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DOI 10121201CPJ0000437694178889b20144175-177 Published Online before print December 20 2013Neurol Clin Pract
Yuta Ichinose Michiaki Miwa Akiko Onohara et al neurodegeneration (BPAN)
Characteristic MRI findings in beta-propeller protein-associated
This information is current as of December 20 2013
httpcpneurologyorgcontent42175fullhtmllocated on the World Wide Web at
The online version of this article along with updated information and services is
Academy of Neurology All rights reserved Print ISSN 2163-0402 Online ISSN 2163-0933continuously since 2011 it is now a bimonthly with 6 issues per year Copyright copy 2014 American
reg is an official journal of the American Academy of Neurology PublishedNeurol Clin Pract
Neurologyreg Clinical Practice Cases
Characteristic MRIfindings in beta-propellerprotein-associatedneurodegeneration (BPAN)Yuta Ichinose MD
Michiaki Miwa MD
Akiko Onohara MD
Kimiko Obi MD PhD
Kazumasa Shindo MD PhD
Hirotomo Saitsu MD PhD
Naomichi Matsumoto MD PhD
Yoshihisa Takiyama MD PhD
A31-year-old woman presented with severe dystonia-parkinsonism She had nonpro-gressive psychomotor retardation and cognitive dysfunction from childhood withoutevidence of dystonia or parkinsonism At age 30 she then developed severe dystoniaand gait disturbance There was neither dystonia nor parkinsonism before age 30
MRI revealed cerebral atrophy and iron accumulation in the globus pallidus and substantia nigra(figure 1 AndashD) The characteristic MRI findings were hyperintensity of the substantia nigra witha central band of hypointensity in T1-weighted axial slices (figure 1 B) Beta-propeller protein-associated neurodegeneration (BPAN) was diagnosed based on MRI findings and identificationof a novel heterozygous mutation in the WDR45 gene (NM_0070753 c51911_51913del)(figure 2) This is a neurodegeneration involving brain iron accumulation (NBIA) characterizedby psychomotor retardation from childhood and dystonia-parkinsonism in midadulthood12
Although we could not analyze the fatherrsquos gene since he had died the mother had no mutationin the WDR45 gene (figure 2) Thus it might be a de novo mutation in the WDR45 gene asreported previously12
L-Dopadecarboxylase inhibitor treatment (200 mgday orally) led to improvement of therigidity and bradykinesia in our patient She became able to move by herself by crawling onher hands and knees and no longer needed meal assistance In addition she became able toutter a few words like ldquothanksrdquo and ldquobyerdquo although the dystonia of the lower limbs remainedunchanged Since T1-weighted hyperintensity of the substantia nigra with a central band ofhypointensity has not been found in other NBIA disorders including neuroferritinopathy
Department of Neurology (YI MM AO KS YT) Interdisciplinary Graduate School of Medicine andEngineering University of Yamanashi Yamanashi Japan Department of Neurology (KO) Juntendo UniversitySchool of Medicine Tokyo Japan and Department of Human Genetics (HS NM) Graduate School of MedicineYokohama City University Yokohama Japan
Funding information and disclosures are provided at the end of the article Full disclosure form informationprovided by the authors is available with the full text of this article at Neurologyorgcp
Correspondence to ytakiyamayamanashiacjp
Neurology Clinical Practice |||||||||||| April 2014 Neurologyorgcp 175
Figure 1 Brain MRI findings in the patient
(A B) T2-weighted MRI shows marked hypointensity in the globus pallidus and substantia nigra in axial slices (C)T1-weighted MRI shows hyperintensity of the substantia nigra with a central band of hypointensity in an axial slice(arrows) (D) T1-weightedMRI shows cerebral atrophy and hyperintensity of the substantia nigra (arrowhead) in a sag-ittal slice
Figure 2 Identification of a novel heterozygous mutation in the WDR45 gene
Electropherograms of the patient and her mother using a forward primer are shown A novel heterozygous mutation(NM_0070753 c51911_51913del underlined) which may result in abnormal splicing was identified in intron8 (splice donor site) of the WDR45 gene in the patient as shown by the double signals due to the 3 bp deletionMeanwhile the mother had no mutation in the WDR45 gene The colored peaks denote nucleotide bases as followsblack guanine red thymine blue cytosine and green adenine
176 copy 2014 American Academy of Neurology
Yuta Ichinose et al
