Myotonic dystrophy type 1 (DM1), an inherited disease affecting muscles, was one of the first described “expanding repeat” disorders. In these 50…
Rare Disease Day 2022: Juvenile Huntington’s Disease
In honor of Rare Disease Day 2022, February 28th, I’m reposting a DNA Science story from nine years ago. February 16th was 12 years since Jane Mervar lost her young daughter to Huntington’s disease (HD). Thank you Jane for always sharing your story! (Updates are in parentheses.)
Looking back, signs that Jane Mervar’s husband, Karl, had HD started when their youngest daughter, Karli, began to have trouble paying attention in school. Karl had become abusive, paranoid, and unemployable due to his drunken appearance. Karli, born in September 1996, was hyperactive and had difficulty following directions. When by age 5 Karli’s left side occasionally stiffened and her movements slowed, Jane began the diagnostic journey that would end with Karli’s diagnosis of HD, which had affected her paternal grandmother.
Soon Karli could no longer skip, hop, or jump. New troubles emerged. ”She had cold sweats, tachycardia, and chronic itching. She fell and suffered chronic pain. By age 6 she was losing her speech and became withdrawn,” Jane recalls. Karli drooled and her speech became unintelligible. By age 7 her weight had plunged, and by age 8 she had developed pneumonia three times, due to difficulty swallowing. By age 9 she required a feeding tube, suffered seizures, and would go long periods without sleep.
An Adult’s Disease in a Child
This isn’t the way that a disease is supposed to run in families, striking child before parent. HD is regarded as a disease of adulthood, but in fact about 10 percent of people with the condition are under age 20 – they have juvenile Huntington’s disease (JHD).
“Horse-and-buggy doctor” George Sumner Huntington first described HD in 1872. As a young man he’d accompanied his father and grandfather on house calls in East Hampton, Long Island, where a few local families had a mysterious movement disorder. The youngest Huntington recalled two very thin women gripped by constant contortions, and several men who staggered about as if intoxicated. He later described the symptoms intensifying “until the hapless sufferer is but a quivering wreck of his former self.”
Dr. Huntington deduced the autosomal dominant inheritance pattern of HD. It affects both sexes. Each child of someone with the disease has a 50:50 chance of sharing the fate. And if the mutation is inherited, the chance of having symptoms is near 100 percent.
Loss of motor control typically begins in the late thirties. But behavioral and cognitive signs are often present years earlier, sometimes unrecognized.
Symptoms in children differ from those in adults – Karli’s problems in school and stiffness were classic — but inside cells, a similar crisis unfolds in a patient of any age.
The Htt gene encodes the protein huntingtin. The gene normally includes up to 35 copies of the DNA triplet CAG, just before the first exon (protein-encoding part). The disease arises when the gene grows – HD is the quintessential “expanding triplet repeat” disorder. The extra genetic material triggers a cascade of destruction, with its most profound effects in the “medium spiny neurons” in the movement centers of the brain.
The Htt gene with too many CAGs encodes a protein with too many contiguous copies of the amino acid glutamine. And that glitch prevents the protein from folding properly. It sticks to itself and to other proteins, blocking axons in neurons of the brain’s striatum, preventing distribution of essential growth factors. The white matter of the brain shrinks.
Changes in behavior and thinking often precede the constant movements that fascinated the young Dr. Huntington. Irritability, loss of impulse control, and aggression are hallmarks. Jane’s husband Karl spent wildly and threatened his family and others with guns. He spent his final years in a nursing home.
An Unusual Mutation
Karl was diagnosed six weeks after Karli in 2002. He was 35, she just 6. They died within weeks of each other in early 2010. But that wasn’t all. Karli’s sister Jacey (who founded jhdkids.com/) was diagnosed in 2004 at age 13, and her sister Erica in 2007 at age 17.
In HD, gene size matters. Most adults have 40 to 60 repeats. Karl had 47 and Karli’s sisters had 47 and 49. But Karli inherited 99 CAGs, a consequence of DNA replication enzymes looping and doubling her father’s 47 repeats. It’s little wonder she got sick so fast — longer repeats mean earlier onset.
Most HD kids with very expanded mutations inherit them from their fathers. This may be due to the different timetables of sperm and egg production. A female at puberty has about 400,000 eggs, each halted on the brink of completing meiosis, when the slippage that expands the gene could happen. But a male releases a quarter of a billion sperm with each ejaculation – that’s many chances over a reproductive lifetime for the gene to be miscopied and grow.
When, and If, to Test
Counting CAG repeats confirms a clinical diagnosis of HD. When genetic testing first became available in the mid 1990s, following a decade of using a less-predictive marker test, concern was that people finding out they have the mutation before symptoms begin would freak out. That hasn’t happened. Nor has testing found many takers. Most “at-risk” individuals, those who know they have one affected parent, choose not to be tested.
