Genetic Counseling in Huntington's Disease: Potential New Challenges on Horizon?

Migliore, Simone; Jankovic, Joseph; Squitieri, Ferdinando

doi:10.3389/fneur.2019.00453

Cited by 38 publications

(23 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Such recommendations aim to extend medicines following future positive trial results to minors, who are still excluded from all clinical experimental therapies. Therefore, the first step is to approach such a young population and their parents through careful counselling [ 35 ] by a clinical diagnosis that needs to be confirmed by a reliable genetic test, whenever allowed [ 36 ]. For instance, the methodology we describe here contributes to reliably detect highly expanded mutations above 200 CAG repeats thanks to the visible smear between the normal and the pathological alleles.…”

Section: Discussionmentioning

confidence: 99%

A Novel Triplet-Primed PCR Assay to Detect the Full Range of Trinucleotide CAG Repeats in the Huntingtin Gene (HTT)

Luca

Morella

Consoli

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

The expanded CAG repeat number in HTT gene causes Huntington disease (HD), which is a severe, dominant neurodegenerative illness. The accurate determination of the expanded allele size is crucial to confirm the genetic status in symptomatic and presymptomatic at-risk subjects and avoid genetic polymorphism-related false-negative diagnoses. Precise CAG repeat number determination is critical to discriminate the cutoff between unexpanded and intermediate mutable alleles (IAs, 27–35 CAG) as well as between IAs and pathological, low-penetrance alleles (i.e., 36–39 CAG repeats), and it is also critical to detect large repeat expansions causing pediatric HD variants. We analyzed the HTT-CAG repeat number of 14 DNA reference materials and of a DNA collection of 43 additional samples carrying unexpanded, IAs, low and complete penetrance alleles, including large (>60 repeats) and very large (>100 repeats) expansions using a novel triplet-primed PCR-based assay, the AmplideX PCR/CE HTT Kit. The results demonstrate that the method accurately genotypes both normal and expanded HTT-CAG repeat numbers and reveals previously undisclosed and very large CAG expansions >200 repeats. We also show that this technique can improve genetic test reliability and accuracy by detecting CAG expansions in samples with sequence variations within or adjacent to the repeat tract that cause allele drop-outs or inaccuracies using other PCR methods.

show abstract

Section: Discussionmentioning

confidence: 99%

A Novel Triplet-Primed PCR Assay to Detect the Full Range of Trinucleotide CAG Repeats in the Huntingtin Gene (HTT)

Luca

Morella

Consoli

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…Advances in genetic diagnostics will add to the number of 'identifiable' conditions in the near future, but specific treatments informed by this research are still a long way away. In the meantime, symptomatic treatments in line with international guidelines recommended by Bachoud-Lévi et al, [33], specialised counselling for different category of CAG repeats, especially in the wake of new advances in gene modifiers as recommended by Migliore et al, [34], adequate rehabilitative services that improve the quality of life, and overall outcomes, need to be developed and sustained.…”

Section: Discussionmentioning

confidence: 99%

Psychiatric morbidity and poor follow-up underlie suboptimal functional and survival outcomes in Huntington's disease

Ratna

Kamble

Sowmya

et al. 2020

Preprint

View full text Add to dashboard Cite

BACKGROUND: Huntington’s disease (HD), an inherited, often late-onset, neurodegenerative disorder, is considered to be a rare, orphan disease. Research into its genetic correlates and services for those affected are inadequate in most low-middle income countries, including India. The apparent ‘incurability’ often deters symptomatic and rehabilitative care, resulting in poor quality of life and sub-optimal outcomes. There are no studies assessing disease burden and outcomes from India. METHODS: We attempted to evaluate individuals diagnosed to have HD at our tertiary-care center between 2013 and 2016 for clinical symptoms, functionality, mortality, follow up status through a structured interview, clinical data from medical records and UHDRS-TFC scoring. RESULTS: Of the 144 patients, 25% were untraceable, and another 17 (11.8%) had already died. Mean age at death and duration of illness at the time of death, were 53 years and 7 years respectively, perhaps due to suicides and other comorbidities at an early age. The patients who could be contacted (n=81) were assessed for morbidity and total functional capacity (TFC). Mean CAG repeat length and TFC score were 44.2 and 7.5 respectively. Most individuals (66%) were in TFC stage I and II and could perhaps benefit from several interventions. The TFC score correlated inversely with duration of illness (p<0.0001). The majority were being taken care of at home, irrespective of the physical and mental disability. There was a high prevalence of psychiatric morbidity (91%) including suicidal tendency (22%). Three of the 17 who died had committed suicide, and several other families reported suicidal history in other family members. Only about half the patients (57%) maintained a regular clinical follow-up. CONCLUSIONS: This study demonstrates the poor follow-up rates, significant suicidality and other psychiatric symptoms, sub-optimal survival durations and functional outcomes highlighting the need for holistic care for the majority who appear to be amenable to interventions.

show abstract

“…In our population, four prenatal and one preimplantation tests were carried out for 4 mothers affected of HD. In these cases, the importance of genetic counselling was revealed, being necessary the translation of the advances in genetic and in-utero techniques into genetic counselling, taking into account the ethical and scienti c principles allowing families to make decisions, including the interruption of pregnancy [37], as one of our cases. It is important because younger generations are likely to be more seriously affected by inheriting a CAG repeat ampli cation, so the detection of the disease and prenatal tests would make it possible to inform and counsel other family members [14].…”

Section: Discussionmentioning

confidence: 99%

Incidence of Huntington disease in a northeastern Spanish region: A 13-year retrospective study at tertiary care centre

Bailo

Lahoz

Marín

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Despite the progress in the knowledge of Huntington disease (HD) in recent years, the epidemiology continues uncertain, so the study of incidence becomes relevant. This is important since various factors (type of population, diagnostic criteria, disease-modifying factors, etc.) make these data highly variable. Therefore, the genetic diagnosis of these patients is important, since it unequivocally allows the detection of new cases.Methods: Descriptive retrospective study with 179 individuals. Incidence of HD was calculated from the ratio of number of symptomatic cases newly diagnosed per 100 000 inhabitants per year during the period 2007-2019 in Aragon (Spain). Results: 50 (27.9%) incident cases of HD (CAG repeat length ≥36) were identified from a total of 179 persons studied. The remaining 129/179 (73.4%) were HD negative (CAG repeat length <36). 29 (58.0%) females and 21 (42.0%) males were confirmed as HD cases. The overall incidence was 64.8 per 100 000 patient-years. 11/50 positive HD cases (22.0%) were identified by performing a predictive test, without clinical symptoms. The minimum number of CAG repeats found was 10 and the most common CAG length among HD negative individuals was 16.Conclusions: Our incidence lied within the range reported for other Caucasian populations. Implementation of new techniques has allowed to determine the exact number of CAG repeats, which is especially important in patients with triplet expansions in an HD intermediate and/or incomplete penetrance allele, both in diagnostic, predictive and prenatal tests.

show abstract

Genetic Counseling in Huntington's Disease: Potential New Challenges on Horizon?

Cited by 38 publications

References 47 publications

A Novel Triplet-Primed PCR Assay to Detect the Full Range of Trinucleotide CAG Repeats in the Huntingtin Gene (HTT)

A Novel Triplet-Primed PCR Assay to Detect the Full Range of Trinucleotide CAG Repeats in the Huntingtin Gene (HTT)

Psychiatric morbidity and poor follow-up underlie suboptimal functional and survival outcomes in Huntington's disease

Incidence of Huntington disease in a northeastern Spanish region: A 13-year retrospective study at tertiary care centre

Contact Info

Product

Resources

About