kai-hsiang chen, md yih-chih kuo, md national taiwan

Common presentations of Uncommonmovement disorders

Presenters: Kai-Hsiang Chen, MDYih-Chih Kuo, MD

National Taiwan University Hospital

July 11th, 2021 1

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Progressive gait disordersPresented by Kai-Hsiang Chen (Stanley)Dep. of Neurology, National Taiwan University Hospital, Hsinchu branch, Taiwan

Outline

Progressive cognitive decline+ variable movement disorders with unique brain MRI findingsPresented by Yih-Chih Kuo (Jacinta)Dep. of Neurology, National Taiwan University Hospital, Biomedical Park branch, Taiwan

Progressive parkinsonism+ variable movement disorders Presented by Kai-Hsiang Chen (Stanley)Dep. of Neurology, National Taiwan University Hospital, Hsinchu branch, Taiwan

Progressive gait disorders

Kai-Hsiang Chen (Stanley), MDDepartment of Neurology, National Taiwan University

Hospital, Hsinchu branch, Taiwan

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Case 1A 47-year-old-woman presented with progressive

gait disturbance for 10 years

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Clinical course24 y/o- Fell from 3rd floor, multiple fracture, received blood transfusion

32 y/o- start to have gait disturbance37 y/o- Progressive gait disturbance and leg stiffness- Neurology OPD: Increased DTR without weakness

47 y/o- Need single cane, urinary urgency with incontinence

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Phenomenology• Spastic gait

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Family History

• No remarkable family history

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Work-up• Serum

• VitB12, folic acid: WNL• Thyroid function: WNL• Autoimmune profile: negative• Tumor markers: negative• HIV Ab: negative

• CSF Study• WBC: 1 (lymphocyte)• Total Protein: 33.1 mg/dL• Glucose: 62 mg/dL• IgG index: 0.36

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MRI results

C-spine T2W

T-spine T1W+CT-spine T2W

Brain FLAIR

Normal findings in brain MRIwith spinal cord mild atrophy

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Lab data• SPG4 gene mutation• Anti-GAD antibody• HTLV-1 antibody

• Paraneoplastic Ab panel

Negative

Positive: blood (117), CSF (16)(Normal range: <1)

Negative

Negative

Final DiagnosisHuman T-lymphotrophic virus-type 1-associated myelopathy

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Clinical features of HTLV-1 associated Myelopathy

• Onset > 40 y/o• Insidious onset; occasional

abruptly in weeks• Slowly progressive• Variable progression rate

• Symptoms: • Onset with Gait disturbance and lower

limb weakness• Early bladder dysfunction• Common back pain, sexual dysfunction• Mild sensory symptoms ~15 years shorter than life expectancy

~6%

Yamano Y et al. Front Microbiol. (2012) 11

key to the diagnosis?

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• Blood transfusion history!• Spinal cord atrophy

Case 2A 36-year-old-man presented with progressive

gait disturbance for 3 years

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Clinical courseNormal developmental milestone at childhood

Elementary school- Intellectual disability, mild- Poor exercise and academic performance (ran slow, jumped low, and fell easily)

20 y/o- Epilepsy, but well controlled by valproic acid and zonisamide

33 y/o - Gait disturbance

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Phenomenology• Spastic gait

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Additional features• Epilepsy• Mild intellectual disability

Neurological Examination

REFLEXGeneralized hyper-reflexiaLeft ankle clonusHoffman's sign: -/+, Babinski's sign: ext/ext

Parkinsonism(-), Dystonia(-), Tremor(-)F-N-F: no dysmetriaGait: Spastic gait

SENSORY-Small fiber:

Pinprick: symmetric Light touch: symmetric-Large fiber:

Vibration: NormalJoint position: Normal

-Romberg test: negative

EOM: full and freeNystagmus: (-), Saccade: normalpursuit: smooth

*No remarkable family history

Labs– All within normal limitsHemogram

WBC 7.62

RBC 5.28

HB 15.0

HCT 45.3

MCV 85.8

MCH 28.4

MCHC 33.1

PLT 241

RDW-CV 13.2

Basic Chemistry

Alb 4.3

AST 18

ALT 17

UN 16.9

CRE 0.9

Na 142

K 4.3

Ca 2.47

P 3.1

Mg 0.79

Infection

HTLV I=II Negative

Immune

ANA 1:40(-)

