Mark ở vũ trụ khác · Another Universe Genes and Rare Diseases #3 · Genetics · Neurology

Huntington's and the villages by the lake

CAG CAGCAG CAG CAG CAG CAG CAG …

Nancy Wexler, the families of Lake Maracaibo (Venezuela) and the gene hunters · Cell · 1993

DiseaseHuntington's: the brain slowly degenerates, causing involuntary movements, memory loss and mood changes
GeneHTT on chromosome 4, where the letters "CAG" repeat too many times
Story1979–1993: a family tree of more than 18,000 people that led to the gene
LabelSolid on the gene · Caution on treatment

Source: The Huntington's Disease Collaborative Research Group (1993), Cell 72(6): 971–983; Wexler et al. (2004), PNAS 101(10): 3498–3503 (18,149 people); GeneReviews "Huntington Disease" (Caron, Wright, Hayden, updated 2020).

For reading and understanding, not a substitute for medical advice.

Recap in 1 minute

Essence

One family, one fearIn 1968 Nancy Wexler's mother was diagnosed with Huntington's. Nancy and her sister each had a 50% chance of carrying the gene.
The villages by the lakeFrom 1979 her team went to Lake Maracaibo every year and charted a family tree of 18,149 people over 10 generations.
1993: the gene is foundThe HTT gene holds a run of repeated CAG letters. In every affected family studied, the run was longer than normal.
Longer means earlier40 repeats or more almost always leads to disease. Longer runs usually mean earlier onset, but cannot predict the year.
To know or not to know?A direct test has existed since 1993, yet in the UK only about 17% of people at risk chose to take it. The right to know comes with the right not to know.

Source: Mail & Guardian 2007, HDBuzz (1968, secondary source); Wexler et al. (2004), PNAS; Cell 1993; GeneReviews (the 40 threshold); Baig et al. (2016), European Journal of Human Genetics (17.4%).

Part 1

The question

If a blood test could tell you at 20 that an incurable disease is waiting for you in middle age, would you want to know? And who gets to decide?

The question is Mark's, based on predictive testing guidelines (MacLeod et al. 2013) and testing uptake data (Baig et al. 2016).

1968–1979A familyA mother falls ill. A father starts a research fund. A daughter sets out.
→
1979–1993A family treeBlood from Lake Maracaibo leads to chromosome 4, then to the gene.
→
1993 to nowA choiceTestable, not yet curable. Whether to know is each person's call.
Part 2

The story

Who, where, when: from a young American doctor in 1872 to a laboratory in 1993.

1872 · A short paperGeorge Huntington, a young doctor raised on Long Island (USA), described a hereditary "chorea" in families he had seen as a boy on his father's rounds. The disease has carried his name ever since.
1950s · By Lake MaracaiboVenezuelan doctor Américo Negrette noticed many people with chorea in the fishing villages along Lake Maracaibo and recognised it as Huntington's disease.
1968 · A diagnosisLeonore Wexler was diagnosed. Her father and three brothers had had the disease. Her husband, psychoanalyst Milton Wexler, started a research fund (today the Hereditary Disease Foundation). Their daughter Nancy, 23, learned she had a 50% risk.
1979 · The first tripNancy Wexler, then a psychologist, led a team to Venezuela. They returned every year: examining people, drawing blood, recording every name, linking every branch of the family.
1983 · A marker on chromosome 4James Gusella's team (Boston) used blood from an American family and the large Venezuelan family to find a DNA marker, G8, that travels with the disease. It was the first genetic disease mapped this way.
26 March 1993 · The geneA collaboration of many labs reported in Cell: the IT15 gene (now HTT) carries an abnormally long CAG repeat in all 75 affected families studied. Ten years from marker to gene.
2004 · The largest family treeA PNAS paper: 18,149 people over 10 generations, 15,409 of them living. One kindred alone had 14,761 people.
2020 · The researcher is also a patientAt 74, Nancy Wexler said publicly that she has the disease she spent her life studying.

Source: Huntington (1872), "On Chorea", Medical and Surgical Reporter (via the biography in PMC6394661); Gusella et al. (1983), Nature 306: 234–238; Cell 72: 971–983 (1993); Wexler et al. (2004), PNAS 101: 3498–3503; Columbia CUIMC press release 2004 (1979). Secondary sources: Mail & Guardian 2007 and HDBuzz (1968, Nancy's age, the fund); Nancy Wexler interview on the Lasker Foundation site (relatives with the disease); New York Times, Denise Grady, 10 March 2020 (2020 disclosure); a review article on Negrette (1950s).

