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A Brief History of Genetic Therapy: Gene Therapy, Antisense Technology, and Genomics
Published in Eric Wickstrom, Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors, 2020
As mentioned, the 1970s ushered in a molecular biology. This new discipline rapidly contributed a set of interrelated protocols and reagents which together allowed for the isolation and characterization of any gene for which a protein counterpart could be identified. Once isolated, these genes could be recombined with DNA from any other biological source. The profound utility of this new recombinant DNA approach was first demonstrated in 1972 when Berg and colleagues introduced recombined bacterial genes into mammalian cells using a DNA virus vector (Jackson et al., 1972). In short order, genes were cloned which had relevance to human disease. In 1981, an experiment was designed to introduce a gene for hypoxanthine guanine phosphoribosyl transferase (HPRT) into cell cultures derived from patients with Lesch-Nyhan syndrome, a hereditary disease characterized by a deficiency of HPRT caused by a defective HPRT gene. The introduction of the recombinant normal gene and the subsequent expression of HPRT corrected the original metabolic defect of the cell (Mulligan et al., 1981).
Cell Culture
Published in Stephen W. Carmichael, Susan L. Stoddard, The Adrenal Medulla 1986 - 1988, 2017
Stephen W. Carmichael, Susan L. Stoddard
In a clinically related study, Bitler and Howard (1986) examined dopamine metabolism in variants of PC12 cells that were deficient in hypoxanthine-guanine phosphoribosyltransferase. They found no correlation between the enzyme activity and endogenous dopamine levels, dopamine uptake, dopamine release, or monoamine oxidase. Transformation of the cells with a hypoxanthine-guanine phosphoribosyltransferase retrovirus restored the enzyme activity and did not adversely affect dopamine metabolism. This study has clinical relevance to the Lesch-Nyhan syndrome which is linked to a deficiency in hypoxanthine-guanine phosphoribosyltransferase.
Offenders with intellectual disabilities
Published in John C. Gunn, Pamela J. Taylor, Forensic Psychiatry, 2014
Pamela J Taylor, William R Lindsay, Gregory O’Brien, John L Taylor
Lesch–Nyhan syndrome occurs almost exclusively in males, caused by gene mutations on the X chromosome, resulting in an almost complete lack of activity of the enzyme hypoxanthine guanine phosphoribosyl transferase (HPRT). This enzyme normally plays a key role in the recycling of the purine bases, hypoxanthine and guanine. When it is inactive purines are not salvaged, but rather degraded, while, also, as a compensatory mechanism, increased synthesis of purines takes place (Deutsch et al., 2005). Uric acid is overproduced, leading to clinical features of gout, and, given the stage of development of the affected person, intellectual disability, spastic cerebral palsy, involuntary, choreoathetoid movements and aggressive behaviour, including self-mutilation, all exacerbated under stressful circumstances (Nyhan, 1976; Palmour, 1983). Selfmutilation is severe and compulsive, with unrestrained patients biting off digits and parts of their lips, even though they experience pain and scream while doing so. Aggression is also compulsive and sufferers have been heard apologizing while hurting others. The mechanisms behind the neurology of the condition are incompletely understood, but may include abnormalities of dopaminergic, GABAergic and glutamatergic neurotransmitter systems (Deutsch et al., 2005).
Established and recent developments in the pharmacological management of urolithiasis: an overview of the current treatment armamentarium
Published in Expert Opinion on Pharmacotherapy, 2020
Mohamed Abou Chakra, Athanasios E. Dellis, Athanasios G. Papatsoris, Mohamad Moussa
There is a global diversity in the prevalence of uric acid (UA) nephrolithiasis. UA stone comprises 8–10% of all kidney stones in the United States. However, its prevalence is higher in patients with type 2 diabetes mellitus and those with obesity. Three significant urinary abnormalities have been described as the main etiologic factors for the development of UA nephrolithiasis; low urinary pH, hyperuricosuria and low urinary volume [108]. Patients with medical conditions that promote profound hyperuricosuria are at high risk of developing uric acid calculi. These conditions include myeloproliferative disorders, and monogenic metabolic disorders, such as Lesch-Nyhan syndrome [109]. In idiopathic UA nephrolithiasis, the urinary pH and the fractional excretion of urate are significantly lower than in control subjects. Since these impairments are believed to be associated with primary gout, the underlying disturbance in idiopathic UA nephrolithiasis may be primary gout. Some but not all patients with primary gout suffer from uric acid stones or display hyperuricemia at a given time [110].
A Child Presenting with Recurrent Corneal Ulcers: Hereditary Sensory and Autonomic Neuropathy IV (HSAN IV)
Published in Neuro-Ophthalmology, 2019
Beena Suresh, Vaishnavi Reddy, Ingo Kurth, Sujatha Jagadeesh
There was anhidrosis and serum uric acid levels were normal (2.7 mg/dl range 1.4–6.7), ruling out Lesch Nyhan syndrome. His nerve conduction studies revealed that the sensory responses were smaller in amplitude but otherwise normal. Hence the provisional diagnosis was HSAN IV or Congenital Insensitivity to Pain and Anhidrosis. In view of recurrent corneal ulcers he underwent a detailed ophthalmological evaluation and was noted to have neurotrophic keratitis with decreased corneal sensation. He was treated with 0.3% Tobramycin eye drops 3 hourly, atropine eye drops and carboxymethyl cellulose eye drops 0.5%w/v for a week and the ulcers healed with a resultant corneal opacity. Subsequently the child presented with recurrence of corneal ulcers and underwent bilateral lateral tarsorrhaphy which had reduced the frequency of his corneal ulcers.
Recent approaches to gout drug discovery: an update
Published in Expert Opinion on Drug Discovery, 2020
Naoyuki Otani, Motoshi Ouchi, Hideo Kudo, Shuichi Tsuruoka, Ichiro Hisatome, Naohiko Anzai
Hypoxanthine, an intermediate metabolite generated through the purine degradation, is involved in two pathways as follows. In a salvage pathway, hypoxanthine is converted to IMP by hypoxanthine phosphoribosyltransferase (HPRT) and reused. Approximately 75% of the daily production is reused via this salvage pathway. In contrast, under total or partial deficiency of HPRT activity condition due to genetic mutation, such as the Lesch-Nyhan syndrome, purines accumulate [9], leading to gout.