Journal of Neurology Research, ISSN 1923-2845 print, 1923-2853 online, Open Access
Article copyright, the authors; Journal compilation copyright, J Neurol Res and Elmer Press Inc
Journal website https://www.neurores.org

Review

Volume 12, Number 3, October 2022, pages 93-113

Review of Huntington’s Disease: From Basics to Advances in Diagnosis and Treatment

Figures

Figure 1.
Figure 1. Cluster worldwide populations with the highest prevalence.
Figure 2.
Figure 2. Prof. Negrete, Americo, who identified the Zulia cluster at Maracaibo, Venezuela.
Figure 3.
Figure 3. Illustrative figure showing how Huntingtin exon 1- represents a particular DNA segment known as a CAG trinucleotide repeat. This fragment is made up of a series of three DNA nitrogenous bases (cytosine, adenine and guanine) that appears multiple times in a row. The normal CAG repetitions are 10 to 35. HD is caused by expansion of that CAG trinucleotide that encodes the 17 AA N-terminal 17; a polyQ tract and 51-residue proline-rich domain (PRD), which is translated into a corresponding polyglutamine tract that turns medium spiny neurons in the striatum exceptionally susceptible to apoptosis, leading to their dysfunction and early death. HD: Huntington’s disease; CAG: cytosine-adenine-guanine.
Figure 4.
Figure 4. Example of the transcription impairment in HD. Mutant htt results in down regulation of certain transcription factors (MSK-1) and sequestration of others, CREB and CBP. HD: Huntington’s disease.
Figure 5.
Figure 5. Non-coding small RNA with each specified function. miRNA: mRNA degradation/block translation; siRNA: mRNA degradation, chromatin condensation; piRNA: interaction piwi family of proteins; lncRNA: chromatin remodelling/transcriptional and post-regulation/precursors for siRNAs.
Figure 6.
Figure 6. Gene expression is by non-coding RNAs. RNA toxicity mechanisms include aberrant protein-RNA interactions and protein sequestration, but also the hairpin secondary structure formed by CAG RNA resemble double-stranded RNA structures that are substrates for Dicer, dividing them into shorter repeats that silence specific genes.
Figure 7.
Figure 7. Summary of mechanisms involved in HD pathogenesis. HD: Huntington’s disease.
Figure 8.
Figure 8. Sphingosine 1 phosphate is a potent signalling lipid. HD has been associated with a significant reduction of the sphingosine 1 phosphate (S1P) which action is mediated by the S1P receptors union. These receptors are located in neurons, astrocytes and oligodendrocytes. Experimental models identified autophagy stimulation, reduction of htt aggregation and activation of AKT and ErK pathways and BDNF production mediated by S1P signalling activation. Extracellularly level S1P stabilizes S1PR expression and activates pro-survival pathways. HD: Huntington’s disease.
Figure 9.
Figure 9. Natural evolution of Huntington’s disease. Functional capacity begins to decline, even from the premanifest stages, increasing motor disability. Regarding suicidal ideation, it is greater in premanifest stages, and begins to decrease as the disease progresses.
Figure 10.
Figure 10. (a) Enlargement of both frontal horns of the lateral ventricles due to caudate atrophy (arrow). Axial T2-weighted sequence. (b) Diffuse bilateral and symmetric hypointense signals in T2 SWAN (magnetic susceptibility) sequence due to abnormal mineral deposition, slight dilation of the anterior extensions and lateral ventricles. Decreased volume of both globus pallidus (atrophy).

Tables

Table 1. Genetic Modifiers of Blood DNA Somatic Expansion Scores of the HTT CAG Repeat
 
SNP IDChrGeneA1A2TRACK-HDEnroll-HDMeta-analysis
βPP-FDRβPP-FDRP-FDR
Shown is the genetics association data for the six SNPs genotyped in TRACK-HD and replicated in Enroll-HD. SNPs are ordered by decreasing P-value of their association with the somatic expansion score in the TRACK-HD cohort. Note that in the preliminary analysis using a slightly larger TRACK-HD cohort including four participants with 39 pure CAG repeats (Q1 = 39) and six non-Caucasians, the association between somatic expansion score and rs20579 in LIG1 was P = 0.072 and rs20579 was thus selected for replication in Enroll-HD. Chr: chromosome; A1: minor allele; β: regression coefficient; P: unadjusted P-value; P-FDR: P-value adjusted for multiple testing using the Benjamini-Hochberg false discovery rate correlation; HD: Huntington’s disease; CAG: cytosine-adenine-guanine; HTT: huntingtin.
rs351215FAN1CG0.060.0030.0340.056.7 × 10-54.0 × 10-44.8 × 10-6
rs17508014MLH3AG-0.0530.0340.034-0.0290.0130.0268.0 × 10-4
rs1478043302RP11-481J13,1AG-0.1070.010.0730.0030.9120.9120.246
rs13825395MSH3AG-0.0450.1010.101-0.0230.0770.1160.009
rs17999773MLH1GA-0.0320.0930.314-0.0340.0090.0260.004
rs2057919MIG1AG-0.0420.1120.314-0.0020.9080.9120.351

 

