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Stéphane Lehéricy, MD, PhD
Institut Cerveau Moelle (ICM) Sorbonne Université
Hôpital de la Salpêtrière, Paris, France
ESNR Advanced Course on Neurodegenerative Diseases
Movement disorders/ Parkinsonism 8th November 2019
Neurodegeneration with brain iron accumulation – NBIA
Objectives
1. Know what an NBIA is
2. Know the main types of NBIA
3. Know the main MRI aspects of NBIA
NBIA – Neurodegeneration with Brain Iron Accumulation
• Heterogeneous group of diseases
• Estimated prevalence: 0.5 / 100,000
• Very variable age at disease onset
• Childhood / Adult Phenotype: Variable Combination
- Dystonia / parkinsonism +++ (chorea) - facial impairment ++
- Pyramidal syndrome +
- Cognitive deterioration +
- Psychiatric disorders +
• MRI:
- Iron deposits in the globus pallidus and SN
- T2 and T2* hyposignal
NBIA – Neurodegeneration with Brain Iron Accumulation
- Iron overload is toxic because it causes activation of oxidative
processes in the cell
- Diseases related to iron metabolism dysfunction
- Aculoplasminemia
- Neuroferritinopathy
- Diseases in which iron accumulation is possibly associated with
neuronal dysfunction of other origin
- Other NBIA
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NBIA – molecular pathogenesis of NBIA syndromes
Di Meio et al., European Journal of Paediatric Neurology 2018 22, 272-284
Iron homeostasis-associated proteins
PKAN (PANK2) Panthotenate Kinase Associated Neurodegeneration
• Onset: Early childhood - 40 years
• Clinical presentation
• Dystonia / parkinsonism
• Spasticity
• Cognitive dysfunction
• Psychiatric disorders
• Retinitis pigmentosa
• Evolution: Progressive with possible steps
Iron homeostasis-associated proteins
Coenzyme A biosynthesis
PKAN (PANK2) Panthotenate Kinase Associated Neurodegeneration
MRI: "eye of the tiger sign", internal pallidum
CoPAN(COASY) – Coenzyme A synthase Associated Neurodegeneration
• Onset: In childhood by motor difficulties
• Clinical presentation- Dystonia / parkinsonism- Spasticity- Cognitive deterioration- Psychiatric disorders- Axonal neuropathy
Iron homeostasis-associated proteins
Coenzyme A biosynthesis
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Dusi et al. Am J Hum Genet 2014
CoPAN(COASY) – Coenzyme A synthase Associated Neurodegeneration
MRI: • Iron deposition in the pallidum and SN • CN and putamen are swollen and T2 hyperintense
9-year-old
19-year-old
Dusi et al. Am J Hum Genet 2014
CoPAN(COASY) – Coenzyme A synthase Associated Neurodegeneration
MRI: • Iron deposition in the pallidum and
SN • Eye of tiger sign• GP calcification
11-year-old
PLAN (PLA2G6) - PhosphoLipase A2G6 associated neurodegeneration
• Onset in early childhood
- Psychomotor decline
- Cerebellar-spastic involvement
- Cognitive deterioration
- Optic atrophy, polyneuropathy
- Death before adulthood
• Onset in young adult
- Dystonia / parkinsonism
- Cognitive deterioration
- Psychiatric disorders
- Optic atrophy
Iron homeostasis-associated proteins
Lipid metabolism
PLAN (PLA2G6) - PhosphoLipase A2G6 associated neurodegeneration
9-year-old girl T2* MRI
McNeill et al. Neurology 2008 Araújo Salomão et al. Arq Neuropsiquiatr. 2016
MRI: iron deposits in pallidum +/- substantia nigra
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MPAN (c19orf12) - Mitochondrial membrane Protein Associated Neurodegeneration
• Onset: Childhood / adolescence / young adult
• Clinical presentation- Dystonia / parkinsonism- Pyramidal signs- Cognitive dysfunction- Psychiatric disorders- Optic atrophy- Axonal motor neuropathy
Iron homeostasis-associated proteins
Lipid metabolism
Schulte et al. Mov Disord 2013
MPAN (c19orf12) - Mitochondrial membrane Protein Associated Neurodegeneration
• MRI: Iron deposition• Globus Pallidus (visibility of the
internal medullary lamina)• Substantia nigra
FAHN (FA2H) – Fatty Acid 2 Hydroxylase associated Neurodegeneration
• Onset: Childhood or adolescence
• Clinical presentation- Dystonia / parkinsonism- Pyramidal damage- Ataxia- Cognitive disorder- Optic atrophy
Iron homeostasis-associated proteins
Lipid metabolism/Myelin synthesis
FAHN (FA2H) – Fatty Acid 2 Hydroxylase associated Neurodegeneration
Kruer et al. Ann Neurol 2010
• Thinning of corpus callosum
• Ponto-cerebellar atrophy
• Iron deposition in GP: T2* hypointense globus pallidus
• Leucopathy: T2/FLAIR white matter hyperintensities
Araújo Salomão et al. Arq Neuropsiquiatr. 2016
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SCP2 - sterol carrier protein mutations
• Onset: Adulthood• Clinical presentation
- Cerebellar spastic syndrome ± dystonia- Deafness
• Biology- High phytanic and pristanic acid
Horvath et al. Neurology 2015
T2 hypersignal: subcortical white matter, Tha, GP, cerebral peduncles, pons
SWI hyposignal: GP, SN, RN, DN
Lipid metabolism
NBIA – Iron homeostasis-associated proteins
• Aceruloplasminemia
- Ceruloplasmin: Feroxidase that
allows iron to exit astrocytes to bind to
extracellular transferrin.
