Clinical course of patients with pantothenate kinase-associated neurodegeneration (PKAN) before and after DBS surgery.

INTRODUCTION: Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive disorder with a progressive clinical course. In addition to symptomatic therapy, DBS has been increasingly recognized as a potential therapeutic strategy, especially in severe cases. Therefore, we wanted to report our experience regarding benefits of DBS in five PKAN cases in 3-year follow-up study. METHODS: Five genetically confirmed PKAN patients from Serbia underwent GPi-DBS. To assess clinical outcome, we reviewed medical charts and applied: Schwab and England Activities of Daily Living Scale (S&E), EQ-5D questionnaire for quality of life, Patient Global Impression of Improvement (GPI-I), Functional Independence Measure (FIM), Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS), Barry Albright Dystonia Scale (BAD). Patients were evaluated in five visits: at the disease onset, 5 years after the onset, before surgery, 6 months and 14-36 months after the surgery. Improvement of 20% was accepted as significant. RESULTS: Overall, dystonia significantly improved after GPi-DBS at 6 and 14-36 months postoperatively, when assessed by the BFMDRS and BAD. However, two patients failed to improve considerably. Four patients reported improvement on GPI-I, while one remained unchanged. Three patients reported significant improvement, when assessed with S&E and FIM. EQ-5D showed the most prominent improvement in the domains of mobility and pain/discomfort. CONCLUSION: Three out of our five patients experienced beneficial effects of the GPi-DBS, in up to 36 months follow-up. Two patients who had not reached significant improvement had longer disease duration; therefore, it might be reasonable to recommend GPi-DBS as soon as dystonia became disabling.

Subthalamic and pallidal oscillatory activity in patients with Neurodegeneration with Brain Iron Accumulation type I (NBIA-I).

OBJECTIVES: Neurodegeneration with Brain Iron Accumulation type I (NBIA-I) is a rare hereditary neurodegenerative disorder with pallidal degeneration leading to disabling generalized dystonia and parkinsonism. Pallidal or subthalamic deep brain stimulation can partially alleviate motor symptoms. Disease-specific patterns of abnormally enhanced oscillatory neuronal activity recorded from the basal ganglia have been described in patients with movement disorders undergoing deep brain stimulation (DBS). Here we studied oscillatory activity recorded from the internal globus pallidus (GPi) and the subthalamic nucleus (STN) to characterize neuronal activity patterns in NBIA-I. METHODS: We recorded local field potentials (LFP) from DBS electrodes in 6 juvenile patients with NBIA-I who underwent functional neurosurgery. Four patients were implanted in the STN and two patients in the GPi. Recordings were performed during wakeful rest. An FFT-based approach was used to analyze the power spectrum in the target area. RESULTS: In all patients we found distinct peaks in the low frequency (7-12 Hz) and in 5 out 6 also in the beta frequency range (15-30 Hz) with the largest beta peak in the patient that presented with the most prominent bradykinesia. No distinct peaks occurred in the gamma frequency range (35-100 Hz). The oscillatory pattern did not differ between STN and GPi. CONCLUSIONS: Here we show for the first time the oscillatory activity pattern in the STN and the GPi in juvenile patients with dystonia plus syndrome due to NBIA-I. The low frequency peak we found is in line with previous studies in patients with isolated idiopathic dystonia. In our cohort, the pallidal beta band activity may be related to more severe motor slowing in dystonia plus syndrome such as NBIA-I. SIGNIFICANCE: Our results further support the link between hyperkinetic motor symptoms such as dystonia and enhanced basal ganglia low frequency activity irrespective of the underlying etiology of dystonia.

[Anesthesia in patients with NBIA : Neurodegeneration with brain iron accumulation]. / Anästhesie bei Patienten mit NBIA : Neurodegeneration mit Eisenablagerung im Gehirn.

BACKGROUND: Neurodegeneration with brain iron accumulation (NBIA) forms a group 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. OBJECTIVE AND METHODS: This article gives a short 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 a set of recommendations. RESULTS: So far only a few 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 a timely premedication visit and evaluation to ensure sufficient time to safely plan and prepare the anesthetic procedure. CONCLUSION: The handling of NBIA patients requires good preparation, including an interdisciplinary team and customized time management. In principle, both general anesthesia as a balanced 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.

