Disorders of Leucine, Isoleucine, and Valine Metabolism

Knerr, Ina; Vockley, Jerry; Gibson, K. Michael

doi:10.1007/978-3-642-40337-8_7

Cited by 12 publications

(7 citation statements)

References 31 publications

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“…Caloric intake provided was in the range of 100 to 150 kcal/kg/day for infants, 80 to 130 for young children, 50 to 120 for older children and 40 to 70 for adolescents and young adults; this was typically increased during intercurrent illnesses and in the setting of raised leucine levels outside our target range of 59 to <400 μM/L. A key approach in our Centre is towards early diagnosis and emergency treatment with close monitoring and multidisciplinary team (MDT) management for our MSUD patients, with target leucine levels as close to normal as possible with <400 μM/L as acceptable upper limit, ideally 100 to 300 μM/L 23,24 . Growth during childhood as well as the teenage years required regular dietetic input with intake of exchanges going from about 4 to over 30 over short periods of weeks for some cases.…”

Section: Discussionmentioning

confidence: 99%

Maple syrup urine disease: Clinical outcomes, metabolic control, and genotypes in a screened population after four decades of newborn bloodspot screening in the Republic of Ireland

O’Reilly

Crushell

Hughes

et al. 2020

J of Inher Metab Disea

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Since 1972, 18 patients (10 females/8 males) have been detected by newborn bloodspot screening (NBS) with neonatal‐onset maple syrup urine disease (MSUD) in Ireland. Patients were stratified into three clusters according to clinical outcome at the time of data collection, including developmental, clinical, and IQ data. A fourth cluster comprised of two early childhood deaths; a third patient died as an adult. We present neuroimaging and electroencephalography together with clinical and biochemical data. Incidence of MSUD (1972‐2018) was 1 in 147 975. Overall good clinical outcomes were achieved with 15/18 patients alive and with essentially normal functioning (with only the lowest performing cluster lying beyond a single SD on their full scale intelligence quotient). Molecular genetic analysis revealed genotypes hitherto not reported, including a possible digenic inheritance state for the BCKDHA and DBT genes in one family. Treatment has been based on early implementation of emergency treatment, diet, close monitoring, and even dialysis in the setting of acute metabolic decompensation. A plasma leucine ≥400 μmol/L (outside therapeutic range) was more frequently observed in infancy or during adolescence, possibly due to infections, hormonal changes, or noncompliance. Children require careful management during metabolic decompensations in early childhood, and this represented a key risk period in our cohort. A high level of metabolic control can be achieved through diet with early implementation of a “sick day” regime and, in some cases, dialysis as a rescue therapy. The Irish cohort, despite largely classical phenotypes, achieved good outcomes in the NBS era, underlining the importance of early diagnosis and skilled multidisciplinary team management.

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Section: Discussionmentioning

confidence: 99%

Maple syrup urine disease: Clinical outcomes, metabolic control, and genotypes in a screened population after four decades of newborn bloodspot screening in the Republic of Ireland

O’Reilly

Crushell

Hughes

et al. 2020

J of Inher Metab Disea

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“…Rare disorders of amino acid metabolism provide further evidence for a central role of metabolism in keeping plasma amino acid levels at homeostatic concentrations [ 198 ]. In fact, many metabolic disorders are diagnosed through the elevation of amino acids, such as disorders of phenylalanine metabolism (phenylalanine elevated, [ 199 ]), tyrosine metabolism (tyrosine elevated, [ 200 ]), the metabolism of sulphur amino acids (methionine elevated, [ 201 ]), urea cycle disorders and related diseases, (glutamine elevated, arginine depleted, [ 202 ]), disorders of glycine, serine and proline metabolism (glycine elevated, serine depleted because mutations affecting synthetic pathways, proline elevated, [ 203 ]) and the metabolism of BCAAs elevated [ 204 ]. Many of these inherited disorders have severe consequences for CNS function, demonstrating a particular sensitivity of this organ to imbalances of amino acid homeostasis.…”

