small microscope

Unusual Cases - why the help of a true specialist in rare genetics is so important

Not all cars, houses, plumbers, electricians - OR doctors- are the same.  Seeing an occasional rare disease case vs. specializing in the diagnosis and management of mitochondrial or other rare disorders brings two very different skill sets to the examination table.  

Several recent cases bring some different but all equally important points to light in regards to seeking opinions from a true specialist. Of note,  in discussing these cases, no identifying information will be revealed and some of the less relevant facts will be altered to preserve patient confidentiality.


A 20 something-year-old young man presented for concerns about the possibility of a mitochondrial disease. The key features in this patient were ptosis or drooping eye lids, and myopathy or muscle weakness. Previous providers had completed mtDNA sequencing and other genetic studies, all negative. 

Based on negative testing, the patient was told he likely did not have a mitochondrial disease but, due to persistent concerns, he presented for a second opinion consultation.

Due to his problem set and, on examination his myopathy and ptosis, I was very concerned about the possibility of an mtDNA deletion syndrome and recommended a muscle biopsy. A muscle biopsy was subsequently completed and mtDNA sequencing and deletion studies were obtained on muscle which identified the common MELAS mutation, confirming a mitochondrial disease not previously detected with next generation mtDNA sequencing in his blood sample. 

Case Pearls

The lessons of this case are important for several reasons. First and foremost, if there is considerable suspicion for mitochondrial disease, that diagnosis should be entertained regardless of negative gene testing. While gene testing is an extremely powerful tool, it has its limitations and negative results does not definitively negate the possibility of an underlying genetic disorder. 

Secondly, with the advent of next generation gene sequencing , the common belief was that even low level heteroplasmic mutations would be identified in blood or saliva samples negating the need for muscle biopsy testing to confirm diagnosis in all but mtDNA deletion cases.  Clearly, this was not the case in this patient. As an internationally known specialist had I not expressed considerable concerns for a mitochondrial disease regardless of the previously negative studies and strongly recommended a muscle biopsy this patient may have remained undiagnosed.  While I rarely do muscle biopsies, which have fallen into extreme disfavor, specialists like me understand when they are still necessary. 


A 20-month-old baby presented with a history of developmental delays and poor growth although she had done well and was developing normally until four months of age. Although she had to history of regression, she had not rolled over until 14 months  and did not sit until 19 months of age, clearly demonstrating developmental problems. In an attempt to identify the cause of her issues, she underwent a host of metabolic screening studies such as lactate, pyruvate, organic acids and amino acids as well as a number of genetic panels including whole genome sequencing, all unremarkable. 

Based on the negative testing, the little girl’s parents were told that no further evaluation was indicated. However, her mother remained concerned because of a drop off in growth and what she believed was some increased tone or spasticity in her daughter’s lower extremities leading to a second opinion evaluation. 

After examining the baby, I indicated that I believed she likely had a neurodegenerative disorder even though she had not clearly lost previously gained skills. As such, I made additional recommendations for a evaluation to include completion of a lysosomal storage disease panel which identified an enzyme deficiency consistent with metachromatic leukodystrophy.  Although we have some additional studies spending to confirm this diagnosis, her clinical presentation and features, despite the lack of white matter disease on brain MRI, are consistent with this disease.

Case Pearls

This case is important for two important reasons. One, is that not all cases of a specific disease look exactly like the classic presentation in a textbook. And, secondly, as emphasized previously, while extraordinarily powerful and a tool I utilize on a weekly basis, genetic testing does not identify all genetic disease so absolute reliance on a specific panel or test to diagnose all patients will leave many without answers. 


These two cases demonstrate the complexities of rare disease diagnosis and the depth and breadth of knowledge required to be a specialist in this arena. Therefore, as patients, parents and families, always recognize that there is tremendous value in knowledge and experience and that a second opinion consultation may bring you the answers you have been searching for, sometimes for years. Obtaining a diagnosis DOES matter. Without a clear diagnosis, treatment plans cannot be implemented and clinical trials cannot be entertained. You wouldn't think of bringing your car to a plumber so why should you seek anything less than a true specialist when faced with an unknown, rare disease? 


Fran D. Kendall, M.D.

This post is not meant to be a recommendation or a substitute for professional advice and services rendered by qualified doctors, allied medical personnel, and other professional services. The responsibility for any use of this information, or for proper medical treatment, rests with you.