Recital Program

Recital program for students of Lexie Hansen, Haley Bradshaw, Eliza Nelson, Kylee Paul, Mark Gubler, Lauren Malouf, Holly Ganoe, and Janessa LeMmon.https://digitalcommons.usu.edu/music_programs/1106/thumbnail.jp

Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis

Tyrosine hydroxylase deficiency is an autosomal recessive disorder resulting from cerebral catecholamine deficiency. Tyrosine hydroxylase deficiency has been reported in fewer than 40 patients worldwide. To recapitulate all available evidence on clinical phenotypes and rational diagnostic and therapeutic approaches for this devastating, but treatable, neurometabolic disorder, we studied 36 patients with tyrosine hydroxylase deficiency and reviewed the literature. Based on the presenting neurological features, tyrosine hydroxylase deficiency can be divided in two phenotypes: an infantile onset, progressive, hypokinetic-rigid syndrome with dystonia (type A), and a complex encephalopathy with neonatal onset (type B). Decreased cerebrospinal fluid concentrations of homovanillic acid and 3-methoxy-4-hydroxyphenylethylene glycol, with normal 5-hydroxyindoleacetic acid cerebrospinal fluid concentrations, are the biochemical hallmark of tyrosine hydroxylase deficiency. The homovanillic acid concentrations and homovanillic acid/5-hydroxyindoleacetic acid ratio in cerebrospinal fluid correlate with the severity of the phenotype. Tyrosine hydroxylase deficiency is almost exclusively caused by missense mutations in the TH gene and its promoter region, suggesting that mutations with more deleterious effects on the protein are incompatible with life. Genotype-phenotype correlations do not exist for the common c.698G>A and c.707T>C mutations. Carriership of at least one promotor mutation, however, apparently predicts type A tyrosine hydroxylase deficiency. Most patients with tyrosine hydroxylase deficiency can be successfully treated with l-dop

Diagnosis and management of glutaric aciduria type I – revised recommendations

Glutaric aciduria type I (synonym, glutaric acidemia type I) is a rare organic aciduria. Untreated patients characteristically develop dystonia during infancy resulting in a high morbidity and mortality. The neuropathological correlate is striatal injury which results from encephalopathic crises precipitated by infectious diseases, immunizations and surgery during a finite period of brain development, or develops insidiously without clinically apparent crises. Glutaric aciduria type I is caused by inherited deficiency of glutaryl-CoA dehydrogenase which is involved in the catabolic pathways of L-lysine, L-hydroxylysine and L-tryptophan. This defect gives rise to elevated glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine which can be detected by gas chromatography/mass spectrometry (organic acids) or tandem mass spectrometry (acylcarnitines). Glutaric aciduria type I is included in the panel of diseases that are identified by expanded newborn screening in some countries. It has been shown that in the majority of neonatally diagnosed patients striatal injury can be prevented by combined metabolic treatment. Metabolic treatment that includes a low lysine diet, carnitine supplementation and intensified emergency treatment during acute episodes of intercurrent illness should be introduced and monitored by an experienced interdisciplinary team. However, initiation of treatment after the onset of symptoms is generally not effective in preventing permanent damage. Secondary dystonia is often difficult to treat, and the efficacy of available drugs cannot be predicted precisely in individual patients. The major aim of this revision is to re-evaluate the previous diagnostic and therapeutic recommendations for patients with this disease and incorporate new research findings into the guideline

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Evaluation of newborn screening : studies in cystic fibrosis and disorders detectable by tandem mass spectrometry

