A 2-year-old girl went to see a paediatric neurologist following concerns that her language and speech development were not progressing as well as expected. After a neurological examination, everything looked as it should. But by 3 years old, her family noticed that she was falling more and more, and her speech was becoming less clear.
This case presents some common symptoms that may be signs of a very rare disease. But rare diseases are rare, and that makes diagnosing them very difficult – even when they’re a textbook case. In this episode, we’ll talk about the pattern of symptoms that characterize this rare disease and, hopefully, how the lessons we learn can help avoid diagnostic odysseys.
“Most paediatric neurologists have seen maybe one case in their entire career, and so they don’t have that experience to allow them to recognize this as a specific combination. And that’s the challenge that most paediatric neurologists face – most clinicians in general – is there are things that we are familiar with because it’s a recognizable pattern,” shares Dr. Jonathan Mink, a paediatric neurologist at the University of Rochester, New York.
The first red flag was the deterioration of motor skills. Her skills weren’t just not progressing, they were getting worse. And from there, she began developing seizures.
Test after test was done. But the tests, even in combination, didn’t point to any one disorder. And although she was presenting classic symptoms of the rare disorder she would later be diagnosed with, her team did not yet know this.
With so many ways to go about making a diagnosis in a child with these symptoms, Dr. Mink decided to run genetic testing.
In medical school, physicians are usually taught to only order tests that will change what you DO, not just what you KNOW. But even when there’s no treatment or cure for the genetic disorder, these tests are still valuable for other reasons.
And for this child, genetic testing finally unlocked the diagnosis of a rare neurological disorder.
For Healthcare Professionals only.
Dr. Mink has been compensated by BioMarin for his participation.
Jonathan W. Mink, MD, PhD
Jonathan W. Mink, MD PhD is the Frederick A. Horner Endowed Distinguished Professor in Paediatric Neurology and Professor of Neurology, Neuroscience, and Paediatrics at the University of Rochester (NY) where he is also Chief of Child Neurology and Vice Chair of Neurology. Dr. Mink received his BA (Biology-Psychology) and MA (Psychology) from Wesleyan University and his MD and PhD (Neuroscience) from Washington University. He completed residency training in Paediatrics and Paediatric Neurology at Washington University / St. Louis Children’s Hospital. After completing a fellowship in Movement Disorders, he joined the faculty in Neurology, Anatomy & Neurobiology, and Paediatrics at Washington University in 1994 before being recruited to the University of Rochester in 2001. He started the University of Rochester Child Neurology Residency in 2003 with one resident per year and expanded to two residents per year in 2006. He stepped down as Program Director in 2013, but continues to have an active role in resident education.
Dr. Mink has an active research program focused on Batten Disease and movement disorders in children. Clinically, he specializes in paediatric movement disorders with special interests in dystonia and Tourette Syndrome. He is recognized internationally for his work and clinical expertise in paediatric movement disorders, Batten Disease, and basal ganglia physiology. Dr. Mink was the recipient of the first Dr. Oliver Sacks Award from the Tourette Association of America in recognition for his many contributions to Tourette Syndrome Research, Education, and Advocacy. He is Co-Director of the University of Rochester Intellectual and Development Disabilities Research Center.
He currently serves on several advisory committees including the Board of Directors of the International Child Neurology Association, the Neurology Review Committee (RRC) of the ACGME, NINDS NST-1 Study Section. He is a past member of NINDS Advisory Council, the NINDS Board of Scientific Counselors, and the FDA Paediatric Advisory Committee. He is past-chair of the Tourette Association of American Scientific Advisory Board. He has served as Associate Editor of Neurology and of Continuum.
Dr. Mink is former President of the Child Neurology Society.
DDx SEASON 5, EPISODE 1
Classic Symptoms of Rare Diseases and Avoiding Diagnostic Odysseys
RAJ: This season of DDx is sponsored by BioMarin Pharmaceutical Inc.
This podcast is intended for healthcare professionals only.