Table 2. Differential Diagnoses of Huntington’s Disease, Autosomal Dominant (AD) and Autosomal Recessive (AR) Phenocopies, With Their Respective Genes Involved and Clinical Findings that Contribute to Reaching the Correct Diagnosis
 
DiseaseGene MtOMIMClinical findings/red flagsAncestry
HDL: Huntington’s disease-like; SCA: spinocerebellar ataxia; DRPLA: dentorubropallidoluisiana; NBIA: neurodegeneration with brain iron accumulation; BHC: Bening hereditary chorea; CA: chorea acanthocytosis; JPH-3: junctophilin-3; TBP: tata box-binding protein; ATXN2: ataxin-2; HRE: hexanucleotide repeat expansion; PRNP: prion protein gene; ATN1: ataxin 1; FTL: ferritin light chain; TITF1: thyroid transcription factor 1; VPS13A: vacuolar protein sorting 13 homolog A.
AD
  HDL2JPH-3606438Circulating acanthocytesAfrican
  SCA 17TBP607136Ataxia choreaEurope
  SCA 2ATXN2183090Nystagmus, impaired saccadic movements and pyramidalismBrazil
  C9orf72HRE614260Early psychiatric and behavioral problems pyramidal features
  HDL1PRPN603218Chorea prionic diseaseAfrican
  DRPLAATN1607462Myoclonus, seizures and/or choreaJapan
  NBIA3FTL606159Chorea replaces parkinsonism
  BHCTITF1610978Childhood disease accompanied by hypothyroidism
AR
  CAVPS13A200150Movement disorders, cognitive decline and behavioral abnormalities

 

Table 3. Summary of Neuroimaging Biomarkers and Its Findings
 
PETRadioligandFindings
PET: positron emission tomography; UHDRS: Unified Huntington Disease Rating Scale; FDG: fluorodeoxyglucose; HD: Huntington’s disease.
Glucose metabolism18F-FDGHypometabolism in the caudate and putamen countered by hypermetabolism in thalamic structures at preclinical stages.
Striatal and Cortical hypometabolism are associated with motor and cognitive symptoms. Changes may precede neuronal loss.
Dopamine D2r11C-βCIT; 11C-TBZ presynaptic tracers. 11C-raclopride**/11C FLB457**Putamen binding correlations: motor score UHDRS; total functional capacity. Reduction cortical and putaminal binding
PDE10A18F-MNI-659***High expression in the median spinous neurons of the striatum (possible therapeutic target)
***Earliest change in carriers premanifest, even 15 to 20 years prior to clinical manifestations
11C-IMA-107
Microglial activation11C-PK11195Cortical and subcortical areas of significantly raised mean 11C-(R)-PK11195 binding in presymptomatic HD gene carriers compared to controls. Predictive 5-year probability of developing HD.

 

Table 4. Summary of the Most Commonly Used Drugs With Their Respective Doses in Each of the Symptoms Associated With Huntington’s Disease
 
SymptomsFeatureTargetDrug groupDrugDoses
Motor symptomsChoreaReduce dopaminergic neurotransmissionTypical neurolepticsHaloperidol0.5 - 10 mg
Atypical neurolepticsClozapine50 - 150 mg
Quetiapine25 - 200 mg
Olanzapine2.5 - 20 mg
Risperidone0.5 - 2 mg
Sigma 1 receptor agonistPridopidine*Post-hoc analysis improved TFC in early HD
Anti-NMDA7 glutamatergic InhibitorAmantadine100 - 400 mg
Presynaptic dopamine-depleting agentsSelectively depletes central monoaminesTetrabenazine12.5 - 200 mg
Deutetrabenazine12.5 - 50 mg
Valbenazine40 - 80 mg
Cognitive symptomsDementiaCholinesterase inhibitorCholinesterase inhibitorRivastigmine1.5 - 13.3 mg
Inflammation regulationp38α MAPK inhibition*NeflamapimodNCT03980938
Anti-glutamatergicNMDA receptor modulation*SAGE-718NCT03787758
Psychiatric symptomsDepressionSSRIsFluoxetine20 - 60 mg
Citalopram20 - 60 mg
Escitalopram10 - 20 mg
Paroxetine20 - 60 mg
Sertraline50 - 200 mg
Tricyclic antidepressantsTricyclic antidepressantsNortriptyline25 - 150 mg
Desipramine100 - 300 mg
Amitriptyline75 - 150 mg
Atypical antipsychoticsOlanzapine2.5 - 10 mg
Risperidone0.5 - 2 mg
Aripiprazole10 - 30 mg
Clozapine50 - 150 mg
Quetiapine25 - 200 mg
Obsessive and/or compulsive symptomsMood-stabilizing antiepileptic drugsAntiepileptic drugsValproate500 - 2,000 mg
Carbamazepine200 - 1,600 mg
Lamotrigine25 - 400 mg
Topiramate25 - 400 mg
AgitationBenzodiazepinesClonazepam0.5 - 6 mg
IrritabilityMorphinan/class I antiarrhythmic agentDextromethorphan/quinidine*NCT03854019
ApathyNorepinephrine/dopamine reuptake inhibitorBupropionNegative results