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Coenzyme A (CoA) is essential for metabolism and protein acetylation. Current knowledge holds that each cell obtains CoA exclusively through biosynthesis via the canonical five-step pathway, starting with pantothenate uptake. However, recent studies have suggested the presence of additional CoA-generating mechanisms, indicating a more complex system for CoA homeostasis. Here, we uncovered pathways for CoA generation through inter-organismal flows of CoA precursors. Using traceable compounds and fruit flies with a genetic block in CoA biosynthesis, we demonstrate that progeny survive embryonal and early larval development by obtaining CoA precursors from maternal sources. Later in life, the microbiome can provide the essential CoA building blocks to the host, enabling continuation of normal development. A flow of stable, long-lasting CoA precursors between living organisms is revealed. This indicates the presence of complex strategies to maintain CoA homeostasis.
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Coenzima A , Microbiota , Animais , Coenzima A/genética , Coenzima A/metabolismo , Drosophila/metabolismo , Feminino , Humanos , Mães , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Zigoto/metabolismoRESUMO
BACKGROUND: Invasive treatments like radiofrequency stereotactic lesioning or deep brain stimulation of the globus pallidus internus can resolve drug-resistant status dystonicus (SD). However, these open procedures are not always feasible in patients with SD. OBJECTIVE: The aim was to report the safety and efficacy of simultaneous asleep bilateral transcranial magnetic resonance-guided focused ultrasound (MRgFUS) pallidotomy for life-threatening SD. METHODS: We performed bilateral simultaneous MRgFUS pallidotomy under general anesthesia in 2 young patients with pantothenate kinase-associated neurodegeneration and GNAO1 encephalopathy. Both patients had medically refractory SD and severe comorbidities contraindicating open surgery. RESULTS: SD resolved at 4 and 12 days after MRgFUS, respectively. Adverse events (intraoperative hypothermia and postoperative facial paralysis) were mild and transient. CONCLUSION: Bilateral simultaneous MRgFUS pallidotomy under general anesthesia is safe and may be a valid alternative therapeutic option for fragile patients. Further studies are needed to assess long-term efficacy of the procedure. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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The well-known eye-of-the-tiger sign features bilateral and symmetrical changes in the globus pallidus, with a central area of high signal and peripheral low signal on T2-weighted MRI. Although formally considered pathognomonic of pantothenate kinase-associated neurodegeneration (PKAN), there are other neurodegenerative or genetic diseases showing similar findings. Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a late-onset ataxia, that was recently associated with biallelic AAGGG repeat expansion in the RFC1 gene. Although its predominant MRI finding is cerebellar atrophy, there may be other less common associated findings. Our aim is to present two cases of CANVAS with associated (pseudo-)eye-of-the-tiger sign, highlighting the possibility of yet another differential diagnosis for this imaging sign.
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Vestibulopatia Bilateral , Ataxia Cerebelar , Doenças Vestibulares , Humanos , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/genética , Vestibulopatia Bilateral/diagnóstico , Vestibulopatia Bilateral/genética , Ataxia , Síndrome , Imageamento por Ressonância Magnética/métodosRESUMO
Coenzyme A (CoA) is an essential cofactor required for over a hundred metabolic reactions in the human body. This cofactor is synthesized de novo in our cells from vitamin B5, also known as pantothenic acid, a water-soluble vitamin abundantly present in vegetables and animal-based foods. Neurodegenerative disorders, cancer, and infectious diseases have been linked to defects in de novo CoA biosynthesis or reduced levels of this coenzyme. There is now accumulating evidence that CoA limitation is a critical pathomechanism in cardiac dysfunction too. In the current review, we will summarize our current knowledge on CoA and heart failure, with emphasis on two primary cardiomyopathies, phosphopantothenoylcysteine synthetase and phosphopantothenoylcysteine decarboxylase deficiency disorders biochemically characterized by a decreased level of CoA in patients' samples. Hence, we will discuss the potential benefits of CoA restoration in these diseases and, more generally, in heart failure, by vitamin B5 and its derivatives pantethine and 4'-phosphopantetheine.