- If no ceruloplasmin, accumulation of
iron in astrocytes and neurons are
deprived of iron.
• Neuroferritinopathy
- Reduced iron storage by ferritin
polymers: iron leak
Iron homeostasis-associated proteins
Aceruloplasminemia
• Onset: Around 50 years (15-70 years)
• Dystonia-parkinsonism (face +++) / cerebellar syndrome
• Characteristic biological abnormalities:- Collapsed ceruloplasminemia- Hyperferritinemia- Low serum iron and copper
Iron homeostasis-associated proteins
• Systemic impairment (often precedes neurological damage)- Diabetes- Retinopathy- Microcytic anemia
• MRI: Diffuse deposits
Aceruloplasminemia
Fasano et al. Mov Disord 2008
Dysarthria, dysphagia, rest tremor, bradykinesia, Dystonia of right upper limbUnable to stand and walkMental slowing apathy, aggressiveness
Progressive changes with rapid worsening
Type 1 diabetesRetinal degeneration
• Mild normocytic anemia • Low serum iron• High ferritin• Ceruloplamin undetectable
56-year-old man
Homozygous deletion of two nucleotides in exon 7 of ceruloplasmin gene causing a premature stop of the protein translation
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Aceruloplasminemia
Fasano et al. Mov Disord 2008
Sister of the previous patient• Anemia • Low serum iron• High ferritin
• Mild akinetic signs
53-year-old female
Homozygous deletion of two nucleotides in exon 7 of ceruloplasmin gene causing a premature stop of the protein translation
Aceruloplasminemia
Araújo Salomão et al. Arq Neuropsiquiatr. 2016
Neuroferritinopathy
• Onset: In general around 40 years
• Clinical presentation• Dystonia and / or chorea and / or
parkinsonism• Cognitive deterioration• Psychiatric disorders• (cerebellar or pyramidal signs)
• Hypoferritinemia (¾)
• Autosomal dominant transmission
Iron homeostasis-associated proteins
Neuroferritinopathy
McNeill et al. Neurology 2008
69-year-old woman
Devos et al. Brain 2009
MRI: diffuse deposits ± cavitations
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Neuroferritinopathy
Nishida et al. J Neurol Sci 2014
44-year-old
Devos et al. Brain 2009
BPAN (WDR45) – Beta-propeller Protein Associated Neurodegeneration
• Biphasic evolution profile
• Non-progressive chronic encephalopathy (early childhood)- Psychomotor delay- Pyramidal attack- Epilepsy- Stereotypies
Iron homeostasis-associated proteins
• Secondary appearance (at adulthood)- Dystonia syndrome / Parkinsonism - Cognitive impairment
• X-linked dominant transmission (girls only)
Autophagosome / Lysosome
Haack et al. Int Rev Neurobiol 2013
BPAN (WDR45) – Beta-propeller Protein Associated Neurodegeneration
MRI: Iron deposition in the pallidum and SN Hyperintense halo in SN in T1 Uchino et al. Mov Disord Clin Practice 2015
BPAN (WDR45) – Beta-propeller Protein Associated Neurodegeneration
MRI at 9 yearsIron deposition in the pallidum and SN No hyperintense halo in SN in T1(video of clinical presentation)
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DCAF17 mutations – Whoudhouse-Sakati syndrome
• Onset: Early childhood or adolescence• Alopecia +++, Deafness ++
Hypogonadism +++, Diabetes ++, Dysthyroidism +Cognitive disorders ++, epilepsy +Dystonia ++
• Leukodystrophy possible
ATP13A2 mutations – Kufor-Rakeb syndrome
• Onset: teenager or young adult• Dystonia-parkinsonism-pyramidal syndrome
Vertical supranuclear paralysisMini myoclonies of the face and fingersCognitive-psychiatric disorders (sometimes inaugural)
Schneider et al. Mov Disord 2008 and 2010
Iron homeostasis-associated proteins
Autophagosome
GBL1 mutations - GM1 type3 gangliosidosis