I have been involved in several areas of newborn screening, and my thesis deals with two of these: -cystic fibrosis and tandem mass spectrometry. It comprises 36 papers describing work carried out between 1981 and 2008. This is arranged in sections to describe the implementation of screening and the evaluation of outcomes for each of these areas, cystic fibrosis and tandem mass spectrometry, as well as papers reviewing important general aspects of newborn screening -a review of current newborn screening, the problems of evaluation of outcome where disorders are very rare, and the ethical issues involved in screening. I believe my major contributions to knowledge and medical practice have been: • Fostering the recognition that the clinical diagnosis of cystic fibrosis was considerably delayed, that newborn screening was feasible in the field, and that patients with pancreatic sufficiency were readily diagnosed by newborn screening; • The evaluation and review of different screening strategies for cystic fibrosis; • The demonstration that identification of cystic fibrosis by screening confers a significant health benefit by greatly reducing hospitalisation in the early years, and providing nutritional and pulmonary benefits later in life; • Initiating screening by tandem mass spectrometry in New South Wales -the first publicly-funded state-wide screening for disorders of amino acid and fatty acid metabolism -and delineating some of the disorders which could and could not be reliably detected by this technology; • Providing the first population-based audit of the rate of diagnosis of these disorders clinically compared with diagnosis by newborn screening; • Providing the first clear demonstration of significant clinical benefits of tandem mass spectrometry screening for the commonest disorder of fatty acid oxidation, medium-chain acyl-CoA dehydrogenase deficiency. • Promoting the proper use of newborn screening programmes by examining the rationale for screening, ethical aspects, and what disorders should and should not be included in newborn screening programmes

Newborn Screening for Lysosomal Disease: Mission Creep and a Taste of Things to Come?

Newborn screening for several lysosomal disorders can now be accomplished successfully for case finding. However, many cases identified do not require immediate intervention and it is not yet clear, for some disorders, if there is a benefit in early diagnosis for those cases, or what should be called a benefit. Diagnosing adult-onset cases, especially when there are quite imperfect genotype-phenotype correlations, represents a significant expansion of what has heretofore been considered the aim of newborn screening. This mission creep should be carefully discussed, and certain aspects of newborn screening strengthened. We should all proceed with caution in this field

Homocystinuria: Reduced folate levels during pyridoxine treatment

Nine patients with homocystinuria due to cystathionine synthase deficiency were treated with pyridoxine: 6 responded biochemically and 5 of these showed marked clinical improvement. Full biochemical response was only obtained slowly in some patients. Response occurred in those patients who were least severely affected by their disease and was consistent within families. No patient experienced a thrombotic episode during pyridoxine treatment. Pretreatment serum and red cell folate levels were normal. All patients showed lowering of folate levels while receiving pyridoxine, and administration of folic acid caused further biochemical improvement in pyridoxine responsive patients and subjective clinical improvement in all. The mechanism for lowering of folate levels during pyridoxine administration may depend upon removal of substrate inhibition of the enzyme N(5) methyltetrahydrofolate homocysteine methyl transferase, due to pyridoxine-induced lowering of the substrate homocysteine. It is suggested that patients with homocystinuria should be given a long trial with pyridoxine and that folic acid should be given in all cases where pyridoxine is used

International perspectives on the cost-effectiveness of tandem mass spectrometry for rare metabolic conditions

Objectives To examine and evaluate the economic evidence regarding the use of tandem mass spectrometry (MS/MS) for the detection of rare metabolic conditions in neonates, and then to consider the transferability of these national-level results to other decision-making contexts.Methods A systematic literature review was undertaken, identifying papers published between January 1997 and March 2008. Thirteen unique cost-effectiveness evaluations were identified and appraised for comparability and transferability of results across settings.Results The primary outcome measure was usually life years gained (LYG) or quality-adjusted life years gained (QALY). The incremental cost-effectiveness ratios (ICER) presented were generally supportive of MS/MS, but showed considerable variation. Differences in assumptions made regarding prevalence and prognosis played a significant role in this variation.Conclusions Differences in study structure, the approach to costing, the choice of intervention, control and outcome measure, and the limit of studies to developed countries makes international generalisation of the cost-effectiveness evidence difficult. The importance of assumptions regarding disease progression and subsequent health care utilisation suggests that further work needs to consider the importance of longer-term follow-up.Tandem mass spectrometry Cost-effectiveness Review Health economics Metabolism