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Studies aimed at supporting different treatment approaches for pantothenate kinase-associated neurodegeneration (PKAN) have revealed the complexity of coenzyme A (CoA) metabolism and the limits of our current knowledge about disease pathogenesis. Here we offer a foundation for critically evaluating the myriad approaches, argue for the importance of unbiased disease models, and highlight some of the outstanding questions that are central to our understanding and treating PKAN.
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Neurodegeneração Associada a Pantotenato-Quinase , Humanos , Coenzima A/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismoRESUMO
AIM: Pantothenate kinase associated neurodegeneration (PKAN) is a severe autosomal recessive rare disease and characterized by iron accumulation in the basal ganglia. To investigate the pathogenesis of this disease in two sibling patients with PANK in a Chinese family, whole-exome variant detection and functional analysis were performed. MATERIALS AND METHODS: Clinical and radiographic investigations were performed in the two brother patients. Whole exome sequencing (WES) was used in mutation detection, and the mutations were confirmed by Sanger sequencing. A longevity cohort genetic database was applied as Chinese urban controls. Bioinformatic analysis was performed to predict the pathogenicity. RESULTS: Compound heterozygous mutations of PANK2 were detected in two sibling brothers with PKAN in a Chinese family: c.510_522del (p.A170fs) and c.1319G > C (p.R440P) in the transcript NM_153638. PANK2: c.510_522del (p.A170fs) was absent in public data and the Chinese urban controls. Bioinformatics analysis showed that the above two variants were pathogenicity. CONCLUSIONS: We identified a rare compound heterozygous combination of PANK2 mutations found in a Chinese family in which two sibling brothers suffered from PKAN. PANK2 c.510_522del (p.A170fs) was the first reported to be a PKAN pathogenic variant.
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Neurodegeneração Associada a Pantotenato-Quinase , Fosfotransferases (Aceptor do Grupo Álcool) , Povo Asiático/genética , China , Humanos , Masculino , Mutação , Neurodegeneração Associada a Pantotenato-Quinase/genética , Neurodegeneração Associada a Pantotenato-Quinase/patologia , Fosfotransferases (Aceptor do Grupo Álcool)/genéticaRESUMO
Human PANK1, PANK2, and PANK3 genes encode several pantothenate kinase isoforms that catalyze the phosphorylation of vitamin B5 (pantothenic acid) to phosphopantothenate, a critical step in the biosynthesis of the major cellular cofactor, Coenzyme A (CoA). Mutations in the PANK2 gene, which encodes the mitochondrial pantothenate kinase (PanK) isoform, have been linked to pantothenate-kinase associated neurodegeneration (PKAN), a debilitating and often fatal progressive neurodegeneration of children and young adults. While the biochemical properties of these enzymes have been well-characterized in vitro, their expression in a model organism such as yeast in order to probe their function under cellular conditions have never been achieved. Here we used three yeast mutants carrying missense mutations in the yeast PanK gene, CAB1, which are associated with defective growth at high temperature and iron, mitochondrial dysfunction, increased iron content, and oxidative stress, to assess the cellular function of human PANK genes and functional conservation of the CoA-controlled processes between humans and yeast. Overexpression of human PANK1 and PANK3 in these mutants restored normal cellular activity whereas complementation with PANK2 was partial and could only be achieved with an isoform, PanK2mtmΔ, lacking the mitochondrial transit peptide. These data, which demonstrate functional conservation of PanK activity between humans and yeast, set the stage for the use of yeast as a model system to investigate the impact of PKAN-associated mutations on the metabolic pathways altered in this disease.
