Editing Huntington's disease (section)

==Diagnosis==

[[Medical diagnosis|Diagnosis]] of the onset of HD can be made following the appearance of physical symptoms specific to the disease.<ref name="lancet07" /> Genetic testing can be used to confirm a physical diagnosis if no family history of HD exists. Even before the onset of symptoms, genetic testing can confirm if an individual or [[embryo]] carries an expanded copy of the trinucleotide repeat (CAG) in the ''HTT'' gene that causes the disease. [[Genetic counseling]] is available to provide advice and guidance throughout the testing procedure and on the implications of a confirmed diagnosis. These implications include the impact on an individual's psychology, career, family-planning decisions, relatives, and relationships. Despite the availability of pre-symptomatic testing, only 5% of those at risk of inheriting HD choose to do so.<ref name="lancet07" />

===Clinical===

[[File:Huntington.jpg|thumb|upright|alt=Cross section of a brain showing undulating tissues with gaps between them,  two large gaps are evenly spaced about the centre.| [[Coronal plane|Coronal]] section from an [[MRI]] [[brain scan]] of a patient with HD, showing [[atrophy]] of the heads of the [[caudate nucleus|caudate nuclei]], enlargement of the frontal horns of the [[lateral ventricles]] (hydrocephalus ''ex vacuo''), and generalized cortical atrophy<ref>{{cite web |vauthors=Gaillard F |title=Huntington's disease |url=http://www.radpod.org/2007/05/01/huntingtons-disease/ |date=1 May 2007 |work=Radiology picture of the day |publisher=www.radpod.org |access-date=24 July 2009 |url-status=dead |archive-url=https://web.archive.org/web/20071022134552/http://radpod.org/2007/05/01/huntingtons-disease/ |archive-date=22 October 2007}}</ref>]]

A [[physical examination]], sometimes combined with a [[psychological examination]], can determine whether the onset of the disease has begun.<ref name="lancet07" />  Excessive unintentional movements of any part of the body are often the reason for seeking medical consultation.  If these are abrupt and have random timing and distribution, they suggest a diagnosis of HD.  Cognitive or behavioral symptoms are rarely the first symptoms diagnosed; they are usually only recognized in hindsight or when they develop further.  How far the disease has progressed can be measured using the unified Huntington's disease rating scale, which provides an overall rating system based on motor, behavioral, cognitive, and functional assessments.<ref name="pmid19111470">{{cite journal | vauthors = Rao AK, Muratori L, Louis ED, Moskowitz CB, Marder KS | title = Clinical measurement of mobility and balance impairments in Huntington's disease: validity and responsiveness | journal = Gait & Posture | volume = 29 | issue = 3 | pages = 433–436 | date = April 2009 | pmid = 19111470 | doi = 10.1016/j.gaitpost.2008.11.002 }}</ref><ref>{{cite web |url=http://huntingtonstudygroup.org/tools-resources/uhdrs/ |title=Unified Huntington's Disease Rating Scale (UHDRS) |access-date=14 April 2009 |work=UHDRS and Database |publisher=HSG |date=1 February 2009 |url-status=live |archive-url=https://web.archive.org/web/20150811064639/http://huntingtonstudygroup.org/tools-resources/uhdrs/ |archive-date=11 August 2015}}</ref> [[Medical imaging]], such as a [[CT scan]] or [[magnetic resonance imaging|MRI scan]], can show atrophy of the caudate nuclei early in the disease, as seen in the illustration to the right, but these changes are not, by themselves, diagnostic of HD. [[Cerebral atrophy]] can be seen in the advanced stages of the disease. [[Functional neuroimaging]] techniques, such as [[functional magnetic resonance imaging]] (fMRI) and [[positron emission tomography]] (PET), can show changes in brain activity before the onset of physical symptoms, but they are experimental tools and are not used clinically.<ref name="lancet07" />