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.

iPSC-derived neuronal models of PANK2-associated neurodegeneration reveal mitochondrial dysfunction contributing to early disease.

Mutations in PANK2 lead to neurodegeneration with brain iron accumulation. PANK2 has a role in the biosynthesis of coenzyme A (CoA) from dietary vitamin B5, but the neuropathological mechanism and reasons for iron accumulation remain unknown. In this study, atypical patient-derived fibroblasts were reprogrammed into induced pluripotent stem cells (iPSCs) and subsequently differentiated into cortical neuronal cells for studying disease mechanisms in human neurons. We observed no changes in PANK2 expression between control and patient cells, but a reduction in protein levels was apparent in patient cells. CoA homeostasis and cellular iron handling were normal, mitochondrial function was affected; displaying activated NADH-related and inhibited FADH-related respiration, resulting in increased mitochondrial membrane potential. This led to increased reactive oxygen species generation and lipid peroxidation in patient-derived neurons. These data suggest that mitochondrial deficiency is an early feature of the disease process and can be explained by altered NADH/FADH substrate supply to oxidative phosphorylation. Intriguingly, iron chelation appeared to exacerbate the mitochondrial phenotype in both control and patient neuronal cells. This raises caution for the use iron chelation therapy in general when iron accumulation is absent.

Knock-down of pantothenate kinase 2 severely affects the development of the nervous and vascular system in zebrafish, providing new insights into PKAN disease.

Pantothenate Kinase Associated Neurodegeneration (PKAN) is an autosomal recessive disorder with mutations in the pantothenate kinase 2 gene (PANK2), encoding an essential enzyme for Coenzyme A (CoA) biosynthesis. The molecular connection between defects in this enzyme and the neurodegenerative phenotype observed in PKAN patients is still poorly understood. We exploited the zebrafish model to study the role played by the pank2 gene during embryonic development and get new insight into PKAN pathogenesis. The zebrafish orthologue of hPANK2 lies on chromosome 13, is a maternal gene expressed in all development stages and, in adult animals, is highly abundant in CNS, dorsal aorta and caudal vein. The injection of a splice-inhibiting morpholino induced a clear phenotype with perturbed brain morphology and hydrocephalus; edema was present in the heart region and caudal plexus, where hemorrhages with reduction of blood circulation velocity were detected. We characterized the CNS phenotype by studying the expression pattern of wnt1 and neurog1 neural markers and by use of the Tg(neurod:EGFP/sox10:dsRed) transgenic line. The results evidenced that downregulation of pank2 severely impairs neuronal development, particularly in the anterior part of CNS (telencephalon). Whole-mount in situ hybridization analysis of the endothelial markers cadherin-5 and fli1a, and use of Tg(fli1a:EGFP/gata1a:dsRed) transgenic line, confirmed the essential role of pank2 in the formation of the vascular system. The specificity of the morpholino-induced phenotype was proved by the restoration of a normal development in a high percentage of embryos co-injected with pank2 mRNA. Also, addition of pantethine or CoA, but not of vitamin B5, to pank2 morpholino-injected embryos rescued the phenotype with high efficiency. The zebrafish model indicates the relevance of pank2 activity and CoA homeostasis for normal neuronal development and functioning and provides evidence of an unsuspected role for this enzyme and its product in vascular development.

Induction of Neuron-Specific Degradation of Coenzyme A Models Pantothenate Kinase-Associated Neurodegeneration by Reducing Motor Coordination in Mice.