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Estresse Oxidativo , Neurodegeneração Associada a Pantotenato-Quinase , Saccharomyces cerevisiae , Humanos , Homeostase , Ferro/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Estresse Oxidativo/genética , Neurodegeneração Associada a Pantotenato-Quinase/metabolismo , Ácido Pantotênico , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismoRESUMO
Hallervorden-Spatz disease (HSD) has been recently renamed to pantothenate kinase-associated neurodegeneration (PKAN) and neurodegeneration with brain iron accumulation (NBIA), mainly due to the unethical behavior of Julius Hallervorden in the National Socialist (NS) euthanasia program of the Nazi Third Reich. The role of the second name giver in the NS euthanasia program is less clear. Hugo Spatz was the director of the Kaiser Wilhelm Institute for Brain Research in Berlin-Buch during World War II (WWII), renamed to Max Planck Institute after 1945. After the war, he headed the Max Planck Institute for Brain Research in Frankfurt am Main. The present study investigates the potential involvement of Hugo Spatz in the NS euthanasia program. In the present study, we compared a list of euthanasia victims from the German Federal Archive Berlin (30.146 cases published after the reunification of Germany, BArch R179) with the files of the collection of specimens from 1940 until 1945 of Hugo Spatz as listed in the Archive of the Max Planck Society Berlin-Dahlem (n = 305). Furthermore, the old term HSD and the new terms PKAN and NBIA were systematically searched in PubMed from 1946, through January 2019 to evaluate the renaming process from HSD to PKAN/NBIA. Following Hugo Spatz's death in 1969 growing evidence indicated that he may have taken part in the NS euthanasia program. This study identifies 4 euthanized victims in the patient files of Hugo Spatz from 1940 to 1945, suggesting involvement of Hugo Spatz in the NS euthanasia program. This further strengthens the argument that the former HSD should be exclusively referred to as PKAN or NBIA.
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Eutanásia , Neurodegeneração Associada a Pantotenato-Quinase , Berlim , Encéfalo , Alemanha , Humanos , MasculinoRESUMO
Panthothenate kinase-associated neurodegeneration (PKAN) is arare neurodegeneration caused by mutations in the pantothenate kinase (PANK2) gene, which is located on chromosome 20p13. These mutations result in iron accumulation in the brain basal ganglia leading to parkinsonism, dysarthria, spasticity, cognitive impairment, and retinopathy. Herein, we report acase of adult-onset PKAN who presented with young-onset action tremor, bradykinesia, dysarthria, and bilateral interossei atrophy. Neuroimaging demonstrated "eye-of-the-tiger signs". Through analyzing PANK2 gene, PANK2 NM_153638:c.1133A>G (p.Asp378 Gly) and PANK2 NM_153638:c.1502 T > A (p.lle501Asn), were detected. In addition, we reviewed the clinical and genetic features and therapeutic strategies for patients with PKAN.
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Neurodegeneração Associada a Pantotenato-Quinase , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Adulto , Humanos , Masculino , Neurodegeneração Associada a Pantotenato-Quinase/genética , Neurodegeneração Associada a Pantotenato-Quinase/patologia , Neurodegeneração Associada a Pantotenato-Quinase/fisiopatologia , Adulto JovemRESUMO
AIM: Evaluation of pediatric palliative home care of families with children suffering from neurodegeneration with brain iron accumulation (NBIA) and their parents. MATERIAL AND METHODS: The children were treated at home by a multidisciplinary team. Densitometry was used to evaluate the condition of the skeletal system. Botulinum toxin was injected into the muscles in doses between 22 and 50 units/kg. The quality of palliative care was assessed on the basis of a specially designed questionnaire for parents. RESULTS: The observations were performed on a group of 9 patients with NBIA. On admission, the median age of patients was 9 years (7-14). The average time of palliative home care was 1569 days (34 days-17 years). The median age at death (6 patients) was 11 years (7-15). The botulinum toxin injections gave the following results: reduction of spasticity and dystonia, reduction of spine and chest deformation, relief of pain and suffering, facilitation of rehabilitation and nursing, prevention of permanent contractures, and reduction of excessive salivation. Bone mineral density and bone strength index were reduced. Two patients experienced pathological fracture of the femur. The body mass index at admission varied between 9.8 and 14.9. In 7 cases, introduction of a ketogenic diet resulted in the increase of body mass and height. The ketogenic diet did not worsen the neurological symptoms. The parents positively evaluated the quality of care. CONCLUSION: Palliative home care is the optimal form of treatment for children with NBIA.
