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New NBIA subtype: Genetic, clinical, pathologic, and radiographic features of MPAN

New NBIA subtype: Genetic, clinical, pathologic, and radiographic features of MPAN
New NBIA subtype: Genetic, clinical, pathologic, and radiographic features of MPAN
Objective: to assess the frequency of mutations in C19orf12 in the greater neurodegeneration with brain iron accumulation (NBIA) population and further characterize the associated phenotype.

Methods: samples from 161 individuals with idiopathic NBIA were screened, and C19orf12 mutations were identified in 23 subjects. Direct examinations were completed on 8 of these individuals, and medical records were reviewed on all 23. Histochemical and immunohistochemical studies were performed on brain tissue from one deceased subject.

Results: a variety of mutations were detected in this cohort, in addition to the Eastern European founder mutation described previously. The characteristic clinical features of mitochondrial membrane protein-associated neurodegeneration (MPAN) across all age groups include cognitive decline progressing to dementia, prominent neuropsychiatric abnormalities, and a motor neuronopathy. A distinctive pattern of brain iron accumulation is universal. Neuropathologic studies revealed neuronal loss, widespread iron deposits, and eosinophilic spheroidal structures in the basal ganglia. Lewy neurites were present in the globus pallidus, and Lewy bodies and neurites were widespread in other areas of the corpus striatum and midbrain structures.

Conclusions: MPAN is caused by mutations in C19orf12 leading to NBIA and prominent, widespread Lewy body pathology. The clinical phenotype is recognizable and distinctive, and joins pantothenate kinase-associated neurodegeneration and PLA2G6-associated neurodegeneration as one of the major forms of NBIA
0028-3878
268-275
Hogarth, P.
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Gregory, A.
15080e77-ce26-4f52-aae6-33bf6972497e
Kruer, M.C.
d17928d1-923a-4b5d-8fb5-d2f88761f79f
Sanford, L.
35e363d1-edb1-46c6-8d38-b3dd3ab39065
Wagoner, W.
c978adfe-466b-4ff3-8a6d-89decbc5a168
Natowicz, M.R.
5234bd3f-b59c-4f75-8074-8b148d20d315
Egel, R.T.
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Subramony, S.H.
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Goldman, J.G.
65a37a27-6d49-45f5-ab2c-e1a627ab1abd
Berry-Kravis, E.
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Foulds, N.C.
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Hammans, S.R.
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Desguerre, I.
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Rodriguez, D.
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Wilson, C.
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Diedrich, A.
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Green, S.
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Tran, H.
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Reese, L.
48914f5e-0614-43e4-93f2-65fd6ed57984
Woltjer, R.L.
b9770c09-69e8-44f7-981a-5270187efe0a
Hayflick, S.J.
ebf13fda-095a-482a-afdd-92bae2c6c002
Hogarth, P.
79c358a0-cd75-492c-9aa2-28bd56dbc731
Gregory, A.
15080e77-ce26-4f52-aae6-33bf6972497e
Kruer, M.C.
d17928d1-923a-4b5d-8fb5-d2f88761f79f
Sanford, L.
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Wagoner, W.
c978adfe-466b-4ff3-8a6d-89decbc5a168
Natowicz, M.R.
5234bd3f-b59c-4f75-8074-8b148d20d315
Egel, R.T.
0ed3535f-4234-49dc-9abf-d534e077dd19
Subramony, S.H.
07d1775f-5877-4fac-a577-9a7c378fed66
Goldman, J.G.
65a37a27-6d49-45f5-ab2c-e1a627ab1abd
Berry-Kravis, E.
a5220538-09f4-4b55-82a4-77735f31162d
Foulds, N.C.
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Hammans, S.R.
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Desguerre, I.
411d67b7-00fc-4a4a-8609-80c153a4c227
Rodriguez, D.
f9160361-c778-4c67-91c8-ccf88912a579
Wilson, C.
8f81973c-e436-4727-97fd-de70017a9f56
Diedrich, A.
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Green, S.
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Tran, H.
f70aeab5-8f41-4170-9c59-d54cd455def5
Reese, L.
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Woltjer, R.L.
b9770c09-69e8-44f7-981a-5270187efe0a
Hayflick, S.J.
ebf13fda-095a-482a-afdd-92bae2c6c002

Hogarth, P., Gregory, A., Kruer, M.C., Sanford, L., Wagoner, W., Natowicz, M.R., Egel, R.T., Subramony, S.H., Goldman, J.G., Berry-Kravis, E., Foulds, N.C., Hammans, S.R., Desguerre, I., Rodriguez, D., Wilson, C., Diedrich, A., Green, S., Tran, H., Reese, L., Woltjer, R.L. and Hayflick, S.J. (2013) New NBIA subtype: Genetic, clinical, pathologic, and radiographic features of MPAN. Neurology, 80 (3), 268-275. (doi:10.1212/WNL.0b013e31827e07be). (PMID:23269600)

Record type: Article

Abstract

Objective: to assess the frequency of mutations in C19orf12 in the greater neurodegeneration with brain iron accumulation (NBIA) population and further characterize the associated phenotype.

Methods: samples from 161 individuals with idiopathic NBIA were screened, and C19orf12 mutations were identified in 23 subjects. Direct examinations were completed on 8 of these individuals, and medical records were reviewed on all 23. Histochemical and immunohistochemical studies were performed on brain tissue from one deceased subject.

Results: a variety of mutations were detected in this cohort, in addition to the Eastern European founder mutation described previously. The characteristic clinical features of mitochondrial membrane protein-associated neurodegeneration (MPAN) across all age groups include cognitive decline progressing to dementia, prominent neuropsychiatric abnormalities, and a motor neuronopathy. A distinctive pattern of brain iron accumulation is universal. Neuropathologic studies revealed neuronal loss, widespread iron deposits, and eosinophilic spheroidal structures in the basal ganglia. Lewy neurites were present in the globus pallidus, and Lewy bodies and neurites were widespread in other areas of the corpus striatum and midbrain structures.

Conclusions: MPAN is caused by mutations in C19orf12 leading to NBIA and prominent, widespread Lewy body pathology. The clinical phenotype is recognizable and distinctive, and joins pantothenate kinase-associated neurodegeneration and PLA2G6-associated neurodegeneration as one of the major forms of NBIA

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e-pub ahead of print date: 26 December 2012
Published date: January 2013
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 346605
URI: http://eprints.soton.ac.uk/id/eprint/346605
ISSN: 0028-3878
PURE UUID: be720c85-3552-46e7-94eb-1dc2bd3f1e27

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Date deposited: 03 Jan 2013 11:24
Last modified: 08 Jan 2022 17:57

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Contributors

Author: P. Hogarth
Author: A. Gregory
Author: M.C. Kruer
Author: L. Sanford
Author: W. Wagoner
Author: M.R. Natowicz
Author: R.T. Egel
Author: S.H. Subramony
Author: J.G. Goldman
Author: E. Berry-Kravis
Author: N.C. Foulds
Author: S.R. Hammans
Author: I. Desguerre
Author: D. Rodriguez
Author: C. Wilson
Author: A. Diedrich
Author: S. Green
Author: H. Tran
Author: L. Reese
Author: R.L. Woltjer
Author: S.J. Hayflick

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