The details of this case study have been changed to protect patient privacy.
RAJ: Today’s case presents something we rarely see: a textbook case of symptoms characterizing a rare genetic disease.
DR. MINK: So the patient is a two-year-old girl who comes to see a paediatric neurologist because of some concerns that her language and speech development is not progressing as well as expected. So at that time, her neurologic examination was normal as was the rest of her physical examination. And six months later at the scheduled follow-up, the girl had not made as much improvement in language and speech as had been expected, but there were no other concerns. But then at three years of age she returned again for a scheduled follow-up. The family is now concerned that she’s become somewhat clumsy. And they noticed that she’d been falling more than she had. And so at this visit on the neurologic examination, her speech was somewhat less intelligible than previously. It was somewhat slurred, and she clearly had some difficulty with coordination that had not been noted before. And then she developed some seizures, and then had a prolonged seizure that led them to take her to their local emergency department. At that time. With the presence of seizures, the loss of coordination, the continued language delay, additional testing was done.
RAJ: But rare diseases are rare… which makes diagnosing them — even when they’re textbook
— very difficult.
DR. MINK: Most paediatric neurologists have seen maybe one case in their entire career, and so they don’t have that experience to allow them to recognize this as a specific combination. And that’s the challenge that most paediatric neurologists face — most clinicians in general — is there are things that we are familiar with because it’s a recognizable pattern.
RAJ: In today’s episode, we’ll talk about the pattern of symptoms that characterize this rare disease and, hopefully, how the lessons we learn can help avoid diagnostic odysseys…
RAJ: This is DDx, a podcast from Figure 1 about how doctors think.
This season is all about rare paediatric disorders.
I’m Dr. Raj Bhardwaj.
Today’s case comes from Dr. Jonathan Mink, a paediatric neurologist at the University of Rochester, New York.
Dr. Mink has been compensated by BioMarin Pharmaceutical Inc. for his participation in this episode.
Chapter 1 – Pattern Recognition
RAJ: Now, let’s go back to the beginning with our patient. When she was first examined by a paediatric neurologist, alarm bells weren’t ringing. Why not?
DR. MINK: So at that time, her neurologic examination was normal as was the rest of her physical examination. And the neurologist discussed with the parents that isolated language and speech developmental delay is a common occurrence, and that many children who have the kinds of delays she had end up having normal developmental outcomes.
RAJ: But after six months the patient didn’t improve.
DR. MINK: At the scheduled follow-up, the girl had not made as much improvement in language and speech as had been expected, but there were no other concerns. And again, her general physical examinations were completely normal and there were no concerns of other neurologic signs or symptoms.
RAJ: At three years of age she returned for a scheduled follow-up.
DR. MINK: This is now one year after the initial concern was raised where the family is now concerned that she’s become somewhat clumsy.
And they noticed that she’d been falling more than she had. And although she had been walking since about 12 months of age, she seemed to be less stable on her feet. And there were concerns that she just wasn’t as engaged in activities as she had been. She had continued to gain a few extra words, but they were concerned that it was harder for them to understand her.
And so at this visit on the neurologic examination, her speech was somewhat less intelligible than previously. It was somewhat slurred, and she clearly had some difficulty with coordination that had not been noted before.
RAJ: The paediatric neurologist’s discussion with the family had now changed. The child’s development wasn’t just not progressing… it was getting worse.
DR. MINK: Now, the discussion was that there was concern that she was actually not only not making expected gains, but there had been some deterioration in her motor functions. She wasn’t walking as well. She seemed to be clumsier.
RAJ: That was a red flag that led to more testing. First, an MRI…
DR. MINK: The MRI scan showed some minor concerns that parts of her brain, the cerebellum, which is in the back of the brain and controls coordination, was not as big as expected. And there was concern there might be some mild atrophy of the brain.
RAJ: When she started having seizures, it became clear her symptoms were progressing and that more testing was needed.
DR. MINK: At that time with the presence of seizures, the loss of coordination, the continued language delay, additional testing was done.
