Rare Diseases

Making the Connection

By Stacey Mancarella

Illustrations by Yesenia Carrero

illustration of photos of unconnected symptoms

A rare but debilitating condition, hereditary amyloidosis (hATTR) presents as seemingly unrelated illnesses that mask the root cause. But increased awareness and new treatment options bring hope for sufferers of this devastating genetic condition.


We hear of it too often in health care. Even with the most diligent doctors and patients, sometimes figuring out the correct diagnosis of a rare medical condition can be a challenge.

Unexplained weight loss and diarrhea. Shortness of breath during exercise. Carpal tunnel syndrome. Weakness and difficulty balancing that gets progressively worse. Tingling or numbness in the hands and feet. Symptoms like these point to different culprits, bringing patients to a variety of specialists and glimmers of hope as they find potential answers. But treating one symptom doesn’t help the others, and everything gets worse.

This particular collection of ailments, among other symptoms, points to hereditary amyloidosis (hATTR), a devastating genetic disease that, up until recently, was considered untreatable. Dr. Fernanda Wajnsztajn is all too familiar with the plight of her patients who have searched in vain for a diagnosis. A neurologist at the UConn Health neuropathy clinic, Wajnsztajn specializes in peripheral neuropathy, damage or disease of the peripheral nervous system.

“Because some of the symptoms of hereditary amyloidosis are also seen in a variety of diseases, some of my patients went to several doctors for years until hATTR was suspected,” she says. “With a detailed history, we are also able to trace the heritage of patients, and, often, patients realize during the interview that some their relatives also have similar symptoms.”

Now these families have options. New drug treatments have been approved to treat neuropathy, the nerve pain, tingling, or numbness that’s a symptom of this little-known disease, and doctors at UConn Health have assembled a team to tackle hATTR head on.

Interpreting the Evidence

Wajnsztajn has been aware of hATTR since her days at Columbia University, where she was involved in research and clinical trials for hATTR therapies. Only about 50,000 people worldwide are affected by hATTR, “but we suspect that many cases go undiagnosed or misdiagnosed,” Wajnzsztajn says. “Our goal is to reach those people.”

Hereditary amyloidosis is caused by a hereditary mutation of the TTR gene. If one parent carries the gene mutation, offspring have a 50 percent chance of inheriting the disease. Hereditary amyloidosis wreaks havoc on the body by depositing amyloid proteins into organs, most commonly the heart, nerves, and digestive tract. These deposits cause the organs to function improperly, which eventually leads to a myriad of debilitating symptoms.

Even though the gene mutation is present at birth, most patients don’t experience symptoms until well into adulthood. And even once symptoms start, it can take years for a proper diagnosis.

“Hereditary amyloidosis is not a well-known disease. The patient can present with a history of heart problems and receive a diagnosis of polyneuropathy, but if the doctor isn’t familiar with it, they won’t put it together. It’s easy to miss,” Wajnsztajn says.

For example, two of the most common symptoms of hereditary amyloidosis are carpal tunnel and cardiomyopathy, or heart muscle disease. Because these two diseases are seemingly unrelated and treated by different kinds of doctors, hereditary amyloidosis can go undetected. The average delay in diagnosis is four years, and in that time, amyloid is continuously deposited into the affected organs, causing symptoms to worsen.

Even with the new treatments, a timely diagnosis is important as the medications cannot reverse the symptoms but only prevent further protein deposits that cause the condition to worsen. The earlier a patient can be identified and a course of treatment initiated, the slower the disease will progress.

Dr. Fernanda Wajnzsztajn (left) and Dr. Sarah Tabtabai discuss a patient case.

Dr. Fernanda Wajnsztajn (left) and Dr. Sarah Tabtabai discuss a patient case.

Case Closed

UConn Health’s multidisciplinary approach can shorten this delay, giving patients relief sooner and stopping hATTR in its tracks. Cardiologists at the Pat and Jim Calhoun Cardiology Center work hand in hand with neurologists from the peripheral nerve disease clinic to examine a patient’s symptoms, get that crucial neuropathy or polyneuropathy diagnosis, and schedule them for genetic testing to confirm a hATTR diagnosis. Once the diagnosis is confirmed, treatment can begin very quickly, and the deposition of amyloid into the organs is halted within weeks — sometimes within days — thanks to neurologists, cardiologists, neuropathy testing, and an infusion center to administer treatment being all in one place.

