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Discovery at Massachusetts General Hospital creates roadmap for a rare disease

NICOLE MEETS SOME OF THEM RIGHT HERE IN BOSTON, IN A SMALL LAB IN BOSTON, A TEAM OF DEDICATED SCIENTISTS, DOCTORS AND GENETICISTS PUSHED THE BOUNDARIES OF MEDICAL KNOWLEDGE. IT’S REALLY HARD TO KNOW WHERE TO LOOK IF WE DON’T KNOW EXACTLY WHAT WE ARE LOOKING FOR. IT’S USEFUL TO NOT STOP LOOKING. THE UNDIAGNOSED DISEASES NETWORK TAKES ON CASES THAT MOST WOULD DISMISS AS TOO COMPLEX, TOO PERPLEXING, OR SIMPLY TOO RARE TO SOLVE. SO THERE’S THOUSANDS OF THESE UNDIAGNOSED PATIENTS. MASSACHUSETTS GENERAL HOSPITAL IS ONE OF 15 LOCATIONS NATIONWIDE OFFERING EXPERTISE IN ADVANCED MEDICAL GENETICS. WE’RE ACTUALLY LOOKING FOR CASES THAT REALLY HAVE ALREADY EXHAUSTED THE THE CLINICAL CARE THAT’S AVAILABLE. THE UN TAKES A DEEP DIVE SEARCHING FOR PATTERNS, CONNECTING RESEARCH DATA AND DOCTORS FROM AROUND THE WORLD. OUR CHROMOSOMES AND OUR GENES ARE JUST REALLY COMPLEX. WE’RE JUST BEGINNING TO SCRATCH THE SURFACE. YEAH, HE NEVER COMPLAINS. SO WHATEVER IS THROWN AT HIM, HE JUST TAKES IT. 19 YEAR OLD RITHVIK KAPALI WASN’T DEALT AN EASY HAND IN LIFE. HIS MOTHER, LAKSHMI, RECALLS HIS FIRST SYMPTOM. AN EXTENDED ABDOMEN WAS NOTICED EVEN BEFORE HE WAS BORN. SO WHEN HE WAS BORN, HE WAS ALMOST STUCK. HE COULD NOT COME OUT BECAUSE HIS BELLY WAS SO BIG. DOCTORS DRAIN THE FLUID AND SEND THE HAPPY NEW FAMILY HOME, UNAWARE OF THE FRIGHTENING, DECADES LONG HEALTH BATTLE THAT LAY AHEAD. BY THE TIME HE WAS TWO, HE WAS NOT ABLE TO DIGEST ANY FOOD. AN ENDOSCOPY WOULD LEAD TO MORE QUESTIONS, AND YET EVEN MORE MEDICAL CHALLENGES. WHEN HE CAME OUT OF THE ANESTHESIA, HE DID NOT LOOK RIGHT. THEY DID AN MRI AND IT WAS HIS FIRST STROKE, LEAVING HIS WHOLE LEFT SIDE PARALYZED. WHEN HE WAS 4 OR 5, HE STARTED LIKE FEELING WEAK IN HIS LEGS. YEAH, HE USED TO COLLAPSE. SO WE TOOK HIM TO A NEUROLOGIST AND THEY DID NOT DO AN MRI. AND SHE SAID, MAYBE HE IS JUST WEAK BECAUSE HIS NUTRITION IS DIFFERENT. AT THE AGE OF EIGHT, AFTER ONE OF HIS MORE THAN 30 SURGERIES, RITHVIK DIDN’T WAKE UP. I CAN STILL REMEMBER THE LOOK ON THE DOCTOR’S FACE. HE HAD A MAJOR STROKE. HE AFFECTED ONE SIXTH OF HIS BRAIN. ONE SIXTH. YEAH, IT WAS GONE JUST LIKE THAT. AND ANOTHER DIAGNOSIS. CEREBRAL VASCULITIS. A CONDITION THAT