Early manifestations of BPAN in a pediatric patient

Okamoto, Nobuhiko; Ikeda, Tomomi; Hasegawa, Tatsuhisa; Yamamoto, Yuto; Kawato, Kazumi; Komoto, Tomohiro; Imoto, Issei

doi:10.1002/ajmg.a.36779

Cited by 31 publications

(40 citation statements)

References 8 publications

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“…The youngest patient reported with these MRI findings is a 6-year-old girl with Rett syndrome-like features diagnosed by whole exome sequencing. 8 In contrast, although our patient underwent her first brain MRI as part of a diagnostic workup for cognitive delay at age 17, which revealed striking findings consistent with BPAN, she did not display any signs or symptoms of neurologic or psychiatric degeneration seen in previously reported subjects with the same MRI findings.…”

Section: Discussioncontrasting

confidence: 59%

Novel WDR45 Mutation and Pathognomonic BPAN Imaging in a Young Female With Mild Cognitive Delay

Long¹,

Abdeen²,

Geraghty³

et al. 2015

Pediatrics

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b-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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Section: Discussioncontrasting

confidence: 59%

Novel WDR45 Mutation and Pathognomonic BPAN Imaging in a Young Female With Mild Cognitive Delay

Long¹,

Abdeen²,

Geraghty³

et al. 2015

Pediatrics

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show abstract

“…The four NBIA-related genes that did not show expression changes are less strongly linked to myelin, although rare cases of WDR45 -linked NBIA 63, 64 and DCAF17 -linked NBIA show subtle white matter changes. 65, 66 The PANK2 protein, involved in coenzyme A metabolism, 67 does not appear to be associated with clear myelin pathology.…”

Section: Discussionmentioning

confidence: 91%

Brain iron accumulation affects myelin-related molecular systems implicated in a rare neurogenetic disease family with neuropsychiatric features

et al. 2016

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The ‘neurodegeneration with brain iron accumulation' (NBIA) disease family entails movement or cognitive impairment, often with psychiatric features. To understand how iron loading affects the brain, we studied mice with disruption of two iron regulatory genes, hemochromatosis (Hfe) and transferrin receptor 2 (Tfr2). Inductively coupled plasma atomic emission spectroscopy demonstrated increased iron in the Hfe−/− × Tfr2mut brain (P=0.002, n ≥5/group), primarily localized by Perls' staining to myelinated structures. Western immunoblotting showed increases of the iron storage protein ferritin light polypeptide and microarray and real-time reverse transcription-PCR revealed decreased transcript levels (P<0.04, n ≥5/group) for five other NBIA genes, phospholipase A2 group VI, fatty acid 2-hydroxylase, ceruloplasmin, chromosome 19 open reading frame 12 and ATPase type 13A2. Apart from the ferroxidase ceruloplasmin, all are involved in myelin homeostasis; 16 other myelin-related genes also showed reduced expression (P<0.05), although gross myelin structure and integrity appear unaffected (P>0.05). Overlap (P<0.0001) of differentially expressed genes in Hfe−/− × Tfr2mut brain with human gene co-expression networks suggests iron loading influences expression of NBIA-related and myelin-related genes co-expressed in normal human basal ganglia. There was overlap (P<0.0001) of genes differentially expressed in Hfe−/− × Tfr2mut brain and post-mortem NBIA basal ganglia. Hfe−/− × Tfr2mut mice were hyperactive (P<0.0112) without apparent cognitive impairment by IntelliCage testing (P>0.05). These results implicate myelin-related systems involved in NBIA neuropathogenesis in early responses to iron loading. This may contribute to behavioral symptoms in NBIA and hemochromatosis and is relevant to patients with abnormal iron status and psychiatric disorders involving myelin abnormalities or resistant to conventional treatments.

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“…Variants of all the other genes listed in Figure , except for WDR45 , have been observed in only 1 or 2 patients, and these genes are described in more detail in Appendix S1 (Supporting information).…”

Section: Clinical or Genetic Diagnosis?mentioning

confidence: 99%

Clinician’s guide to genes associated with Rett‐like phenotypes—Investigation of a Danish cohort and review of the literature

et al. 2018

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The differential diagnostics in Rett syndrome has evolved with the development of next generation sequencing-based techniques and many patients have been diagnosed with other syndromes or variants in newly described genes where the associated phenotype(s) is yet to be fully explored. The term Rett-like refers to phenotypes with distinct overlapping features of Rett syndrome where the clinical criteria are not completely fulfilled. In this study we have combined a review of Rett-like disorders with data from a Danish cohort of 35 patients with Rett-like phenotypes emphasizing the diagnostic overlap with Pitt-Hopkins syndrome, Cornelia de Lange syndrome with SMC1A variants, and epileptic encephalopathies, for example, due to STXBP1 variants. We also found a patient with a pathogenic variant in KCNB1, which has not been previously linked to a Rett-like phenotype. This study underlines the clinical and genetic heterogeneity of a Rett syndrome spectrum, and provides an overview of the Rett syndrome-related genes described to date, and hence serves as a guide for diagnosing patients with Rett-like phenotypes.

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Early manifestations of BPAN in a pediatric patient

Cited by 31 publications

References 8 publications

Novel WDR45 Mutation and Pathognomonic BPAN Imaging in a Young Female With Mild Cognitive Delay

Novel WDR45 Mutation and Pathognomonic BPAN Imaging in a Young Female With Mild Cognitive Delay

Brain iron accumulation affects myelin-related molecular systems implicated in a rare neurogenetic disease family with neuropsychiatric features

Clinician’s guide to genes associated with Rett‐like phenotypes—Investigation of a Danish cohort and review of the literature

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