Anti-ENA Negative(0.13)

C3 117.00

C4 19.00

RA factor <10.10

Anti-dsDNA 23.96

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Brain and C spine MRI

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Genetic results: Whole Exome Sequencing• De novo heterozygous KIF1A mutation, c.3400G>A (p.Asp1134Asn)

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Final DiagnosisAutosomal dominant spastic paraplegia (SPG30)

Journal of Korean Medical Science 2004European Journal of Human Genetics (2020) 28:40-49 20

cerebellar atrophy

posterior white matter hyperintensity

dentate nuclei hyperintensity

thin posterior corpus callosum

frontal lobe atrophy

ex vacuo ventricular dilatation

Nicita F, et al. J Med Genet 2020;0:1–9.21

SPG30 Spectrum

• Previously cases showed AR inherited• The 2nd or 3rd most common AD HSP (less than SPG4 and SPG3 in different cohort)• 8% in all verified HSP cases• Brain and spine MRI could be normal

Pure spastic Parparesis

Autosomal Dominant mental retardationtype 9

HereditarySensory Neuropathy

Cerebellar Ataxia

Epilepsy

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Rudenskaya et al, BMC neurology (2020) 20:290D’Amore et al., Frontiers in Neurology 2018

European Journal of Human Genetics (2020) 28:40-49


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• Complicated HSP without abnormalities in MRI• Increasing prevalence of SPG30 in HSP!

Case 3A 63-year-old man with progressive gait

disturbance for 5 Years

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• Episodic right leg painful spasm for 5 years• Onset during sleep, walking, driving• Exaggerated by acoustic stimulation

• Progressive bilateral lower legs tightness with gait disturbance

• No sensory or sphincter problems

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Clinical course

Phenomenology• Gait stiffness, like a robot

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Additional features• Painful muscle cramps

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Family pedigree

666

HTN

AS AS

63 62

30

• No remarkable family history

Laboratory Findings

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Blood

Hb (g/dL) 16.5

Plt (K/uL) 166

WBC (K/uL) 10.28

AST (U/L) 30

ALT (U/L) 39

Cre (0.9) 0.9

Vit B12(pg/ml)

765

Folic Acid(ng/ml)

6.92

Rheumatology

ANA 1:40(-)

C3 (mg/dL) 88.1

C4 (mg/dL) 25.1

RA Factor <9.19

IgG (mg/dL) 1420.00

HLA-B27 Negative

Tumor marker

AFP (ng/mL) <2.0

CA-125 (U/mL) 4.9

PSA (ng/mL) 1.381

CEA (ng/mL) 2.29

CA19-9 (U/mL) 10.2

Endocrine/Infection

Cortisol (ug/dL) 7.37

ACTH (pg/mL) 17.4

HTLV I+II (-)

Cerebral Spinal Fluid

RBC(x10/9/uL)

0

WBC(x10/9/uL)

0

Total protein(mg/dL)

49.5

Albumin(mg/dL)

26

Glucose(mg/dL)

80

IFE Albumin only

IgG (mg/dL) 5.25 (IgGindex=0.55)

Cytology Negative formalignant cell

Brain and Spinal Cord MRI

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Anti-GAD Ab• Serum=74.5 U/mL (normal range: < 0.8 U/mL)• CSF=13.7 U/mL (normal: non-detectable)

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Final DiagnosisStiff-person syndrome

Electrophysiological assessment in SPS

Diazepam injection

Clapping

Active MUAP in paraspinal muscle Exteroceptive stimulation

Stiff-person syndrome and related disorder 2020Muscle and Nerve 2006

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SPS spectrum

Stiff-person syndrome, startle and other immune-mediated movement disorders– new insights, Balint and Bhatia 2018

SPS: Stiff-person syndromeSLS: Stiff-limb syndromePERM: Progressive encephalomyelitis with rigidity and myoclonusCerebellar ataxia

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• Painful spasm without definite spasticity• Stiff, “Robotic” gait!