CAUSES INFLAMMATION OF THE BLOOD VESSELS IN THE BRAIN FOR 15 YEARS, THE KAPALI FAMILY LIVED IN A CONSTANT STATE OF. WHAT’S NEXT? WE LOST COUNT HOW MANY TIMES WE ENDED UP CALLING 911. OR MAYBE RUNNING TO HOSPITAL IN THE MIDDLE OF THE NIGHT. BUT IN 2021, THE UN MADE A FASCINATING DISCOVERY. DOCTOR DAVID SCHWEITZER WAS SEARCHING FOR AN EXPERT TO EXPLAIN SOME OF HRITHIK’S SYMPTOMS. DID THEY ALL CONNECT SOMEHOW? TURNS OUT THAT EXPERT WAS RIGHT DOWN THE HALL. HE HAD A VERY PARTICULAR PATTERN IN THE VASCULATURE THAT SHOWED THEM VERY STRAIGHTENED OUT IN THE BRAIN, VERY NARROWED AT THE SAME TIME THAT OTHER PARTS OF THE VASCULATURE WERE DILATED. EVERY ORGAN THAT HAD THESE TYPE OF CELLS, CALLED SMOOTH MUSCLE CELLS, WERE AFFECTED OR NOT FUNCTIONING CORRECTLY. AND I THOUGHT, THIS IS A SMOOTH MUSCLE DISEASE FOR SURE. TEAMS DID THE RIGHT GENETIC TESTING. THEY SENT A PANEL WHERE THIS PARTICULAR VARIANT ON THE CONTRACTILE PROTEINS OF THE SMOOTH MUSCLE APPEAR, AND THEY WERE NEGATIVE AND THEY SENT THEM AGAIN. AND THEY WERE NEGATIVE. MOST OF THE GENETIC DISEASES THAT RESEARCHERS KNOW ABOUT TODAY ARE CAUSED BY MUTATIONS IN PROTEIN CODING GENES. THERE ARE 23,000 IN THE HUMAN BODY. THERE ARE TEN TIMES AS MANY NON-CODING GENES. BUT GENETIC TESTING DOESN’T LOOK THERE. THIS IS THE FIRST GENETIC NON-CODING VASCULAR DISEASE THAT HAS EVER BEEN FOUND. RITHVIK HAD NO ANSWERS BECAUSE, AS IT TURNS OUT, THERE WAS NO DIAGNOSTIC MAP. THEY HAVE TO LOOK EVEN FURTHER INTO THESE PARTS OF THE DNA THAT DO NOT PRODUCE PROTEINS. BUT REGULATE THOSE PARTS OF THE GENOME THAT PRODUCE THE PROTEINS. RITHVIK IS THE ONLY KNOWN PERSON IN THE WORLD WITH THIS PARTICULAR MUTATION OF THE MICRO RNA. OPENING AN ENTIRE CHAPTER OF HUMAN DISEASE. YOU KNOW, IF HE’S LUCKY, HOPEFULLY HE WILL FIND A TREATMENT MAYBE NEXT 5 TO 10 YEARS. BUT IF NOT, WE HOPE THAT IT WILL HELP, YOU KNOW, GENERATIONS DOWN THE LINE. WOW. AND AS YOU JUST HEARD NICOLE SAY, THAT RITHVIK IS THE ONLY PERSON KNOWN IN THE WORLD TO BE DIAGNOSED WITH THIS CONDITION, RIGHT? BUT LIKE WITH MANY OF THESE RARE DISEASES, THERE ARE LIKELY OTHERS WHO JUST HAVEN’T BEEN DIAGNOSED BECAUSE THE SYMPTOMS ARE SO COMPLEX AND SO DIVERSE. AND OF COURSE, OUR UNDERSTANDING OF THE HUMAN GENOME AND UNRAVELING IT IS STILL SO IN ITS INFANCY. REALLY, WE’RE JUST BEGINNING TO UNDERSTAND THAT. ALL RIGHT.

