The Experts below are selected from a list of 438 Experts worldwide ranked by ideXlab platform
Hirotomo Saitsu - One of the best experts on this subject based on the ideXlab platform.
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a male case with aâ propeller protein associated neurodegeneration bpan with somatic mosaic mutation in WDR45
Journal of Alzheimers Disease & Parkinsonism, 2016Co-Authors: Jun Takeuchi, Hirotomo Saitsu, Naomichi Matsumoto, Akitoshi Takeda, Yoshiaki ItohAbstract:A 44 year old male presented with gait disturbance and showed rigidity, bradykinesia and small steppage gait. In his infancy, he had mental and motor retardation. MRI revealed pathognomonic iron deposition. He was diagnosed to have β-propeller protein-associated neurodegeneration (BPAN) with a de novo somatic mosaic mutation in WDR45.
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A Male Case with ò-Propeller Protein-Associated Neurodegeneration(BPAN) with Somatic Mosaic Mutation in WDR45
Journal of Alzheimers Disease & Parkinsonism, 2016Co-Authors: Jun Takeuchi, Hirotomo Saitsu, Naomichi Matsumoto, Akitoshi Takeda, Yoshiaki ItohAbstract:A 44 year old male presented with gait disturbance and showed rigidity, bradykinesia and small steppage gait. In his infancy, he had mental and motor retardation. MRI revealed pathognomonic iron deposition. He was diagnosed to have β-propeller protein-associated neurodegeneration (BPAN) with a de novo somatic mosaic mutation in WDR45.
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a novel WDR45 mutation in a patient with static encephalopathy of childhood with neurodegeneration in adulthood senda
American Journal of Medical Genetics Part A, 2014Co-Authors: Tadashi Ozawa, Hirotomo Saitsu, Reiji Koide, Yasuhiro Nakata, Naomichi Matsumoto, Kazushi Takahashi, Imaharu Nakano, Satoshi OrimoAbstract:Static encephalopathy of childhood with neurodegeneration in adulthood (SENDA) is an X-linked dominant neurodegenerative disorder, and is classified as a subtype of neurodegeneration with brain iron accumulation. Recently, de novo heterozygous mutations in WDR45 at Xp11.23 have been reported in patients with SENDA. We report the clinical and neuroradiological findings of a patient with SENDA with a novel c.322del mutation in WDR45. In this patient, characteristic MRI findings were useful for diagnosis. © 2014 The Authors. American Journal of Medical Genetics published by Wiley Periodicals, Inc.
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A novel WDR45 mutation in a patient with static encephalopathy of childhood with neurodegeneration in adulthood (SENDA).
American journal of medical genetics. Part A, 2014Co-Authors: Tadashi Ozawa, Hirotomo Saitsu, Reiji Koide, Yasuhiro Nakata, Naomichi Matsumoto, Kazushi Takahashi, Imaharu Nakano, Satoshi OrimoAbstract:Static encephalopathy of childhood with neurodegeneration in adulthood (SENDA) is an X-linked dominant neurodegenerative disorder, and is classified as a subtype of neurodegeneration with brain iron accumulation. Recently, de novo heterozygous mutations in WDR45 at Xp11.23 have been reported in patients with SENDA. We report the clinical and neuroradiological findings of a patient with SENDA with a novel c.322del mutation in WDR45. In this patient, characteristic MRI findings were useful for diagnosis.
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de novo WDR45 mutation in a patient showing clinically rett syndrome with childhood iron deposition in brain
Journal of Human Genetics, 2014Co-Authors: Chihiro Ohba, Mitsuko Nakashima, Shin Nabatame, Yoshitaka Iijima, Kiyomi Nishiyama, Yoshinori Tsurusaki, Noriko Miyake, Fumiaki Tanaka, Keiichi Ozono, Hirotomo SaitsuAbstract:De novo WDR45 mutation in a patient showing clinically Rett syndrome with childhood iron deposition in brain
Esther Meyer - One of the best experts on this subject based on the ideXlab platform.
