A flow chart for the evaluation of chorea

Ruth H. Walker, MB., Ch.B., Ph.D.

Departments of Neurology, James J. Peters Veterans Affairs Medical Center, Bronx, NY, and Mount Sinai School of Medicine, New York, NY
ruth.walker@mssm.edu
Patient with
chorea Infant/child Streptococcal?
+ve
Age of sore throat, rheumatic
Autosomal recessive/sporadic heart disease Sydenham's chorea
Onset?
ASO, anti-DNAse
B titers
Lesch-Nyhan syndrome
Confirm with gene test Tardive dyskinesia
Autosomal Adult
X-linked Inheritance? Normal
recessive

Delayed

Autosomal Medication- Yes

Check Childhood onset, Direct
Yes dominant Time course?
gouty arthritis, MRI; normal induced? Immediate or side effect
uric acid self-mutilation?
Fe in basal dose related
Calcium Acute infarct in
ganglia ? deposition posterior limb of
in basal internal capsule. Infantile bilateral
Phospholipase-associated
ganglia. Diffusion- No
Normal No Pantothenate CT scan weighted MRI
striatal necrosis;
neurodegeneration ?PDE10A mutations
kinase-associated Yes No (see review by
neurodegeneration Yes Structural lesion; Tonduti et al. 2016)
•Mix blood 1:1 with 0.9% NaCl containing 10IU/ml heparin
•Incubate at room temperature for 30-120 min on a shaker •Childhood onset PKAN: T2 weighted MRI Stroke, tumor
•Take 5+ microphotographs from each wet preparation •Occasional later onset Yes Leigh’s syndrome,
(phase-contrast microscope) •Pigmentary retinopathy
MRI arteriovenous malformation, Lactate/
•Count cells with spicules: normal value < 6.3 % •Dystonia
•10% have acanthocytosis
PANK2 Normal PLA2G6 calcification (SLC20A2, pyruvate other mitochrondrial?
Lubag No Ceruloplasmin?
No No Yes mutation? mutation? PDGFRB, PDGFB, XPR1?), etc Confirm with gene test
Acanthocytosis? Filipino? Confirm with
gene test
GPR88 Basal ganglia
No mutations? No
Typical phenotype = dystonia- necrosis?
parkinsonism, but should be Other neurodegeneration No
Yes considered in any Filipino with an
with brain iron
unexplained movement disorder, Caudate Yes
including women Yes Accumulation disorder… White matter GNA01 Recent Post-infectious
nucleus
FAHN, MPAN, BPAN… lesions mutations? Yes infection? striatal necrosis
•Full panel of 23 Kell abs usually available atrophy?
Courtesy of Dr Hans H. Jung, Zürich at regional blood centers; •Childhood onset
•Ask to “exclude McLeod phenotype” Pseudo- Aceruloplasminemia •Seizures (variable)
•Delayed myelination
dominant or normal MRI Yes Features
•Iron overload
inheritance? •Diabetes mellitus in 20’s (from pancreatic iron)
suggestive of Yes Work-up for inherited
Gordon Holmes syndrome/ metabolic
Liver enzymes or Kx and Kell •Middle-age onset
RNF216 mutations? metabolic diseases;
creatine kinase ags
McLeod syndrome •Retinal degeneration (from iron deposition) disease?
•Parkinsonism/dystonia, orofacial involvement is typical organic/amino acids, lysosomal
•Behavioural changes/ •hypogonadism
•Dementia usually later
psychopathology •dementia
•Seizures Fasano et al. 2008 •MRI may not show Fe accumulation (Skidmore et al. 2007)
•ataxia
Enzymes, skin biopsy etc
•Peripheral neuropathy Gradient echo T2* No
Normal •Hyporeflexia
Normal •Cardiomyopathy
No Normal Negative
•Hepatosplenomegaly
?
Normal Kayser- Normal
McNeill et al 2008
Fast spin echo Fleischer Ceruloplasmin? Creatine kinase Liver enzymes
rings? Diagnosis Diagnosis
Yes Ferritin 24hr Cu
Lactate/ Normal Chorein chorein
mutations? excretion?
pyruvate Normal assay Normal
Dobson-Stone et al. 2004
Normal
Contact – danek@lmu.de
Recent
Neuroferritinopathy liver No +ve +ve
+ve
disease?
No
•Middle-age onset
•Parkinsonism/dystonia
Wilson’s disease Metabolic
•Occasional ataxia, spasticity
Ataxia? work-up (2) Metabolic
•Dementia rare •Dystonia/parkinsonism/dystonia more common Normal Anti-phospholipid ab Normal work-up (1)
•Adolescent onset Electrolytes
•Risus sardonicus
SLE, other autoimmune
Mitochondrial Chorea-acanthocytosis •Psychiatric disease Yes Polycythemia vera Glucose
Yes huntingtin Celiac disease Pregnancy test
disorder? Confirm with gene test HIV, B12, RPR TSH
Confirm with gene test mutation? Normal Acquired hepatocerebral Pb
•Behavioural changes/psychiatric disease But can be normal degeneration Frataxin
Friedreich’s ataxia
•Self-mutilation of lips, tongue, other body parts in pre-menopausal
•Seizures women with
mutation?
•Hyporeflexia
•Hepatomegaly
Huntington’s No
Ferritin level? neuroferritinopathy
•Onset in childhood
•Ataxia may be absent
disease Chorea is a common movement disorder, the etiology of which is •Reflexes increased or decreased
•Cardiomyopathy •Onset in childhood
rarely identifiable from its appearance. The identification of genetic •Susceptible to radiation
•Risk of malignancy, infection
causes for some of the inherited choreas has facilitated their •Elevated α-feto-protein
Courtesy Dr Jane Zheng, UNC-CH C9ORF2 C9ORF72
mutation? diagnosis, in addition to increasing the spectrum of phenotypes for
disease Ataxia-telangiectasia
other disorders in which chorea may occur less often. A number of Telangiectasia?
•Variable phenotype Confirm with ATM mutation
•Often upper motor neuron clues in the family and medical history, clinical examination, and
signs
No •Reduced penetrance laboratory findings may inform the diagnosis. Whilst we typically
•Variable age of onset
consider these simultaneously when evaluating the patient with
African chorea, there is a need for an algorithm to generate consideration of Yes Ataxia with oculomotor
Yes Junctophilin-3 α-feto- Senataxin
Yes ancestry? No some of the rarer etiologies.
Huntington’s disease-like 2 protein mutation? apraxia type 2
mutation? (may be
•Onset in childhood
•Behavioural changes/psychiatric disease occult) •Peripheral neuropathy
•May have more dystonia/parkinsonism?
•10% have acanthocytosis
This flow chart aims to present the various factors which facilitate •Elevated creatine kinase
No Iron in basal making the correct diagnosis, and the appropriate testing to consider Consider AD
ganglia? Consider AD
depending upon previous test results. The list of differential diagnoses Aprataxin spinocerebellar
ataxias
and X-linked
mutation? pathways
Spinocerebellar ataxia 1,2,3,8,12,17, Yes SCA/DRPLA Non-diagnostic
of chorea is ever-evolving with advances in the molecular biology of e.g. homozygosity?

