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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).
Peripheral Autonomic Neuropathies
Published in David Robertson, Italo Biaggioni, Disorders of the Autonomic Nervous System, 2019
The Lesch-Nyhan syndrome, a disorder of purine metabolism, is characterized by hyperuricemia and excessive uric acid production. It is X-linked and manifests profound neurological dysfunction, including spasticity, choreoathetosis, self-mutilation and mental retardation. There is an almost total absence of the enzyme hypoxanthine-guanine-phosphoribosyl transferase (HGPRT). The pathogenesis of behavioural and neurological disturbances in patients with HGPRT deficiency is not known. Because of self-mutilating behaviour induced in animals by caffeine or amphetamine administration, it has been suggested that this part of the Lesch-Nyhan syndrome results from altered function in central nervous system pathways affected by these agents. A study of patients with the HGPRT deficiency and self-mutilating behaviour shows a unique pattern of adrenergic dysfunction. Plasma dopamine beta-hydroxylase, an enzyme which catalyzes noradrenaline formation from dopamine, is elevated. This enzyme is released simultaneously into the synaptic cleft with noradrenaline. Though this enzyme was elevated in patients with Lesch-Nyhan syndrome, none of them had autonomic manifestations of excessive adrenergic activity such as hypertension, tachycardia or mydriasis. But clinical evaluation of adrenergic responsiveness such as the cold pressor test showed that the normally expected rise in blood pressure (due to vasoconstriction) was absent in those with the HGPRT deficiency syndrome who also exhibited self-mutilation. The mechanism of this failure of vasoconstriction is not known. Any implied relationship to high plasma dopamine beta-hydroxylase activity remains conjectural. The experimentally induced self-mutilation of animals by caffeine injection may link this behavioural abnormality to the endorphin system, since caffeine is a potent stimulator of plasma, but not cerebrospinal fluid beta-endorphin release.
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.
CRISPR-based RNA editing: diagnostic applications and therapeutic options
Published in Expert Review of Molecular Diagnostics, 2019
Diana Gulei, Lajos Raduly, Ioana Berindan-Neagoe, George Adrian Calin
RNA-based gene therapy could rapidly evolve into clinical practice if we take into consideration that for some pathologies, only partial restoration of protein homeostatic activity is sufficient for significant disease amelioration – e.g. Lesch-Nyhan syndrome can switch to a mild form of hyperuricemia after 8% improvement in enzyme activity [29]. Moreover, potential off-target effects in one RNA molecule will be much attenuated than in the case of DNA editing strategies due to the temporary nature of the RNA molecules and also the editing will take place only in the cells that actually express the targeted gene.