Enhance MSUD pathophysiology with causal chain

references_cache/DOI_10.1002_jmd2.12419.md

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+---
+reference_id: "DOI:10.1002/jmd2.12419"
+title: "Computational structural genomics and clinical evidence suggest <scp>BCKDK</scp> gain‐of‐function may cause a potentially asymptomatic maple syrup urine disease phenotype"
+authors:
+- Emily Singh
+- Young‐In Chi
+- Jessica Kopesky
+- Michael Zimmerman
+- Raul Urrutia
+- Donald Basel
+- Jessica Scott Schwoerer
+journal: JIMD Reports
+year: '2024'
+doi: 10.1002/jmd2.12419
+content_type: abstract_only
+---
+
+# Computational structural genomics and clinical evidence suggest <scp>BCKDK</scp> gain‐of‐function may cause a potentially asymptomatic maple syrup urine disease phenotype
+**Authors:** Emily Singh, Young‐In Chi, Jessica Kopesky, Michael Zimmerman, Raul Urrutia, Donald Basel, Jessica Scott Schwoerer
+**Journal:** JIMD Reports (2024)
+**DOI:** [10.1002/jmd2.12419](https://doi.org/10.1002/jmd2.12419)
+
+## Content
+
+AbstractMaple syrup urine disease (MSUD) is a disorder of branched‐chain amino acid metabolism caused by a defect in the branched‐chain α‐ketoacid dehydrogenase (BCKD) complex (OMIM #248600). The hallmark presentation is encephalopathic crisis in neonates, but can also present with metabolic decompensation, developmental delays, and feeding difficulties. Biochemical evidence for MSUD includes elevated branched‐chain amino acids (BCAA) and the pathognomonic presence of alloisoleucine. The BCKD complex contains several subunits associated with autosomal recessive MSUD, while its regulatory proteins have less well‐defined disease associations. We report on two families with the same BCKDK variant (c.1115C>G (p.Thr372Arg)). Probands were detected on newborn screening and demonstrated biochemical evidence of MSUD. The variant was identified in reportedly asymptomatic parents and additional family members who had elevated BCAA and alloisoleucine, following an autosomal dominant pattern of inheritance. To better define the functional effect of the variant on the kinase, we completed molecular modeling using sequence‐based (2D), structural‐based (3D), and dynamic‐based (4D) analyses. The BCKDK variant modeling indicated a gain‐of‐function which leads to impaired BCAA catabolism consistent with the biochemical evidence in this cohort. Combining the evidence gained from molecular modeling with the absence of metabolic decompensation in our patients and several adult family members, despite encountering stressors typically problematic in classic MSUD, we suggest that heterozygous gain‐of‐function variants in BCKDK may represent a novel biochemical phenotype of MSUD with a benign clinical course.

references_cache/DOI_10.1007_s11011-022-01109-y.md

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+---
+reference_id: "DOI:10.1007/s11011-022-01109-y"
+title: Branched-chain amino acids (BCAA) administration increases autophagy and the autophagic pathway in brain tissue of rats submitted to a Maple Syrup Urine Disease (MSUD) protocol
+authors:
+- Karoline Teixeira Fermo
+- Isabela da Silva Lemos
+- Hemelin Resende Farias
+- Marina Peyrot Rosso
+- Pauline Souza Effting
+- Guilhian Leipnitz
+- Emílio Luiz Streck
+journal: Metabolic Brain Disease
+year: '2023'
+doi: 10.1007/s11011-022-01109-y
+content_type: unavailable
+---
+
+# Branched-chain amino acids (BCAA) administration increases autophagy and the autophagic pathway in brain tissue of rats submitted to a Maple Syrup Urine Disease (MSUD) protocol
+**Authors:** Karoline Teixeira Fermo, Isabela da Silva Lemos, Hemelin Resende Farias, Marina Peyrot Rosso, Pauline Souza Effting, Guilhian Leipnitz, Emílio Luiz Streck
+**Journal:** Metabolic Brain Disease (2023)
+**DOI:** [10.1007/s11011-022-01109-y](https://doi.org/10.1007/s11011-022-01109-y)
+
+## Content

