This presentation focuses on clinical approach to chorea . A small discussion on treatment has also been included. comments are welcome .

1. APPROACH TO CHOREA
Dr Srimant Pattnaik
DMPDT, Neuromedicine
BIN, Kolkata

2. Basal ganglia circuit

4. Summary
Pathway Receptor Net output Disease related
Direct D1 Excitatory Hypokinesia
Indirect D2 Inhibitory Hyperkinesia

5. Movement disorder
Paucity of movement
(hypokinesia/Akinetic rigid)
Too much movement
(Hyperkinesia)
JERKY NON JERKY

6. Jerky hyperkinetic
• Myoclonus
• Chorea
• Tics
• Balism
Non jerky hyperkinetic
• Tremor
• Dystonia
Athetosis

7. Describing ‘Chorea’..
• Word Chorea derived from choros or choreia
meaning dance ; suggests fluidity
• Hyperkinetic movement disorder consists of
irregular , unpredictable , brief, jerky
movements that “flow” randomly from one
body part to another
• Parakinesia , motor impersistence

8. Hemibalism
• Balism (greek word): to throw
• High frequency chorea
• Proximal distribution
• violent, flinging, incoordinated, involuntary
• Mono-,hemi-, para-, bi-: hemi- most common
• Hemiballism may evolve into chorea with time

9. Athetosis
• Involuntary Slow writhing movement of the
extrimity
• Older concept :Low frequency chorea
• Newer concept : distal mobile dystonia
• Chorea may evolve into athetosis with time
(ballismuschoreaathetosis )

10. Approach to chorea
• History
• Examination
• Forming differential diagnosis
• Investigation
• Final Diagnosis
• Treatment

11. History
• Age at onset
• Mode of onset
• Progression
• Past medical history
• Family history

12. Age at Onset
Adult onset : Childhood onset
• Huntington disease
• Vascular chorea
Sydenhams
CP
wilson
Juvenile HD
Benign Hereditary Chorea
AT
Choreoacanthocytosis

13. • Infectious , drug induced chorea can appear at
any age

14. Mode of onset
• Acute
• Subacute
• Chronic

15. Acute onset chorea
• Stroke
• Non ketotic hyperglycemia
• Drug induced
• Chorea gravidarum
• Electrolyte abnormality:
Hypo/hypernatremia
Hypo/hypercalcemia
Hypomagnesemia

16. Sub acute Chorea
• Infectious
• Autoimmune
• Drug induced

17. Chronic onset chorea
• Neurodegenerative conditions

18. childhood adult
Acute infection Stroke , HONK
Subacute Sydenhams Autoimmune
Chronic BHC,CP HD

19. Progression
• Intermittent/fluctuating
• Static
• Progressive

20. Intermittent/ fluctuating
• Drug induced
• PKC
• Autoimmune
• Metabolic

21. Static
• BHC
• Structural basal ganglia lesions

22. progressive
• Neurodegenerative disease

23. Past medical history
• Vascular risk factor: stroke
• Diabetes : HONK
• Recurrent miscarriage , migraine , thrombotic events: SLE,
APLA
• Hemodialysis / Alcoholism / Malnutrition : Extrapontine
myelinolysis
• HIV infection/HIV riskfactors: opportunistic infections
including toxoplasmosis, progressive multifocal
leukoencephalopathy, HIV encephalitis
• Pregnancy : chorea gravidarum
• OC pills /HRT
• Liver disease

24. Family history
• AD
– HD
– SCA17,
– C9orf72-related HD phenocopy
– HDL2
– DRPLA, neuroferritinopathy,SCA1, SCA2, SCA3, SCA7,HDL1
• AR:
– choreaacanthocytosis
– Aceruloplasminemia.
– HDL
• X-linked
– Mcleod syndrome

25. Absence of a family history
does not exclude a genetic disorder
• de novo mutations (including unstable
trinucleotide repeats)
• Premature death of asymptomatic carriers,
• Partial penetrance
• Phenotypic variability
• Nonpaternity

