Genetic Choreas

Diagnosis

Gene

Location

Protein product

Mutation

Useful tests

Movement disorder

Other neurological features

Usual age of onset

HD/IT15

4p15

Huntingtin

Expanded CAG repeats

–

Chorea, dystonia, parkinsonism

Ataxia, seizures (juvenile onset)

Inv. related to repeats

HDL1

PRNP

20p12

Prion protein

192 nucleotide insertion

–

Chorea, rigidity

Seizures (variable)

20–40 years

HDL2

JPH

16q24.3

Junctophilin-3

Expanded CAG/CTG repeats

Acanthocytosis + /−

Chorea, dystonia parkinsonism

Hyperreflexia

Inv. related to repeats

Spinocerebellar ataxia 1

SC1

6p23

Ataxin-1

Expanded CAG repeats

–

Chorea, dystonia

Ataxia, eye movement abnormalities, peripheral neuropathy

Inv. related to repeats

Spinocerebellar ataxia 2

SCA2

12q24

Ataxin-2

Expanded CAG repeats

–

Chorea, dystonia, parkinsonism, tremor

Ataxia, eye movement abnormalities, peripheral neuropathy

Inv. related to repeats

Spinocerebellar ataxia 3

MJD1

14q32.1

Ataxin-3

Expanded CAG repeats

–

Chorea, dystonia parkinsonism

Ataxia, eye movement abnormalities, peripheral neuropathy

Inv. related to repeats

Spinocerebellar ataxia 17

TBP

6q.27

TATA box-binding protein

Expanded CAA/CAG repeats

–

Chorea, dystonia parkinsonism

Ataxia, hyperreflexia

Inv. related to repeats

DRPLA

12p13.31

Atrophin-1

Expanded CAG repeats

–

Chorea, myoclonus

Ataxia, seizures

Inv. related to repeats

Benign hereditary chorea

TITF–1 (NKX2.1)

other

14q13.1

Thyroid transcription factor 1; other

Transversions, deletions, substitutions

–

Chorea

Mild ataxia

Childhood

Neuroferritinopathy

FTL

19q13.3

Ferritin light chain

Adenine insertion

Serum ferritin

Chorea, dystonia, parkinsonism

Spasticity, rigidity

40–55 years

Paroxysmal exertional dyskinesia

SLC2A1

1p34.2

Glucose transporter GLUT1

Deletion, missense

Low CSF/serum glucose ratio

Chorea, dystonia

Seizures

Childhood

Reproduced with permission from Walker RH, “Chorea: Differential diagnosis and treatment” in Continuum: Movement Disorders, ed. Espay A, © American Academy of Neurology

Abbreviations: DPRLA dentatorubropallidoluysian atrophy, HD Huntington’s disease, HDL2 Huntington’s disease-like 2, inv inversely

Table 8.2

Molecular features of autosomal recessive, X-linked, and mitochondrial choreiform disorders

Diagnosis	Inheritance	Gene	Location	Protein product	Mutation	Useful tests	Movement disorder	Other neurological features	Usual age of onset
Chorea-acanthocytosis	AR	VPS13	9q21	Chorein	Many	Acanth; CK, LFTs; chorein Western blot	Chorea, dystonia, parkinsonism, od	Seizures, pn self-mutilation	20–50 years
PLAN	AR	PLA2G6	22q12-q13	Phospholipase A	Many	–	Chorea, dystonia	Ataxia	Childhood
Aceruloplasminemia	AR	CP	3q23	Ceruloplasmin	Nonsense	Ceruloplasmin, glucose	Chorea, dystonia	Ataxia, retinal degeneration	30–50 years
Wilson’s disease	AR	ATP7B	13q14.3	Copper-transporting ATPase 2	Many	Ceruloplasmin	Coarse tremor, dystonia, parkinsonism	Psychiatric disease	6–55 years
HDL3	AR	NK	4p15.3	NK	NK	–	Chorea, dystonia	Seizures, spasticity, ataxia	Childhood
Infantile bilateral striatal necrosis	AR, mitochondrial	NK	19q13.32-13.41, mitochondrial	–	–	–	Chorea	Dysarthria, pendular nystagmus, oa	Infancy
Ataxia-telangiectasia	AR	ATM	11q22.3	Serine-protein kinase ATM	Many	Alpha-fetoprotein	Chorea	Ataxia, oculomotor apraxia, dysarthria	Early childhood
Ataxia with oculomotor apraxia I	AR	APTX	9p13.3	Aprataxin	Many	Hypoalbuminemia, high cholesterol	Chorea, dystonia	Ataxia, oculomotor apraxia, pn	Childhood
Ataxia with oculomotor apraxia 2	AR	SETX	9q34	Senataxin	Truncation	Alpha-fetoprotein, high cholesterol	Chorea, dystonia	Ataxia, oculomotor apraxia, pn	Childhood
Friedreich’s ataxia	AR	Frataxin	9p13	Frataxin	Trinucleotide expansions, deletion	–	Dystonia, chorea	Ataxia, spasticity, myoclonus	Childhood
Non-ketotic hyperglycinemia	AR	Several	Several	Glycine cleavage enzymes	Many	Glycine	Encephalopathy, chorea	Ataxia, ophthalmoplegia	Child/adult
Recessive hereditary methemoglobinemia type II	AR	DIA1	22q13-qter	NADPH-cytochrome b ₅reductase	Many	Methemoglobin	Chorea, dystonia	Encephalopathy	Child/adult
Beta-ketothiolase deficiency	AR	ACAT1/T2	11q22.3	Mitochondrial acetoacetyl-CoA thiolase	Various	Urinary organic acids	Chorea, myoclonus	Ataxia, developmental delay	Childhood
Pyruvate dehydrogenase deficiency	AR/X-linked	Several	Several	PDH; various subunits	Various	Lactate, pyruvate	Chorea, dystonia, parkinsonism	Encephalopathy, seizures, pn, ataxia	Child/adult
McLeod syndrome	X-linked recessive	XK	Xp21	XK	Deletions, missense, insertions	Acanth; Kx, Kell ags; CK, LFTs	Chorea, dystonia, parkinsonism, od	Seizures, pn, myopathy	40–70 years
Lubag	X-linked recessive	DYT3	Xq13.1	Multiple transcript system	Missense, deletions	–	Dystonia, chorea parkinsonism, tremor, myoclonus	–	10–40 years
Lesch-Nyhan syndrome	X-linked recessive	HPRT	Xq26-27	Hypoxanthine phosphoribosyltransferase	Many	Hyperuricemia	Chorea, dystonia	Spasticity, self-mutilation	Infancy
Leigh syndrome	Mitochondrial	Many	Many	Many	Many	Elevated lactate/pyruvate	Chorea, dystonia	Hypotonia, cn, ataxia, seizures	Infancy

Reproduced with permission from Walker RH, “Chorea: Differential diagnosis and treatment” in Continuum: Movement Disorders, ed. Espay A, © American Academy of Neurology

Abbreviations: acanth acanthocytosis, AR autosomal recessive, cn cranial neuropathy, HDL3 Huntington’s disease-like 3, NK not known, oa optic atrophy, od orofacial dyskinesias, PKAN pantothenate kinase-associated neurodegeneration, pn peripheral neuropathy

Conclusion

Chorea is a feature of many familial conditions. While HD remains the most likely diagnosis in those cases with a clear autosomal dominant inheritance, other diagnoses need to be considered. The availability of genetic testing now greatly aids the diagnostic process, though as always, a careful history and examination will greatly narrow the likely possibilities.

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