Summary of progressive gait disorders

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• Gait abnormality sometimes looks alike • Treatable etiology should be ruled out first• For late onset complicated HSP, gene sequencing for SPG30 should be

considered

Case 4A 35 y/o woman with progressive writing difficulty and

slurred speech for 10 years

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Clinical courseNormal developmental milestone

Age 20s- progressive difficulty in writing, sometimes with painful spasms- progressive slurred speech

Age 30s- Unsteady gait, fall twice- left hand and foot abnormal posturing- Impaired ability at work

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Phenomenology• Prominent craniocervical/axial dystonia + blepharospasm• Parkinsonism (bradykinesia)• Dysdiadochokinesia and mild ataxia• Gait: dystonic gait, wide base (+)

Additional features• Cognitive impairment• Psychiatric symptoms (depression, emotional liability, impulsivity, OCDs)

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Family pedigree• No associated family history• No consanguineous marriage

●

Breast cancer

CAD

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Localization and etiology• Multi-system involvements

- Basal ganglia, cerebellum, corticospinal tract, frontal-subcortical circuitry

• Etiology- Secondary: toxic-metabolic, structural, drug-induced (less likely for chronic, progressive course without systemic illness)- Wilson’s disease- SCA 3, SCA 17, DRPLA (Dentato-rubral-pallido-luysian atrophy)

- Dystonia-plus syndromes: DYT 12 (rapid-onset dystonia-parkinsonism), DYT 3 (X-Linked

Dystonia-Parkinsonism), DYT 16 (Early-onset dystonia parkinsonism)

- Neuroacanthocytosis- NBIA (neurodegeneration with brain iron accumulation)

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Work-up• Blood panels:

- autoimmune profile, endocrine profile (thyroid/adrenal) WNL- serum ceruloplasmin, 24-hour urine copper WNL- Blood smear: no acanthocytosis• Electrodiagnostic studies: NCV, SSEP, MEP WNL• Eye findings: KF ring(-), cherry-red spot(-),

pigmentary retinopathy(-)• Genetic panels: no mutation identified on

mitochondria DNA point mutation analysis, SCA 1, 2, 3, 6, 17, DRPLA

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“eye of the tiger” on T2-weighted MRI

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Genetic analysis: Direct Sanger sequencingCompound heterozygous PANK2 p.N500I/p.L111E mutation

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Final DiagnosisPantothenate Kinase-Associated Neurodegeneration (PKAN)

Neurodegeneration with brain iron accumulation (NBIA)• A group of rare inherited disorders with abnormal iron accumulation in the basal

ganglia, mainly the globus pallidus (GP) and substantia nigra (SN)• PKAN is the most common subtype of NBIA

Hogarth P. JMD, 2015; 8(1): 1-13.44

Pantothenate Kinase-Associated Neurodegeneration (PKAN)

N Engl J Med 2003;348:33-40. 45

~68%

More spasticity

More cognitive/psychiatry involvement

PKAN in Asians patientsmore segmental dystonia, less pyramidal involvement, less mental impairment

Lee CH, et al., Scientific World Journal. 2013;19:860539 46

Clinical characteristics of Korean adults with atypical PKAN (N=15)

Lee JH et al., J Mov Disord 2016;9(1):20-27 47

• Limb dystonia (80%)• Craniocervical dystonia (53%)• Gait disturbance (80%)• Dysarthria (67%)


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craniocervical dystonia + multi-system involvement

Eye of the tiger sign on T2W MRI

Case 5A 27 y/o man with rapid progressive generalized rigidity

and slow response for 1 year

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Age 25- cognitive decline (impaired ability at work as a waiter)- drop plates and easily tripped over

Age 27- generalized tightness of four limbs, gradually became bed-bound- slurred speech, swallowing difficulty- poor family supportive system

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Phenomenology• Dystonia (generalized dystonia, retrocolis)• Spontaneous upgoing toe• Parkinsonism (rigidity, bradykinesia)• Frontal releasing signs: grasp +/+, snouting +, glabellar +• Spasticity(+), hyper-reflexia

