huntington 's disease ( hd ) is an autosomal dominant , progressive neurodegenerative disorder characterized by chorea , subcortical dementia and psychiatric symptoms .
the causal hd gene has been identified as it15 , which has cag repeats in the open reading frame ( orf , in exon 1 ) just following the 5end of the gene .
it leads to the translation of a protein , huntingtin , whose function is unknown .
huntingtin forms intraneuronal inclusion bodies which lead to neuronal dysfunction followed by neuronal death due to apoptosis .
the therapeutic strategies for hd are diverse , ranging from the classical drug therapies to the modern molecular strategies .
one of the treatment options is the use of drugs with neuroprotective potential , like lithium .
lithium has demonstrated diverse molecular effects reversing well - described pathophysiological changes such as increased oxidative stress , apoptosis , inflammation , environmental stress , glial dysfunction , neurotrophic factor deficiency , excitotoxicity as well as mitochondrial and endoplasmic reticulum disruption .
lithium acts by inhibiting a protein- kinase called glycogen synthase kinase 3 ( gsk3 ) that has important actions on the intracellular signal transmission by protein phosphorylation .
inhibition of this enzyme appears to have a neuroprotector effect in neurodegenerative diseases such as amyotrophic lateral sclerosis , spinocerebellar ataxia type 1 and huntington 's disease .
we report three patients with huntington 's disease , who showed good response to treatment with low dose lithium .
mrs . a , a 48-year - old homemaker , presented in 2008 with a three - year history of involuntary movements of the trunk and the hands , which had worsened over the previous 7 - 8 months .
family history was not available . on examination , ocular saccades were slow ; she had generalized choreiform movements involving hands legs , lips and the trunk ; dystonia of hands and feet and ataxic gait .
a genetic analysis for huntington 's disease was performed after obtaining written informed consent which showed cag repeat expansion .
patient was started on lithium 150 mg , once daily , along with carbamazepine 200 mg twice a day .
patient is on regular follow up for the last four years and is maintaining the same improvement .
b , a 58-year - old male , presented in 2001 with a history of abnormal movements .
, the movements were disabling , irregular , would worsen with anxiety and disappear during sleep .
patient had a significant family history of hd ; involving both parents and 7 out of 9 siblings , totally 9 affected first - degree relatives . on examination , patient was noted to have severe generalized chorea involving the hands , legs , trunk and the neck .
patient was admitted in 2009 with a worsening of movements over the previous 6 months and weight loss of about 6 kg .
all investigations including prostate specific antigen and chest x - ray were normal and the weight loss was attributed to nutritional causes .
family members reported that the patient was able to eat well and had no behavioral symptoms .
the patient has been on follow up for the last three years and maintains status quo .
c , a 51-year - old lady presented in 2002 with history of psychiatric symptoms for the previous 8 years .
onset was sudden with symptoms of being anxious , accusing the family members of neglect , and being violent toward family members .
patient also had history of non - rhythmic quasi - purposive movements of hands which she attributed to anxiety .
family history revealed that her mother had movement disorder and an early death . on examination , patient c had choreic movements of the limbs , anxiety and depressive symptoms .
a diagnosis of hd was made which was confirmed by genetic analysis , which showed expanded cag repeats in the huntingtin 's locus .
patient was initially started on carbamazepine 400 mg and clonazepam 4 mg / day . over the next one year
, patient developed psychotic symptoms like delusions of reference and persecution toward her family members and was also started on quetiapine up to 300 mg .
two years later , patient had sudden deterioration in symptoms with worsening of chorea and onset of cognitive decline  memory disturbances and apraxia , which made her completely dependent for all activities of daily living . during this time , she also developed significant mood swings .
for the last 3 years , patient has been on a combination of lithium 300 mg , carbamazepine 800 mg , quetiapine 300 mg and clonazepam 2 mg / day .
patient 's husband reported no further deterioration over 3 years in cognition or movements in the patient .
however , she continued to be dependent on husband for activities of daily living and eventually died due to cardiac arrest .
mrs . a , a 48-year - old homemaker , presented in 2008 with a three - year history of involuntary movements of the trunk and the hands , which had worsened over the previous 7 - 8 months .
family history was not available . on examination , ocular saccades were slow ; she had generalized choreiform movements involving hands legs , lips and the trunk ; dystonia of hands and feet and ataxic gait .
a genetic analysis for huntington 's disease was performed after obtaining written informed consent which showed cag repeat expansion .
patient was started on lithium 150 mg , once daily , along with carbamazepine 200 mg twice a day .
patient is on regular follow up for the last four years and is maintaining the same improvement .
b , a 58-year - old male , presented in 2001 with a history of abnormal movements .