aceruloplasminemia and pantothenate kinase-associated neurodegeneration this findingshould facilitate the diagnosis of BPAN
REFERENCES1 Haack TB Hogarth P Kruer MC et al Exome sequencing reveals de novo WDR45 mutations causing
a phenotypically distinct X-linked dominant form of NBIA Am J Hum Genet 2012911144ndash11492 Saitsu H Nishimura T Muramatsu K et al De novo mutations in the autophagy gene WDR45 cause
static encephalopathy of childhood with neurodegeneration in adulthood Nat Genet 201345445ndash449
STUDY FUNDINGNo targeted funding reported
DISCLOSURESY Ichinose MMiwa A Onohara K Obi and K Shindo report no disclosures H Saitsu receives fundingfrom a Grant-in-Aid for Scientific Research (B) from the Japan Society for the Promotion of ScienceN Matsumoto serves on editorial advisory boards for Clinical Genetics Journal of Human Genetics andAmerican Journal of Medical Genetics Part A receives funding from the Ministry of Health Labour andWelfare the Japan Science and Technology Agency a Grant-in-Aid for Scientific Research on InnovativeAreas (Foundation of Synapse and Neurocircuit Pathology) from the Ministry of Education CultureSports Science and Technology of Japan a Grant-in-Aid for Scientific Research from the Japan Societyfor the Promotion of Science and a grant from the Takeda Science Foundation Y Takiyama serves onthe editorial advisory board for Rinsho Shinkeigaku Full disclosure form information provided by theauthors is available with the full text of this article at Neurologyorgcp
Whatrsquos New in Clinical PracticeNeurologyreg Clinical Practice now has podcasts available for download Thepodcasts are introduced by Editor John R Corboy MD FAAN who highlightspapers from the current issue The interview that follows features authors discussingpapers in more depth and bringing clinical implications to the fore
Neurology Clinical Practice |||||||||||| April 2014 Neurologyorgcp 177
Characteristic MRI findings in beta-propeller protein-associated neurodegeneration (BPAN)
DOI 10121201CPJ0000437694178889b20144175-177 Published Online before print December 20 2013Neurol Clin Pract
Yuta Ichinose Michiaki Miwa Akiko Onohara et al neurodegeneration (BPAN)
Characteristic MRI findings in beta-propeller protein-associated
This information is current as of December 20 2013
ServicesUpdated Information amp
httpcpneurologyorgcontent42175fullhtmlincluding high resolution figures can be found at
References httpcpneurologyorgcontent42175fullhtmlref-list-1
This article cites 2 articles 0 of which you can access for free at
Subspecialty Collections
sonismhttpcpneurologyorgcgicollectionparkinsons_disease_parkinParkinsons diseaseParkinsonism
httpcpneurologyorgcgicollectionmriMRI
httpcpneurologyorgcgicollectionall_geneticsAll Geneticsfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpcpneurologyorgmiscaboutxhtmlpermissionsor in its entirety can be found online atInformation about reproducing this article in parts (figurestables)
Reprints
httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
Neurologyreg Clinical Practice Cases
Characteristic MRIfindings in beta-propellerprotein-associatedneurodegeneration (BPAN)Yuta Ichinose MD
Michiaki Miwa MD
Akiko Onohara MD
Kimiko Obi MD PhD
Kazumasa Shindo MD PhD
Hirotomo Saitsu MD PhD
Naomichi Matsumoto MD PhD
Yoshihisa Takiyama MD PhD
A31-year-old woman presented with severe dystonia-parkinsonism She had nonpro-gressive psychomotor retardation and cognitive dysfunction from childhood withoutevidence of dystonia or parkinsonism At age 30 she then developed severe dystoniaand gait disturbance There was neither dystonia nor parkinsonism before age 30
MRI revealed cerebral atrophy and iron accumulation in the globus pallidus and substantia nigra(figure 1 AndashD) The characteristic MRI findings were hyperintensity of the substantia nigra witha central band of hypointensity in T1-weighted axial slices (figure 1 B) Beta-propeller protein-associated neurodegeneration (BPAN) was diagnosed based on MRI findings and identificationof a novel heterozygous mutation in the WDR45 gene (NM_0070753 c51911_51913del)(figure 2) This is a neurodegeneration involving brain iron accumulation (NBIA) characterizedby psychomotor retardation from childhood and dystonia-parkinsonism in midadulthood12
Although we could not analyze the fatherrsquos gene since he had died the mother had no mutationin the WDR45 gene (figure 2) Thus it might be a de novo mutation in the WDR45 gene asreported previously12