RAJ: Another symptom led to another test, an electroencephalogram, or EEG…
DR. MINK: She had an EEG to try to identify what type of seizures they were and because of the accumulation of symptoms.
RAJ: And then, another…
DR. MINK: At that point, it was recommended that they pursue genetic testing to look for different causes of a developmental regression.
RAJ: But the tests, even in combination, didn’t point to any one disorder.
DR. MINK: Seizures are very common in young children. Developmental delay is very common in young children. The loss of coordination and balance is not as common, but still there’s a very large range of disorders that can cause these. With the MRI scan not showing a specific finding that points to one specific kind of disorder, the list of possibilities is very broad. I would say probably between a hundred and 200 possible different disorders.
RAJ: So at this point, the doctor’s conversation with the parents went something like this…
DR. MINK: One is the concern that this is an underlying neurologic disorder that affects multiple aspects of their child. She’s having epilepsy now. She’s having coordination problems, and her development has not been on target and raises a very distinct possibility that this could be a genetic disorder.
RAJ: There are many ways to go about making a diagnosis in a child with these symptoms.
DR. MINK: Some of them are very specific like genetic tests and some are a little bit more general. Along with genetic testing, often some other blood testing is done where results may come back within several days, but they tend to be less specific and less likely to give a specific diagnosis.
RAJ: In medical school, we’re usually taught to only order tests that will change what you DO, not just what you KNOW… But even when there’s no treatment or cure for the genetic disorder, these tests are still valuable for other reasons…
DR. MINK: One reason is for family planning for family guidance. Is this a disorder that occurs in other family members or could occur in other family members? And if it is a disorder that is likely to recur, would that affect the parent’s decision or other family member’s decision about having additional children. And then the second reason is just peace of mind. I want to know what’s going on with this child. Finally, sometimes doing a genetic test early can save the expense and also the long path of doing other diagnostic tests before the thought of a genetic disorder is really top of the list.
Chapter 2: Diagnosis and Lessons
RAJ: In our patient, genetic testing revealed a diagnosis of CLN2 Disease, or Neuronal ceroid lipofuscinosis 2 (also known as TPP1 deficiency). This is a neurodegenerative disorder caused by an enzyme deficiency.
This deficiency causes a buildup of storage material in the cells which can lead to delayed speech, progressive loss of motor function, seizures, vision loss, dementia and eventually death.
DR. MINK: We have come to learn that if a child has seizures and trouble with movement or coordination or some other movement disorder, then it’s highly likely that this will be a genetic disorder. And I’m much more likely to go to genetic testing early in those children. Whereas if it’s one symptom in isolation, then there are many other possibilities that are not genetic that I would consider first.
RAJ: The road to diagnosis is not one traveled alone. It’s always a team effort. Reassessing and reevaluating symptoms play an important role in revealing more clues and helping to refine the DDx.
RAJ: And for the family, the patient, and the specialist, it’s often a race against time as well.
DR. MINK: I think the most important thing for listeners to know is that CLN2 disease and other diseases like it get worse with time. And so for clinicians, I think it’s always important to tell families if there’s something new that you’re concerned about, don’t wait, tell me about it. And for families, the same thing is that there’s something new that’s concerning in a child that does not have a clear diagnosis that may be the most important, new clue that will lead to a specific diagnosis.
RAJ: Thanks to Dr. Mink for speaking with us.
This is DDx, a podcast by Figure 1.
Figure 1 is an app that lets doctors share clinical images and knowledge about difficult to diagnose cases.
I’m Dr. Raj Bhardwaj, host and story editor of DDx.
You can follow me on Twitter at Raj BhardwajMD.
Head over to figure one dot com slash ddx, where you can find full show notes, photos and speaker bios.
This season of DDx is brought to you by BioMarin Pharmaceutical Inc.
This podcast is intended for healthcare professionals only.
For more information on diagnostic testing, go to paediatricseizures.com.
Thanks for listening.