Additional features• Cognitive impairment (memory decline)• Psychiatry involvement not very prominent

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Family pedigree• No consanguineous marriage

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Localization and etiology• Multi-system involvements

- Basal ganglia, cerebellum, corticospinal tract, frontal-subcortical circuitry

• Etiology:- Secondary: not likely due to positive family history- Hereditary degenerative disease: SCAs, Huntington disease Westphal variant, neuroacanthocytosis, NBIA…etc. with possible AD inheritance

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Work-up• Autoimmune profile, albumin, ammonia, CK, TSH/free T4, e-, VDRL WNL• Serum Cu: 814 ug/L, Serum ceruloplasmin: WNL• MMSE: cannot evaluate• Fundoscopy: negative findings• Gene: SCA 1, SCA 2, SCA 3 and IT-15 gene: negative

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“eye of the tiger” on T2-weighted MRI

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Genetic analysis: whole exome sequencing

frameshift insertion

WT

HET

Heterozygous C19orf12 (c.273_274insA:p.P92Tfs*9) mutationCo-segregation within the family

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Final Diagnosismitochondrial membrane protein-associated neurodegeneration

(MPAN)

MPAN (Mitochondrial Membrane Protein-Associated Neurodegeneration)

Neurology. 2013 Jan 15;80(3):268-75 57

• Accounts for ~10% in NBIA syndromes, multiple system presentation (in addition to dystonia, spasticity, and parkinsonism, characterized with marked cognitive decline, neuropsychiatric abnormalities, and a motor neuronopathy)

• Previously viewed as only AR inheritance, but now with more AD families reported

A. Gregory et al., Mol Genet Genomic Med. (2019)

Subtypes of NBIAsPKAN PLAN MPAN BPAN FAHN CoPAN KRS WSS NF ACP

AR AR AR/AD XLD AR AR AR AR AD AR

PANK2 PLA2G6 C19orf12 WDR45 FA2H COASY ATP13A2 DCAF17 FTL CPLipidMitoCoA

Lipid LipidMito

Autophagy Lipid CoA MitoAutophagy

undetermined Iron Iron

childhood Infantilechildhood

childhoodearly adult

childhood childhood childhood juvenile childhood mid-life adult

GP, SN, STN GP, SN GP, SN SN, GP GP, SN GP, SN Putamen, caudate,

GP

GP, SN Widespread (BG, TH,

Cerebellum, cortex)

Widespread (BG, TH, Cerebellum,

cortex)

Typical eye of

tiger sign (EOT)

Cerebellar atrophy

Optic atrophy

Occasional with “EOT”;mostly with isointense

medial medullary

lamina of GP

Halo SN (T1) WML (PVWM, parietal)Ponto-

cerebellar atrophy, Thin

corpus callosum

T2 hyper- in caudate/put

amen

All atrophy WML (PVWM, fronto-

parietal)

Occasional with “EOT”;Mostly with cavitation

involving GP and

putamen

Iron in liver, pancreas,

myocardium

Rubens Paulo Araújo et al, A diagnostic approach for neurodegeneration with brain iron accumulation: clinical features, genetics and brain imaging, Arq Neuropsiquiatr 2016;74(7)

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Eye-of-tiger-sign on brain MRI• Low T2 signal in the globus pallidus: abnormal accumulation of iron (Fe3+)

- Iron is absent in CNS at birth, but deposits in life in healthy adults, with the highest concentrations occurring in the globus pallidus and substantia nigra as metalloprotein ferritin, while serum CSF iron/ferritin level are normal

• Central high signal: gliosis and spongiosis (increased water content, and neuronal loss with disintegration, vacuolization, and cavitation of the neuropil)

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Eye of tiger sign in NBIA syndromesPKAN

(typical central gliosis)MPAN

(isointense medial medullary lamina of GP)

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Neuroferritinopathy(more diffuse changes, and GP cavitation)

Lee J-H, Yun JY, Brain MRI Pattern Recognition in Neurodegeneration With Brain Iron Accumulation. Front. Neurol. 11:1024, 2020McNeil et al, T2∗ and FSE MRI distinguishes four subtypes of neurodegeneration with brain iron accumulation. Neurology. (2008) 70:1614–9.


