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.
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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.
Adrenomyeloneuropathy (AMN) is the adult onset of X-linked adrenoleukodystrophy. AMN patients generally have spinal cord dysfunction, which leads to the initial symptoms that include difficulties in walking or a change in the walking pattern. The average age at which symptoms first appear is 28, but onset can occur anywhere from the second to the fifth decades of life.
Phenylketonuria (PKU) is an inherited disorder that increases the levels of a substance called phenylalanine in the blood. Phenylalanine is a building block of proteins (an aminoacid) that is obtained through the diet. PKU is caused by a wide range of mutations in the PAH gene (12q22-q24.2) coding for phenylalanine hydroxylase. Non-PAH mutations have been reported to cause a disorder known as hyperphenylalaninemia due to BH4 deficiency (see this term). Mutation frequency varies among different ethnic groups. Lower levels or absence of the phenylalanine hydroxylase enzyme underlie the clinical manifestations, as a result of toxic accumulation of phenylalanine in the blood and brain.
Niemann-Pick disease is a condition that affects many body systems. It has a wide range of symptoms that vary in severity. Niemann-Pick disease is divided into four main types: type A, type B, type C1, and type C2. These types are classified on the basis of genetic cause and the signs and symptoms of the condition.
Niemann-Pick disease type C (NP-C) is a lysosomal lipid storage disease (see this term) characterized by variable clinical signs, depending on the age of onset, such as prolonged unexplained neonatal jaundice or cholestasis, isolated unexplained splenomegaly, and progressive, often severe neurological symptoms such as cognitive decline, cerebellar ataxia, vertical supranuclear gaze palsy (VSPG), dysarthria, dysphagia, dystonia, seizures, gelastic cataplexy, and psychiatric disorders.