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

Penelope (Penny) Hogarth, Allison Gregory, Michael C. Kruer, Lynn Sanford, Wendy Wagoner, Marvin R. Natowicz, Robert T. Egel, S. H. Subramony, Jennifer G. Goldman, Elizabeth Berry-Kravis, Nicola C. Foulds, Simon R. Hammans, Isabelle Desguerre, Diana Rodriguez, Callum Wilson, Andrea Diedrich, Sarah Green, Huong Tran, Lindsay Reese, Randall (Randy) WoltjerSusan Hayflick

Research output: Contribution to journalArticle

89 Citations (Scopus)

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 kinaseassociated neurodegeneration and PLA2G6-associated neurodegeneration as one of the major forms of NBIA.

Original languageEnglish (US)
Pages (from-to)268-275
Number of pages8
JournalNeurology
Volume80
Issue number3
DOIs
StatePublished - Jan 15 2013

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Membrane Proteins
Lewy Bodies
Mutation
Neurites
Neuroaxonal Dystrophies
Iron
Phenotype
Corpus Striatum
Globus Pallidus
Mitochondrial Proteins
Brain
Mitochondrial Membranes
Mutation Rate
Mesencephalon
Basal Ganglia
Medical Records
Dementia
Age Groups
Pathology
Neurodegeneration with brain iron accumulation (NBIA)

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

New NBIA subtype : Genetic, clinical, pathologic, and radiographic features of MPAN. / Hogarth, Penelope (Penny); Gregory, Allison; Kruer, Michael C.; Sanford, Lynn; Wagoner, Wendy; Natowicz, Marvin R.; Egel, Robert T.; Subramony, S. H.; Goldman, Jennifer G.; Berry-Kravis, Elizabeth; Foulds, Nicola C.; Hammans, Simon R.; Desguerre, Isabelle; Rodriguez, Diana; Wilson, Callum; Diedrich, Andrea; Green, Sarah; Tran, Huong; Reese, Lindsay; Woltjer, Randall (Randy); Hayflick, Susan.

In: Neurology, Vol. 80, No. 3, 15.01.2013, p. 268-275.

Research output: Contribution to journalArticle

Hogarth, PP, Gregory, A, Kruer, MC, Sanford, L, Wagoner, W, Natowicz, MR, Egel, RT, Subramony, SH, Goldman, JG, Berry-Kravis, E, Foulds, NC, Hammans, SR, Desguerre, I, Rodriguez, D, Wilson, C, Diedrich, A, Green, S, Tran, H, Reese, L, Woltjer, RR & Hayflick, S 2013, 'New NBIA subtype: Genetic, clinical, pathologic, and radiographic features of MPAN', Neurology, vol. 80, no. 3, pp. 268-275. https://doi.org/10.1212/WNL.0b013e31827e07be
Hogarth, Penelope (Penny) ; Gregory, Allison ; Kruer, Michael C. ; Sanford, Lynn ; Wagoner, Wendy ; Natowicz, Marvin R. ; Egel, Robert T. ; Subramony, S. H. ; Goldman, Jennifer G. ; Berry-Kravis, Elizabeth ; Foulds, Nicola C. ; Hammans, Simon R. ; Desguerre, Isabelle ; Rodriguez, Diana ; Wilson, Callum ; Diedrich, Andrea ; Green, Sarah ; Tran, Huong ; Reese, Lindsay ; Woltjer, Randall (Randy) ; Hayflick, Susan. / New NBIA subtype : Genetic, clinical, pathologic, and radiographic features of MPAN. In: Neurology. 2013 ; Vol. 80, No. 3. pp. 268-275.
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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 kinaseassociated neurodegeneration and PLA2G6-associated neurodegeneration as one of the major forms of NBIA.",
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T2 - Genetic, clinical, pathologic, and radiographic features of MPAN

AU - Hogarth, Penelope (Penny)

AU - Gregory, Allison

AU - Kruer, Michael C.

AU - Sanford, Lynn

AU - Wagoner, Wendy

AU - Natowicz, Marvin R.

AU - Egel, Robert T.

AU - Subramony, S. H.

AU - Goldman, Jennifer G.

AU - Berry-Kravis, Elizabeth

AU - Foulds, Nicola C.

AU - Hammans, Simon R.

AU - Desguerre, Isabelle

AU - Rodriguez, Diana

AU - Wilson, Callum

AU - Diedrich, Andrea

AU - Green, Sarah

AU - Tran, Huong

AU - Reese, Lindsay

AU - Woltjer, Randall (Randy)

AU - Hayflick, Susan

PY - 2013/1/15

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N2 - 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 kinaseassociated neurodegeneration and PLA2G6-associated neurodegeneration as one of the major forms of NBIA.

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