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WDR45 mutation in atypical rett syndrome with brain iron accumulation
Movement Disorders Clinical Practice, 2015Co-Authors: Sarah J Crisp, Esther Meyer, Allison Gregory, Hayley Archer, Susan J Hayflick, Manju A Kurian, Rajith De SilvaAbstract:Keywords: BPAN ; Rett syndrome; WDR45; neurodegeneration with brain iron accumulation; developmental delay
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A RETT-LOOK-ALIKE WITH BRAIN IRON ACCUMULATION
Journal of Neurology Neurosurgery and Psychiatry, 2013Co-Authors: Sarah J Crisp, Esther Meyer, Allison Gregory, Hayley Archer, Susan J Hayflick, Manju A Kurian, Rajith De SilvaAbstract:A 31-year old female presented with progressive loss of motor and social skills, on a background of previously static global developmental delay. Her history and examination were consistent with atypical Rett syndrome, but MECP2 sequencing failed to demonstrate a pathogenic mutation. Magnetic resonance imaging (MRI) of brain in adulthood revealed a pattern of iron accumulation in the basal ganglia and cerebral peduncles characteristic of the newly described entity of beta-propeller protein-associated neurodegeneration (BPAN). 1–3 Genetic analysis confirmed the presence of a novel mutation in the associated WDR45 gene on the X-chromosome. Video data demonstrating the patient9s phenotype, detailed MRI findings and their discrimination from other forms of brain iron accumulation are presented. Classically, the clinical features of BPAN are global developmental delay in childhood and neurological degeneration in adulthood, with progressive dystonia, parkinsonism and dementia. 2 However, our patient presented predominantly with a Rett-like phenotype, features of which may be present in approximately 25% of BPAN cases. 2 The proportion of patients with atypical Rett syndrome, particularly those with negative conventional genetic tests, who actually have BPAN remains to be established. Like Rett syndromes, this disorder is more common in females consistent with sensitivity to X-inactivation. 1 The phenotypic variability may be attributable to variation in the pattern of inactivation.
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exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct x linked dominant form of nbia
American Journal of Human Genetics, 2012Co-Authors: Tobias B Haack, Michael C. Kruer, Esther Meyer, Allison Gregory, Penelope Hogarth, Lynn Sanford, Thomas Wieland, Thomas Schwarzmayr, Elisabeth GrafAbstract:Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic disorders characterized by abnormal iron deposition in the basal ganglia. We report that de novo mutations in WDR45, a gene located at Xp11.23 and encoding a beta-propeller scaffold protein with a putative role in autophagy, cause a distinctive NBIA phenotype. The clinical features include early-onset global developmental delay and further neurological deterioration (parkinsonism, dystonia, and dementia developing by early adulthood). Brain MRI revealed evidence of iron deposition in the substantia nigra and globus pallidus. Males and females are phenotypically similar, an observation that might be explained by somatic mosaicism in surviving males and germline or somatic mutations in females, as well as skewing of X chromosome inactivation. This clinically recognizable disorder is among the more common forms of NBIA, and we suggest that it be named accordingly as beta-propeller protein-associated neurodegeneration.
Mitsuko Nakashima - One of the best experts on this subject based on the ideXlab platform.
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WDR45 mutations in three male patients with West syndrome
Journal of Human Genetics, 2016Co-Authors: Mitsuko Nakashima, Kyoko Takano, Yu Tsuyusaki, Shinsaku Yoshitomi, Masayuki Shimono, Yoshihiro Aoki, Mitsuhiro Kato, Noriko Aida, Takeshi Mizuguchi, Satoko MiyatakeAbstract:West syndrome is an early-onset epileptic encephalopathy characterized by clustered spasms with hypsarrhythmia seen on electroencephalogram (EEG). West syndrome is genetically heterogeneous, and its genetic causes have not been fully elucidated. WD Repeat Domain 45 ( WDR45 ) resides on Xp11.23, and encodes a member of the WD repeat protein interacting with phosphoinositides (WIPI) family, which is crucial in the macroautophagy pathway. De novo mutations in WDR45 cause beta-propeller protein-associated neurodegeneration characterized by iron accumulation in the basal ganglia. In this study, we performed whole exome sequencing of individuals with West syndrome and identified three WDR45 mutations in three independent males (patients 1, 2 and 3). Two novel mutations occurred de novo (patients 1 and 2) and the remaining mutation detected in a male patient (patient 3) and his affected sister was inherited from the mother, harboring the somatic mutation. The three male patients showed early-onset intractable seizures, profound intellectual disability and developmental delay. Their brain magnetic resonance imaging scans showed cerebral atrophy. We found no evidence of somatic mosaicism in the three male patients. Our findings indicate that hemizygous WDR45 mutations in males lead to severe epileptic encephalopathy.