BACKGROUND: Pantothenate kinase-associated neurodegeneration, PKAN, is an inherited disorder characterized by progressive impairment in motor coordination and caused by mutations in PANK2, a human gene that encodes one of four pantothenate kinase (PanK) isoforms. PanK initiates the synthesis of coenzyme A (CoA), an essential cofactor that plays a key role in energy metabolism and lipid synthesis. Most of the mutations in PANK2 reduce or abolish the activity of the enzyme. This evidence has led to the hypothesis that lower CoA might be the underlying cause of the neurodegeneration in PKAN patients; however, no mouse model of the disease is currently available to investigate the connection between neuronal CoA levels and neurodegeneration. Indeed, genetic and/or dietary manipulations aimed at reducing whole-body CoA synthesis have not produced a desirable PKAN model, and this has greatly hindered the discovery of a treatment for the disease. OBJECTIVE, METHODS, RESULTS AND CONCLUSIONS: Cellular CoA levels are tightly regulated by a balance between synthesis and degradation. CoA degradation is catalyzed by two peroxisomal nudix hydrolases, Nudt7 and Nudt19. In this study we sought to reduce neuronal CoA in mice through the alternative approach of increasing Nudt7-mediated CoA degradation. This was achieved by combining the use of an adeno-associated virus-based expression system with the synapsin (Syn) promoter. We show that mice with neuronal overexpression of a cytosolic version of Nudt7 (scAAV9-Syn-Nudt7cyt) exhibit a significant decrease in brain CoA levels in conjunction with a reduction in motor coordination. These results strongly support the existence of a link between CoA levels and neuronal function and show that scAAV9-Syn-Nudt7cyt mice can be used to model PKAN.

Pantothenate kinase-associated neurodegeneration (PKAN) and PLA2G6-associated neurodegeneration (PLAN): review of two major neurodegeneration with brain iron accumulation (NBIA) phenotypes.

Neurodegeneration with brain iron accumulation (NBIA) comprises a heterogeneous group of disorders characterized by the presence of radiologically discernible high brain iron, particularly within the basal ganglia. A number of childhood NBIA syndromes are described, of which two of the major subtypes are pantothenate kinase-associated neurodegeneration (PKAN) and PLA2G6-associated neurodegeneration (PLAN). PKAN and PLAN are autosomal recessive NBIA disorders due to mutations in PANK2 and PLA2G6, respectively. Presentation is usually in childhood, with features of neurological regression and motor dysfunction. In both PKAN and PLAN, a number of classical and atypical phenotypes are reported. In this chapter, we describe the clinical, radiological, and genetic features of these two disorders and also discuss the pathophysiological mechanisms postulated to play a role in disease pathogenesis.

Mitochondrial membrane protein associated neurodegenration: a novel variant of neurodegeneration with brain iron accumulation.

BACKGROUND: Recently, mutations in an open-reading frame on chromosome 19 (C19orf12) were identified as a novel genetic factor in neurodegeneration with brain iron accumulation (NBIA). Because of the mitochondrial localization of the derived protein, this variant is referred to as mitochondrial membrane protein-associated neurodegeneration with brain iron accumulation (MPAN). METHODS/RESULTS: We describe the clinical phenotype and MRI of 3 newly identified individuals with MPAN due to either previously reported or novel homozygous or compound heterozygous genetic alterations in C19orf12. CONCLUSIONS: MPAN is characterized by a juvenile-onset, slowly progressive phenotype with predominant lower limb spasticity, generalized dystonia, and cognitive impairment. Typical additional features include axonal motor neuropathy and atrophy of the optic nerve. MRI showed iron deposition in the globus pallidus and substantia nigra without the eye-of-the-tiger sign, which is typical for PKAN, the most frequent form of NBIA.

Dementia means number of things - the overlap of neurodegeneration with brain iron accumulation (NBIA) and Alzheimer changes: an autopsy case.

In humans overlap between various neurodegenerative disorders is a well known phenomenon. We reported a case of a 77-year-old woman with parkinsonism, dystonia, psychiatric symptoms and progressing dementia misdiagnosed at the age of 51 years as Parkinson's disease. Histopathological examination of the patient's brain performed 26 years after the disease onset revealed numerous axonal spheroids and iron deposits in structures of the nigro-pallido-striatal system that enabled to diagnose neurodegeneration with brain iron accumulation (NBIA) (former Hallervorden-Spatz syndrome), and changes characteristic for Alzheimer's disease (AD). NBIA is a group of rare clinically and genetically heterogeneous diseases of the extrapyramidal system which common feature is abnormal iron storage in the basal ganglia. Disturbed iron metabolism is also one of the hypothetical patho-mechanisms of AD. A coexistence of morphological changes characteristic for AD and NBIA in our patient suggests that similar molecular mechanisms may be involved in pathogenesis of various neurodegenerative processes, especially in disorders with iron dyshomeostasis. This case contributes also to the increasing evidence of NBIA heterogeneity.