Discovery at Massachusetts General Hospital creates roadmap for a rare disease

In a small lab in Boston, a team of scientists, doctors, and geneticists is pushing the boundaries of medical knowledge. They’re part of the Undiagnosed Diseases Network — a nationwide initiative tackling the most complex and rare medical cases.The UDN works on cases many would dismiss as unsolvable.Millions of patients across the U.S. live with undiagnosed conditions.Massachusetts General Hospital is one of 15 centers offering expertise in advanced medical genetics through the Undiagnosed Diseases Network.The team dives deep, searching for patterns, connecting global research, and studying the complexities of human DNA.Nineteen-year-old Rithvik wasn’t dealt an easy hand in life. His first symptom — a distended abdomen — was detected before he was even born.Over the years, his symptoms spiraled into a series of medical mysteries:Digestive issues by age 2.A stroke during an endoscopy at age 2, leaving his left side paralyzed.Frequent collapses due to unexplained weakness.By age 8, after one of 30 surgeries, Rithvik suffered a catastrophic stroke, losing 1/6 of his brain function.Multiple initial diagnoses, from Moyamoya to cerebral vasculitis, never fully explained Rithvik’s condition.In 2021, the UDN made a groundbreaking discovery. Dr. David Sweetser, searching for connections among Rithvik’s symptoms, identified a unique pattern in his vasculature: narrow blood vessels in the brain but dilated ones in the body.The team continued to look deeper — beyond the 23,000 protein-coding genes typically analyzed in genetic tests. They uncovered something unprecedented: Rithvik’s condition was caused by a mutation in a non-coding gene — a part of DNA that doesn’t produce proteins but regulates the genome. This was the first genetic non-coding vascular disease ever identified.Rithvik’s case is more than a medical breakthrough — it’s a beacon of hope for undiagnosed patients worldwide. His discovery opens doors to studying non-coding genes, an area 10 times larger than what we currently understand.Thanks to the UDN, Rithvik and his family finally have answers — and the medical world has a new frontier to explore.

BOSTON —

The UDN works on cases many would dismiss as unsolvable.

Millions of patients across the U.S. live with undiagnosed conditions.
Massachusetts General Hospital is one of 15 centers offering expertise in advanced medical genetics through the Undiagnosed Diseases Network.

The team dives deep, searching for patterns, connecting global research, and studying the complexities of human DNA.

Nineteen-year-old Rithvik wasn’t dealt an easy hand in life. His first symptom — a distended abdomen — was detected before he was even born.

Over the years, his symptoms spiraled into a series of medical mysteries:

Digestive issues by age 2.
A stroke during an endoscopy at age 2, leaving his left side paralyzed.
Frequent collapses due to unexplained weakness.
By age 8, after one of 30 surgeries, Rithvik suffered a catastrophic stroke, losing 1/6 of his brain function.

Multiple initial diagnoses, from Moyamoya to cerebral vasculitis, never fully explained Rithvik’s condition.

In 2021, the UDN made a groundbreaking discovery. Dr. David Sweetser, searching for connections among Rithvik’s symptoms, identified a unique pattern in his vasculature: narrow blood vessels in the brain but dilated ones in the body.

The team continued to look deeper — beyond the 23,000 protein-coding genes typically analyzed in genetic tests. They uncovered something unprecedented: Rithvik’s condition was caused by a mutation in a non-coding gene — a part of DNA that doesn’t produce proteins but regulates the genome. This was the first genetic non-coding vascular disease ever identified.

Rithvik’s case is more than a medical breakthrough — it’s a beacon of hope for undiagnosed patients worldwide. His discovery opens doors to studying non-coding genes, an area 10 times larger than what we currently understand.

Thanks to the UDN, Rithvik and his family finally have answers — and the medical world has a new frontier to explore.