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Generalized dystonia + multi-system involvement? Lots of DDx…MPAN can also present with AD inheritance + Eye of tiger sign

Maria Stamelou et al, Movement Disorders, Vol. 28, No. 10, 2013

Case 6A 25 y/o man with slowly progressive cerebellar ataxia

since early childhood

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Early childhood- easy falls and unsteadiness, poor academic/physical performance

19 y/o- Insidious onset of no-no type head shaking

25 y/o- more unsteadiness, but with a slow progression course

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Phenomenology• Cerebellar signs

- Eye signs: saccadic pursuit, hypermetric saccade, gaze-evoked nystagmus- FNF, HNS: bilateral minimal dysmetria- Failed tandem gait- No-no type head tremor• Spasticity (+), hyper-reflexia(+)• Lower limbs decreased vibration sense

Additional features• Cognitive impairment since childhood

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Family pedigree• No consanguineous marriage

I

II

1 2

1 2 326 y/o 25 y/o 24 y/o

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Localization and etiology

• Localization:- Cerebellum, corticospinal tract, frontal-subcortical circuit, peripheral nerve

• Etiology: slowly progressive, secondary cause less likely- Autosomal recessive spinocerebellar ataxia (SCA)- Sporadic acquired ataxia (Vitamin E deficiency, toxin, anti-GAD syndrome)- Storage diseases (inborn error, cerebrotendinous xanthomatosis)- Other neurodegenerative disorder

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Work-up for cerebellar ataxia• Vitamin E: within normal limits• Tandem mass, Plasma amino acid, Urine organic acid : within normal

limits• Screening of Niemann-Pick disease and adrenoleukodystrophy : normal• SCA 1, 2, 3, 6, 17, DRPLA: normal• Mitochondrial gene 3243: normal

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2014 (19 Y/O)

2020 (25 Y/O)

T2 FLAIR T2 T2 MRI “eye of the tiger”

Genetic analysis: whole exome sequencing

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De novo heterozygous AFG3L2 (c.2021_2023delCCT) mutation

Sanger sequencing traces confirm the mutation not in the parents

Image of the Integrative Genomics Viewer (IGV)

Pin-Shiuan Chen, et al, Eye-of-Tiger Sign in Globus Pallidus: A Novel Radiological Feature of Spinocerebellar Ataxia Type 28; Movement Disorders, 2021DOI: 10.1002/mds.28699

Final Diagnosisspinocerebellar ataxia 28 (SCA 28)

Functional assay: mitochondrial interconnectivity in skin fibroblast

• significant reduction of mitochondrial interconnectivity and increase in fragmented mitochondria in fibroblast in the patient

70Pin-Shiuan Chen, et al, Eye-of-Tiger Sign in Globus Pallidus: A Novel Radiological Feature of Spinocerebellar Ataxia Type 28; Movement Disorders, 2021

DOI: 10.1002/mds.28699

AFG3L2 mutation

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• AFG3L2 gene : AFG3 Like Matrix AAA Peptidase Subunit 2

• Encodes m-AAA metalloprotease complex at the inner mitochondrial membrane (IM), to maintain mitochondrial connectivity, highly expressed in cerebellar Purkinje cells

Heterozygous: SCA 28 Homozygous: spastic ataxia 5 (SPAX 5)AD inherence AR inherence

Young adulthood onset (around 26.5 y/o) Infancy or early childhood onset• Slowly progressive cerebellar ataxia, Spasticity• Ocular problems (ptosis, gazed-evoked nystagmus,

slow saccade, ophthalmoplegia)• Dysarthria• Parkinsonism (rigidity, bradykinesia)

• Cerebellar ataxia, spasticity• Myoclonic epilepsy / Tonic-clonic seizure• Dysphagia, Oculomotor apraxia• Axonal peripheral sensorimotor

neuropathy → distal lower limbs muscle atrophy and weakness


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Slowly progressive “Spastic-Ataxia” + multi-system involvement“Eye of the tiger sign” on brain MRI + cerebellar atrophy

But minimal interval changes!