26. Examination
• Phenomenology
• Distribution
• Associated movement disorder
• Associated systemic feature

27. Distribution
• Orolingual dyskinesia : drug induced TD
• Orofacial chorea( frequently associated with
dystonia) :chorea-acanthocytosis ,McLeod syndrome,
early feature neuroferritinopathy
• Feeding dystonia: classically described in chorea-
acanthocytosis, but can also be found in McLeod
syndrome, tardive dyskinesia, pantothenate kinase
associated neurodegeneration, and Lesch-Nyhan
syndrome.
• Cervical/truncal chorea dystonia :distinctive feature
of advanced choreaacanthocytosis, but is also
described in McLeod syndrome and advanced HD

28. • Hemichorea or hemiballismus : focal structural
brain lesion secondary to a vascular event,
nonketotic hyperglycemia, and, rarely, an
opportunistic infection in HIV.
• Hemichorea is a presenting feature of other
conditions without a documentable focal brain
lesion:autoimmune chorea including Sydenham
chorea and paraneoplastic syndromes as well as
variant Creutzfeldt-Jakob disease.
• Conversely, conditions such as nonketotic
hyperglycemia can present as generalized chorea

29. Associated movement disorder
• Choreo dystonia: HD, HD phenocopies, DRPLA
• Choreoathetosis: CP
• Parkinsonism : late stages of HD, Juvenile
onset HD
• Ataxia: SCA
• Eye movement abnormality: HD, SCA
• polyneuropathy in neuroacanthocytosis

30. Associated systemic feature
• Organomegaly, cardiac involvement :
neuroacanthocytosis
• Malar rash, arthritis : SLE
• Anemia, diabetes,retinal
degeneration:aceruloplasminemia.
• Stigma of chronic liver failure can suggest acquired
hepatocerebral degeneration, in which patients can
present with orobuccal chorea resembling tardive
dyskinesia, in addition to dystonia, parkinsonism, and
ataxia, as well as cognitive and behavioral problems.
• Kayser-Fleischer rings are observed inWilson disease.

31. Etiology of chorea
• Non Genetic
• Genetic

32. Non genetic causes of chorea
• Vascular
• Infective
• Traumatic
• Autoimmune
• Metabolic
• Inherited
• Neoplastic
• Drugs
• Endocrine

33. Vascular
• Patients with vascular-related chorea typically
present with an acute or subacute onset of
chorea of one side of the body (hemichorea)
• Most common cause of unilateral sporadic
chorea
• Of all patients with vascular-related abnormal
movements, those with chorea have the shortest
time interval between stroke and onset of
involuntary movement(on average about 4 days)
and patients with parkinsonism have the longest
interval (on average 120 days)

34. • The majority of patients with focal chorea or
hemichorea after stroke have the motor
deficit on the same side as the abnormal
movement
• a minority does not have any motor deficits
• only a very few cases showed contralateral
motor deficit.
• Involuntary movements tend to persist
despite recovery of the motor deficit.

35. • Of all involuntary movement disorders
following stroke, chorea is the most common
• Patients with vascular chorea are older (on
average 61–75 years), and patients with
dystonia are younger (on average 48 years)
than patients with other involuntary abnormal
movements related to stroke .

36. • The prognosis of vascular chorea is good, though many
are left with functional impairment
• Stroke is the most common underlying cause in
patients who have spontaneous improvement of their
hemichorea
• functional prognosis is significantly better in patients
with cortical strokes than those with subthalamic
lesions, which could be related to the fact that
hemichorea in the former group may be caused by
transient hypoperfusion or functional disconnection
rather than destruction of the basal ganglia-
thalamocortical circuitry.

37. Other causes of vascular chorea
• Essential thrombocythemia (one case
reported)
• Polycythemia rubra vera (elderly, primarily
females)
• Posterior reversible encephalopathy syndrome
• Postpump chorea (more frequent in children)

38. Drug induced chorea
• Most common cause of bilateral sporadic
chorea
• commonly two groups identified
• Tardive Dyskinesia
• Levodopa Induced Dyskinesia in levpdopa
treated parkinson patients
•

39. Tardive Dyskinesia
• Develops in context with chronic dopamine
receptor blockade
• In patients taking antipsychotics
• Metoclopramide has emerged as a leading
cause
• Drugs usually take 6 weeks for receptor
blockade

40. Character of TD
• Stereotypy : It is typical of a drug-induced movement
disorder and features repetition of the same
movement over time
• Suppressibility : Involuntary movements can be
suppressed or improved by an effort of will in patients
with TD or LID whereas most patients with HD cannot.
• TD and L-dopa-induced chorea may be more
pathophysiologically similar to each other than either is
to HD
• Speech : It is usually affected in patients with HD but is
not in cases of TD.