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de novo WDR45 mutation in a patient showing clinically rett syndrome with childhood iron deposition in brain
Journal of Human Genetics, 2014Co-Authors: Chihiro Ohba, Mitsuko Nakashima, Shin Nabatame, Yoshitaka Iijima, Kiyomi Nishiyama, Yoshinori Tsurusaki, Noriko Miyake, Fumiaki Tanaka, Keiichi Ozono, Hirotomo SaitsuAbstract:De novo WDR45 mutation in a patient showing clinically Rett syndrome with childhood iron deposition in brain
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De novo WDR45 mutation in a patient showing clinically Rett syndrome with childhood iron deposition in brain
Journal of Human Genetics, 2014Co-Authors: Chihiro Ohba, Mitsuko Nakashima, Shin Nabatame, Yoshitaka Iijima, Kiyomi Nishiyama, Yoshinori Tsurusaki, Noriko Miyake, Fumiaki Tanaka, Keiichi Ozono, Hirotomo SaitsuAbstract:Rett syndrome (RTT) is a neurodevelopmental disorder mostly caused by MECP2 mutations. We identified a de novo WDR45 mutation, which caused a subtype of neurodegeneration with brain iron accumulation, in a patient showing clinically typical RTT. The mutation (c.830+1G>A) led to aberrant splicing in lymphoblastoid cells. Sequential brain magnetic resonance imaging demonstrated that iron deposition in the globus pallidus and the substantia nigra was observed as early as at 11 years of age. Because the patient showed four of the main RTT diagnostic criteria, WDR45 should be investigated in patients with RTT without MECP2 mutations.
Michael C. Kruer - One of the best experts on this subject based on the ideXlab platform.
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Lessons from a pair of siblings with BPAN
European Journal of Human Genetics, 2016Co-Authors: Yuri A Zarate, Julie R Jones, Melanie A Jones, Francisca Millan, Jane Juusola, Annette Vertino-bell, G Bradley Schaefer, Michael C. KruerAbstract:Neurodegeneration with brain iron accumulation (NBIA) encompasses a heterogeneous group of inherited progressive neurological diseases. Beta-propeller protein-associated neurodegeneration (BPAN) has been estimated to account for ~7% of all cases of NBIA and has distinctive clinical and brain imaging findings. Heterozygous variants in the WDR45 gene located in Xp11.23 are responsible for BPAN. A clear female predominance supports an X-linked dominant pattern of inheritance with proposed lethality for germline variants in hemizygous males. By whole-exome sequencing, we identified an in-frame deletion in the WDR45 gene (c.161_163delTGG) in the hemizygous state in a 20-year-old man with a history of profound neurocognitive impairment and seizures. His higher functioning 14-year-old sister, also with a history of intellectual disability, was found to carry the same variant in the heterozygous state. Their asymptomatic mother was mosaic for the alteration. From this pair of siblings with BPAN we conclude that: (1) inherited WDR45 variants are possible, albeit rare; (2) hemizygous germline variants in males can be viable, but likely result in a more severe phenotype; (3) for siblings with germline variants, males should be more significantly affected than females; and (4) because gonadal and germline mosaicism are possible and healthy female carriers can be found, parental testing for variants in WDR45 should be considered.