An illustrative three-generation family tree. Squares are male, circles female, filled shapes carry the disease allele. Each child of a carrier has a one-in-two chance of inheriting it. This is an illustration, not a real family. illustrative family tree (not a real family) carries alleledoes not
Why such a huge family tree? In 1979 nobody could read genes directly. To find which stretch of DNA travels with the disease, you had to compare many people in one family: who is affected, who is not, and which DNA they share.Source: reasoning after Gusella et al. (1983) and Wexler et al. (2004); the figure is Mark's illustration.
Context: why Venezuela?

In the villages along Lake Maracaibo, many generations lived close together and families were large, so one disease allele passed through a great many relatives. For geneticists it was a rare "natural laboratory". For the people there it was a grief stretching over generations.

The team collected more than 4,000 blood samples (secondary source). Those samples later helped find genes for other diseases too.

Source: Wexler et al. (2004), PNAS (83 kindreds, family size); Franklin Institute page on Nancy S. Wexler and New York Genome Center (more than 4,000 samples, secondary source).

Part 3

How the gene works, in 3 sentences

1. Everyone has two copies of HTT. Inside it, the three letters C-A-G repeat many times; when the run is too long (from 36, more surely from 40), the huntingtin protein comes out faulty and brain cells slowly fail.

2. One faulty copy is enough (dominant inheritance), so each child of a carrier has a 50% chance of receiving it, sons and daughters alike.

3. The repeat does not sit still: it can grow when passed to a child (especially through the father), and it grows inside brain cells over the years.

A ruler of CAG repeat counts. 26 or fewer: normal. 27 to 35: intermediate, the carrier does not get the disease but the repeat may grow in children. 36 to 39: at risk, may not develop disease. 40 or more: will develop the disease given a normal lifespan. number of "CAG" repeats in the HTT gene CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG …CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG … ≤ 2627–3536–39≥ 40 normalintermediateno disease, maygrow in childrenat riskmay notdevelop diseasewill developgiven a normal lifespan
Reading the test result means reading one number. The lab counts the CAG repeats on each copy of the gene and places them in these four ranges. Near a boundary, a genetics doctor needs to explain the result.Source: GeneReviews "Huntington Disease" (36–39 reduced penetrance, ≥40 full penetrance); ARUP Consult, University of Utah (≤26 normal, 27–35 intermediate). Block widths are illustrative, not to scale.
Dominant inheritance. One parent has one long copy and one normal copy; the other has two normal copies. Four possibilities for a child: two receive the long copy, two do not. Each birth is 50%, independent of siblings. each birth: 50%, like tossing a coin one parent the other carrier carrier not not 2 of 4 possibilities = 50% for each child
There is no "two siblings already have it, so the third will be spared". Every birth is a fresh coin toss.Source: GeneReviews "Huntington Disease" (autosomal dominant, 50% risk for each child). The figure is an illustrative diagram.
More: why can the disease come earlier in the next generation?

Long repeats, especially when passed through sperm, tend to grow. That is why most very early cases (before about age 20, often more than 60 repeats) inherit the gene from the father. Earlier onset in later generations is called "anticipation".

The disease is not only about movement. GeneReviews describes Huntington's as a progressive disorder of movement, thinking and mental health: trouble concentrating and planning, depression or irritability can come before abnormal movements.

Source: reviews of early-onset Huntington's (PMC1801258; PMC9291924); GeneReviews "Huntington Disease".

Part 4

Fact check: what is true and what is myth

14 things often said about Huntington's, checked against the original sources. Tap a row to see why.

People with Huntington's per 100,000, from a 2012 meta-analysis: about 5.70 in Europe, North America and Australia; about 0.40 in three Asian studies. people affected per 100,000 (2012 meta-analysis) Europe, N. America, Australia5.70 Asia (3 studies)0.40 same gene, very different frequency by region
"Rare" depends on where you are. Asian studies report far lower figures; part of the gap may be missed diagnoses. Mark found no figures specific to Vietnam.Source: Pringsheim et al. (2012), Movement Disorders 27(9). Checked 16 October 2026.
SOLIDHuntington's is caused by an overlong CAG repeat in the HTT gene on chromosome 4

A longer-than-normal repeat was present in all 75 affected families in the 1993 paper (Cell 72: 971–983); confirmed by GeneReviews.

SOLIDEach child of a carrier has a 50% chance of inheriting it

Autosomal dominant; each birth is independent (GeneReviews).

SOLIDThe Lake Maracaibo family tree covers more than 18,000 people

18,149 people, 10 generations, 15,409 living, 83 kindreds (Wexler et al. 2004, PNAS).

SOLIDVery early cases usually inherit the gene from the father

The repeat grows more easily through sperm (review PMC1801258). This does not make inheritance from the mother safe: the risk is still 50%.

SOLIDNancy Wexler, who led the gene hunt, also has the disease

She went public in 2020, at 74 (New York Times, 10 March 2020; secondary source).

SOLIDInternational guidelines: predictive testing from age 18, with counselling before and after

Consistent from the IHA/WFN guidelines of 1994 to MacLeod et al. (2013), Clinical Genetics.