mutations? MRI movement disorders. This algorithm which is open to further

DRPLA? White matter
Yes
lesions? development in the light of new knowledge, and may indeed become
•Ataxia, eye movement abormalities, peripheral
Cryopyrin-associated Ataxia with oculomotor Autoimmune
neuropathy etc are typical, but may be pure HD phenocopy somewhat obsolete as whole exome/genome sequencing becomes
•DRPLA – myoclonus, dementia, dystonia typical
No periodic syndrome? apraxia type 1 non-paraneoplastic
Yes more available.
Huntington’s •Deafness
•Onset in childhood
syndrome
disease-like 1?
•Elevated anti-cardiolipin IgG
•Peripheral neuropathy
Neoplasm
•Mutation of NLPR3 Negative workup
This flow chart does not necessarily indicate the temporal course of •Elevated cholesterol evaluation;
Hypotonia, •hypoalbuminemia Anti-Hu, Yo, +ve Paraneoplastic
ADCY-5 dyskinesia
Hyperreflexia,
Yes the diagnostic work-up of chorea, especially if the family history is not CRMP-5, GAD65
Facial movements, Non-progressive, No NMDA, VGCC syndrome
Adenylate cyclase-5 Paroxysmal/fluctuating no dementia?
known, but should be used a guideline to generate the consideration Caspr2, LGI-1,
mutation movements? of various clinical entities in light of the available information. striational Creutzfeldt-Jakob
Prion Single Yes ……..
No PLED’s? disease
Thyroid, mutation? case?
MRI findings?
+ve
No -ve (chorea more common
pulmonary,
Consider atypical forms of CSF 14-3-3 in new variant)
involvement? No
Benign hereditary chorea No AD, X-linked or AR disorders, Confirmed by pathology
NKX2.1 (TITF-1) mutation Other FTD syndrome? No depending upon inheritance -ve
CACNA1A mutation?
VCP, FUS, UBQLN2