Frontotemporal dementia-amyotrophic lateral sclerosis complex is simulated by neurodegeneration with brain iron accumulation.

We describe a case of late onset neurodegeneration with brain iron accumulation (NBIA) presenting as frontotemporal dementia (FTD) with amyotrophic lateral sclerosis (ALS). A male patient presented at age 66 with change of personality: disinhibition, emotional blunting, and socially inappropriate behavior, coupled with dysarthria, dystonia, and corticospinal tract involvement. Magnetic resonance imaging showed general cortical atrophy, iron deposits in the globus pallidus, and the "eye of the tiger" sign. Neuropsychologic performance was globally reduced, especially executive functions. Fluorodeoxyglucose positron emission tomography showed hypometabolism predominantly in frontal and temporal areas. Repeated neurophysiologic examinations showed signs of chronic denervation. The patient was diagnosed with NBIA but fulfilled consensus criteria for FTD and had a clinical picture of ALS, without neurophysiologic confirmation. Our finding introduces NBIA as a possible cause of FTD and as a differential diagnosis of the FTD-ALS complex.

Neurodegeneration with brain iron accumulation: clinical, radiographic and genetic heterogeneity and corresponding therapeutic options.

BACKGROUND: Neurodegeneration with brain iron accumulation (NBIA), formerly known as Hallervorden-Spatz syndrome, is a heterogeneous group of disorders with different treatment options. CASE REPORTS: In the first case, progressively generalizing dystonic symptoms appeared during childhood. A mutation in the gene encoding pantothenate kinase 2 (PANK2) was found. Brain MRI showed bilateral hypersignals within the globus pallidi on T2-weighted images. The patient was successfully treated by pallidal deep brain stimulation (DBS). In the second case an adult onset with parkinsonism was observed, for which no PANK2 mutation was found. T2-weighted brain MR images revealed multiple significant hyposignals (suggestive of iron deposits) localised in the cerebellar dentate nuclei and in the globi pallidi, the red nuclei and the substantia nigra. An antiparkinsonian treatment was proposed. CONCLUSION: The clinical, radiographic and genetic heterogeneity of NBIA has to be underlined.

Pantothenate kinase-associated neurodegeneration with increased lentiform nuclei cerebral blood flow.

We report a case of pantothenate kinase-associated neurodegeneration with increased regional cerebral blood flow (rCBF) in bilateral lentiform nuclei on technetium Tc-99m ethyl cysteinate dimer single-photon emission CT (ECD-SPECT). A 6-year-old boy presented with opisthotonus. T2*-weighted MR images revealed areas of marked hypointensity with a hyperintense focus in bilateral globus pallidus, creating the characteristic eye-of-the-tiger appearance. ECD-SPECT showed increased rCBF in bilateral lentiform nuclei.

Staged bilateral stereotactic pallidothalamotomy for life-threatening dystonia in a child with Hallervorden-Spatz disease.

Hallervorden-Spatz disease (HSD) is a rare disorder characterized by progressive motor dysfunction and dementia. Dystonia is the most prominent and disabling symptom, responding only to a modest extent to pharmacological therapy. At the moment, only a few cases have been reported to improve dystonia and even fewer to resolve status dystonicus for a longer period in children. The authors present the case of a 10-year-old boy who had progressive generalized dystonia, resulting in spontaneous femur fracture and life-threatening swallowing and respiratory disability. As a rescue solution, staged bilateral pallidothalamotomy was performed. Postoperatively, Burke-Fahn-Marsden Dystonia Rating Scale and Dystonia Disability Rating Scale improved (from 116 and 30 points to 41 and 18 points, respectively) and painful dystonia was resolved, which was still continuous 4 years later (47 and 20 points). Stereotactic staged bilateral pallidothalamotomy should be considered as a potential treatment in the management of life-threatening generalized dystonia related to HSD.