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Serviços de Assistência Domiciliar , Distúrbios do Metabolismo do Ferro/terapia , Distrofias Neuroaxonais/terapia , Fármacos Neuromusculares/farmacologia , Cuidados Paliativos/métodos , Adolescente , Doenças Ósseas/tratamento farmacológico , Doenças Ósseas/etiologia , Toxinas Botulínicas/farmacologia , Criança , Distonia/tratamento farmacológico , Distonia/etiologia , Feminino , Humanos , Distúrbios do Metabolismo do Ferro/complicações , Distúrbios do Metabolismo do Ferro/tratamento farmacológico , Distúrbios do Metabolismo do Ferro/enfermagem , Masculino , Espasticidade Muscular/tratamento farmacológico , Espasticidade Muscular/etiologia , Dor Musculoesquelética/tratamento farmacológico , Dor Musculoesquelética/etiologia , Distrofias Neuroaxonais/complicações , Distrofias Neuroaxonais/tratamento farmacológico , Distrofias Neuroaxonais/enfermagemRESUMO
Pantothenate Kinase-associated Neurodegeneration (PKAN) belongs to a wide spectrum of diseases characterized by brain iron accumulation and extrapyramidal motor signs. PKAN is caused by mutations in PANK2, encoding the mitochondrial pantothenate kinase 2, which is the first enzyme of the biosynthesis of Coenzyme A. We established and characterized glutamatergic neurons starting from previously developed PKAN Induced Pluripotent Stem Cells (iPSCs). Results obtained by inductively coupled plasma mass spectrometry indicated a higher amount of total cellular iron in PKAN glutamatergic neurons with respect to controls. PKAN glutamatergic neurons, analyzed by electron microscopy, exhibited electron dense aggregates in mitochondria that were identified as granules containing calcium phosphate. Calcium homeostasis resulted compromised in neurons, as verified by monitoring the activity of calcium-dependent enzyme calpain1, calcium imaging and voltage dependent calcium currents. Notably, the presence of calcification in the internal globus pallidus was confirmed in seven out of 15 genetically defined PKAN patients for whom brain CT scan was available. Moreover, we observed a higher prevalence of brain calcification in females. Our data prove that high amount of iron coexists with an impairment of cytosolic calcium in PKAN glutamatergic neurons, indicating both, iron and calcium dys-homeostasis, as actors in pathogenesis of the disease.
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Cálcio/metabolismo , Ferro/metabolismo , Mitocôndrias/metabolismo , Neurônios/metabolismo , Neurodegeneração Associada a Pantotenato-Quinase/metabolismo , Adolescente , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Cálcio/efeitos adversos , Calpaína/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Citoplasma/fisiologia , Feminino , Homeostase , Humanos , Células-Tronco Pluripotentes Induzidas , Lactente , Ferro/efeitos adversos , Imageamento por Ressonância Magnética , Masculino , Espectrometria de Massas , Microscopia Eletrônica , Mitocôndrias/enzimologia , Mitocôndrias/ultraestrutura , Neurônios/fisiologia , Neurônios/ultraestrutura , Neurodegeneração Associada a Pantotenato-Quinase/patologia , Fosfotransferases (Aceptor do Grupo Álcool) , Tomografia Computadorizada por Raios X , Adulto JovemRESUMO
Panthothenate kinase-associated neurodegeneration (PKAN, OMIM 234200), is an inborn is an autosomal recessive inborn error of metabolism caused by pathogenic variants in PANK2. PANK2 encodes the enzyme pantothenate kinase 2 (EC 2.7.1.33), an essential regulatory enzyme in CoA biosynthesis. Clinical presentation includes dystonia, rigidity, bradykinesia, dysarthria, pigmentary retinopathy and dementia with variable age of onset ranging from childhood to adulthood. In order to provide an accurate incidence estimate of PKAN, we conducted a systematic review of the literature and databases for pathogenic mutations and constructed a bioinformatic profile for pathogenic missense variants in PANK2. We then studied the gnomAD cohort of ~140,000 unrelated adults from global populations to determine the allele frequency of the variants in PANK2 reported pathogenic for PKAN and for those additional variants identified in gnomAD that met bioinformatics criteria for being potentially pathogenic. Incidence was estimated based on three different models using the allele frequencies of pathogenic PKAN variants with or without those bioinformatically determined to be potentially pathogenic. Disease incidence calculations showed PKAN incidence ranging from 1:396,006 in Europeans, 1:1,526,982 in Africans, 1:480,826 in Latino, 1:523,551 in East Asians and 1:531,118 in South Asians. These results indicate PKAN is expected to occur in approximately 2 of every 1 million live births globally outside of Africa, and has a much lower incidence 1 in 1.5 million live births in the African population.