===Predictive genetic testing===

Because HD follows an autosomal dominant pattern of inheritance, a strong motivation exists for individuals who are at risk of inheriting it to seek a diagnosis. The genetic test for HD consists of a blood test, which counts the numbers of CAG repeats in each of the ''HTT'' alleles.<ref name="pmid15717026">{{cite journal | vauthors = Myers RH | title = Huntington's disease genetics | journal = NeuroRx | volume = 1 | issue = 2 | pages = 255–262 | date = April 2004 | pmid = 15717026 | pmc = 534940 | doi = 10.1602/neurorx.1.2.255 }}</ref> [[Cutoff (reference value)|Cutoffs]] are given as follows:
* At 40 or more CAG repeats, full [[penetrance]] allele (FPA) exists.<ref name=Die-Smulders2013>{{cite journal | vauthors = de Die-Smulders CE, de Wert GM, Liebaers I, Tibben A, Evers-Kiebooms G | title = Reproductive options for prospective parents in families with Huntington's disease: clinical, psychological and ethical reflections | journal = Human Reproduction Update | volume = 19 | issue = 3 | pages = 304–315 | date = May 2013 | pmid = 23377865 | doi = 10.1093/humupd/dms058 | doi-access = free }} {{cite journal | vauthors = de Die-Smulders CE, de Wert GM, Liebaers I, Tibben A, Evers-Kiebooms G | title = Reproductive options for prospective parents in families with Huntington's disease: clinical, psychological and ethical reflections | journal = Human Reproduction Update | volume = 19 | issue = 3 | pages = 304–315 | year = 2013 | pmid = 23377865 | doi = 10.1093/humupd/dms058 | doi-access = free }}</ref> A "[[positive test]]" or "positive result" generally refers to this case. A positive result is not considered a diagnosis, since it may be obtained decades before the symptoms begin. However, a negative test means that the individual does not carry the expanded copy of the gene and will not develop HD.<ref name="lancet07" /> The test will tell a person who originally had a 50% chance of inheriting the disease if their risk goes up to 100% or is eliminated. Persons who test positive for the disease will develop HD sometime within their lifetimes, provided they live long enough for the disease to appear.<ref name="lancet07" />
* At 36 to 39 repeats, incomplete or reduced penetrance allele (RPA) may cause symptoms, usually later in the adult life.<ref name=Die-Smulders2013/> The maximum risk is 60% that a person with an RPA will be symptomatic at age 65, and 70% at 75.<ref name=Die-Smulders2013/>
* At 27 to 35 repeats, intermediate allele (IA), or large normal allele, is not associated with symptomatic disease in the tested individual, but may expand upon further inheritance to give symptoms in offspring.<ref name=Die-Smulders2013/>
* With 26 or fewer repeats, the result is not associated with HD.<ref name=Die-Smulders2013/>

Testing before the onset of symptoms is a life-changing event and a very personal decision.<ref name="lancet07" /> The main reason given for choosing to test for HD is to aid in career and family decisions.<ref name="lancet07" /> Predictive testing for Huntington's disease has been available via linkage analysis (which requires testing multiple family members) since 1986 and via direct mutation analysis since 1993.<ref>{{cite journal | vauthors = Baig SS, Strong M, Rosser E, Taverner NV, Glew R, Miedzybrodzka Z, Clarke A, Craufurd D, Quarrell OW | title = 22 Years of predictive testing for Huntington's disease: the experience of the UK Huntington's Prediction Consortium | journal = European Journal of Human Genetics | volume = 24 | issue = 10 | pages = 1396–1402 | date = October 2016 | pmid = 27165004 | pmc = 5027682 | doi = 10.1038/ejhg.2016.36 }}</ref> At that time, surveys indicated that 50–70% of at-risk individuals would have been interested in receiving testing, but since predictive testing has been offered far fewer choose to be tested.<ref name="pmid23297124">{{cite journal | vauthors = Forrest Keenan K, Simpson SA, Miedzybrodzka Z, Alexander DA, Semper J | title = How do partners find out about the risk of Huntington's disease in couple relationships? | journal = Journal of Genetic Counseling | volume = 22 | issue = 3 | pages = 336–344 | date = June 2013 | pmid = 23297124 | doi = 10.1007/s10897-012-9562-2 | s2cid = 15447709 }}</ref> Over 95% of individuals at risk of inheriting HD do not proceed with testing, mostly because it has no treatment.<ref name="lancet07" /> A key issue is the anxiety an individual experiences about not knowing whether they will eventually develop HD, compared to the impact of a positive result.<ref name="lancet07" /> Irrespective of the result, stress levels are lower two years after being tested, but the risk of suicide is increased after a positive test result.<ref name="lancet07" /> Individuals found to have not inherited the disorder may experience [[survivor guilt]] about family members who are affected.<ref name="lancet07" /> Other factors taken into account when considering testing include the possibility of discrimination and the implications of a positive result, which usually means a parent has an affected gene and that the individual's siblings will be at risk of inheriting it.<ref name="lancet07" /> In one study, genetic discrimination was found in 46% of individuals at risk for Huntington's disease. It occurred at higher rates within personal relationships than health insurance or employment relations.<ref name="pmid20468061">{{cite journal | vauthors = Erwin C, Williams JK, Juhl AR, Mengeling M, Mills JA, Bombard Y, Hayden MR, Quaid K, Shoulson I, Taylor S, Paulsen JS | title = Perception, experience, and response to genetic discrimination in Huntington disease: the international RESPOND-HD study | journal = American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics | volume = 153B | issue = 5 | pages = 1081–1093 | date = July 2010 | pmid = 20468061 | pmc = 3593716 | doi = 10.1002/ajmg.b.31079 }}</ref> [[Genetic counseling]] in HD can provide information, advice and support for initial decision-making, and then, if chosen, throughout all stages of the testing process.<ref name="geneticcounselling">{{cite journal | vauthors = Burson CM, Markey KR | title = Genetic counseling issues in predictive genetic testing for familial adult-onset neurologic diseases | journal = Seminars in Pediatric Neurology | volume = 8 | issue = 3 | pages = 177–186 | date = September 2001 | pmid = 11575847 | doi = 10.1053/spen.2001.26451 }}</ref> Because of the implications of this test, patients who wish to undergo testing must complete three counseling sessions which provide information about Huntington's.<ref name="pmid22114233">{{cite journal | vauthors = Smith JA, Michie S, Stephenson M, Quarrell O | title = Risk Perception and Decision-making Processes in Candidates for Genetic Testing for Huntington's Disease: An Interpretative Phenomenological Analysis | journal = Journal of Health Psychology | volume = 7 | issue = 2 | pages = 131–144 | date = March 2002 | pmid = 22114233 | doi = 10.1177/1359105302007002398 | s2cid = 40182214 }}</ref>

