A look into the complex world of genetic disorders, their histories, and how we treat them.
By Ian MacArthur
The shores of Lake Maracaibo are populated by thousands of indigenous Venezuelans that live simply in stilted huts and subsist on the lake’s marine bounty, many in extreme poverty. These societies are archetypal third-world slums, devoid of proper sanitation and other modern amenities. However, the people of Lake Maracaibo are very unique. Before they reach adolescence, many of the villagers begin to make spontaneous, erratic motions. Their arms and legs begin jerking about at random. These symptoms worsen as they grow older and debilitating dementia, hallucinations, and depression set in. Within twenty years of onset, many of these villagers will have died. While most die of pneumonia due to motor and cognitive degeneration, many simply take their own lives to escape unbearable suffering.
The people of Lake Maracaibo are plagued by Huntington’s disease, a rare genetic disorder caused by a mutation in a gene located on the short arm of chromosome four. With a global prevalence of only 5 in every 100,000 people, Huntington’s qualifies as an orphan disease. First identified in 1872 by George Huntington, the disease was first noted for the involuntary, erratic motion of limbs exhibited by patients of the disease.
In the DNA of afflicted individuals, the so called huntingtin gene experiences a repetitive expansion of cytosine, adenine, and guanine nucleotides. This makes Huntington’s a member of a family of genetic maladies termed trinucleotide repeat disorders. The CAG codon codes for the amino acid glutamine, and the presence of more than 36 repetitions of the codon in the gene results in the deformation of the huntingtin protein due to an overabundant polyglutamine domain. While the exact function of the huntingtin protein is not fully understood, the effects of the mutated protein are catastrophic. The over-elongated proteins accumulate in neurons and clump together, disrupting normal cellular processes and eventually leading to widespread cell death. Neuronal death is responsible for the degenerative neurological symptoms of the disease.
Huntington’s follows a dominant mode of inheritance, meaning that only one mutated huntingtin allele is required for an individual to become symptomatic. A parent carrier of the gene has a 50% chance of passing it on to their child. Tragically, the onset of Huntington’s in most patients does not occur until middle age, often after an individual has had children. It is this aspect of the disease that makes Lake Maracaibo such a unique case.
In the town of Barranquitas, on the shores of the lake, researchers discovered adolescents and children as young as nine years old among those suffering from Hungtington’s. It was the DNA of these patients that helped scientists in the 1980s isolate the huntingtin gene based on the hundreds of CAG repetitions it contained. It was thus found that the more CAG repeats a patient had, the earlier he or she would become symptomatic. Although this proved to be momentous in understanding the pathology of Huntington’s, the disease remains an enigma. No cure currently exists, nor does any effective symptomatic treatment. Future methods of genomic and proteomic manipulation may hold the key to finally beating this horrifying disease, and it is in these yet undiscovered methods that the hope of Huntington’s patients lie.