Hajirnis et al. Mov Disord Clin Practice 2015
AP4M1 – adaptor protein complex-4 mutations
• Onset: Early childhood• Clinical presentation
Mental retardation, facial dysmorphismSpastic Pyramidal Syndrome and DeficitSecondary Motor Degradation / Parkinsonian and Dystonic Syndrome
Roubertie et al. Neurology Genetics 2018
Case 1 Case 2 Control
DDHD1 mutations
• Onset: Early childhood usually
• DDHD1 encodes the membrane associated phosphatidic acid specific phospholipase a1 (mPA-PLA1, participates to plasmatic membrane remodelling)
• Clinical presentationPure spastic paraparesis or associated with Axonal Neuropathy, Cerebellar AtaxiaRetinopathy, Optic NeuropathyCognitive decline and psychiatric disorders
Dard et al. Eur J Medical Genetics 2017
• Thin corpus callosum • T2* hyposignal of the
globus pallidus
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GTPBP2 mutations
• Onset: Early childhood
• GTPBP2 gene encodes GTP-binding protein 2
• Clinical presentationMental retardation and behavioral disordersAtaxia +/- dystoniaMotor neuropathyRetinopathy
Jaberi et al. Neurobiol Aging 2016
• Vermian atrophy• SWI hyposignal of the
globus pallidus and SN
SummaryFrequency onset MRI
PKAN +++ Child Eye of tigerYoung adult
PLAN ++ Child GP ± SNYoung adult
MPAN ++ Child GP + SNYoung adult Int med Lamina
BPAN ++ Early childhood GP + SNSN rim
Aceruloplasminemia + Adult (40) diffuse
Ferritinopathy + Adult (50) diffusecavitations
FAHN + Child GPTeenager Leucopathy
CoPAN + Child GP + SNHST2 striatum
NBIA: treatment
• Chelating treatment of iron passing the BBB?
• Deferiprone
• N = 6 PKAN patients / open label trial (Cossu et al, PRD, 2014): 4-year stabilization / reduction of MRI iron overload
• N = 9 PKAN patients / open label trial (Zorzi et al. Mov Disord, 2011): no evolution over 6 months / decrease in iron overload
• N = 5 PKAN / open (Rohani, Neurol Int, 2018): no change over 18 months / decrease in iron overload
• Symptomatic treatment dystonia-parkinsonism• Pharmacological treatment• Local treatment• Surgical treatment (Timmermann, Brain, 2010)
Take home messages
• Several genes encoding genes in• Iron metabolism• Lipid metabolism• Lysosomal activity • Autophagic processes
• Very variable age at disease onset: • Childhood => Adult
• Variable Combination• Movement disorder, painful dystonia, parkinsonism, • Mental disability• Retinopathy, optic atrophy, axonal neuropathy, diabetes, cerebellar syndrome• Early death
• MRI• Iron deposits in the globus pallidus and SN• SWI, T2 and T2* hyposignal
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ICM – Institut Cerveau Moelle (Paris, Hôpital de la Salpêtrière)ICM – U1127, Inserm, CNRS 7225, Sorbonne UniversitéServices de neuroradiologie et neurologie
Isabelle ArnulfEmma BiondettiLydia ChougarBertrand DegosClaire EwenczykCécile GalleaFatma GargouriRahul GauravDavid GrabliSmaranda Leu-SemenescuFanny MochelNadya PyatigorskayaEmmanuel RozeSophie SanglaMarie Vidailhet
SummaryFrequency onset MRI Clues
PKAN +++ Child Eye of tiger retinopathyYoung adult
PLAN ++ Child GP ± SN optic atrophyYoung adult axonal neuropathy
MPAN ++ Child GP + SN optic atrophyYoung adult Int M Lamina axonal neuropathy
BPAN ++ Early childhood GP + SN Dominant X transm
SN rim Biphasic evolution
Aceruloplasminemia + Adult (40) diffuse Diabetes, anemia, retonopathy, cereb
Ferritinopathy + Adult (50) diffuse Dominantstriatal HST2 Hypoferrinemia
FAHN + Child GP Optic atrophy Teenager Leucopathy Cereballar synd
CoPAN + Child GP + SN Axonal neuropathy Strital HST2
Summary
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