A flow chart for the evaluation of Ruth H. Walker, MB., Ch.B., Ph.D. Departments of , James J. Peters Veterans Affairs Medical Center, Bronx, NY, and Mount Sinai School of Medicine, New York, NY [email protected] Patient with

chorea Streptococcal? Age of Infant/child +ve Autosomal recessive/sporadic sore throat, rheumatic Sydenham's chorea Onset? disease ASO, anti-DNAse Lesch-Nyhan syndrome B titers Confirm with gene test Tardive Autosomal Adult X-linked Inheritance? Normal recessive

Delayed

Autosomal Medication- Yes Direct Check Yes Childhood onset, 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 ganglia. Diffusion- No Phospholipase-associated CT scan weighted MRI ; Normal No Pantothenate striatal kinase-associated Yes ?PDE10A No (see review by neurodegeneration •Mix 1:1 with 0.9% NaCl containing 10IU/ml heparin Yes Structural ; Tonduti et al. 2016) •Incubate at room temperature for 30-120 min on a shaker •Childhood onset PKAN: T2 weighted MRI , 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 PANK2 Normal PLA2G6 calcification (SLC20A2, other mitochrondrial? Lubag •10% have acanthocytosis Ceruloplasmin? pyruvate No No Yes ? No mutation? PDGFRB, PDGFB, XPR1?), etc Confirm with gene test Acanthocytosis? Filipino? Confirm with gene test GPR88 No No Typical phenotype = - mutations? necrosis? , but should be Other neurodegeneration considered in any Filipino with an No Yes with brain iron unexplained , Caudate Yes including women Yes Recent Post-infectious Accumulation disorder… White matter GNA01 nucleus FAHN, MPAN, BPAN… 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- • (variable) •Delayed myelination dominant or normal MRI Yes Features inheritance? •Iron overload suggestive of Yes •Diabetes mellitus in 20’s (from pancreatic iron) Gordon Holmes syndrome/ Work-up for inherited Liver or Kx and Kell •Middle-age onset metabolic McLeod syndrome •Retinal degeneration (from iron deposition) RNF216 mutations? disease? metabolic diseases; creatine kinase ags •Parkinsonism/dystonia, orofacial involvement is typical •Behavioural changes/ •hypogonadism organic/amino acids, lysosomal • usually later psychopathology •dementia •MRI may not show Fe accumulation (Skidmore et al. 2007) •Seizures Fasano et al. 2008 • Enzymes, skin biopsy etc • Gradient echo T2* No

Normal •Hyporeflexia Normal •Cardiomyopathy No Normal Negative •Hepatosplenomegaly ? Normal Kayser- McNeill et al 2008 Normal Fast spin echo Fleischer Ceruloplasmin? Creatine kinase Liver enzymes rings? Diagnosis Diagnosis Yes 24hr Cu Lactate/ Normal Chorein mutations? chorein excretion? pyruvate Normal assay Normal Dobson-Stone et al. 2004 Normal Contact – [email protected] Recent No +ve liver +ve +ve disease? No •Middle-age onset Wilson’s disease Metabolic •Parkinsonism/dystonia Metabolic •Occasional ataxia, Ataxia? work-up (2) •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 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 •Self-mutilation of lips, tongue, other body parts in pre-menopausal Frataxin women with Friedreich’s ataxia •Seizures mutation? •Hyporeflexia Ferritin level? neuroferritinopathy •Hepatomegaly Huntington’s No •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 causes for some of the inherited has facilitated their •Risk of malignancy, infection C9ORF2 C9ORF72 •Elevated α-feto-protein Courtesy Dr Jane Zheng, UNC-CH diagnosis, in addition to increasing the spectrum of phenotypes for mutation? disease other disorders in which chorea may occur less often. A number of Telangiectasia? Ataxia-telangiectasia •Variable phenotype Confirm with ATM mutation •Often upper motor clues in the family and medical history, clinical examination, and No signs •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 α-feto- Senataxin Yes Ataxia with oculomotor Yes Junctophilin-3 Yes ancestry? No Huntington’s disease-like 2 some of the rarer etiologies. protein mutation? apraxia type 2 mutation? (may be •Onset in childhood •Behavioural changes/psychiatric disease occult) •May have more dystonia/parkinsonism? •Peripheral neuropathy •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 Consider AD ganglia? spinocerebellar depending upon previous test results. The list of differential diagnoses Aprataxin and X-linked mutation? pathways of chorea is ever-evolving with advances in the molecular biology of e.g. homozygosity? 1,2,3,8,12,17, Yes SCA/DRPLA Non-diagnostic MRI movement disorders. This algorithm which is open to further DRPLA? mutations? White matter Yes lesions? development in the light of new knowledge, and may indeed become •Ataxia, movement abormalities, peripheral Autoimmune neuropathy etc are typical, but may be pure HD phenocopy Cryopyrin-associated somewhat obsolete as whole exome/ sequencing becomes Ataxia with oculomotor •DRPLA – , dementia, dystonia typical periodic syndrome? apraxia type 1 non-paraneoplastic No more available. Yes Huntington’s •Deafness syndrome •Elevated anti-cardiolipin IgG •Onset in childhood Neoplasm disease-like 1? •Mutation of NLPR3 •Peripheral neuropathy Negative workup This flow chart does not necessarily indicate the temporal course of •Elevated cholesterol evaluation; , •hypoalbuminemia Anti-Hu, Yo, +ve Paraneoplastic Hyperreflexia, ADCY-5 dyskinesia 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 known, but should be used a guideline to generate the consideration Paroxysmal/fluctuating no dementia? Caspr2, LGI-1, mutation movements? of various clinical entities in light of the available information. striational Creutzfeldt-Jakob Single Yes …….. No PLED’s? disease Thyroid, mutation? case? +ve MRI findings? (chorea more common No pulmonary, -ve CSF 14-3-3 in new variant) involvement? No Consider atypical forms of Benign hereditary chorea No AD, X-linked or AR disorders, Confirmed by pathology NKX2.1 (TITF-1) mutation Other FTD syndrome? depending upon inheritance -ve No CACNA1A mutation? VCP, FUS, UBQLN2