Section: Systemic Amino Acid Homeostasismentioning

confidence: 99%

Amino acid homeostasis and signalling in mammalian cells and organisms

Bröer

2017

Biochemical Journal

413

340

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Cells have a constant turnover of proteins that recycle most amino acids over time. Net loss is mainly due to amino acid oxidation. Homeostasis is achieved through exchange of essential amino acids with non-essential amino acids and the transfer of amino groups from oxidised amino acids to amino acid biosynthesis. This homeostatic condition is maintained through an active mTORC1 complex. Under amino acid depletion, mTORC1 is inactivated. This increases the breakdown of cellular proteins through autophagy and reduces protein biosynthesis. The general control non-derepressable 2/ATF4 pathway may be activated in addition, resulting in transcription of genes involved in amino acid transport and biosynthesis of non-essential amino acids. Metabolism is autoregulated to minimise oxidation of amino acids. Systemic amino acid levels are also tightly regulated. Food intake briefly increases plasma amino acid levels, which stimulates insulin release and mTOR-dependent protein synthesis in muscle. Excess amino acids are oxidised, resulting in increased urea production. Short-term fasting does not result in depletion of plasma amino acids due to reduced protein synthesis and the onset of autophagy. Owing to the fact that half of all amino acids are essential, reduction in protein synthesis and amino acid oxidation are the only two measures to reduce amino acid demand. Long-term malnutrition causes depletion of plasma amino acids. The CNS appears to generate a protein-specific response upon amino acid depletion, resulting in avoidance of an inadequate diet. High protein levels, in contrast, contribute together with other nutrients to a reduction in food intake.

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“…Deficiency of methylmalonyl‐CoA mutase (MUT) resulted in disorders of propionate degradation derived in part from the catabolism of isoleucine and valine, as well as other propionate precursors, such as threonine and methionine (Knerr et al . 2014). Methylcrotonyl‐CoA carboxylase 1 (MCCC1), a member of the biotin‐containing family of enzymes that catalyze the conversion of 3‐methylcrotonyl‐CoA to 3‐methylglutaconyl‐CoA MCCC1, plays an essential role in the catabolism of valine, leucine and isovalerate (Chen 2001).…”

Section: Resultsmentioning

confidence: 99%

Weighted gene co‐expression network analysis reveals potential candidate genes affecting drip loss in pork

Zhao

Wang

et al. 2020

Animal Genetics

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Drip loss is an essential evaluation indicator for pork quality. It is closely related to other meat quality indicators, including water-holding capacity, water loss rate and pH value at 45 min (pH 1) and 24 h post-mortem (pH 2), and is influenced by environmental and genetic factors and their interactions. We previously conducted differentially expressed gene analysis to identify candidate genes affecting drip loss using eight individuals with extremely high-and low-drip loss selected from 28 purebred Duroc pigs. Using 28 identical samples, in the present study, we performed weighted gene co-expression network analysis with drip loss and drip loss-related traits, including water-holding capacity, water loss rate, pH 1 and pH 2. A total of 25 modules were identified, and five of them correlated with at least two drip loss or drip loss-related traits. After functional enrichment analysis of genes in the five modules, three modules were found to be critical, as their genes were significantly involved in amino acid metabolism, immune response and apoptosis, which have potential relationships with drip loss. Furthermore, we identified five candidate genes affecting drip loss in one critical module, AASS, BCKDHB, ALDH6A1, MUT and MCCC1, as they overlapped with differentially expressed genes detected in our previous study, exhibited protein-protein interactions and had potential biological functions in affecting drip loss according to the literature. The outcomes of the present study enhance our understanding of the molecular mechanisms underlying drip loss and will aid in improving the pork quality.

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Disorders of Leucine, Isoleucine, and Valine Metabolism

Cited by 12 publications

References 31 publications

Maple syrup urine disease: Clinical outcomes, metabolic control, and genotypes in a screened population after four decades of newborn bloodspot screening in the Republic of Ireland

Maple syrup urine disease: Clinical outcomes, metabolic control, and genotypes in a screened population after four decades of newborn bloodspot screening in the Republic of Ireland

Amino acid homeostasis and signalling in mammalian cells and organisms

Weighted gene co‐expression network analysis reveals potential candidate genes affecting drip loss in pork

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