Because testing raises complicated psychosocial issues, and because onset is usually in the fourth decade, it’s generally not recommended for those under 18. But when the young person has symptoms, it’s a different story.
Martha A. Nance MD, medical director of the Struthers Parkinson’s Center and the director of the HD Center of Excellence at Hennepin County Medical Center, both in Minneapolis, and author of The Juvenile HD Handbook, explains the nuances. “It’s important to distinguish diagnostic testing in a child who is having problems from presymptomatic testing in a child whose parent has HD or is at-risk for HD but has no neurologic or psychiatric symptoms.”
Presymptomatic testing doesn’t make much sense, Dr. Nance says. “No treatment hinges on getting an early test result, and the things that people do are probably a good idea whether you have the abnormal gene or not, or at least won’t hurt, such as exercising and eating right.”
For children and teens, Dr. Nance says, the psychosocial repercussions of learning test results when there aren’t symptoms can be huge. “The parent who tests his asymptomatic 10-year-old because of guilt, concern, or a desire to plan, removes that child’s freedom to choose. There’s a 90 percent chance that child, if able to decide for himself, wouldn’t want to be tested.” (That trend has persisted.)
Another problem is that it can be very hard to tell when symptoms start, and if they indicate HD or something else. Does a teen who can no longer multi-task at a restaurant job have the family legacy? Is anxiety or irritability due to HD?
The multi-generational nature of the disease complicates matters. “We’re hesitant to diagnose HD in a 13-year-old from a challenging home environment, usually an affected father who probably isn’t working and may have bizarre behavior. The last thing we want to do is take a kid who is profoundly depressed or acting out, whose father is dying of HD, and do a gene test that shows he has a mutation of a size that generally causes symptom onset in a person’s 40s. Then we have just done a predictive test in an unstable 13-year-old,” Dr. Nance explains.
Very few physicians are trained to recognize JHD. Specialists in movement disorders work with older adults, such as those with Parkinson’s disease, and pediatricians rarely encounter HD. “So a child with HD symptoms will either be seen by a pediatric neurologist who knows little about HD, or by an HD neurologist who knows little about kids,” Dr. Nance says.
Diagnosis typically takes 2 to 7 years as physicians await obvious motor symptoms, or a clear decline in cognitive function. This is too long for families to wait. Dr. Nance and others are working to find better tools to determine when a child’s challenging behavior is just “being a teenager” or some other problem, and when it is due to the onset of HD.
A Therapeutic Challenge
Repeat mutations are among the most difficult to counter, for they are unlike the genetic glitches behind other conditions. They can’t be fixed by replacing an enzyme, by countering a biochemical buildup with diet, or even by sending in a normal-length gene, for there’s already one there.
The HD mutation is of the nefarious “gain-of-function” variety – it does something new, something unexpected. (COVID lingo borrows the term, like it does “variant” and “wild type,” altering the classical meanings.) Even refolding the errant protein, as has worked so well in treating cystic fibrosis, hasn’t happened. Silencing the extra triplets may be the way to go – antisense, RNAi, and zinc finger nuclease approaches (but even those have hit roadblocks).
Basic research must keep drug candidates coming (this recent DNA Science post describes harnessing DNA repair). But support should also focus on the daily challenges that people like Jane Mervar face. She and her daughters have done much for the HD and rare disease communities by sharing their story, which I’ve only touched on here. Even if a gene therapy or repurposed drug or nutritional supplement is never found, there’s still much that health professionals can do to help families with HD. Jane explains how:
“The docs I respect and trust the most are those who can explain what is occurring, and if they cannot help they seek the person who knows the best answer … Teams of specialists helped me keep Karli at home until the end. The last 6 months were the most difficult, meeting her spirit and comfort needs. But she passed on her terms, and I knew we gave it our all.”
Jane wrote on Facebook on February 16, on the 12th anniversary of Karli’s passing:
“I often wonder who she would have become, what she would have looked like and how amazing it would feel to hear her voice and to give her the tightest hug! I was SOOOO lucky to be her mom and have 3 other amazing daughters. There is no easy way to lose a child and grief never ends. But love never dies.”
More than 300 million people suffer from a rare disease, about half of them children. About 80 percent of the diseases are genetic. Only about 5 percent of recognized rare diseases have approved treatments – and some conditions affect only a few people, sometimes even just one. People with rare diseases are at especially high risk of developing severe COVID-19, if affected. So as we stash our masks and inch towards a new normalcy, let’s not forget them, and the others for whom an infection would be far more than a scratchy throat and the sniffles.