, the movements were disabling , irregular , would worsen with anxiety and disappear during sleep .
patient had a significant family history of hd ; involving both parents and 7 out of 9 siblings , totally 9 affected first - degree relatives . on examination ,
patient was noted to have severe generalized chorea involving the hands , legs , trunk and the neck .
patient was admitted in 2009 with a worsening of movements over the previous 6 months and weight loss of about 6 kg .
all investigations including prostate specific antigen and chest x - ray were normal and the weight loss was attributed to nutritional causes .
family members reported that the patient was able to eat well and had no behavioral symptoms .
the patient has been on follow up for the last three years and maintains status quo .
c , a 51-year - old lady presented in 2002 with history of psychiatric symptoms for the previous 8 years .
onset was sudden with symptoms of being anxious , accusing the family members of neglect , and being violent toward family members .
patient also had history of non - rhythmic quasi - purposive movements of hands which she attributed to anxiety .
family history revealed that her mother had movement disorder and an early death . on examination ,
a diagnosis of hd was made which was confirmed by genetic analysis , which showed expanded cag repeats in the huntingtin 's locus .
patient was initially started on carbamazepine 400 mg and clonazepam 4 mg / day . over the next one year
, patient developed psychotic symptoms like delusions of reference and persecution toward her family members and was also started on quetiapine up to 300 mg .
two years later , patient had sudden deterioration in symptoms with worsening of chorea and onset of cognitive decline  memory disturbances and apraxia , which made her completely dependent for all activities of daily living . during this time , she also developed significant mood swings .
for the last 3 years , patient has been on a combination of lithium 300 mg , carbamazepine 800 mg , quetiapine 300 mg and clonazepam 2 mg / day .
patient 's husband reported no further deterioration over 3 years in cognition or movements in the patient .
however , she continued to be dependent on husband for activities of daily living and eventually died due to cardiac arrest .
huntington 's disease ( hd ) is an autosomal dominant progressive neurodegenerative disorder caused by an expanded polyglutamine ( poly q ) tract within huntingtin protein and is characterized by neuronal loss mainly in the striatum and the cortex .
genetically , hd is caused by a mutation in the gene located on chromosome4p 16.3 .
the disease - causing mutation in the first exon of huntingtin ( htt ) gene is the expansion of a polymorphic cag repeat that is completely penetrant once it has reached 40 triplets .
neuropathologically , the mutant huntington protein ( mhtt ) abnormally interacts with a variety of proteins and accumulates in the neuronal nucleus forming an inclusion body which is the hallmark of hd and leads to eventual cell death .
in addition to the well - documented use of lithium as a mood stabilizing drug , primarily in the treatment of bipolar disorder , recent in vitro and in vivo studies in animal models have increasingly indicated that lithium can be used in the treatment of chronic neurodegenerative diseases like huntington 's disease .
various pharmacological and gene manipulation studies support the notion that lithium 's main mechanisms of action may be its ability to inhibit gsk3[68 ] as well as induce brain - derived neurotrophic factor - mediated ( bdnf ) signaling , leading to enhanced cell survival by alteration of a wide variety of downstream effectors .
lithium is shown to promote the action of anti - apoptotic proteins , such as heat - shock protein ( hsp ) , insulin like growth factor ( igf ) , vascular endothelial growth factor ( vegf ) and other neurotrophic factors .
lithium can directly or indirectly modulate proteins involved in neuronal survival / differentiation which may account for its neuroprotective effects.[1012 ] by inhibiting n - methyl - d - aspartate receptor - mediated calcium influx , lithium also contributes to calcium homeostasis and suppresses calcium - dependent activation of pro - apoptotic signaling pathways .
lithium is found to enhance autophagy of toxic aggregates in huntington 's disease in various models of hd .
it acts by increasing mtor - independent autophagy by inhibiting inositol monophosphatase ( impase ) and reducing inositol and ip3 levels .
induction of autophagy by lithium leads to enhanced clearance of mutant huntingtin fragments associated with huntington 's disease ( hd ) .
these mechanisms might allow therapeutic doses of lithium to protect neuronal cells from diverse insults that would otherwise lead to massive cell death .
lithium also stimulates proliferation of stem cells , including neuronal and astroglial progenitor cell proliferation in the sub ventricular zone , hippocampus , striatum and forebrain protecting against apoptosis .
the stimulation of endogenous neural stem cells and neurogenesis may explain why lithium increases brain cell density and volume in patients with bipolar disorder .
in this report , we have described the use of lithium to prevent the progression of the huntington 's disease .
all patients reported here were started on low doses of lithium after explaining the rationale , possible side - effects and off label use of the drug .
the patients were on regular follow up and reported no worsening of either psychiatric symptoms or choreic movements for a significant period .
in these patients , lithium was started in order to alleviate the distress caused by the choreic movements and mood swings .
though rating of the movements was not done , there appears be some benefit in prescribing lithium to patients with huntington 's disease for slowing the progression of chorea and preventing mood swings .
this report signifies the use of lithium as a neuroprotective agent . it may be beneficial to explore the possibility of use of other psychotropic drugs in the treatment of neurodegenerative disorders
 huntington 's disease is characterized by choreic movements , psychiatric disorders , striatal atrophy with selective small neuronal loss , and autosomal dominant inheritance . the genetic abnormality is cag expansion in huntingtin gene . 
 newer therapeutic strategies are evolving to treat this progressive disorder . 
 the neuroprotective agents are one such group of drugs being tried . 
 lithium has been used to treat huntington 's disease in the past due to its neuroprotective effects . 
 though the precise mechanism of action is not clear , lithium can directly or indirectly modulate proteins involved in neuronal survival / differentiation which may account for its neuroprotective effects . 
 we report three patients with huntington 's disease in whom lithium prevented the progression of chorea and also helped stabilize mood . 
INTRODUCTION
CASE REPORTS
Case 1
Case 2
Case 3
DISCUSSION