[Type I neurodegeneration with brain iron accumulation, (NBIA-I, formerly Hallervorden-Spatz disease). Part II -- neuropathologic manifestation, novel genetic aspects and pathogenesis]. / Zwyrodnienie osrodkowego ukladu nerwowego z odkladaniem sie zelaza w mózgu, typu pierwszego (dawniej choroba Hallervordena-Spatza). Czesc II--Obraz histopatologiczny, nowe aspekty genetyczne oraz patogeneza.

In NBIA-1 major histopathological changes in the central nervous system are observed mostly in the subcortical pallido-nigral system. They consist in the presence of brown pigment deposits (containing iron), axonal spheroids, as well as Lewy neurities and cytoplasmic inclusions in the oligodendroglia (both the latter contain pathological alfa-synuclein). However, the histopathological pattern is most the diversified as regards the intensity and range of typical structural changes. The gene of the disease has been very recently identified and mapped on the short arm of the chromosome 20p13.-p12.3. The discovery of the NBIA-1 gene is a great advance in the search for a causal cure for this devastating disease. Its etiopathogenesis has not been fully explained yet. However, the gene identification allows to hypothesize that vitamin B5 metabolism may be disturbed at least in some NBIA-1 patients. Disturbance of vitamin B5 metabolism may cause an oxidative stress leading to degenerative and atrophic changes, most pronounced in the subcortical pallido-nigral system and in the retina.

[Neurodegeneration with brain iron accumulation, type-I (NBIA-I) (formerly Hallervorden-Spatz, disease). Par I: clinical manifestation and treatment]. / Zwyrodnienie osrodkowego ukladu nerwowego z odkladaniem sie zelaza w mózgu, typu pierwszego (dawniej choroba Hallervordena-Spatza). Czesc i--obraz kliniczny oraz leczenie.

This is a rare syndrome, most likely of several genetically determined neurodegenerative disorders with similar pathogenesis. Two forms of the disease are distinguished: familial occurring in about 50% of cases and sporadic with about 15% of cases in which parental consanguinity is found. Clinically, NBIA-1 is characterised by a slow progression of extrapyramidal symptoms and progressive dementia, mostly in children. Relentlessly progressive course is obvious, but the progress may be very slow, taking sometimes several dozen of years. Four subtypes of the disease have been thus far distinguished: early childhood, late childhood, adult onset and with protracted course. The clinical diagnosis of NBIA-1 is only probable because specific abnormalities have not as yet been detected in laboratory investigations. However, NBIA-1 should be suspected, if extrapyramidal symptoms are observed, such as dystonia, choreoathetosis, muscular rigidity, moreover dementia, retinal degeneration and/or optic nerve atrophy and characteristic magnetic resonance imaging (so called "the eye-of-the tiger" sign). At present, only comprehensive symptomatic treatment is possible.

Late-onset neurodegeneration with brain iron accumulation type 1: expanding the clinical spectrum.

We report on two patients with pathologically proven neurodegeneration with brain iron accumulation type 1 (NBIA-1) with late onset and atypical presentations. One patient experienced gradual onset of shuffling gait, rigidity, bradykinesia, and increasing postural instability at age 85 years. He died a few weeks after developing acute hemiballismus at age 90 years. Histopathology revealed marked neuronal loss in the internal segment of the globus pallidum, astrocytosis, axonal spheroids, and extensive iron deposition consistent with NBIA-1. No additional lesions were found to explain the hemiballismus. The second patient experienced fulminant dementia evolving to total disability and death within 2 months. Autopsy showed typical NBIA-1 pathology. We conclude that NBIA-1 pathology can develop at any age, and that the phenotype should be expanded to include late-onset parkinsonism. The relationship to hemiballismus and adult-onset dementia is less clear.

Enfermedad de hallervorden-spatz: manifestaciones clínico-radiológicas

Se presenta el caso de una paciente de 18 años con diagnóstico de enfermedad de Hallervorden-Spatz cuya sintomatología neurológica progrsiva con movimientos anormales en miembros inferiores y superiores, disartria y deterioro mental se inicio desde la edad de 4 años. El examen de resonancia magnética que demuestra depósitos de hiero anormales en los globos pálidos y en la sustancia nigra confirma la impresión clínica de la enfermedad