41. • Pattern of body part involvement :
Orobuccolingual movements are often first to
appear in patients with TD and have a
repetitive pattern, whereas in HD on occasion,
they first appear in the face but they may
resemble winking, smiling, grimacing,
shrugging, or gesturing

42. • Semi-purposiveness of abnormal movements : The
association of involuntary limb movements in some
voluntary activities is often observed in patients with
HD, but they are rare in TD. This combination has been
referred to as semi- purposefulmovements because
they may mimic a fragment of normal motor activity
commonly of the automatic but voluntary kind.
• Eye movements : No abnormalities are seen in patients
with TD; however, they are an early sign of HD. They
feature slow initiation of saccades, saccadic intrusions
of pursuits, oculomotor impersistence, and impaired
optokinetic nystagmus.

43. • Motor impersistence : Oculomotor, tongue, and
grip impersistence are highly suggestive of HD
and are not seen in TD.
• Associated movement disorders : Dystonia,
tremor, or other associated involuntary
movements are common in TD.
• Myoclonus can be present in juvenile or
childhood HD patients
• Other neurological signs : Hung up refl exes and
gait imbalance are frequently seen in HD but not
in DIC.

45. Levodopa induced dyskinesia
• Seen in patients with chronic levodopa therapy
• Classified as
• peak of dose or high dose dyskinesia : upper limb
predominant
• diphasic or low dose dyskinesia : lower limb
predominant
• Pulsatile stimulation of dopamine receptor is
central to pathogenesis
• Hence these patients benefit with continuous
therapy

46. Infectious causes of chorea
• Encephalitis (West Nile virus, mumps,
measles, varicella zoster)
• Human immunodeficiency virus (HIV) (eg,
secondary focal lesion due to toxoplasmosis,
primary central nervous system lymphoma,
HIV encephalitis)
• Tuberculosis, cysticercosis, borreliosis,
neurosyphilis, diphtheria
• Variant Creutzfeldt-Jakob disease

47. Autoimmune chorea
• Sydenhams chorea
• Pediatric autoimmune neuropsychiatric disorders
associated with streptococcal infections (PANDAS)
• Behçet disease
• Celiac disease
• Demyelinating disease (rare)
• Sjogren syndrome
• Systemic lupus erythematosus/antiphospholipid
syndrome

48. Antibody associated (paraneoplastic or idiopathic)
• Associated with neoplasia:
– collapsin response mediator protein-5 (CRMP5) (small cell lung
carcinoma and thymoma)
– Hu (small cell lung carcinoma)
– Yo, antineuronal nuclear antibody (ANNA) type 1 and type 2, N-
methyl-Daspartate (NMDA) subunit NR1 (ovarian tumor)
• Idiopathic:
– NMDA subunit NR1 (45% of cases)
– leucine-rich, glioma inactivated 1 (LgI1)
– contactin-associated proteinlike 2 (CASPR2)
– glutamic acid decarboxylase 65 (GAD65)
– IgLON family member 5 (IgLON5)

49. Sydenham chorea
• Sydenham’s chorea (SC), one of the major
criteria for the diagnosis of rheumatic fever, is
the most common form of autoimmune
chorea.
• The typical age of onset of SC is 5–15 years
• females are more affected than males.
• Chorea usually develops 4–8 weeks after a
group A beta-hemolytic streptococcal (GABHS)
pharyngitis.

50. • Classically, chorea in SC is generalized; however,
hemi-chorea occurs in about one-quarter of
patients.
• Although symptoms can be mild, even in these
instances difficulty with grooming, feeding, and
handwriting can interfere with daily activities in
school or work.
• Other neurologic symptoms in SC can include
motor impersistence, hypometric saccades,
reduced muscle tone, tics, clumsiness, dysarthria,
and weakness.

