Molecular Mechanisms of Polyglutamine Pathology and Lessons Learned from Huntington’s Disease

Identification of polymorphic repeating units on DNA as a cause of many neurological disorders has introduced a new concept in molecular biology: Dynamic mutations. Many of the identified dynamic mutations involve expansion of trinucleotide repeats within disease genes. Nine neurodegenerative disorders are currently known to be caused by expanding CAG trinucleotide repeats. These are Huntington’s Disease (HD), Dentato-Rubral Pallidoluysian Atrophy (DRPLA), Spinal and Bulbar Muscular Atrophy (SBMA), and Spinocerebellar Ataxia (SCA) Type 1, 2, 3, 6, 7 and 17. All are inherited in an autosomal dominant fashion except for SBMA, which is X-linked recessive. In all polyQ diseases, the disease mutation involves an increase in the number of CAG repeats within the coding regions of the respective genes. Since CAG triplets encode glutamine in the proteins, diseases caused by CAG repeat expansions are known as “Polyglutamine (polyQ) Diseases”. PolyQ diseases share certain clinical, neuropathological and molecular findings. The most widely studied polyQ disease is HD. In HD and other polyQ diseases, conformational change in the mutant protein causes abnormal folding and proteolysis of the protein, leading to the formation of a toxic polyQ fragment, which aggregates and causes neuronal dysfunction and selective neuronal death in the brain.

Cerebellum: Its Anatomy, Functions and Diseases

Cerebellum is the largest part of the hindbrain and weighs about 150 g. It is enshrined in posterior cranial fossa behind the pons and medulla oblongata and separated from these structures by cavity of fourth ventricle. It is connected to brainstem by three fibre tracts known as cerebellar peduncles. Cerebellum controls the same side of body. It precisely coordinates skilled voluntary movements by controlling strength, duration and force of contraction, so that they are smooth, balanced and accurate. It is also responsible for maintaining equilibrium, muscle tone and posture of the body. This is achieved through the use of somatic sensory information in modulating the motor output from the cerebrum and brainstem. Sherrington regarded cerebellum as the head ganglion of the proprioceptive system. Dysfunction of cerebellum along with degenerative diseases of cerebellum such as spinocerebellar ataxia, multiple sclerosis, malignant tumours, etc. may culminate into disequilibrium, hypotonia, difficulty in talking, sleeping, maintaining muscular coordination and dyssynergia which at times may be life threatening. Hence, knowledge of anatomy of cerebellum is imperative for neuroanatomists and neurosurgeons.

Biomarkers of Diseases: Their Role in Emergency Medicine

Biomarkers have been playing an increasingly significant role in clinical decision making processes worldwide. Numerous studies are being undertaken across the globe in the elusive search for the ideal biomarker for each clinical condition. In the emergency department, where rapid diagnosis of various diseases like acute coronary syndromes, pulmonary embolism, heart failure, sepsis, acute renal failure etc. is of utmost importance, specific biomarkers can expedite the time to diagnosis and treatment. To enumerate, the following biomarkers have proved their worth within the setting of emergency departments across the world. The role of cardiac troponins and CK-MB has been well established in the clinical algorithms to detect myocardial infarction. Newer markers like Heart Fatty Acid Binding Protein (H-FABP), BNP, Pro BNP as well as Ischemia modified albumin (IMA) are coming into the fray in the detection of cardiovascular emergencies, especially in the detection of heart failure. Novel biomarkers like Mid-region Proadrenomedullin (MR-proADM) are found to be useful in sepsis along with Tumour necrosis factor-alpha (TNF-alpha), Interleukins and Presepsin in burns patients. Human neutrophil gelatinase-associated lipocalin (NGAL) levels can detect renal failure much earlier than conventional methods. S100 calcium binding protein B (S100B) has been found to be useful in detection of CNS injury and hence can be used to avoid unnecessary radiation to patients in the form of CT scans. Point of care testing of many of these biomarkers in the Emergency department itself paves way for a revolutionary step in faster emergency care delivery and better patient outcomes.