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Newly Characterized Forms of Neurodegeneration with Brain Iron Accumulation
Current Neurology and Neuroscience Reports, 2013Co-Authors: Joshua M. Doorn, Michael C. KruerAbstract:Neurodegeneration with brain iron accumulation (NBIA) comprises a group of brain iron deposition syndromes that lead to mixed extrapyramidal features and progressive dementia. Historically, there has not been a clearly identifiable molecular cause for many patients with clinical and radiologic features of NBIA. Recent discoveries have shown that mutations in C19orf12 or WDR45 can lead to NBIA. C19orf12 mutations are inherited in an autosomal recessive manner, and lead to a syndrome similar to that caused by mutations in PANK2 or PLA2G6 . In contrast, WDR45 mutations lead to a distinct form of NBIA characterized by spasticity and intellectual disability in childhood followed by the subacute onset of dystonia–parkinsonism in adulthood. WDR45 mutations act in an X-linked dominant manner. Although the function of C19orf12 is largely unknown, WDR45 plays a key role in autophagy. Each of these new forms of NBIA thus leads to a distinct clinical syndrome, and together they implicate new cellular pathways in the pathogenesis of these disorders.
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β-Propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation.
Brain : a journal of neurology, 2013Co-Authors: Susan J Hayflick, Tobias B Haack, Michael C. Kruer, Allison Gregory, Manju A Kurian, Henry H Houlden, James Anderson, Nathalie Boddaert, Lynn Sanford, Sami I HarikAbstract:Neurodegenerative disorders with high iron in the basal ganglia encompass an expanding collection of single gene disorders collectively known as neurodegeneration with brain iron accumulation. These disorders can largely be distinguished from one another by their associated clinical and neuroimaging features. The aim of this study was to define the phenotype that is associated with mutations in WDR45, a new causative gene for neurodegeneration with brain iron accumulation located on the X chromosome. The study subjects consisted of WDR45 mutation-positive individuals identified after screening a large international cohort of patients with idiopathic neurodegeneration with brain iron accumulation. Their records were reviewed, including longitudinal clinical, laboratory and imaging data. Twenty-three mutation-positive subjects were identified (20 females). The natural history of their disease was remarkably uniform: global developmental delay in childhood and further regression in early adulthood with progressive dystonia, parkinsonism and dementia. Common early comorbidities included seizures, spasticity and disordered sleep. The symptoms of parkinsonism improved with l-DOPA; however, nearly all patients experienced early motor fluctuations that quickly progressed to disabling dyskinesias, warranting discontinuation of l-DOPA. Brain magnetic resonance imaging showed iron in the substantia nigra and globus pallidus, with a 'halo' of T1 hyperintense signal in the substantia nigra. All patients harboured de novo mutations in WDR45, encoding a beta-propeller protein postulated to play a role in autophagy. Beta-propeller protein-associated neurodegeneration, the only X-linked disorder of neurodegeneration with brain iron accumulation, is associated with de novo mutations in WDR45 and is recognizable by a unique combination of clinical, natural history and neuroimaging features.
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Beta-propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation
Brain, 2013Co-Authors: Susan J Hayflick, Tobias B Haack, Michael C. Kruer, Allison Gregory, Manju A Kurian, Henry H Houlden, Nathalie Boddaert, Lynn Sanford, James C. Anderson, Sami I HarikAbstract:Neurodegenerative disorders with high iron in the basal ganglia encompass an expanding collection of single gene disorders collectively known as neurodegeneration with brain iron accumulation. These disorders can largely be distinguished from one another by their associated clinical and neuroimaging features. The aim of this study was to define the phenotype that is associated with mutations in WDR45, a new causative gene for neurodegeneration with brain iron accumulation located on the X chromosome. The study subjects consisted of WDR45 mutation-positive individuals identified after screening a large international cohort of patients with idiopathic neurodegeneration with brain iron accumulation. Their records were reviewed, including longitudinal clinical, laboratory and imaging data. Twenty-three mutation-positive subjects were identified (20 females). The natural history of their disease was remarkably uniform: global developmental delay in childhood and further regression in early adulthood with progressive dystonia, parkinsonism and dementia. Common early comorbidities included seizures, spasticity and disordered sleep. The symptoms of parkinsonism improved with l-DOPA; however, nearly all patients experienced early motor fluctuations that quickly progressed to disabling dyskinesias, warranting discontinuation of l-DOPA. Brain magnetic resonance imaging showed iron in the substantia nigra and globus pallidus, with a ‘halo’ of T1 hyperintense signal in the substantia nigra. All patients harboured de novo mutations in WDR45, encoding a beta-propeller protein postulated to play a role in autophagy. Beta-propeller protein-associated neurodegeneration, the only X-linked disorder of neurodegeneration with brain iron accumulation, is associated with de novo mutations in WDR45 and is recognizable by a unique combination of clinical, natural history and neuroimaging features.