51. • In rare instances the associated hypotonia can be so
profound as to be completely disabling, a variant
known as chorea paralytica or chorea mollis.
• Neuropsychiatric symptoms, including obsessive
compulsive behaviors, personality changes, emotional
lability, distractibility, irritability, anxiety, age-regressed
behaviors, and anorexia, are common and frequently
predate the appearance of chorea.
• After improvement of their motor symptoms, many
patients with SC continue to have a high rate of anxiety
and depressionas well as difficulty with cognitive tasks
requiring attention and processing speed

52. • Classically, SC is expected to resolve in 1–6
months
• recurrences of chorea are not uncommon,
occurring in 15–40% of patients
• Identified triggers for relapses have included
poor prophylactic penicillin adherence, the
use of oral contraceptive agents, and
pregnancy

53. Metabolic / Endocrine
• Hyperglycemia (nonketotic)
• Acquired hepatolenticular degeneration
(advanced liver disease)
• Electrolyte imbalance
(hypoglycemia/hypercalcemia, hypomagnesemia,
hyponatremia)
• Hyperthyroidism
• Hypoglycemia
• Vitamin B12 deficiency (more frequently found as
a cause of chorea in children)

54. Miscellaneous
• Carbon monoxide intoxication
• Hydrocephalus
• Postanoxic/cerebral palsy
• Psychogenic chorea

55. Genetic Chorea
• Adult onset
• Childhood onset

56. Adult onset Genetic causes of chorea
1. Common neurodegnerative conditions where
chorea is a prominent symptom
2. Rare neurodegenerative conditions where
chorea is a prominent symptom
3. Neurodegenerative conditions where chorea
is a rare manifestation

57. COMMON NEURODEGNERATIVE CONDITIONS WHERE
CHOREA IS A PROMINENT SYMPTOM
• Huntington’s Disease
• HDL4/SCA17
• C9orf72 related HD phenocopy
• HDL2

58. NEURODEGERATIVE CONDITIONS WHERE CHOREA IS A
RARE MANIFESTATION
• SCA1
• SCA2
• SCA3
• Wilson Disease
• PKND
• Friedreich ataxia
• Pallidonigroluysian atrophy
• Lubag disease

59. RARE NEURODEGENERATIVE CONDITIONS WHERE
CHOREA IS A PROMINENT SYMPTOM
• Chorea-acanthocytosis
• Mcleod syndrome
• HDL1
• DRPLA
• Neuroferritinopathy
• Aceruloplasminemia

60. Huntington disease
• Huntington’s disease (HD) is a progressive and
fatal neurodegenerative disorder caused by an
expanded trinucleotide CAG sequence in
huntingtin gene (HTT) on chromosome 4
• Autosomal dominant
• HD manifests with chorea, cognitive and
psychiatric symptoms
• inverse correlation between age of onset and the
size of the CAG repeat expansion
• Phenomenon of anticipation

63. Neuropathology in HD
1. Neuronal loss and gliosis in the cortex and
striatum (caudate and putamen)
2. Early loss of medium-sized, spiny striatal
neurons: SNc, GPe, SNr, GPi
3. Loss of large (17 to 44 μm) striatal
interneurons
4. Loss (<40%) of neurons in SN
5. Intranuclear inclusions and dystrophic
neurons in cortex and striatum

64. Natural History

65. Clinical Presentation of HD
• Motor onset (60%), behavioral onset (15%),
mixed onset(25%)
• A change in the ability to generate saacadic
eye novements : earliest sign
• Parakinesia : hiding the chorea with associated
voluntary movement
• Motor impersistence
• Late stages : bradykinesia , parkinsonism
• Dysarthria , dysphagia

66. • Behavioral symptom occur almost in all
patients
• Early features :Irritability/anxiety/mood
changes
• Depression in 30% cases
• May predate motor symptoms
• Seem to improve in late stages

67. • Cognitive changes are universal
• Subcortical dementia

68. Biomarker
• Clinical
• Biological

69. Clinical biomarker
• Cognitive measure : Stroop word reading,
symbol,digit modalities and circle tracing
• Quantitative measure : grip force and speeded
tapping
• Psychiatric measure: apathy

70. Biological marker
• Blood biomarker :neurofilament light (NFL)
protein
• CSF biomarker : mHTT

71. Diagnosis
• Most cost effective test is genetic testing for
mHTT
• Genetic testing for the mHTT mutation can be
either diagnostic or predictive
• A CAG repeat more than 37 is diagnostic

72. Gross feature

73. Schema

74. CT

75. MRI

76. Prion Disease: Huntington's Disease-Like 1
• Huntington's disease-like 1 (HDL1) is a rare
presentation of autosomal dominant familial
prion disease, first reported in 2001.
• It is caused by eight (sometimes six) extra
repeats of the octapeptide region in the prion
protein (PrP) gene (PRNP).
• Mean onset age is in early adulthood between 20
to 45 years.
• Mean survival time is 1 to 10 years, and rapid
progression is suspicious of this cause