Counseling and guidelines on the use of genetic testing for HD have become models for other genetic disorders, such as autosomal dominant [[cerebellar ataxia]].<ref name="lancet07" /><ref name="pmid12849232">{{cite journal | vauthors = Hayden MR | title = Predictive testing for Huntington's disease: a universal model? | journal = The Lancet. Neurology | volume = 2 | issue = 3 | pages = 141–142 | date = March 2003 | pmid = 12849232 | doi = 10.1016/S1474-4422(03)00317-X | s2cid = 39581496 }}</ref><ref>{{cite journal | vauthors =  | title = Guidelines for the molecular genetics predictive test in Huntington's disease. International Huntington Association (IHA) and the World Federation of Neurology (WFN) Research Group on Huntington's Chorea | journal = Neurology | volume = 44 | issue = 8 | pages = 1533–1536 | date = August 1994 | pmid = 8058167 | doi = 10.1212/WNL.44.8.1533 | s2cid = 28018134 }}</ref> [[Predictive testing|Presymptomatic testing]] for HD has also influenced testing for other illnesses with genetic variants such as [[polycystic kidney]] disease, familial [[Alzheimer's disease]] and [[breast cancer]].<ref name="pmid12849232"/> The European Molecular Genetics Quality Network have published yearly external quality assessment scheme for molecular genetic testing for this disease and have developed best practice guidelines for genetic testing for HD to assist in testing and reporting of results.<ref name=Losekoot2012>{{cite journal | vauthors = Losekoot M, van Belzen MJ, Seneca S, Bauer P, Stenhouse SA, Barton DE | title = EMQN/CMGS best practice guidelines for the molecular genetic testing of Huntington disease | journal = European Journal of Human Genetics | volume = 21 | issue = 5 | pages = 480–486 | date = May 2013 | pmid = 22990145 | pmc = 3641377 | doi = 10.1038/ejhg.2012.200 }}</ref>

===Preimplantation genetic diagnosis===

[[Embryo]]s produced using [[in vitro fertilisation|''in vitro'' fertilization]] may be genetically tested for HD using [[preimplantation genetic diagnosis]]. This technique, where one or two cells are extracted from a typically 4- to 8-cell embryo and then tested for the genetic abnormality, can then be used to ensure embryos affected with HD genes are not implanted, so any offspring will not inherit the disease. Some forms of preimplantation genetic diagnosis—non-disclosure or exclusion testing—allow at-risk people to have HD-free offspring ''without'' revealing their own parental genotype, giving no information about whether they themselves are destined to develop HD. In exclusion testing, the embryo's DNA is compared with that of the parents and grandparents to avoid inheritance of the chromosomal region containing the HD gene from the affected grandparent. In nondisclosure testing, only disease-free embryos are replaced in the uterus while the parental genotype and hence parental risk for HD are never disclosed.<ref>{{cite journal | vauthors = Schulman JD, Black SH, Handyside A, Nance WE | title = Preimplantation genetic testing for Huntington disease and certain other dominantly inherited disorders | journal = Clinical Genetics | volume = 49 | issue = 2 | pages = 57–58 | date = February 1996 | pmid = 8740912 | doi = 10.1111/j.1399-0004.1996.tb04327.x | s2cid = 45703511 }}</ref><ref>{{cite journal | vauthors = Stern HJ, Harton GL, Sisson ME, Jones SL, Fallon LA, Thorsell LP, Getlinger ME, Black SH, Schulman JD | title = Non-disclosing preimplantation genetic diagnosis for Huntington disease | journal = Prenatal Diagnosis | volume = 22 | issue = 6 | pages = 503–507 | date = June 2002 | pmid = 12116316 | doi = 10.1002/pd.359 | s2cid = 33967835 }}</ref>