Summary of variable movement disorders with unique brain MRI findings

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• Previous a hallmark of PKAN• But not pathognomonic! Should be viewed as an imaging phenocopy in other

conditions with errors in iron metabolism/transport/homeostasis- Other subtypes of NBIAs (MPAN, Neuroferritinopathy…etc.)- Certain ataxia syndromes (DRPLA, SCA-28…etc.)- Multiple sclerosis, Parkinson’s disease…etc.- Others rarely reported: Wilson disease, MS, PD, Atypical parkinsonism (CBD, PSP, MSA…etc.), CO intoxication

Lee J-H, Yun JY, Brain MRI Pattern Recognition in Neurodegeneration With Brain Iron Accumulation. Front. Neurol. 11:1024, 2020

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Summary of variable movement disorders with unique brain MRI findings

multiple neurological presentations(cognitive decline, parkinsonism, dystonia, ataxia, spasticity)

“Eye of the tiger sign” on brain MRI

NBIAsespecially PKAN (or MPAN, NF)

SCA 28

Mainly Dystonia + Parkinsonism

(craniocervical dystonia,dystonic Opisthotonus)

Mainly Ataxia + Parkinsonism

Slow progression

Progressive parkinsonism + variable movement disorders

Kai-Hsiang Chen (Stanley), MDDepartment of Neurology, National Taiwan University

Hospital, Hsinchu branch, Taiwan

75

Case 7A 26-year-old man with progressive neck force

turn to the right side for 2 months

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Clinical courseNormal developmental milestone in the childhood

26 y/o (Nov 2019)- Insidious onset slowly progression neck turning to the right side- Trunk tilting to the right as well

- He came from Philippine and worked in Taiwan - Not taking any antipsychotics- No traumatic history- Without urge to move sensation

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Phenomenology• Cervical dystonia, truncal dystonia• Parkinsonism

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Family pedigree

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Lab: no obvious abnormal findings

80

WBC 5.8 1000/uLCreatinine 0.88 mg/dLALT/GPT 11 U/LTotal CK 114

Ceruloplasmin 19.5 mg/dL

Cu 72.2 ug/dLCu(Copper)(U) (once) 1.0 ug/dL

Blood smearMicrocytic( + ), Normocytic( + ), Macrocytic( - )Target cells( - ), Basophilic stippling( - )Acanthocytosis (-)

NCV: Normal

Brain MRI

81

Genetic analysis: Dystonia NGS panel

82

Case

Control

Heterozygous TAF1 c.94C>T (p.Arg32Cys) mutation

Final DiagnosisDYT3 (Lubag disease)

DYT3• Gene:TAF1 gene, X-linked • Mostly from Philippines (Panay island)• Adult-onset, mean age 40 years old• 94% start with focal dystonia and becomes generalized usually within

5 years then followed by overt parkinsonism• Cognitive impairment usually mild• Unique presentation: tongue protrusion or phasic knee bending gait• Good candidate for Gpi DBS treatment

Stephen et al., MDCP 2020Lehn et al., MDCP 2014 83


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• Young onset generalized dystonia plus mild parkinsonism feature• Ethnicity also important when considering the differentials

Case 8A 24-year-old women with occasional jerks and

clumsiness for 9 years

85

Clinical courseNormal birth and developmental milestone in the childhood

15 y/o- Slowly progressive involuntary jerky movements in upper limbs

20 y/o- Speech disturbance with frequent interruption- Clumsiness in writing

24 y/o- Neurology visit

86

Phenomenology• Cervical dystonia• Parkinsonism (left side)• Myoclonus

87

Brain Image & Lab Data• TRODAT: decreased uptake in right putamen (arrow)

• Brain MRI: unremarkable• Autoimmune, albumin,

ammonia, CK, TSH/free T4, Na/K/Ca/Mg, VDRL: wnl• Serum Cu: 814 ug/L• Serum ceruloplasmin: WNL• EEG: normal• MMSE: 29/30

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Family pedigree

?