CAUTION"Huntington's is very rare everywhere"

5.70 versus 0.40 per 100,000 depending on region (Pringsheim 2012). A 2016 study found about 1 in 400 people in the general population have 36 or more CAG repeats, but mostly 36–38, which rarely leads to disease (Kay et al. 2016, Neurology).

CAUTION"A gene therapy now slows Huntington's"

AMT-130: the company reported 75% slowing after 36 months in 12 high-dose patients, compared with an external control group, not a randomised placebo trial (press release, 24 September 2025). The application awaits the FDA; not approved (checked 16 October 2026).

CAUTION"The faulty protein poisons brain cells for the patient's whole life"

A 2025 study of more than 500,000 cells found the CAG repeat keeps growing inside neurons; cells only fail quickly once they pass about 150 repeats. Most of the time the gene is "a ticking clock" (Handsaker et al. 2025, Cell 188: 623–639).

FALSE"Knowing your CAG count tells you the year you will get sick"

The CAG count is the strongest factor, but people with the same count still vary widely in age of onset; other genes and environment play a part (Wexler et al. 2004).

FALSE"The disease skips a generation"

A dominant disease does not skip. It only looks that way when a parent died early of something else, carried 36–39 repeats without symptoms, or carried an intermediate repeat that grew in the child (GeneReviews; ARUP).

FALSE"Huntington's is just a movement disorder"

It also affects thinking and mental health, sometimes before abnormal movements appear (GeneReviews).

FALSE"27–35 CAG repeats means you will get the disease"

Intermediate range: the carrier is not at risk, but the repeat may grow when passed to a child (ARUP; GeneReviews).

FALSE"Most people at risk get tested"

In the UK, 1993–2014, only about 17.4% of people at 50% risk had a predictive test; more than 80% chose not to know yet (Baig et al. 2016).

Source: as given in each row; full list in Part 9.

Part 5

Where things stand today

The gene was found in 1993, but as of October 2026 no drug has been approved to slow the disease. Current drugs only ease symptoms.

March 2021 · A "huntingtin-lowering" drug stopsThe phase 3 trial of tominersen stopped dosing on the advice of an independent monitoring board: benefits did not outweigh risks.
January 2025 · A DNA clock inside cellsA Broad Institute team measured cell by cell: the CAG repeat keeps growing in neurons, and cells fail once they pass about 150 repeats. A new direction: slow the growth of the repeat.
September 2025 · Gene therapy AMT-130A one-time injection into the brain. The company reported: the high dose slowed progression by 75% after 36 months, compared with an external control group, in 12 people. No placebo group, not yet peer reviewed.
July 2026 · Roche ends tominersenThe phase 2 trial (GENERATION HD2) lowered the faulty protein but showed no clear clinical benefit after 16 months.
Q3 2026 · Waiting for the FDAThe FDA agreed that an accelerated-approval filing for AMT-130 is reasonable; the press reports it has been filed. Four-year data (September 2026) missed one statistical test. No decision yet.

Source: Handsaker et al. (2025), Cell 188(3): 623–639; uniQure press release 24 September 2025 and Q2 2026 update (29 July 2026); EHDN statement on Roche's community letter of 9 July 2026; HDBuzz and HDA on GENERATION HD1 (secondary); Pharmacally and Stocktwits, September 2026, on the filing and four-year data (secondary); GeneReviews (symptomatic treatment). Checked 16 October 2026: re-check before posting.

Part 6

Rating

Scores are Mark's rating based on the sources in Part 9, not data from a study.

How solid the gene science is
5/5
Impact on genetics
5/5
Treatment so far
2/5
Lessons for readers
4/5
What worked
  • The gene was found thanks to a family tree built on the community's own blood
  • An accurate test, with a counselling protocol copied worldwide
  • Opened the way to finding genes for many other diseases
What has not yet
  • After 30+ years, no approved drug slows the disease
  • Knowing the gene does not predict the year of onset
  • The Venezuelan donors have not benefited in proportion

One family turned fear into a map: finding the gene is done, curing the disease is still on the road.

More: why "Solid" overall but "Caution" on drugs?

The gene part has been confirmed in thousands of families across many countries over 30 years. The drug part has two failed attempts (tominersen) and one promising approach that so far rests on a few dozen people and an external control group (AMT-130). The two parts do not share the same certainty.

The "More" box and the line about donors are Mark's commentary, based on sourced facts in Parts 2 to 5.

Part 7

Lessons: learn to ask before you want to know

For reading and understanding, not a substitute for medical advice. These are habits of understanding, not treatment advice.

