Approach to chorea by dr srimant pattnaik

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

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

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

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

6. 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

7. 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

8. 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 )

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

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

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

12. Infectious , drug induced chorea can appear at any age

13. Mode of onset Acute Subacute Chronic

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

15. Sub acute Chorea Infectious Autoimmune Drug induced

16. Chronic onset chorea Neurodegenerative conditions

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

18. Progression Intermittent/fluctuating Static Progressive

19. Intermittent/ fluctuating Drug induced PKC Autoimmune Metabolic

20. Static BHC Structural basal ganglia lesions

21. progressive Neurodegenerative disease

22. 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

23. 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

24. 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

25. Examination Phenomenology Distribution Associated movement disorder Associated systemic feature

26. 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

27. 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

28. 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

29. 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.

30. Etiology of chorea Non Genetic Genetic

31. Non genetic causes of chorea V ascular I nfective T raumatic A utoimmune M etabolic I nherited N eoplastic D rugs E ndocrine

32. 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)

33. 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.

34. 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 .

35. 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.

36. 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)

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

38. 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

39. 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.

40. 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

41. 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 .

42. 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.

43. 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

44. 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

45. 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

46. 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)

47. 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 .

48.  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.

49. 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 depression as well as difficulty with cognitive tasks requiring attention and processing speed

50. 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

51. 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)

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

53. Genetic Chorea Adult onset Childhood onset

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

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

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

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

58. 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

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

60. Natural History

61. 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

62. 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

63. Cognitive changes are universal Subcortical dementia

64. Biomarker Clinical Biological

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

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

67. 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

68. Gross feature

69. Schema

70. CT

71. MRI

72. 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

73. 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.

74. 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.

75. 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

76. 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 .

77. 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

78. 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.

79. 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.

80. 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

81. 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

82. 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.

83. Huntington's Disease‐Like Syndrome Associated with  C9orf72 Repeat 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.

84. 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)

85. 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.

86. 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.

87. 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

88. 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.

89. 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.

90. 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.

91. 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

92. 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..

93. 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)

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

95. 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.

96. 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.

97. 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

98. 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.

99. 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 .

100. 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.

101. 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 .

102. Childhood onset Genetic causes of chorea wilson Juvenile HD Benign Hereditary Chorea AT Choreoacanthocytosis

103. Juvenile HD Younger onset Rapid course Akinetic rigid syndrome

104. 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.

105. 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 .

106. 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.

107. 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.

108. TREATMENT

109. 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.

110. 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

111. 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

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

113. Sydenhams Chorea