80 y/o 80 y/o

61 y/o 57 y/o 54 y/o 52 y/o 50 y/o 49 y/o

24 y/o 22 y/o

Cervical dystonia, spasmodic dysphonia

Cervical dystonia, myoclonus,

dopa-responsive left hemi-parkinsonism

89

Heterozygous ANO3 gene (DYT24) mutation, c.A2053G (p.S685G) on exon 21

Genetic analysis: NGS Movement disorder Panel

90

Final DiagnosisDYT24

Phenotype Spectrum of DYT24—ANO3

• More than 25 known ANO3 pathogenic variants• Autosomal dominant inheritance• Age of onset: 3 to 69• Summarized clinical presentation:

• Common:• Cervical dystonia, oropharyngeal dystonia• Blepharospasm• Postural tremor (familial essential tremor-like)• Myoclonus (multifocal, could be similar to DYT11)

• Uncommon:• Motor and vocal tics• motor impersistence in tongue• Chorea • Parkinsonism (levodopa responsive)

Am J Hum Genet 2012: 91(6): 1041-1050Mov Disord 2014; 29(7): 928-934

Mov Disord 2016; 31(8): 1251-1252Mov Disord 2017:32(4): 549-559

BMC Medical Genetics 2016; 17:93Parkin Related Disord 2018; 50: 124-125

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DDx of hereditary dystonia or dystonia plus syndromes

Parkinsonism Relat Disord 2014;20: 137 -142.

Case 9A 51-year-old women with acute onset difficult

pronunciation and hands movements

93

Clinical courseNormal birth and developmental milestone in the childhood

51 y/o (Dec 20th 2010), after hard working day- acute onset difficult pronouncing her voice- easily squinting her eyes

Two weeks later- Involuntary movement in her both hands- Jaw clenching tightly intermittently- then no further progression of symptoms

94

Family Pedigree

80 Years old, CAD

82 years old

95

Lab Study• Ceruloplasmin: 23.1 mg/dL• Serum Copper: 1197 ppb (normal)• Calcium: 2.42 mmol/L• T4: 0.886 ng/dL, TSH: 1.44 uIU/mL• GOT/GPT: 13/11 Cr: 0.6 Lactate: 1.16• ANA/Anti-ENA: Negative

96

TRODAT Brain MRI

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G T C A T C A T G G T C A C C G G C G A T C A C C C C A T C A C G GWild type

V I M V T G D H P I TV I M V T G N H P I T

Courtesy to Prof. Du-Hsueh Yeh 98

Heterozygous ATP1A3 (c.G1825A/p.D609N) substitution

Genetic analysis

Final DiagnosisDYT12 (Rapid-Onset Dystonia-Parkinsonism)

Rapid-Onset Dystonia-Parkinsonism (RDP, DYT12)ATP1A3 Mutation

• Na+/K+ transporting ATPase subunit α3

• Autosomal dominant inherited, De novo mutation also been reported

• Onset age: 4-50 years old

• Disease spectrum: Rapid-onset Dystonia-Parkinsonism (RPD)Alternative Hemiplegia of Childhood (AHC),CAPOS (Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, Sensorineural hearing loss) Pediatric encephalopathy with epilepsy

99Salles et al., Frontiers in Neurology 2021

Salles et al., Frontiers in Neurology 2021 100


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• Triggering factors: alcoholic binges, psychologic stress, excessive exercise• Acute onset, from days to weeks, then stationary• Rostro-caudal topological gradient of involvement (face>arm>leg)

Summary of progressive parkinsonism

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• Recognize the typical presentation of diseases with combined phenomenology• Closely observe the patient’s family members• De novo mutation always occurred

1

3

2

Progressive gait disorders- Treatable etiology should be ruled out first

Take home message

Progressive cognitive decline+ variable movement disorders with unique brain MRI findings- Eye of tiger sign is previous a hallmark of PKAN but

might also present in other types of NBIA or SCAs

Progressive parkinsonism+ variable movement disorders - Recognize the typical presentation of the combined

different phenomenology

104

Thank you for your attention!

National Taiwan University Hospital

kai-hsiang chen, md yih-chih kuo, md national taiwan

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