Huntington disease (HD) phenocopies are conditions characterized by a phenotype similar to HD but without a pathogenic repeat expansion in the HTT gene. The percentage of patients who have an HD phenotype but subsequently are shown not to carry a repeat expansion ranges from 2% to 40%, depending on the ethnicity and the geographic location of the population studied, as well as the resources available for investigation of the underlying causes. In descending order of frequency, genetic causes are Huntington Disease-like 2/JHP3, spinocerebellar ataxia genes (SCA17/TBP, SCA12/PPP2R2B and SCA3/ATXN3, CACNA1A), and frontotemporal dementia genes (C9orf72, and VCP). In addition, it has been established that a growing list of acquired causes may also mimic HD, including autoimmune illnesses such as primary antiphospholipid syndrome, paraneoplastic chorea, and anti-IGLON5. Here we aim to review the epidemiology, aetiology, clinical and laboratory findings of the wide range of conditions associated with HD phenocopies, and proceed to suggest a practical diagnostic approach to the investigation of HD phenocopies taking into account the age at onset, ethnicity, and geographic location of individuals.

BackgroundHuntington's Disease-like 2 (HDL2) presents complexities in diagnosis due to its similarity to Huntington's Disease (HD). Limited research highlights gaps in knowledge about management and genetic counselling for the condition. HDL2 is rare but an important differential diagnosis for individuals with HD-like symptoms who have tested negative for HD.ObjectiveThis review aimed to synthesise published clinical and genetic data on HDL2, identify knowledge gaps, and serve as a resource for healthcare professionals supporting individuals affected by or at risk of HDL2.MethodsA mixed method integrative systematic review of four databases (Medline, Embase, Scopus, and PsycINFO) generated 323 peer-reviewed articles, of which 36 were included. Data about clinical features, genetic testing and counselling, and patient experiences were interpreted via narrative synthesis.ResultsThe majority of included studies explored the clinical features, genetic testing results and medical histories of individuals with HDL2. A total of 109 people with HDL2 were reported. Limited data was obtained about genetic counselling, management and support, and experiences of those with HDL2 and their families. Findings related to seven categories: DNA repeat length and impact on phenotype, age of onset and disease duration, family history, African ancestry, neurological characteristics, clinical characteristics, and experiences and support.ConclusionsThis review highlights the importance of understanding the reduced penetrance range and early psychiatric symptoms in HDL2 for accurate genetic counselling and interpretation of test results. Adapting existing protocols for HD and qualitatively collecting patient experiences can inform the development of a HDL2 genetic testing and counselling protocol. Huntington's Disease-like 2 (HDL2) is a rare condition that can look very similar to Huntington's Disease (HD), which often makes it hard to diagnose. People who have symptoms like those seen in HD but test negative for HD may have HDL2 instead. This paper adds a new depth compared to a previous overview on HDL2 by Krause and co-authors in 2024.1 Here, we have used systematic methods to look at all the available research on HDL2 to better understand the condition and to help doctors and genetic counsellors support individuals and families affected by it. We searched four major research databases and found 36 relevant studies including 109 people with HDL2. Most of these focused on the medical and genetic features of people with HDL2. However, we found very little research on how to support people living with the condition or how to provide genetic counselling to families at risk. The main findings included information about how the condition is inherited, the role of African ancestry, symptoms that often appear early (especially psychiatric symptoms), and the length of time people have the condition for. Our review shows that more research is needed on how to support people with HDL2 and their families. Understanding early symptoms involved can help improve diagnosis and counselling. In the meantime, adapting support approaches used for Huntington's Disease may be helpful.

Huntington's Disease-like 2 (HDL2), caused by a CAG repeat expansion in JPH3, closely resembles HD. All reported HDL2 patients to date have some African ancestry. While both disorders exist in the Caribbean, their relative frequency and clinical characteristics remain largely unknown. To characterize HD and HDL2 patients in Martinique. We retrospectively analyzed all HD and HDL2 patients evaluated over 20 years at a single neurology center in Martinique, collecting longitudinal clinical features, UHDRS scores, and repeat lengths. In Martinique, combined HD and HDL2 minimum prevalence was 7.77/100,000. We ascertained 24 HD individuals, from 16 pedigrees, and 18 HDL2 individuals, from two pedigrees, one being the most extensive HDL2 pedigree yet reported. Because most HDL2 patients belong to a single large pedigree, the data must be interpreted with caution as familial clustering may introduce bias. HDL2 cases were predominantly male (83% vs. 45% in HD). Motor symptoms were the most frequent initial manifestation in both. Repeat length negatively correlated with estimated onset age in both diseases. Longitudinal motor (UHDRS-TMS) and functional capacity (UHDRS-TFC) scores in HDL2 revealed progressive worsening similar to HD. Inter- and intra-familial clinical and genetic heterogeneity was obvious in both diseases. Anticipation was not exclusively reserved to paternal transmissions in HDL2. HDL2 is nearly as prevalent as HD in Martinique. The study reinforces the similarities between HD and HDL2 in genotype-phenotype correlation and disease course, while highlighting heterogeneity and germline instability in HDL2. Interpretation is limited by the small number of HDL2 families.