===Prenatal testing===

Obtaining a [[prenatal diagnosis]] for an embryo or [[fetus]] in the womb is also possible, using fetal genetic material acquired through [[chorionic villus sampling]]. An [[amniocentesis]] can be performed if the pregnancy is further along, within 14–18 weeks. This procedure looks at the amniotic fluid surrounding the baby for indicators of the HD mutation.<ref>{{cite web|title=Predictive Testing for Huntington's Disease|url=http://predictivetestingforhd.com/testing-for-hd/prenatal-testing/amniocentesis/|access-date=7 May 2013|year=2011|url-status=live|archive-url=https://web.archive.org/web/20130122124510/http://predictivetestingforhd.com/testing-for-hd/prenatal-testing/amniocentesis/|archive-date=22 January 2013}}</ref> This, too, can be paired with exclusion testing to avoid disclosure of parental genotype. Prenatal testing can be done when parents have been diagnosed with HD, when they have had genetic testing showing the expansion of the ''HTT'' gene, or when they have a 50% chance of inheriting the disease. The parents can be counseled on their options, which include [[termination of pregnancy]], and on the difficulties of a child with the identified gene.<ref name="pmid15758612">{{cite journal | vauthors = Kuliev A, Verlinsky Y | title = Preimplantation diagnosis: a realistic option for assisted reproduction and genetic practice | journal = Current Opinion in Obstetrics & Gynecology | volume = 17 | issue = 2 | pages = 179–183 | date = April 2005 | pmid = 15758612 | doi = 10.1097/01.gco.0000162189.76349.c5 | s2cid = 9382420 }}</ref><ref>{{cite web|title=Guidelines for Genetic Testing for Huntington's Disease|url=http://dwb4.unl.edu/chem/chem869n/chem869nlinks/www.hdfoundation.org/testread/hdsatest.htm|publisher=Heredity Disease Foundation|access-date=7 May 2013|url-status=dead|archive-url=https://web.archive.org/web/20150626005614/http://dwb4.unl.edu/Chem/CHEM869N/CHEM869NLinks/www.hdfoundation.org/testread/hdsatest.htm|archive-date=26 June 2015}}</ref>

In addition, in at-risk pregnancies due to an affected male partner, noninvasive prenatal diagnosis can be performed by analyzing [[cell-free fetal DNA]] in a blood sample taken from the mother (via [[venipuncture]]) between six and 12 weeks of pregnancy.<ref name=Die-Smulders2013/> It has no procedure-related risk of miscarriage.<ref name=Die-Smulders2013/>

===Differential diagnosis===

About 99% of HD diagnoses based on the typical symptoms and a [[family history (medicine)|family history]] of the disease are confirmed by genetic testing to have the expanded trinucleotide repeat that causes HD. Most of the remaining are called [[Huntington's disease-like syndrome|HD-like (HDL) syndromes]].<ref name="lancet07" /><ref name="HD-LIKE"/> The cause of most HDL diseases is unknown, but those with known causes are due to mutations in the [[PRNP|prion protein gene]] (HDL1), the [[JPH3|junctophilin 3 gene]] (HDL2), a recessively inherited unknown gene (HDL3—only found in two families and poorly understood), and the gene encoding the [[TATA binding protein|TATA box-binding protein]] ([[Spinocerebellar ataxia|SCA17, sometimes called HDL4]]). Other autosomal dominant diseases that can be misdiagnosed as HD are [[dentatorubral-pallidoluysian atrophy]] and [[Adult-onset basal ganglia disease|neuroferritinopathy]]. Also, some [[autosomal recessive]] disorders resemble sporadic cases of HD. These include [[chorea acanthocytosis]] and [[pantothenate kinase-associated neurodegeneration]]. One [[Sex linkage|X-linked]] disorder of this type is [[McLeod syndrome]].<ref name="HD-LIKE">{{cite journal | vauthors = Schneider SA, Walker RH, Bhatia KP | title = The Huntington's disease-like syndromes: what to consider in patients with a negative Huntington's disease gene test | journal = Nature Clinical Practice. Neurology | volume = 3 | issue = 9 | pages = 517–525 | date = September 2007 | pmid = 17805246 | doi = 10.1038/ncpneuro0606 | s2cid = 9052603 }}</ref>