L-Dopadecarboxylase inhibitor treatment (200 mgday orally) led to improvement of therigidity and bradykinesia in our patient She became able to move by herself by crawling onher hands and knees and no longer needed meal assistance In addition she became able toutter a few words like ldquothanksrdquo and ldquobyerdquo although the dystonia of the lower limbs remainedunchanged Since T1-weighted hyperintensity of the substantia nigra with a central band ofhypointensity has not been found in other NBIA disorders including neuroferritinopathy
Department of Neurology (YI MM AO KS YT) Interdisciplinary Graduate School of Medicine andEngineering University of Yamanashi Yamanashi Japan Department of Neurology (KO) Juntendo UniversitySchool of Medicine Tokyo Japan and Department of Human Genetics (HS NM) Graduate School of MedicineYokohama City University Yokohama Japan
Funding information and disclosures are provided at the end of the article Full disclosure form informationprovided by the authors is available with the full text of this article at Neurologyorgcp
Correspondence to ytakiyamayamanashiacjp
Neurology Clinical Practice |||||||||||| April 2014 Neurologyorgcp 175
Figure 1 Brain MRI findings in the patient
(A B) T2-weighted MRI shows marked hypointensity in the globus pallidus and substantia nigra in axial slices (C)T1-weighted MRI shows hyperintensity of the substantia nigra with a central band of hypointensity in an axial slice(arrows) (D) T1-weightedMRI shows cerebral atrophy and hyperintensity of the substantia nigra (arrowhead) in a sag-ittal slice
Figure 2 Identification of a novel heterozygous mutation in the WDR45 gene
Electropherograms of the patient and her mother using a forward primer are shown A novel heterozygous mutation(NM_0070753 c51911_51913del underlined) which may result in abnormal splicing was identified in intron8 (splice donor site) of the WDR45 gene in the patient as shown by the double signals due to the 3 bp deletionMeanwhile the mother had no mutation in the WDR45 gene The colored peaks denote nucleotide bases as followsblack guanine red thymine blue cytosine and green adenine
176 copy 2014 American Academy of Neurology
Yuta Ichinose et al
aceruloplasminemia and pantothenate kinase-associated neurodegeneration this findingshould facilitate the diagnosis of BPAN
REFERENCES1 Haack TB Hogarth P Kruer MC et al Exome sequencing reveals de novo WDR45 mutations causing
a phenotypically distinct X-linked dominant form of NBIA Am J Hum Genet 2012911144ndash11492 Saitsu H Nishimura T Muramatsu K et al De novo mutations in the autophagy gene WDR45 cause
static encephalopathy of childhood with neurodegeneration in adulthood Nat Genet 201345445ndash449
STUDY FUNDINGNo targeted funding reported
DISCLOSURESY Ichinose MMiwa A Onohara K Obi and K Shindo report no disclosures H Saitsu receives fundingfrom a Grant-in-Aid for Scientific Research (B) from the Japan Society for the Promotion of ScienceN Matsumoto serves on editorial advisory boards for Clinical Genetics Journal of Human Genetics andAmerican Journal of Medical Genetics Part A receives funding from the Ministry of Health Labour andWelfare the Japan Science and Technology Agency a Grant-in-Aid for Scientific Research on InnovativeAreas (Foundation of Synapse and Neurocircuit Pathology) from the Ministry of Education CultureSports Science and Technology of Japan a Grant-in-Aid for Scientific Research from the Japan Societyfor the Promotion of Science and a grant from the Takeda Science Foundation Y Takiyama serves onthe editorial advisory board for Rinsho Shinkeigaku Full disclosure form information provided by theauthors is available with the full text of this article at Neurologyorgcp
Whatrsquos New in Clinical PracticeNeurologyreg Clinical Practice now has podcasts available for download Thepodcasts are introduced by Editor John R Corboy MD FAAN who highlightspapers from the current issue The interview that follows features authors discussingpapers in more depth and bringing clinical implications to the fore
Neurology Clinical Practice |||||||||||| April 2014 Neurologyorgcp 177
Characteristic MRI findings in beta-propeller protein-associated neurodegeneration (BPAN)
DOI 10121201CPJ0000437694178889b20144175-177 Published Online before print December 20 2013Neurol Clin Pract
Yuta Ichinose Michiaki Miwa Akiko Onohara et al neurodegeneration (BPAN)
Characteristic MRI findings in beta-propeller protein-associated