references_cache/DOI_10.1038_s41467-022-30880-w.md

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+---
+reference_id: "DOI:10.1038/s41467-022-30880-w"
+title: Neonatal gene therapy achieves sustained disease rescue of maple syrup urine disease in mice
+authors:
+- Clément Pontoizeau
+- Marcelo Simon-Sola
+- Clovis Gaborit
+- Vincent Nguyen
+- Irina Rotaru
+- Nolan Tual
+- Pasqualina Colella
+- Muriel Girard
+- Maria-Grazia Biferi
+- Jean-Baptiste Arnoux
+- Agnès Rötig
+- Chris Ottolenghi
+- Pascale de Lonlay
+- Federico Mingozzi
+- Marina Cavazzana
+- Manuel Schiff
+journal: Nature Communications
+year: '2022'
+doi: 10.1038/s41467-022-30880-w
+content_type: abstract_only
+---
+
+# Neonatal gene therapy achieves sustained disease rescue of maple syrup urine disease in mice
+**Authors:** Clément Pontoizeau, Marcelo Simon-Sola, Clovis Gaborit, Vincent Nguyen, Irina Rotaru, Nolan Tual, Pasqualina Colella, Muriel Girard, Maria-Grazia Biferi, Jean-Baptiste Arnoux, Agnès Rötig, Chris Ottolenghi, Pascale de Lonlay, Federico Mingozzi, Marina Cavazzana, Manuel Schiff
+**Journal:** Nature Communications (2022)
+**DOI:** [10.1038/s41467-022-30880-w](https://doi.org/10.1038/s41467-022-30880-w)
+
+## Content
+
+AbstractMaple syrup urine disease (MSUD) is a rare recessively inherited metabolic disorder causing accumulation of branched chain amino acids leading to neonatal death, if untreated. Treatment for MSUD represents an unmet need because the current treatment with life-long low-protein diet is challenging to maintain, and despite treatment the risk of acute decompensations and neuropsychiatric symptoms remains. Here, based on significant liver contribution to the catabolism of the branched chain amino acid leucine, we develop a liver-directed adeno-associated virus (AAV8) gene therapy for MSUD. We establish and characterize the Bckdha (branched chain keto acid dehydrogenase a)−/− mouse that exhibits a lethal neonatal phenotype mimicking human MSUD. Animals were treated at P0 with intravenous human BCKDHA AAV8 vectors under the control of either a ubiquitous or a liver-specific promoter. BCKDHA gene transfer rescued the lethal phenotype. While the use of a ubiquitous promoter fully and sustainably rescued the disease (long-term survival, normal phenotype and correction of biochemical abnormalities), liver-specific expression of BCKDHA led to partial, though sustained rescue. Here we show efficacy of gene therapy for MSUD demonstrating its potential for clinical translation.

references_cache/DOI_10.1038_srep28775.md

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+---
+reference_id: "DOI:10.1038/srep28775"
+title: Metformin inhibits Branched Chain Amino Acid (BCAA) derived ketoacidosis and promotes metabolic homeostasis in MSUD
+authors:
+- Davis S. Sonnet
+- Monique N. O’Leary
+- Mark A. Gutierrez
+- Steven M. Nguyen
+- Samiha Mateen
+- Yuehmei Hsu
+- Kylie P. Mitchell
+- Antonio J. Lopez
+- Jerry Vockley
+- Brian K. Kennedy
+- Arvind Ramanathan
+journal: Scientific Reports
+year: '2016'
+doi: 10.1038/srep28775
+content_type: abstract_only
+---
+
+# Metformin inhibits Branched Chain Amino Acid (BCAA) derived ketoacidosis and promotes metabolic homeostasis in MSUD
+**Authors:** Davis S. Sonnet, Monique N. O’Leary, Mark A. Gutierrez, Steven M. Nguyen, Samiha Mateen, Yuehmei Hsu, Kylie P. Mitchell, Antonio J. Lopez, Jerry Vockley, Brian K. Kennedy, Arvind Ramanathan
+**Journal:** Scientific Reports (2016)
+**DOI:** [10.1038/srep28775](https://doi.org/10.1038/srep28775)
+
+## Content
+
+AbstractMaple Syrup Urine Disease (MSUD) is an inherited disorder caused by the dysfunction in the branched chain keto-acid dehydrogenase (BCKDH) enzyme. This leads to buildup of branched-chain keto-acids (BCKA) and branched-chain amino acids (BCAA) in body fluids (e.g. keto-isocaproic acid from the BCAA leucine), leading to numerous clinical features including a less understood skeletal muscle dysfunction in patients. KIC is an inhibitor of mitochondrial function at disease relevant concentrations. A murine model of intermediate MSUD (iMSUD) shows significant skeletal muscle dysfunction as by judged decreased muscle fiber diameter. MSUD is an orphan disease with a need for novel drug interventions. Here using a 96-well plate (liquid chromatography- mass spectrometry (LC-MS) based drug-screening platform we show that Metformin, a widely used anti-diabetic drug, reduces levels of KIC in patient-derived fibroblasts by 20–50%. This Metformin-mediated effect was conserved in vivo; Metformin-treatment significantly reduced levels of KIC in the muscle (by 69%) and serum (by 56%) isolated from iMSUD mice and restored levels of mitochondrial metabolites (e.g. AMP and other TCA). The drug also decreased the expression of mitochondrial branched chain amino transferase (BCAT) which produces KIC in skeletal muscle. This suggests that Metformin can restore skeletal muscle homeostasis in MSUD by decreasing mitochondrial KIC production.