Four habits: genetic counselling before testing; ask what the result means and what it does not; remember that not knowing is also a right; when reading breakthrough news, ask who the comparison group was. 1 · counselling firstthen the blood drawbring someone along 2 · ask about the numberwhat it means, and doesn'twhich range, how certain 3 · right not to knoweach person decideseven within one family 4 · reading "breakthroughs"compared with whom? how many?press release or peer review? The Huntington's story is about people who get to choose to know, or not to know.
Each habit rests on something sourced in this piece. The counselling protocol from international guidelines; result ranges from GeneReviews; testing uptake from Baig (2016); how to read drug news from the AMT-130 case.Source: MacLeod et al. (2013); GeneReviews; Baig et al. (2016). The habits are Mark's suggestions.
Ask about genetic counsellingIf someone in the family is affected, the first question for a doctor is: where can I get genetic counselling before and after testing?
Ask which range your number falls in"What is my repeat count, which range is it in, and what does it NOT tell me?" (for example, it cannot tell the year of onset).
Respect those not ready to knowOne person's result can reveal the risk of siblings and parents. Talk as a family before testing.
Read new-drug news with three questionsCompared with whom (placebo or outside data)? How many people? Company press release or peer-reviewed paper?
Self-check: read a "breakthrough" story in 5 minutes

1. Find a news story about a new drug for any disease.

2. Underline: number of participants, comparison group, follow-up time.

3. Where does it come from: a company, a hospital, or a peer-reviewed journal?

4. Has a regulator (FDA, EMA, a health ministry) approved it, or has it only been "filed"?

5. Rewrite the story as one honest sentence. Example: "In 12 people, compared with outside data, the disease progressed more slowly; not approved."

The self-check is Mark's suggestion, not a protocol from a study.

Part 8

Further reading

Alice Wexler (1995), Mapping FateA memoir by Nancy's sister about the family, the fear and the gene hunt.
GeneReviews, "Huntington Disease"The most complete medical review, with a section on genetic counselling.
HDBuzz (hdbuzz.net)Huntington's research news written by scientists in plain language, in many languages.
MSD Manual, "Huntington Disease"A medical reference, also available in Vietnamese.
Genes and Rare Diseases #04: A drop of blood from the heelAnother genetic disease, but this time knowing early prevents harm: PKU and newborn screening.
Part 9

Sources

The main sources are original papers, professional guidelines and medical databases. The working environment blocks PubMed and NCBI Bookshelf, so figures were checked against excerpts of those pages in search results, without opening the full text. Secondary sources are marked. Checked 16 October 2026.

  1. The Huntington's Disease Collaborative Research Group (1993), "A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes", Cell 72(6): 971–983. PubMed
  2. Gusella JF, Wexler NS, Conneally PM et al. (1983), "A polymorphic DNA marker genetically linked to Huntington's disease", Nature 306: 234–238.
  3. Wexler NS and the U.S.–Venezuela Collaborative Research Project (2004), "Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset", PNAS 101(10): 3498–3503. PMC
  4. Caron NS, Wright GEB, Hayden MR, "Huntington Disease", GeneReviews (1998, updated 2020). NCBI Bookshelf
  5. ARUP Consult, "Huntington Disease" (CAG ranges ≤26 and 27–35). arupconsult.com
  6. Pringsheim T et al. (2012), "The incidence and prevalence of Huntington's disease: a systematic review and meta-analysis", Movement Disorders 27(9).
  7. Kay C et al. (2016), "Huntington disease reduced penetrance alleles occur at high frequency in the general population", Neurology.
  8. Baig SS et al. (2016), "22 years of predictive testing for Huntington's disease: the experience of the UK Huntington's Prediction Consortium", European Journal of Human Genetics.
  9. MacLeod R et al. (2013), "Recommendations for the predictive genetic test in Huntington's disease", Clinical Genetics; update of the IHA/WFN guidelines (1994).
  10. Handsaker RE et al. (2025), "Long somatic DNA-repeat expansion drives neurodegeneration in Huntington's disease", Cell 188(3): 623–639. PubMed
  11. Huntington G (1872), "On Chorea", Medical and Surgical Reporter (Philadelphia); biography "George Huntington (1850–1916)". PMC
  12. uniQure, AMT-130 results press release (24 September 2025) and Q2 2026 update (29 July 2026); EHDN, statements on the AMT-130 results (2025) and on Roche ending GENERATION HD2 (July 2026). ehdn.org
  13. Secondary sources: New York Times, Denise Grady, 10 March 2020 (Nancy Wexler's disclosure); Mail & Guardian 2007 and HDBuzz (1968, the fund, Nancy's age); interview on laskerfoundation.org; Franklin Institute and New York Genome Center (more than 4,000 samples); Columbia CUIMC press release 2004; HDBuzz, HDA (GENERATION HD1, 2021); Fierce Biotech, July 2026; Pharmacally, Stocktwits, September 2026 (AMT-130 filing, four-year data); a review article on Américo Negrette.