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exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct x linked dominant form of nbia
American Journal of Human Genetics, 2012Co-Authors: Tobias B Haack, Michael C. Kruer, Esther Meyer, Allison Gregory, Penelope Hogarth, Lynn Sanford, Thomas Wieland, Thomas Schwarzmayr, Elisabeth GrafAbstract:Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic disorders characterized by abnormal iron deposition in the basal ganglia. We report that de novo mutations in WDR45, a gene located at Xp11.23 and encoding a beta-propeller scaffold protein with a putative role in autophagy, cause a distinctive NBIA phenotype. The clinical features include early-onset global developmental delay and further neurological deterioration (parkinsonism, dystonia, and dementia developing by early adulthood). Brain MRI revealed evidence of iron deposition in the substantia nigra and globus pallidus. Males and females are phenotypically similar, an observation that might be explained by somatic mosaicism in surviving males and germline or somatic mutations in females, as well as skewing of X chromosome inactivation. This clinically recognizable disorder is among the more common forms of NBIA, and we suggest that it be named accordingly as beta-propeller protein-associated neurodegeneration.
Susan J Hayflick - One of the best experts on this subject based on the ideXlab platform.
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Chapter 19 - Neurodegeneration with brain iron accumulation
2018Co-Authors: Susan J Hayflick, Ma Kurian, Penelope HogarthAbstract:Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of disorders affecting children and adults. These rare disorders are often first suspected when increased basal ganglia iron is observed on brain magnetic resonance imaging. For the majority of NBIA disorders the genetic basis has been delineated, and clinical testing is available. The four most common NBIA disorders include pantothenate kinase-associated neurodegeneration (PKAN) due to mutations in PANK2, phospholipase A2-associated neurodegeneration caused by mutation in PLA2G6, mitochondrial membrane protein-associated neurodegeneration from mutations in C19orf12, and beta-propeller protein-associated neurodegeneration due to mutations in WDR45. The ultrarare NBIA disorders are caused by mutations in CoASY, ATP13A2, and FA2H (causing CoA synthase protein-associated neurodegeneration, Kufor-Rakeb disease, and fatty acid hydroxylase-associated neurodegeneration, respectively). Together, these genes account for disease in approximately 85% of patients diagnosed with an NBIA disorder. New NBIA genes are being recognized with increasing frequency as a result of whole-exome sequencing, which is also facilitating early ascertainment of patients whose phenotype is often nonspecific.
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novel WDR45 mutation and pathognomonic bpan imaging in a young female with mild cognitive delay
Pediatrics, 2015Co-Authors: Michelle Long, Susan J Hayflick, Nishard Abdeen, Michael T Geraghty, Penelope Hogarth, Sunita VenkateswaranAbstract:β-propeller protein-associated neurodegeneration (BPAN) is a recently identified X-linked dominant form of neurodegeneration with brain iron accumulation caused by mutations in the WDR45 gene. BPAN commonly presents as global developmental delay in childhood with rapid onset of parkinsonism and dementia in early adulthood and associated pathognomonic changes seen on brain MRI. In this case report, we present a pediatric patient with mild cognitive delay and pathognomonic MRI changes indicative of BPAN preceding neurologic deterioration who is found to have a novel de novo mutation in the WDR45 gene.
