Mohamed Kazamel, MD, is an associate professor of neurology at the University of Alabama at Birmingham (UAB). He serves as director of the UAB Autonomic Testing Laboratory and assistant director of the Shin J. Oh Muscle and Nerve Histopathology Laboratory. Dr. Kazamel is also the sole neurologist member of the Porphyrias Consortium (PC). His research focuses on investigating the characteristics of autonomic neuropathy in acute hepatic porphyrias (AHPs). Here, he shares his start in rare disease research, exciting discoveries, and future goals.
What inspired you to become a researcher in the rare disease space?
I joined the PC at the end of 2020 when I was approached by Dr. Robert J. Desnick, the principal investigator of the consortium.
The porphyrias were diseases that we all once studied in medical school. However, during training and practice, they are very rarely talked about in our clinical rounds. This reflects the rarity of the diseases and their variable clinical presentations that could masquerade under more common neurologic and psychiatric diagnoses. The diagnostic delay in AHPs could be up to 15 years. Patients continue to suffer and oftentimes get labeled with psychiatric conditions like somatoform and conversion disorders while they have an organic neurologic disorder. Although the clinical presentation is mainly neurologic, these patients are typically taken care of by our fellow hepatologists.
The continuous suffering of patients and the presence of large gaps of knowledge in the pathophysiology of porphyric neuropathy both inspired me to seek more answers for these patients and to help my fellow hepatologist, hematologist, and geneticist members of the PC.
What has been your biggest “aha” moment as a scientist?
One of the main moments was when we started discussing with other members of the PC what we know about the electrodiagnostic features of porphyric neuropathy being a motor-predominant neuropathy, at least from the nerve conduction studies standpoint with sparing of the sensory nerves. I mentioned to my collaborators that this would make sense if the site of pathology is not only the nerves themselves, but mainly the nerve roots. The nerve roots are known to have a less restrictive blood-nerve barrier and are likely more vulnerable to the effect of neurotoxic porphyrinogen molecules like the delta aminolaevulinic acid (ALA).
Can you tell us about a recent discovery and what it means for patients and physicians?
On further discussing the last assumption with Dr. Elena Pischik, chair of the Department of Neurology, Consultative and Diagnostic Center with Polyclinics, St. Petersburg, Russia, whose PhD study focused on characterizing porphyric neuropathy, it was brought up that most of her patients started having low back pain before the development of limb pain and/or weakness. This further supported the hypothesis of porphyric neuropathy being originally a nerve root problem.
I think we should raise awareness of this important finding, as this will put porphyric neuropathy on the radar of any neurologist or ER physician confronted with an acute or subacute limb weakness preceded by low back pain. I believe that this would certainly shorten the significant diagnostic delay and reduce the frequency of misdiagnosis, which will lead to earlier interventions and better outcomes.
Can you tell us about the Porphyrias Consortium, how it came together, and what role it has played in your work?
The PC comprises six main sites housed by tertiary academic medical centers spread all over the country, as well as several satellite sites. While members of the consortium are mainly hepatologists, hematologists, and geneticists by training, we all work together in the consortium to take care of our porphyria patients. This is, of course, in addition to the significant collaboration between the PC members on several research projects. The consortium provides an excellent opportunity of mentorship for someone who is a mid-career clinical researcher like me.
What do you see ahead for the Porphyrias Consortium and your rare disease research?
I see further collaboration and a lot of work to be done! There are still large gaps of knowledge in the field. Most of the earlier electrophysiologic reports included AHP cases that were not genetically confirmed and did not correlate the severity of nerve injury with the disease duration and/or the number of earlier attacks.
The reasons why AHP patients present predominantly with dysautonomic manifestations (both acute and chronic) remain unclear. The pathogenesis of the chronic pain that occurs between attacks is still not fully understood. While the recent introduction of siRNA treatment decreased the frequency of attacks, its long-term effects on motor recovery, chronic pain, and dysautonomic manifestations remain to be determined.
These are all important research questions that should constitute aims for future research projects. I look forward to more years of collaboration with other members of the PC to address these questions and promote our knowledge about such an interesting disease.
The Porphyrias Consortium (PC) is part of the Rare Diseases Clinical Research Network (RDCRN), which is funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Division of Rare Diseases Research Innovation (DRDRI). PC is funded under grant number U54DK083909 as a collaboration between NCATS and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).