Two treatment options currently exist, one that’s infused intravenously every three weeks, the other given by weekly subcutaneous injection. These new treatments work by inhibiting the body’s ability to create the amyloid protein. They reduce the amount of the protein the liver can make by 84 percent, improving the patient’s quality of life. Clinical trials are ongoing, with the hope that such medications can treat other types of amyloidosis as well.

“Before medicines like this came along, there was really no therapy for this particular heart disease. It’s progressive and very debilitating, and the hereditary type, in particular, occurs in younger people,” says Dr. Sarah Tabtabai, cardiologist at the Pat and Jim Calhoun Cardiology Center at UConn Health.

Previously attempted treatments for hATTR symptoms were drastic, sometimes including heart transplants or heart and liver transplants, Tabtabai says. But with the new medications, “patients have had good outcomes with both their neurologic disease and their heart disease, and it sort of keeps things at bay.”

Close collaboration between the departments makes everything go smoothly for patients who have already waited so long for answers, says Wajnsztajn.

“We work very closely with cardiology to obtain the appropriate exams for diagnosis as quickly as possible. Despite being a challenging or daunting diagnosis, our patients feel fortunate that they finally have answers, and we are able to provide the most advanced treatments along with the support necessary,” she says.

Because of the high rate of misdiagnosis, the companies that produce the new medications are currently offering free screenings for patients with suspected hereditary amyloidosis. A patient simply has to schedule the genetic test at UConn Health, and the billing is handled directly through the hospital, creating a streamlined process for the patient.

Early diagnosis of hATTR can also bring awareness to family members who might be afflicted.

“Once a patient is diagnosed with hereditary amyloidosis, we can test blood relatives as well to identify any members of their family who may also have this disease,” Tabtabai says. “The hope is that, down the line, we can offer medications like this sooner, before patients become symptomatic or right at the onset of symptoms so that they fare even better as time goes on.”

Lab Discovery Could Lead to Prader-Willi Treatment

DNA strand


Stem cell researchers at UConn Health have reversed Prader-Willi syndrome in brain cells growing in the lab, findings they recently published in Human Molecular Genetics.

The discovery provides clues that could lead to a treatment for Prader-Willi, a genetic disorder that occurs in about one out of every 15,000 births, and is the most common genetic cause of life-threatening childhood obesity.

Unlike many genetic syndromes that are caused by a mutation in a gene, people with Prader-Willi often have the right gene available — it’s simply that it’s been silenced.

The gene is silenced because it is on the part of their chromosome they inherited from their mother, and for mysterious reasons our cells use the father’s copy of this gene. But if the father’s copy is missing, the cells can’t express that gene at all.

UConn Health’s Maeva Langouet, a post-doctoral fellow; Marc Lalande, professor emeritus of genetics and genome sciences; and their colleagues wondered if it was possible to reverse the silencing of the mother’s copy.

Unlike many genetic syndromes that are caused by a mutation in a gene, people with Prader-Willi often have the right gene available — it’s simply that it’s been silenced.

The researchers noticed that a certain protein, called ZNF274, was involved in the process. It silences many other genes as well, but in those cases it usually acts with another protein. On the Prader-Willi region of our DNA, the protein seems to act alone, they said.

So Langouet and Lalande took stem cells donated by Prader-Willi patients and carefully deleted ZNF274. They then encouraged the stem cells to grow into neurons, a type of brain cell. And the cells seemed normal. They grew and developed, as expected.

Critically, the new cells also expressed the maternal copy of the Prader-Willi region.

“We still need to figure out if knocking out ZNF274 is doing anything else” that might be undesirable, says Langouet.

And many other questions still need to be answered: Does this work directly in human brain cells? Will it only work in embryos, or can it help the brain develop normally even after birth?

Currently, there is no cure for Prader-Willi syndrome, and most research has been targeted towards treating specific symptoms. For many individuals affected by the disorder, the elimination of some of the most difficult aspects of the syndrome, such as the insatiable appetite and obesity, would represent a significant improvement in quality of life and the ability to live independently.

But in the future, this new line of research may offer a therapeutic approach for kids with Prader-Willi, Langouet says.

The research was funded by the Foundation for Prader-Willi Research, the Cascade Fellowship, and the CT Regenerative Medicine Fund.