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Neurodegeneração Associada a Pantotenato-Quinase/epidemiologia , Alelos , Substituição de Aminoácidos , Biologia Computacional/métodos , Bases de Dados Genéticas , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genética Populacional , Humanos , Incidência , Neurodegeneração Associada a Pantotenato-Quinase/diagnóstico , Neurodegeneração Associada a Pantotenato-Quinase/genética , Fenótipo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Vigilância da PopulaçãoRESUMO
Extrapyramidal movement disorders comprise hypokinetic-rigid and hyperkinetic or mixed forms, most of them originating from dysfunction of the basal ganglia (BG) and their information circuits that have been briefly reviewed in part 1 of the papers on neuropathology and pathogenesis of extrapyramidal movement disorders. The classification of hyperkinetic forms distinguishes the following: (1) chorea and related syndromes; (2) dystonias (dyskinesias); (3) tics and tourette disorders; (4) ballism; (5) myoclonic and startle disorders; and (6) tremor syndromes. Recent genetic and molecular classification distinguishes the following: (1) polyglutamine disorders (Huntington's disease and related disorders); (2) pantothenate kinase associated neurodegeneration; (3) Wilson's disease and related disorders; and (4) other hereditary neurodegenerations without hitherto detected genetic or specific markers. The diversity of phenotypes is related to the deposition of pathologic proteins in distinct cell populations, causing neurodegeneration due to genetic and environmental factors, but there is frequent overlap between various disorders. Their etiopathogenesis is still poorly understood but is suggested to result from an interaction between genetic and environmental factors, multiple etiologies, and noxious factors (protein mishandling, mitochondrial dysfunction, oxidative stress, excitotoxicity, energy failure, chronic neuroinflammation), being more likely than one single factor. Current clinical consensus criteria have increased the diagnostic accuracy of most neurodegenerative movement disorders, but for their definite diagnosis, histopathological confirmation is required. A timely overview of the neuropathology and pathogenesis of the major hyperkinetic movement disorders is presented.
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Transtornos dos Movimentos/patologia , Transtornos dos Movimentos/fisiopatologia , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Humanos , Transtornos dos Movimentos/genéticaRESUMO
Neurodegeneration with brain iron accumulation (NBIA) comprises a heterogeneous group of progressive disorders with the common feature of excessive iron deposition in the brain. Over the last decade, advances in sequencing technologies have greatly facilitated rapid gene discovery, and several single-gene disorders are now included in this group. Identification of the genetic bases of the NBIA disorders has advanced our understanding of the disease processes caused by reduced coenzyme A synthesis, impaired lipid metabolism, mitochondrial dysfunction, and defective autophagy. The contribution of iron to disease pathophysiology remains uncertain, as does the identity of a putative final common pathway by which the iron accumulates. Ongoing elucidation of the pathogenesis of each NBIA disorder will have significant implications for the identification and design of novel therapies to treat patients with these disorders.
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Encéfalo/metabolismo , Variação Genética , Distúrbios do Metabolismo do Ferro/genética , Distúrbios do Metabolismo do Ferro/fisiopatologia , Ferro/metabolismo , Doenças Neurodegenerativas/genética , Animais , Autofagia/genética , Encéfalo/fisiopatologia , Ceruloplasmina/deficiência , Ceruloplasmina/genética , Ceruloplasmina/metabolismo , Coenzima A/biossíntese , Fosfolipases A2 do Grupo VI/genética , Fosfolipases A2 do Grupo VI/metabolismo , Humanos , Distúrbios do Metabolismo do Ferro/metabolismo , Metabolismo dos Lipídeos/genética , Camundongos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Distrofias Neuroaxonais/genética , Distrofias Neuroaxonais/metabolismo , Distrofias Neuroaxonais/fisiopatologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/metabolismoRESUMO
AIM: Pantothenate-kinase-associated neurodegeneration (PKAN), which is characterised by iron accumulation in the basal ganglia, is a rare autosomal recessive neurodegenerative disorder caused by pantothenate kinase 2 (PANK2) gene mutations. The PANK2 gene is located on chromosome 20p13 and encodes pantothenate kinase. Herein, we identified one patient with PKAN who had mutations in the PANK2 gene. MATERIALS AND METHODS: We performed clinical and radiographic investigations, and diagnosed this disease at the clinical and genetic levels. RESULTS: It is worth mentioning that the patient displayed an eye-of-the-tiger sign. Through scanning the exons and flanking intronic sequences of PANK2 in patient and control subjects, we report a compound heterozygote c. 260A > G (NM_001324191) and c.405dupC (NM_153638) for PANK2 mutations in a Chinese patient with clinical manifestation of progressive prosopospasm, dysarthria and gait disturbance. Bioinformatics analysis showed that two variants exhibited highly conserved residues across species. CONCLUSION: we reported a patient presenting with atypical PKAN, and identified novel compound heterozygous PANK2 gene mutations..