references_cache/DOI_10.1091_mbc.11.5.1919.md

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+---
+reference_id: "DOI:10.1091/mbc.11.5.1919"
+title: "Branched Chain Amino Acids Induce Apoptosis in Neural Cells without Mitochondrial Membrane Depolarization or Cytochrome<i>c</i>Release: Implications for Neurological Impairment Associated with Maple Syrup Urine Disease"
+authors:
+- Philippe Jouvet
+- Pierre Rustin
+- Deanna L. Taylor
+- Jennifer M. Pocock
+- Ursula Felderhoff-Mueser
+- Nicholas D. Mazarakis
+- Catherine Sarraf
+- Umesh Joashi
+- Mary Kozma
+- Kirsty Greenwood
+- A. David Edwards
+- Huseyin Mehmet
+journal: Molecular Biology of the Cell
+year: '2000'
+doi: 10.1091/mbc.11.5.1919
+content_type: abstract_only
+---
+
+# Branched Chain Amino Acids Induce Apoptosis in Neural Cells without Mitochondrial Membrane Depolarization or Cytochrome<i>c</i>Release: Implications for Neurological Impairment Associated with Maple Syrup Urine Disease
+**Authors:** Philippe Jouvet, Pierre Rustin, Deanna L. Taylor, Jennifer M. Pocock, Ursula Felderhoff-Mueser, Nicholas D. Mazarakis, Catherine Sarraf, Umesh Joashi, Mary Kozma, Kirsty Greenwood, A. David Edwards, Huseyin Mehmet
+**Journal:** Molecular Biology of the Cell (2000)
+**DOI:** [10.1091/mbc.11.5.1919](https://doi.org/10.1091/mbc.11.5.1919)
+
+## Content
+
+Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by a deficiency in branched chain α-keto acid dehydrogenase that can result in neurodegenerative sequelae in human infants. In the present study, increased concentrations of MSUD metabolites, in particular α-keto isocaproic acid, specifically induced apoptosis in glial and neuronal cells in culture. Apoptosis was associated with a reduction in cell respiration but without impairment of respiratory chain function, without early changes in mitochondrial membrane potential and without cytochrome c release into the cytosol. Significantly, α-keto isocaproic acid also triggered neuronal apoptosis in vivo after intracerebral injection into the developing rat brain. These findings suggest that MSUD neurodegeneration may result, at least in part, from an accumulation of branched chain amino acids and their α-keto acid derivatives that trigger apoptosis through a cytochrome c-independent pathway.