77. • Familial prion disease may produce a diverse range of
phenotypes, even within the same pedigree.
• It may resemble HD with prominent personality
change, psychiatric symptoms and cognitive decline,
chorea, rigidity, and dysarthria.
• Limb and truncal ataxia and seizures may be present.
• Prion disease may also present with behavioral or
psychiatric symptoms, cognitive impairment, visual
disturbance, cerebellar signs, myoclonus, and rigidity
and other neurological signs, evolving to mutism and
immobility.

78. • The characteristic electroencephalogram (EEG) features
seen in sporadic Creutzfeldt-Jakob disease (CJD) (i.e,
generalized bi- or triphasic periodic sharp wave complexes)
are less frequently seen in the genetic prion variant.
• Similarly, detection of the 14-3-3 protein in the
cerebrospinal fluid (CSF) is less consistently present in
genetic compared to sporadic CJD, while tau protein in CSF
may be prominently elevated in both types.
• Neuropathologic examination in HDL1 revealed atrophy
and prion deposition in the basal ganglia, frontal and
temporal lobes, and cerebellar cortex. In comparison to
other prion diseases, spongiosis is not prominent.

79. HDL2
• Huntington's disease-like 2 (HDL2) caused by
mutations in junctophilin 3 (JPH3)
• It is frequent in black South Africans of Sub-
Saharan decent
• Neuropathologically, both HDL2 and HD show
marked cortical and striatal neurodegeneration,
as well as neuronal protein aggregates staining
positive for anti-ubiquitin antibodies and
expanded polyglutamine tracts

80. • there may be more brainstem involvement in
HD compared to HDL2, which is rather
concentrated to cortical involvement (with
prominent occipital atrophy).
• Neuroimaging may reveal generalized brain
atrophy, predominantly affecting the caudate
heads and putamina.

81. Spinocerebellar Ataxia Type 17:
Huntington's Disease-Like 4
• Triplet repeat expansions in the TATA box-
binding protein (TBP) gene located on
chromosome 6q27 cause Huntington's
disease-like 4 (HDL4) as well as
spinocerebellar ataxia type 17 (SCA17)
• Inheritance is autosomal-dominant

82. • The clinical phenotype of HDL4/SCA17 is
markedly heterogeneous
• age at onset ranges from age 3 to 75 years.
• Cerebellar ataxia is the most common clinical
feature (95%),
• usually presenting with a slowly progressive
course, but rapid progression resembling
paraneoplastic disorders or prion disease have
been reported.

83. • Extrapyramidal signs (73%), in particular
dystonia, chorea, and dementia (76%), frequently
occur in SCA17.
• Furthermore, pyramidal signs, epilepsy, and
psychiatric disturbances are not uncommon.
• A true HDL presentation occurs only in a subset
of SCA17 cases.
• Notably, other forms of SCAs may also present
with chorea and should be kept in mind in
patients with an ataxic HDL phenotype, in
particular SCA 1, 2, and 3.

84. DRPLA
• Dentatorubral-pallidoluysian atrophy (DRPLA) (or Naito-Oyanagi
disease) shares many key characteristics of HD and the HDLs.
• It is a trinucleotide repeat disorder with autosomal dominant
inheritance.
• The repeat expansions in exon 5 of the atrophin 1 (ATN1) gene
range from 49 to 88 compared to eight to 25 repeats in healthy
individuals.
• The repeat length correlates inversely with age of onset and
directly with disease severity, and marked anticipation occurs with
longer stretches, particularly in the context of paternal
transmission.
• Dentatorubral-pallidoluysian atrophy clusters in Japan, where the
prevalence is estimated to be similar to the prevalence of HD. The
condition is rare in other countries

85. • The clinical presentation of DRPLA is very
heterogeneous and shows an age-dependent
phenotype.
• Juvenile-onset cases develop severe
progressive myoclonus epilepsy and cognitive
decline.
• Adult-onset DRPLA features ataxia,
choreoathetosis, and dementia as cardinal
features that may resemble HD

86. • Common MRI findings include cerebellar and
brainstem (in particular pontine) atrophy.
• Adult-onset DRPLA furthermore displays
diffuse hyperintense white matter lesions, a
distinguishing feature to HD.