This information is current as of December 20 2013
ServicesUpdated Information amp
httpcpneurologyorgcontent42175fullhtmlincluding high resolution figures can be found at
References httpcpneurologyorgcontent42175fullhtmlref-list-1
This article cites 2 articles 0 of which you can access for free at
Subspecialty Collections
sonismhttpcpneurologyorgcgicollectionparkinsons_disease_parkinParkinsons diseaseParkinsonism
httpcpneurologyorgcgicollectionmriMRI
httpcpneurologyorgcgicollectionall_geneticsAll Geneticsfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpcpneurologyorgmiscaboutxhtmlpermissionsor in its entirety can be found online atInformation about reproducing this article in parts (figurestables)
Reprints
httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
Figure 1 Brain MRI findings in the patient
(A B) T2-weighted MRI shows marked hypointensity in the globus pallidus and substantia nigra in axial slices (C)T1-weighted MRI shows hyperintensity of the substantia nigra with a central band of hypointensity in an axial slice(arrows) (D) T1-weightedMRI shows cerebral atrophy and hyperintensity of the substantia nigra (arrowhead) in a sag-ittal slice
Figure 2 Identification of a novel heterozygous mutation in the WDR45 gene
Electropherograms of the patient and her mother using a forward primer are shown A novel heterozygous mutation(NM_0070753 c51911_51913del underlined) which may result in abnormal splicing was identified in intron8 (splice donor site) of the WDR45 gene in the patient as shown by the double signals due to the 3 bp deletionMeanwhile the mother had no mutation in the WDR45 gene The colored peaks denote nucleotide bases as followsblack guanine red thymine blue cytosine and green adenine
176 copy 2014 American Academy of Neurology
Yuta Ichinose et al
aceruloplasminemia and pantothenate kinase-associated neurodegeneration this findingshould facilitate the diagnosis of BPAN
REFERENCES1 Haack TB Hogarth P Kruer MC et al Exome sequencing reveals de novo WDR45 mutations causing
a phenotypically distinct X-linked dominant form of NBIA Am J Hum Genet 2012911144ndash11492 Saitsu H Nishimura T Muramatsu K et al De novo mutations in the autophagy gene WDR45 cause
static encephalopathy of childhood with neurodegeneration in adulthood Nat Genet 201345445ndash449
STUDY FUNDINGNo targeted funding reported
DISCLOSURESY Ichinose MMiwa A Onohara K Obi and K Shindo report no disclosures H Saitsu receives fundingfrom a Grant-in-Aid for Scientific Research (B) from the Japan Society for the Promotion of ScienceN Matsumoto serves on editorial advisory boards for Clinical Genetics Journal of Human Genetics andAmerican Journal of Medical Genetics Part A receives funding from the Ministry of Health Labour andWelfare the Japan Science and Technology Agency a Grant-in-Aid for Scientific Research on InnovativeAreas (Foundation of Synapse and Neurocircuit Pathology) from the Ministry of Education CultureSports Science and Technology of Japan a Grant-in-Aid for Scientific Research from the Japan Societyfor the Promotion of Science and a grant from the Takeda Science Foundation Y Takiyama serves onthe editorial advisory board for Rinsho Shinkeigaku Full disclosure form information provided by theauthors is available with the full text of this article at Neurologyorgcp
Whatrsquos New in Clinical PracticeNeurologyreg Clinical Practice now has podcasts available for download Thepodcasts are introduced by Editor John R Corboy MD FAAN who highlightspapers from the current issue The interview that follows features authors discussingpapers in more depth and bringing clinical implications to the fore
Neurology Clinical Practice |||||||||||| April 2014 Neurologyorgcp 177
Characteristic MRI findings in beta-propeller protein-associated neurodegeneration (BPAN)
DOI 10121201CPJ0000437694178889b20144175-177 Published Online before print December 20 2013Neurol Clin Pract
Yuta Ichinose Michiaki Miwa Akiko Onohara et al neurodegeneration (BPAN)
Characteristic MRI findings in beta-propeller protein-associated
This information is current as of December 20 2013
ServicesUpdated Information amp
httpcpneurologyorgcontent42175fullhtmlincluding high resolution figures can be found at
References httpcpneurologyorgcontent42175fullhtmlref-list-1
This article cites 2 articles 0 of which you can access for free at
Subspecialty Collections
sonismhttpcpneurologyorgcgicollectionparkinsons_disease_parkinParkinsons diseaseParkinsonism
