Genomic Medicine for Rare Diseases – Dr. Berge Minassian
By: Jennifer Rilestone
Early breakthroughs in medical genetics were made through the study of single-gene, fully penetrant Mendelian genetic diseases. With easily characterized patterns of inheritance, these diseases (sickle-cell anemia, Huntington’s disease, Muscular Dystrophy, Cystic Fibrosis; see Timeline) provided the first models for learning how the alteration of a single nucleotide—residing in a single gene and coding for a single amino acid of a single protein—could severely disrupt the functioning of the human body. Today, the genetic cause of many of the most common Mendelian diseases has been discovered. What remain are the rare diseases—those that appear in just a few families, isolated populations, or even a single family.
Dr. Berge Minassian has devoted his career to these orphaned conditions, particularly those that he has encountered in medical practice as a neurologist. As a clinician-scientist, Minassian strives to provide more than a diagnosis to patients and families dealing with these poorly recognized conditions—he aims to find a cure.
As a neurology resident in Los Angeles, Minassian was first propelled to join a research team searching for the causative gene for Lafora disease. Arguably the worst disease of teenage onset, Lafora disease is often diagnosed in early adolescence with the onset of myoclonic seizures, and progresses over the course of several years to include atonic seizures, ataxia, and—most significantly—severe dementia. After about 10 years of protracted suffering, Lafora disease is eventually fatal in early adulthood. “It’s a disease that is horrible clinically, so anything we can do would make a huge, huge benefit and remove a ton of pain from innocent adolescents and their families.” After coming to Toronto and bridging competition between the research group in LA and one at McGill (where Minassian was once a medical student), he discovered the first Lafora disease gene. This was followed later by his discovery of two others, as well one in dogs (see Genomic Medicine: gone to the dogs?, page 39, IMS Magazine Summer 2012). A diagnosis of Lafora disease can now be confirmed genetically, and research in the Minassian lab continues to uncover the details of the underlying mechanism.
Unlike other neurological diseases that can be as complex as the brain itself, Lafora disease is caused by a comparatively simple problem. In Lafora disease, the mechanisms of glycogen synthesis are altered, such that starch-like inclusions (“Laforabodies”) are instead formed in the dendrites and cell bodies of neurons.Minassian says, “Compared to other brain diseases, it’s a simpler scientific problem. That’s what pushes me ahead. This is a case where we can find a cure for a brain disease.” In fact, simply by blocking glycogen synthesis, researchers in Minassian’s group have successfully cured mice harbouringLafora disease gene mutations. It is now a matter of translating that work to humans.
As with Lafora disease, many rare diseases are the result of very simple biological causes. Common diseases are multifactorial and complex in their pathophysiology; they are often polygenic and may include environmental influences.Minassian prefers to study rare diseases: “To really understand how the brain works, we need experiments in which a single variable is altered at a time. That’s what these rare diseases are—they are experiments of nature where one piece of the puzzle is removed.”
Work in Minassian’s lab has also uncovered the genetic cause of a rare muscle disease—X-linked myopathy with excessive autophagy (XMEA). In that disease, subtle changes in the expression of a V-ATPase carrier protein prevent the proper acidification of autophagic vesicles. This process appears to be critical for muscle function, and leads to progressive muscle weakness over the patient’s lifetime. Research in Minassian’s laboratory is now focused on finding ways to reverse this acidification defect.
Finally, recent advances in genomic technology have transformed the study of rare diseases from a process that takes many years to being on the verge of clinical use. A major advance in this respect comes from current research in Minassian’slaboratory. A family with an unknown neurological disease was diagnosed using next-generation whole exome sequencing. The mutation—causing a complex, infantile-onset movement disorder in several cousins—interrupts the packaging of dopamine (and related neurotransmitters) in the brain. With biochemical understanding of the mutation’s effect, a treatment was selected from among approved Parkinson’s disease drugs and the patients have experienced a remarkable and sustained recovery. Realization of the promise of genomic medicine for diagnosing rare diseases is imminent.
Where successes in the study of rare diseases lead, success for the more common and complex diseases will follow. The ability to rapidly sequence the entire genome of an individual will ensure the capture of nucleotide changes that may have been missed by earlier technologies that assayed genetic markers or sequenced only genetic exons. With new genomic tools in hand, Minassian is embarking upon the search for the genetic causes of the more common, extremely complex epilepsies—including juvenile myoclonic epilepsy, childhood absence epilepsy, and Rolandic epilepsy.