87. Huntington's Disease‐Like Syndrome Associated
with C9orf72Repeat Expansions
• Repeat expansions in C9orf72 have been associated
with autosomal dominant frontotemporal dementia
and/or amyotrophic lateral sclerosis. However, the
recognized clinical phenotype is expanding
• recently it has been suggested that C9orf72 expansions
may be the most common genetic cause of HD
phenocopies.
• The mean age at onset was 43 years (range 8–60).
• presence of prominent pyramidal features may be a
red flag to consider c9orf72 repeat expansions in an
HDL patient.

88. Huntington's Disease, Huntington's Disease Look‐Alikes, and Benign Hereditary Chorea: What's New?
Huntington's Disease, Huntington's Disease Look‐Alikes, and Benign Hereditary Chorea: What's New?, Volume: 3, Issue: 4, Pages: 342-354, First published: 27 January 2016, DOI: (10.1002/mdc3.12312)

89. Neuroferritinopathy
• Elevated serum ferritin levels are the red flag for
neuroferritinopathy, a progressive autosomal dominant
neurodegenerative disease caused by mutations in the ferritin light
chain gene (FTL1) located on chromosome 19q13.
• Disease onset is usually in midlife, but early onset (in teenage years)
and late onset (in the sixth decade) may occur.
• Ferritin is a ubiquitous iron storage protein, and dysfunction results
in formation of iron-rich intranuclear and intracytoplasmic inclusion
bodies, not only within neurons and glia in the brain but also in
peripheral nerves, skin, muscles, liver, and even the kidneys. Iron
deposition is particularly prominent in the basal ganglia.

90. • Typically, the disease presents with
asymmetric chorea or dystonia.
• Other clinical features such as
bradykinesia/parkinsonism, hyperreflexia,
dysarthria, frontal lobe syndrome, and
dementia may be variably present.
• Cognitive deficits and psychiatric features
appear to be less prominent compared to HD.
• Treatment is symptomatic.

91. • Magnetic resonance imaging findings in
neuroferritinopathy may include
– progressive cystic degeneration of the basal ganglia,
particularly cavitation of the globus pallidus and
putamen
– thalamic hypointense lesions on T2-weighted images
reflecting iron deposits in addition to cortical atrophy.
• In rare cases, a pattern resembling the eye-of-
the-tiger sign, which is otherwise described in
pantothenate kinase-associated
neurodegeneration, has been reported in
neuroferritinopathy

92. Primary Familial Brain Calcification,
Formerly Known as Fahr's Disease
• Primary familial brain calcification (PFBC) is
genetically heterogeneous
• Variably characterized by a combination of
movement disorders (mostly dystonia,
parkinsonism), ataxia, cognitive impairment, and
behavioral changes.
• The condition is also often referred to as Fahr's
disease, or idiopathic basal ganglia calcification
• However, this does not account for the fact that
imaging abnormalities often extend beyond the
basal ganglia.

93. • Inheritance is usually autosomal dominant, and
recently four genes (SLC20A2, PDGFB, PDGFRB, XPR1)
have been identified as cause of PFBC, accounting for
about half of the cases.
• The encoded proteins are involved in phosphate
transportation.
• Of note, clinical presentations with prominent or
isolated chorea have rarely been reported
• Computed tomography imaging will give the clue and is
thus an important step in the workup of patients with a
HDL clinical presentation.

94. Huntington's Disease‐Like 3
• Huntington's disease-like 3 is an autosomal
recessive HDL neurodegenerative disorder
described in a Saudi Arabian family.
• Considering the early onset and the recessive
pattern of inheritance, HDL3 clearly differs from
the other HDL syndromes
• The clinical phenotype was complex, with
childhood-onset mental deterioration, speech
disturbance, dystonia, chorea, and other
extrapyramidal and pyramidal features.

95. • Magnetic resonance imaging showed
progressive atrophy of the caudate nuclei
bilaterally and the frontal cortex, and a link to
HD was suggested by the authors.
• The causative gene still remains unclear, but
the disease locus initially was mapped to
chromosome 4p15.3.
• No similar families have been described to
date

96. Huntington's Disease‐Like Chorea‐Dementia
Syndrome Associated with FRRS1L Mutations
• Seen in a consanguineous Saudi Arabian
family with four siblings presenting with
juvenile onset chorea, dementia, and seizures
• normal HTT alleles
• homozygous premature truncation mutations
in FRRS1L, an AMPA receptor complex
constituent..