httpcpneurologyorgcgicollectionmriMRI
httpcpneurologyorgcgicollectionall_geneticsAll Geneticsfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpcpneurologyorgmiscaboutxhtmlpermissionsor in its entirety can be found online atInformation about reproducing this article in parts (figurestables)
Reprints
httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
aceruloplasminemia and pantothenate kinase-associated neurodegeneration this findingshould facilitate the diagnosis of BPAN
REFERENCES1 Haack TB Hogarth P Kruer MC et al Exome sequencing reveals de novo WDR45 mutations causing
a phenotypically distinct X-linked dominant form of NBIA Am J Hum Genet 2012911144ndash11492 Saitsu H Nishimura T Muramatsu K et al De novo mutations in the autophagy gene WDR45 cause
static encephalopathy of childhood with neurodegeneration in adulthood Nat Genet 201345445ndash449
STUDY FUNDINGNo targeted funding reported
DISCLOSURESY Ichinose MMiwa A Onohara K Obi and K Shindo report no disclosures H Saitsu receives fundingfrom a Grant-in-Aid for Scientific Research (B) from the Japan Society for the Promotion of ScienceN Matsumoto serves on editorial advisory boards for Clinical Genetics Journal of Human Genetics andAmerican Journal of Medical Genetics Part A receives funding from the Ministry of Health Labour andWelfare the Japan Science and Technology Agency a Grant-in-Aid for Scientific Research on InnovativeAreas (Foundation of Synapse and Neurocircuit Pathology) from the Ministry of Education CultureSports Science and Technology of Japan a Grant-in-Aid for Scientific Research from the Japan Societyfor the Promotion of Science and a grant from the Takeda Science Foundation Y Takiyama serves onthe editorial advisory board for Rinsho Shinkeigaku Full disclosure form information provided by theauthors is available with the full text of this article at Neurologyorgcp
Whatrsquos New in Clinical PracticeNeurologyreg Clinical Practice now has podcasts available for download Thepodcasts are introduced by Editor John R Corboy MD FAAN who highlightspapers from the current issue The interview that follows features authors discussingpapers in more depth and bringing clinical implications to the fore
Neurology Clinical Practice |||||||||||| April 2014 Neurologyorgcp 177
Characteristic MRI findings in beta-propeller protein-associated neurodegeneration (BPAN)
DOI 10121201CPJ0000437694178889b20144175-177 Published Online before print December 20 2013Neurol Clin Pract
Yuta Ichinose Michiaki Miwa Akiko Onohara et al neurodegeneration (BPAN)
Characteristic MRI findings in beta-propeller protein-associated
This information is current as of December 20 2013
ServicesUpdated Information amp
httpcpneurologyorgcontent42175fullhtmlincluding high resolution figures can be found at
References httpcpneurologyorgcontent42175fullhtmlref-list-1
This article cites 2 articles 0 of which you can access for free at
Subspecialty Collections
sonismhttpcpneurologyorgcgicollectionparkinsons_disease_parkinParkinsons diseaseParkinsonism
httpcpneurologyorgcgicollectionmriMRI
httpcpneurologyorgcgicollectionall_geneticsAll Geneticsfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpcpneurologyorgmiscaboutxhtmlpermissionsor in its entirety can be found online atInformation about reproducing this article in parts (figurestables)
Reprints
httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
DOI 10121201CPJ0000437694178889b20144175-177 Published Online before print December 20 2013Neurol Clin Pract
Yuta Ichinose Michiaki Miwa Akiko Onohara et al neurodegeneration (BPAN)
Characteristic MRI findings in beta-propeller protein-associated
This information is current as of December 20 2013
ServicesUpdated Information amp
httpcpneurologyorgcontent42175fullhtmlincluding high resolution figures can be found at
References httpcpneurologyorgcontent42175fullhtmlref-list-1
This article cites 2 articles 0 of which you can access for free at
Subspecialty Collections
sonismhttpcpneurologyorgcgicollectionparkinsons_disease_parkinParkinsons diseaseParkinsonism
httpcpneurologyorgcgicollectionmriMRI
httpcpneurologyorgcgicollectionall_geneticsAll Geneticsfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpcpneurologyorgmiscaboutxhtmlpermissionsor in its entirety can be found online atInformation about reproducing this article in parts (figurestables)
Reprints
httpcpneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online