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Neurodegeneração Associada a Pantotenato-Quinase/genética , Neurodegeneração Associada a Pantotenato-Quinase/patologia , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Adulto , Povo Asiático/genética , China , Feminino , Heterozigoto , Humanos , Masculino , Mutação , LinhagemRESUMO
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.
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Anestesia/métodos , Distúrbios do Metabolismo do Ferro/fisiopatologia , Neurodegeneração Associada a Pantotenato-Quinase/fisiopatologia , HumanosRESUMO
Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a form of Neurodegeneration with Brain Iron Accumulation (NBIA) associated with mutations in the pantothenate kinase 2 gene (PANK2). The PANK2 catalyzes the first step of coenzyme A (CoA) biosynthesis, a pathway producing an essential cofactor that plays a key role in energy and lipid metabolism. The majority of PANK2 mutations reduces or abolishes the activity of the enzyme. In around 10% of cases with PKAN, the presence of deformed red blood cells with thorny protrusions in the circulation has been detected. Changes in membrane protein expression and assembly during erythropoiesis were previously explored in patients with PKAN. However, data on red blood cell membrane phospholipid organization are still missing in this disease. In this study, we performed lipidomic analysis on red blood cells from Italian patients affected by PKAN with a particular interest in membrane physico-chemical properties. We showed an increased number of small red blood cells together with membrane phospholipid alteration, particularly a significant increase in sphingomyelin (SM)/phosphatidylcholine (PC) and SM/phosphatidylethanolamine (PE) ratios, in subjects with PKAN. The membrane structural abnormalities were associated with membrane fluidity perturbation. These morphological and functional characteristics of red blood cells in patients with PKAN offer new possible tools in order to shed light on the pathogenesis of the disease and to possibly identify further biomarkers for clinical studies.
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Membrana Eritrocítica/química , Lipídeos de Membrana/sangue , Neurodegeneração Associada a Pantotenato-Quinase/sangue , Neurodegeneração Associada a Pantotenato-Quinase/fisiopatologia , Fosfolipídeos/sangue , Adulto , Biomarcadores/sangue , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , Membrana Eritrocítica/fisiologia , Feminino , Humanos , Ferro/metabolismo , Imageamento por Ressonância Magnética , Masculino , Fluidez de Membrana , Lipídeos de Membrana/química , Proteínas de Membrana/genética , Mitocôndrias/enzimologia , Mitocôndrias/ultraestrutura , Mutação , Neurodegeneração Associada a Pantotenato-Quinase/genética , Fosfolipídeos/química , Adulto JovemRESUMO
BACKGROUND: Neurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous group of disorders associated with progressive impairment of movement, vision, and cognition. The disease is initially diagnosed on the basis of changes in brain magnetic resonance imaging which indicate an abnormal brain iron accumulation in the basal ganglia. However, the diagnosis of specific types should be based on both clinical findings and molecular genetic testing for genes associated with different types of NBIA, including PANK2, PLA2G6, C19orf12, FA2H, ATP13A2, WDR45, COASY, FTL, CP, and DCAF17. The purpose of this study was to investigate disease-causing mutations in two patients with distinct NBIA disorders. CASE PRESENTATION: Whole Exome sequencing using Next Generation Illumina Sequencing was used to enrich all exons of protein-coding genes as well as some other important genomic regions in these two affected patients. A deleterious homozygous four-nucleotide deletion causing frameshift deletion in PANK2 gene (c.1426_1429delATGA, p.M476 fs) was identified in an 8 years old girl with dystonia, bone fracture, muscle rigidity, abnormal movement, lack of coordination and chorea. In addition, our study revealed a novel missense mutation in PLA2G6 gene (c.3G > T:p.M1I) in one and half-year-old boy with muscle weakness and neurodevelopmental regression (speech, motor and cognition). The novel mutations were also confirmed by Sanger sequencing in the proband and their parents. CONCLUSIONS: Current study uncovered two rare novel mutations in PANK2 and PLA2G6 genes in patients with NBIA disorder and such studies may help to conduct genetic counseling and prenatal diagnosis more accurately for individuals at the high risk of these types of disorders.