97. Neuroacanthocytosis
• I. Normal lipids
• 1. Autosomal dominant
– a. Without inclusions
– b. With polyglutamine-containing neuronal inclusions
• 2. Autosomal recessive: 9q21 (73 exons)
– a. Multiple mutations in the chorea acanthocytosis gene
coding for chorein
• 3. Sporadic
• II. Hypobetalipoproteinemia
• III. Abetalipoproteinemia
• IV. Aprebetalipoproteinemia
• V. Hypoprebetalipoproteinemia
– 1. HARP syndrome: Hypoprebetalipoproteinemia,
acanthocytosis, retinitis pigmentosa, and pallidal degeneration:
similar to NBIA-1 (HSD)
• VI. X-linked (McLeod syndrome)

98. • Both chorea-acanthocytosis (ChAc) and
McLeod syndrome are core
neuroacanthocytosis syndromes characterized
by neurodegeneration of the basal ganglia and
red cell acanthocytosis

99. Chorea-acanthocytosis
• Chorea-acanthocytosis is a rare autosomal
recessive neurodegenerative disorder due to
mutations in the VPS13A gene on
chromosome 9 encoding for chorein.
• Chorea-acanthocytosis causes movement
disorders (including chorea, dystonia,
parkinsonism, and tics), cognitive impairment,
and psychiatric features with great similarities
to HD.

100. • However, clinical characteristics such as dystonia with
prominent orofacial involvement with tongue
protrusion, involuntary tongue- and lip-biting, head
thrusts, and rubber man-like appearance may indicate
a diagnosis distinct from classic HD.
• Furthermore, seizures (which occur infrequently in
late-onset HD) are seen in half of the patients, and
myopathy and axonal neuropathy are common.
• The disease usually starts in the 20s and progresses
slowly over 15 to 30 years.

101. • Blood tests reveal elevated levels of creatine
phosphokinase in most cases.
• The detection of acanthocytes often remains elusive,
although the probability to detect the characteristic
deformed erythrocytes can be increased by using a 1:1
dilution with physiological saline and phase contrast
microscopy.
• However, many hematology laboratories no longer prepare
wet blood films due to health and safety policies and
analysis of the protein (chorein) levels is therefore
recommended.
• Neuroradiologically, findings include progressive striatal
atrophy with a maximum in the caudate head

102. • Neuroradiologically, findings include progressive
striatal atrophy with a maximum in the caudate
head. Post
• mortem examinations have shown a neuronal
loss and gliosis predominantly affecting the
caudate nucleus, putamen, globus pallidus,
thalamus, and substantia nigra.
• In comparison to HD, no significant cortical
pathology or specific neuropathologic features as
inclusion bodies have been detected.

103. McLeod syndrome
• McLeod syndrome is inherited in an X-linked matter (thus
mainly affecting men) caused by mutations in the XK gene.
• The erythrocyte phenotype is defined as reduced Kell and
absent Kx antigen expression on the cell surface (of note,
Kell is the third most important erythrocyte antigen system
after ABO and rhesus)
• the clinical phenotype significantly overlaps with ChAc.
• Peripheral sensorimotor neuropathy and areflexia, as well
as the presence of cardiomyopathy, are typical and
distinctive features (not seen in ChAc).
• Imaging features are similar to ChAc, that is, atrophy of the
caudate nucleus and putamen.

104. RNF216‐Mediated Neurodegeneration
• Mutations in RNF216 have recently been found in
families with hypogonadotropic hypogonadism,
ataxia, and dementia.
• They are also associated with the so-called 4H-
syndrome(hypodontia and hypomyelination,
alongside ataxia and hypogonadotropic
hypogonadism).
• The clinical phenotype consisted of chorea,
behavioral problems, and severe dementia as the
core features in all patients.

105. • Brain imaging consistently showed white
matter lesions and cerebellar atrophy.
• Low gonadotropin serum levels could be
demonstrated in the index family and may be
the clue toward this diagnosis pointing away
from typical HD.
• The gene encodes a ubiquitin E3 ligase.