references_cache/DOI_10.1093_hmg_ddq507.md

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+---
+reference_id: "DOI:10.1093/hmg/ddq507"
+title: Phenylbutyrate therapy for maple syrup urine disease
+authors:
+- Nicola Brunetti-Pierri
+- Brendan Lanpher
+- Ayelet Erez
+- Elitsa A. Ananieva
+- Mohammad Islam
+- Juan C. Marini
+- Qin Sun
+- Chunli Yu
+- Madhuri Hegde
+- Jun Li
+- R. Max Wynn
+- David T. Chuang
+- Susan Hutson
+- Brendan Lee
+journal: Human Molecular Genetics
+year: '2011'
+doi: 10.1093/hmg/ddq507
+content_type: unavailable
+---
+
+# Phenylbutyrate therapy for maple syrup urine disease
+**Authors:** Nicola Brunetti-Pierri, Brendan Lanpher, Ayelet Erez, Elitsa A. Ananieva, Mohammad Islam, Juan C. Marini, Qin Sun, Chunli Yu, Madhuri Hegde, Jun Li, R. Max Wynn, David T. Chuang, Susan Hutson, Brendan Lee
+**Journal:** Human Molecular Genetics (2011)
+**DOI:** [10.1093/hmg/ddq507](https://doi.org/10.1093/hmg/ddq507)
+
+## Content

references_cache/DOI_10.1093_qjmed_hcae104.md

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+---
+reference_id: "DOI:10.1093/qjmed/hcae104"
+title: Genotypic and phenotypic spectrum of maple syrup urine disease in Zhejiang of China
+authors:
+- X Yang
+- R Yang
+- T Zhang
+- D J Tan
+- R Pan
+- Z Chen
+- D Wu
+- C Chen
+- Y Xu
+- L Zhang
+- X Li
+- Q Shu
+- L Hu
+journal: "QJM: An International Journal of Medicine"
+year: '2024'
+doi: 10.1093/qjmed/hcae104
+content_type: abstract_only
+---
+
+# Genotypic and phenotypic spectrum of maple syrup urine disease in Zhejiang of China
+**Authors:** X Yang, R Yang, T Zhang, D J Tan, R Pan, Z Chen, D Wu, C Chen, Y Xu, L Zhang, X Li, Q Shu, L Hu
+**Journal:** QJM: An International Journal of Medicine (2024)
+**DOI:** [10.1093/qjmed/hcae104](https://doi.org/10.1093/qjmed/hcae104)
+
+## Content
+
+Abstract
+
+Background
+Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder originating from defects in the branched-chain α-ketoacid dehydrogenase (BCKDH) complex encoded by BCKDHA, BCKDHB and DBT. This condition presents a spectrum of symptoms and potentially fatal outcomes. Although numerous mutations in the BCKDH complex genes associated with MSUD have been identified, the relationship between specific genotypes remains to be fully elucidated.
+
+
+Aim
+Our objective was to predict the pathogenicity of these genetic mutations and establish potential links between genotypic alterations and the clinical phenotypes of MSUD.
+
+
+Design
+Retrospective population-based cohort.
+
+
+Methods
+We analyzed 20 MSUD patients from the Children’s Hospital at Zhejiang University School of Medicine (Hangzhou, China), recorded from January 2010 to December 2023. Patients’ blood samples were collected by heel-stick through neonatal screening, and amino acid profiles were measured by tandem mass spectrometry. In silico methods were employed to assess the pathogenicity, stability and biophysical properties. Various computation tools were utilized for assessment, namely PredictSNP, MAGPIE, iStable, Align GVGD, ConSurf and SNP effect.
+
+
+Results
+We detected 25 distinct mutations, including 12 novel mutations. The BCKDHB gene was the most commonly affected (53.3%) compared to the BCKDHA gene (20.0%) and DBT gene (26.7%). In silico webservers predicted all novel mutations were disease-causing.
+
+
+Conclusions
+This study highlights the genetic complexity of MSUD and underscores the importance of early detection and intervention. Integrating neonatal screening with advanced sequencing methodologies is pivotal in ensuring precise diagnosis and effective management of MSUD, thereby significantly improving the prognosis for individuals afflicted with this condition.