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Fosfolipases A2 do Grupo VI/genética , Doenças Neurodegenerativas/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Sequência de Aminoácidos , Encéfalo/diagnóstico por imagem , Criança , Análise Mutacional de DNA , Discinesias/diagnóstico , Discinesias/genética , Distonia/diagnóstico , Distonia/genética , Éxons , Feminino , Mutação da Fase de Leitura , Deleção de Genes , Redes Reguladoras de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Debilidade Muscular/diagnóstico , Debilidade Muscular/genética , Doenças Neurodegenerativas/diagnóstico , Polimorfismo GenéticoRESUMO
BACKGROUND: Pantothenate kinase-associated neurodegeneration is a progressive neurological disorder occurring in both childhood and adulthood. The objective of this study was to design and pilot-test a disease-specific clinical rating scale for the assessment of patients with pantothenate kinase-associated neurodegeneration. METHODS: In this international cross-sectional study, patients were examined at the referral centers following a standardized protocol. The motor examination was filmed, allowing 3 independent specialists in movement disorders to analyze 28 patients for interrater reliability assessment. The scale included 34 items (maximal score, 135) encompassing 6 subscales for cognition, behavior, disability, parkinsonism, dystonia, and other neurological signs. RESULTS: Forty-seven genetically confirmed patients (30 ± 17 years; range, 6-77 years) were examined with the scale (mean score, 62 ± 21; range, 20-106). Dystonia with prominent cranial involvement and atypical parkinsonian features were present in all patients. Other common signs were cognitive impairment, psychiatric features, and slow and hypometric saccades. Dystonia, parkinsonism, and other neurological features had a moderate to strong correlation with disability. The scale showed good internal consistency for the total scale (Cronbach's α = 0.87). On interrater analysis, weighted kappa values (0.30-0.93) showed substantial or excellent agreement in 85% of the items. The scale also discriminated a subgroup of homozygous c.1583C>T patients with lower scores, supporting construct validity for the scale. CONCLUSIONS: The proposed scale seems to be a reliable and valid instrument for the assessment of pediatric and adult patients with pantothenate kinase-associated neurodegeneration. Additional validation studies with a larger sample size will be required to confirm the present results and to complete the scale validation testing. © 2017 International Parkinson and Movement Disorder Society.
Assuntos
Pessoas com Deficiência , Distonia/diagnóstico , Neurodegeneração Associada a Pantotenato-Quinase/diagnóstico , Transtornos Parkinsonianos/diagnóstico , Índice de Gravidade de Doença , Adolescente , Adulto , Idoso , Criança , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Estudos Transversais , Distonia/etiologia , Humanos , Transtornos Mentais/diagnóstico , Transtornos Mentais/etiologia , Pessoa de Meia-Idade , Transtornos da Motilidade Ocular/diagnóstico , Transtornos da Motilidade Ocular/etiologia , Neurodegeneração Associada a Pantotenato-Quinase/complicações , Neurodegeneração Associada a Pantotenato-Quinase/genética , Transtornos Parkinsonianos/etiologia , Projetos Piloto , Reprodutibilidade dos Testes , Adulto JovemRESUMO
Two clinical forms of pantothenate kinase-associated neurodegeneration (PKAN) have been described: typical PKAN and atypical PKAN. Atypical PKAN has later onset and a slower course of disease. This report describes two siblings with the atypical form of PKAN, combining dystonia, irritability and a dysmorphia syndrome. In addition, a review of the literature was carried out for all published cases of atypical PKAN to gather descriptions of its various clinical presentations, age of onset and MRI findings, and to highlight the different treatments used for PKAN patients.