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WDR45 mutation in atypical rett syndrome with brain iron accumulation
Movement Disorders Clinical Practice, 2015Co-Authors: Sarah J Crisp, Esther Meyer, Allison Gregory, Hayley Archer, Susan J Hayflick, Manju A Kurian, Rajith De SilvaAbstract:Keywords: BPAN ; Rett syndrome; WDR45; neurodegeneration with brain iron accumulation; developmental delay
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A RETT-LOOK-ALIKE WITH BRAIN IRON ACCUMULATION
Journal of Neurology Neurosurgery and Psychiatry, 2013Co-Authors: Sarah J Crisp, Esther Meyer, Allison Gregory, Hayley Archer, Susan J Hayflick, Manju A Kurian, Rajith De SilvaAbstract:A 31-year old female presented with progressive loss of motor and social skills, on a background of previously static global developmental delay. Her history and examination were consistent with atypical Rett syndrome, but MECP2 sequencing failed to demonstrate a pathogenic mutation. Magnetic resonance imaging (MRI) of brain in adulthood revealed a pattern of iron accumulation in the basal ganglia and cerebral peduncles characteristic of the newly described entity of beta-propeller protein-associated neurodegeneration (BPAN). 1–3 Genetic analysis confirmed the presence of a novel mutation in the associated WDR45 gene on the X-chromosome. Video data demonstrating the patient9s phenotype, detailed MRI findings and their discrimination from other forms of brain iron accumulation are presented. Classically, the clinical features of BPAN are global developmental delay in childhood and neurological degeneration in adulthood, with progressive dystonia, parkinsonism and dementia. 2 However, our patient presented predominantly with a Rett-like phenotype, features of which may be present in approximately 25% of BPAN cases. 2 The proportion of patients with atypical Rett syndrome, particularly those with negative conventional genetic tests, who actually have BPAN remains to be established. Like Rett syndromes, this disorder is more common in females consistent with sensitivity to X-inactivation. 1 The phenotypic variability may be attributable to variation in the pattern of inactivation.
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β-Propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation.
Brain : a journal of neurology, 2013Co-Authors: Susan J Hayflick, Tobias B Haack, Michael C. Kruer, Allison Gregory, Manju A Kurian, Henry H Houlden, James Anderson, Nathalie Boddaert, Lynn Sanford, Sami I HarikAbstract:Neurodegenerative disorders with high iron in the basal ganglia encompass an expanding collection of single gene disorders collectively known as neurodegeneration with brain iron accumulation. These disorders can largely be distinguished from one another by their associated clinical and neuroimaging features. The aim of this study was to define the phenotype that is associated with mutations in WDR45, a new causative gene for neurodegeneration with brain iron accumulation located on the X chromosome. The study subjects consisted of WDR45 mutation-positive individuals identified after screening a large international cohort of patients with idiopathic neurodegeneration with brain iron accumulation. Their records were reviewed, including longitudinal clinical, laboratory and imaging data. Twenty-three mutation-positive subjects were identified (20 females). The natural history of their disease was remarkably uniform: global developmental delay in childhood and further regression in early adulthood with progressive dystonia, parkinsonism and dementia. Common early comorbidities included seizures, spasticity and disordered sleep. The symptoms of parkinsonism improved with l-DOPA; however, nearly all patients experienced early motor fluctuations that quickly progressed to disabling dyskinesias, warranting discontinuation of l-DOPA. Brain magnetic resonance imaging showed iron in the substantia nigra and globus pallidus, with a 'halo' of T1 hyperintense signal in the substantia nigra. All patients harboured de novo mutations in WDR45, encoding a beta-propeller protein postulated to play a role in autophagy. Beta-propeller protein-associated neurodegeneration, the only X-linked disorder of neurodegeneration with brain iron accumulation, is associated with de novo mutations in WDR45 and is recognizable by a unique combination of clinical, natural history and neuroimaging features.
