Transthyretin Amyloidosis (ATTR) is a protein aggregation disorder, caused by abnormal extracellular deposition of transthyretin (TTR), a transport protein carrying retinol and thyroxin (T4) in blood and cerebrospinal fluid. The amyloidogenic process in ATTR is characterized by the dissociation of native TTR tetramers into unstable monomers that unfold and aggregate leading to the formation of amyloid fibrils. Deposits of fibrilar TTR and toxic intermediates cause nervous system and/or heart pathology resulting in death within 5-15 years of onset.
Huntington’s disease (HD) is a neurodegenerative disorder caused by a CAG triplet repeat expansion in the huntingtin gene, which encodes an expanded polyglutamine stretch in the huntingtin protein, and leads to a ‘toxic gain of function’ of the protein. Neurodegeneration occurs most prominently in the striatum, where GABAergic medium-sized spiny projection neurons are preferentially lost. HD is characterized by chorea, behavioral and psychiatric manifestations which lead to progressive dementia and death 15-20 years after the onset of clinical symptoms. Abnormal movements in HD occur as a result of basal ganglia circuit disorder and are mediated by overactive dopamine neurotransmission.
Tardive dyskinesia is an iatrogenic syndrome of persistent abnormal involuntary movements that occur as a complication of drugs that competitively block dopamine receptors, particularly the D2 receptor, but possibly also the D3 receptor. It was first described in patients who were treated for schizophrenic psychosis with antipsychotics, but can also occur in patients without psychiatric disorders that are using dopamine receptor antagonists for other indications, such as gastrointestinal complaints, dystonia or Tourette’s syndrome. These abnormal movements appear late in the course of treatment and they persist even after discontinuation of the medication.
Adrenoleukodystrophy is a X-linked hereditary metabolic disorder caused by mutations in ABCD1, a peroxisomal ATP-binding cassette transporter, resulting in the accumulation of very-long-chain fatty acids (VLCFA) in organs and plasma. It presents as adrenal insufficiency, slowly progressive axonal degeneration of the spinal cord resulting in spastic paraparesis, and in some cases, rapidly progressive cerebral inflammatory demyelination causing death after 2 years.
Duchenne muscular dystrophy
Duchenne muscular dystrophy (DMD) is an X-linked inherited progressive muscle-wasting disease caused by nonsense or frame shift loss of function mutations in the dystrophin gene. DMD affects approximately 1 in 3500 male births, and is one of the most common and severe forms of muscular dystrophy. Diagnosis generally occurs between 2 and 4 years of age when children begin to demonstrate early hallmarks of the disease including delayed motor milestones and enlarged calf muscles. Independent ambulation is lost between 10 and 12 years of age, and premature death occurs in the late twenties to early thirties due to respiratory and/or cardiac failure.
Glioblastoma Multiforme (GBM) is an aggressive and devastating brain cancer with a poor survival rate. Although relatively uncommon (~1.4% of adult malignancies), malignant gliomas including the most common subtype GBM, remain devastating tumours due to progressive neurological morbidity and poor survival, with most GBM patients dying within a year of diagnosis.