NBIA – Neurodegeneration with Brain Iron Accumulation · NBIA – molecular pathogenesis of NBIA...

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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


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


Coenzyme A biosynthesis

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Dusi et al. Am J Hum Genet 2014


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


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


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


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


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


Aceruloplasminemia

• Onset: Around 50 years (15-70 years)

• Dystonia-parkinsonism (face +++) / cerebellar syndrome

• Characteristic biological abnormalities:- Collapsed ceruloplasminemia- Hyperferritinemia- Low serum iron and copper


• 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


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


• Secondary appearance (at adulthood)- Dystonia syndrome / Parkinsonism - Cognitive impairment

• X-linked dominant transmission (girls only)

Autophagosome / Lysosome

Haack et al. Int Rev Neurobiol 2013


MRI: Iron deposition in the pallidum and SN Hyperintense halo in SN in T1 Uchino et al. Mov Disord Clin Practice 2015


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


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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NBIA – Neurodegeneration with Brain Iron Accumulation · NBIA – molecular pathogenesis of NBIA...

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