106. Childhood onset Genetic causes of
chorea
1. wilson
2. Juvenile HD
3. Benign Hereditary Chorea
4. AT
5. Choreoacanthocytosis

107. Juvenile HD
• Younger onset
• Rapid course
• Akinetic rigid syndrome

108. Benign Hereditary Chorea
• Benign hereditary chorea (BHC) is a rare autosomal
dominant disease that is characterized by
nonprogressive chorea, with early onset in childhood
and absence of dementia and caudate atrophy.
• Several mutations in the associated small TITF1 (NKX2-
1) gene and also deletions (in some cases also
encompassing adjacent genes) have been described
• The encoded thyroid transcription factor 1 is essential
for the organogenesis of the lungs, thyroid, and basal
ganglia—and symptoms may involve these organs and
systems.

109. • The typical clinical phenotype is infancy-onset
hypotonia and chorea.
• Other movement disorders, such as myoclonus,
dystonia, motor and vocal tics, tremor, and ataxia,
may be associated.
• Recently, recurrent drop attacks with frequent falls
in the absence of EEG abnormalities have been
reported.
• Chorea may improve or resolve in adulthood;
however, it may also persist as mild chorea or
convert to disabling myoclonus.
• Notably, learning difficulties are not infrequent, and
involvement of thyroid (67%) and lung (46%) may
also occur.
• Importantly, a link to malignancies, most frequently
those affecting the lung, is increasingly reported.

110. ADCY5‐Associated Neurological Disease: A New
Cause of Childhood‐Onset Chorea and Dystonia
• The clinical characteristics entail infancy- to adolescence-
onset chorea (motor impersistence) that may be combined
with dystonia and/or myoclonus mainly involving limbs,
neck, and/or face, and sometimes episodic or paroxysmal
• In contrast to the classic paroxysmal dyskinesia associated
with PRRT2, GLUT1, or MR1 gene mutations sudden
movement, prolonged physical activity, caffeine, or alcohol
are not specific triggers).
• Worsening of movements during sleep (probably during
arousal rather than during drowsiness) may be a
characteristic feature.
• In more severe cases, marked hypotonia and delayed
motor milestones may be present.

111. Investigation
1. Test for thyroid function, renal and liver function, electrolytes,
erythrocytesedimentation rate, antinuclear antibodies, antiYdouble-
stranded DNA antibodies, anticardiolipin antibodies, and lupus
anticoagulant.
2. Perform brain MRI.
3. If inconclusive or known family history of chorea, perform genetic
test for Huntington disease. If the latter genetic test is negative,
consider spinocerebellar ataxia type 17 and C9orf72 in white
individuals, and Huntington diseaseYlike syndrome type 2 in
subjects with black African ancestry.
4. Test for acanthocytes in peripheral fresh blood film. A single
negative test is not sufficient to rule out the presence of
acanthocytes and should be done in a laboratory with appropriate
expertise; perform three assays.

112. TREATMENT

116. TETRABENAZINE
• VMAT2 helps in uptake of monoamines into
synaptic vesicles
• TBZ is a potent reversible VMAT2 blocker
• Its action lasts for 16–24 h.
• Metabolized in liver by CYP2D6
• The greatest binding density for TBZ is in the
caudate nucleus, nucleus accumbens,
and,putamen areas.

117. TBZ dosing
• Initial recommended dose of TBZ is 12.5 mg once daily in
the morning.
• Then a dose of 12.5 mg twice a day in the morning and
evening is used in the subsequent week.
• The dose should be increased by 12.5 mg every week till
the best effective and tolerated dose is selected .
• If any patient needs more than 37.5–50 mg TBZ dose per
day, then the dosing should be divided in regimen of 3
times a day
• Maximum limit for each dose is 25 mg.
• Patients who require more than 50 mg/day should be
tested for CYP2D6 genotype.
• More than 100 mg/day of TBZ is not advised for any patient

118. Side effects
• The common side effects of TBZ are somnolence,,
acute akathisia, insomnia, fatigue, agitation,
depression, anxiety, nausea, diarrhea, and
parkinsonism
• These side effects can be controlled by titrating
or reducing the dose of TBZ.
• Because of this reason, these side effects are
termed as dose limiting side effects
• Serious side effects include NMS and Suicide
tendency in depressed patients

120. Recent advances in HD
• Pridopidine
• Rilmenidine
• KD3010
• Bexarotene
• VX15
• Genome editing
• ASO

121. Sydenhams Chorea