulation

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.