references_cache/DOI_10.1101_2023.07.31.551364.md

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+---
+reference_id: "DOI:10.1101/2023.07.31.551364"
+title: Reactive nitrogen species inhibit branched chain alpha-ketoacid dehydrogenase complex and impact muscle cell metabolism
+authors:
+- Nicholas L. Arp
+- Gretchen Seim
+- Jordyn Josephson
+- Jing Fan
+year: '2023'
+doi: 10.1101/2023.07.31.551364
+content_type: abstract_only
+---
+
+# Reactive nitrogen species inhibit branched chain alpha-ketoacid dehydrogenase complex and impact muscle cell metabolism
+**Authors:** Nicholas L. Arp, Gretchen Seim, Jordyn Josephson, Jing Fan
+**DOI:** [10.1101/2023.07.31.551364](https://doi.org/10.1101/2023.07.31.551364)
+
+## Content
+
+Abstract
+Branched chain α-ketoacid dehydrogenase complex (BCKDC) is the rate limiting enzyme in branched chain amino acid (BCAA) catabolism, a metabolic pathway with great importance for human health. BCKDC belongs to the mitochondrial α-ketoacid dehydrogenase complex family, which also includes pyruvate dehydrogenase complex (PDHC) and oxoglutarate dehydrogenase complex (OGDC). Here we revealed that BCKDC can be substantially inhibited by reactive nitrogen species (RNS) via a mechanism similar to what we recently discovered with PDHC and OGDC — modifying the lipoic arm on its E2 subunit. In addition, we showed that such reaction between RNS and the lipoic arm of the E2 subunit can further promote inhibition of the E3 subunits of α-ketoacid dehydrogenase complexes. We examined the impacts of this RNS-mediated BCKDC inhibition in muscle cells, an important site of BCAA metabolism, and demonstrated that the nitric oxide production induced by cytokine stimulation leads to a strong inhibition of BCKDC activity and BCAA oxidation in myotubes and myoblasts. More broadly, nitric oxide production reduced the level of functional lipoic arms across the multiple α-ketoacid dehydrogenases and led to intracellular accumulation of their substrates (α-ketoacids), reduction of their products (acyl-CoAs), and a lower cellular energy charge. This work revealed a new mechanism for BCKDC regulation, demonstrated its biological significance, and elucidated the mechanistic connection between RNS-driven inhibitory modifications on the E2 and E3 subunits of α-ketoacid dehydrogenases. Together with previous work, we revealed a general mechanism for RNS to inhibit all α-ketoacid dehydrogenases, which has numerous physiological implications across multiple cell types.

references_cache/DOI_10.1172_jci67217.md

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+---
+reference_id: "DOI:10.1172/jci67217"
+title: Biochemical correlates of neuropsychiatric illness in maple syrup urine disease
+authors:
+- Emilie R. Muelly
+- Gregory J. Moore
+- Scott C. Bunce
+- Julie Mack
+- Don C. Bigler
+- D. Holmes Morton
+- Kevin A. Strauss
+journal: Journal of Clinical Investigation
+year: '2013'
+doi: 10.1172/jci67217
+content_type: unavailable
+---
+
+# Biochemical correlates of neuropsychiatric illness in maple syrup urine disease
+**Authors:** Emilie R. Muelly, Gregory J. Moore, Scott C. Bunce, Julie Mack, Don C. Bigler, D. Holmes Morton, Kevin A. Strauss
+**Journal:** Journal of Clinical Investigation (2013)
+**DOI:** [10.1172/jci67217](https://doi.org/10.1172/jci67217)
+
+## Content

references_cache/DOI_10.1186_s12887-024-05266-0.md

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+---
+reference_id: "DOI:10.1186/s12887-024-05266-0"
+title: "Maple syrup urine disease diagnosed in a resource-limited setting in an infant in Nepal: a case report"
+authors:
+- Sujata Baidya
+- June Thapa
+- Anuradha Kadel
+- Nikita Kharal
+- Machhindra Lamichhane
+- Raju Kumar Dubey
+- Mithileshwer Raut
+- Aseem Bhattarai
+- Eans Tara Tuladhar
+- Vijay Kumar Sharma
+- Apeksha Niraula
+journal: BMC Pediatrics
+year: '2024'
+doi: 10.1186/s12887-024-05266-0
+content_type: unavailable
+---
+
+# Maple syrup urine disease diagnosed in a resource-limited setting in an infant in Nepal: a case report
+**Authors:** Sujata Baidya, June Thapa, Anuradha Kadel, Nikita Kharal, Machhindra Lamichhane, Raju Kumar Dubey, Mithileshwer Raut, Aseem Bhattarai, Eans Tara Tuladhar, Vijay Kumar Sharma, Apeksha Niraula
+**Journal:** BMC Pediatrics (2024)
+**DOI:** [10.1186/s12887-024-05266-0](https://doi.org/10.1186/s12887-024-05266-0)
+
+## Content