Huntington disease-like 2 (HDL2) is an autosomal dominant disorder caused by an abnormal CAG/CTG repeat in exon 2A of junctophilin-3. This is the most common Huntington's Disease phenocopy and is characterized by psychiatric, cognitive, and movement disorders. This study aimed to describe the clinical phenotype of HDL2 patients in Brazil and compare the findings with those in the literature. This was a descriptive, observational study with a cross-sectional and retrospective component that evaluated 33 genetically confirmed HDL2 patients. Clinical data were collected using the Unified Huntington's Disease Rating Scale (UHDRS) and additional scales assessing sleep, mood, and cognition. The sample had a balanced gender distribution and was predominantly comprised of white individuals. Median disease duration was 11 years, median age at diagnosis was 44 years, and CAG repeats were 47. On the non-motor scales, the median scores were 33 points for fatigue, 31 points for apathy, and 18 points for depression. A significant negative correlation was observed between CAG repeat length and age at symptom onset (r = -0.76, p = 0.002). The median diagnosis delay was 4.5 years. While some findings, such as sex ratio and median CAG repeat length, were consistent with those of previous cohorts, this Brazilian sample exhibited longer diagnostic delays, an older age at assessment, and more severe motor scores. However, due to the small sample size, the results should be interpreted cautiously. Larger studies are needed to confirm these associations. Huntington disease-like 2 (HDL2) typically presents in midlife with a relentless progressive triad of movement, emotional, and cognitive abnormalities that lead to death within ten to 20 years. HDL2 cannot be differentiated from Huntington disease (HD) clinically. Neurologic abnormalities include chorea, hypokinesia (rigidity, bradykinesia), dysarthria, abnormalities of eye movements and gait, and hyperreflexia in the later stages of the disease. There is a strong correlation between the duration of the disease and the progression of motor and cognitive signs and symptoms. The diagnosis of HDL2 is established in a proband with characteristic clinical findings and heterozygous expansion of 40 or more CTG trinucleotide repeats in JPH3 identified by molecular genetic testing. Treatment of manifestations: Treatment is symptomatic and is presumably similar to that for HD and other neurodegenerative disorders – although this must be considered speculative pending objective data. Pharmacologic agents that may suppress abnormal movements include tetrabenazine and its derivatives or low-dose neuroleptic agents such as fluphenazine and haloperidol. Remove loose rugs and clutter from the individual's home and minimize or eliminate the need for stairs to help prevent falls and other injuries; physical therapy evaluation and treatment for mobility issues; speech therapy, communication devices, and environmental modifications for dysarthria; speech-language pathology and nutrition referrals for dysphagia; food should be prepared in such a manner as to prevent choking; feeding changes when needed to minimize risk of aspiration; driving may need to be curtailed or limited to prevent risk of accidents; planning for financial matters; environmental interventions for cognitive issues; antidepressants, antipsychotics, mood stabilizers (lithium, valproic acid, carbamazepine, and lamotrigine), electroconvulsive therapy, and occasionally stimulants may improve psychiatric manifestations. Education about the course of disease; social work and care coordination support. Surveillance: Annual evaluation or more frequently as needed to assess motor skills including gait and abnormal movements; physical therapy assessment of mobility and appropriate strategies or devices to minimize falls; assess cognitive skills and driving safety to assure that affected individuals do not present a danger to themselves or others; assess weight, nutrition, swallowing, and risk of aspiration in order to implement feeding changes when necessary; assess for psychiatric manifestations, including mood, suicidality, anxiety, irritability, and apathy; assess sleep and sexual concerns; assess family needs; assess planning for future (financial, legal issues). Agents/circumstances to avoid: Any agents that increase ataxia should be used with caution; begin psychoactive medicines at lower doses and increase doses carefully; minimize polypharmacy, which may increase the risk of delirium. HDL2 is inherited in an autosomal dominant manner. Most individuals with HDL2 have an affected parent. At conception, each child of an individual with HDL2 has a 50% chance of inheriting the HDL2-causing allele. Offspring who inherit a pathogenic (full-penetrance) HDL2-causing allele (≥40 CTG repeats) are considered at risk of developing HDL2 in their lifetime; offspring who inherit an allele of questionable significance (29-39 CTG repeats) may or may not develop manifestations of HDL2. Testing of asymptomatic adults at risk for HDL2 is possible once a heterozygous expansion of a CTG repeat in JPH3 has been identified in an affected family member. Testing for the JPH3 CTG repeat expansion in the absence of definite manifestations of the disease is predictive testing. Prudence suggests following the same genetic testing guidelines used for HD, including counseling prior to testing, a confidant to serve as a social support, and availability of counseling following the disclosure of genetic results. If the presence of an HDL2-causing allele has been confirmed in the affected parent or in an affected relative of the at-risk parent, prenatal and preimplantation genetic testing are possible.

A trinucleotide repeat expansion of the JPH3 gene causes Huntington disease-like 2 (HDL2), clinically indistinguishable from Huntington's disease and is considered a disease unique to African and Afro-descendant populations. We identified five HDL2 families from the Costa Chica region of southern Pacific Mexico. Because the Mexican population is admixed, we aimed to determine the ancestral origin of the expansion and define the mutation-carrying haplotype using microarray genomic data. Sixteen individuals (Nine symptomatic, three asymptomatic mutation carriers and four healthy non-carriers) were included. Global and local ancestry were estimated using whole-genome microarray data. Principal component and quadratic discriminant analysis (QDA) were used to infer the most likely origin of the haplotypes, complemented by the SMOTE-Tomek sampling strategy. Mean ancestry proportions were 16.26, 27.33, and 56.39% for African, European, and Native American components, respectively. A 1.1 Mb segment inferred as African flanking the JPH3 mutation locus was shared by at least one of the homologous chromosomes of all mutation carriers. Phased genotype analysis revealed a common 746 Kb haplotype containing the mutation that includes 412 SNPs. This shared haplotype was consistently inferred to be of African origin. QDA classified this haplotype as Yoruba in 78.3% of the resampling iterations. Ancestry analysis suggests that the JPH3 repeat expansion identified in our patients is a founder mutation of African origin. Other founder mutations causing rare genetic diseases in Mexico show how the admixture process in Latin America has contributed to the high prevalence of disease in certain geographical regions.