Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes

Strauss, Kevin A.; Carson, Vincent J; Soltys, Kyle; Young, Millie; Bowser, Lauren E.; Puffenberger, Erik G.; Brigatti, Karlla W.; Williams, Katie B; Robinson, Donna L.; Hendrickson, Christine; Beiler, Keturah; Taylor, Cora; Haas‐Givler, Barbara; Chopko, Stephanie A.; Hailey, Jennifer; Muelly, Emilie; Shellmer, Diana A.; Radcliff, Zachary; Rodrigues, Ashlin S.; Loeven, KaLynn K.; Heaps, Adam D.; Mazariegos, George; Morton, D. Holmes

doi:10.1016/j.ymgme.2020.01.006

Cited by 112 publications

(133 citation statements)

References 49 publications

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“…MSUD arises from biallelic loss of function mutations in one of the genes that encode BCKDC subunits. Decreased BCKDC activity results in the failure of BCKAs to be oxidized into their respective end products, leading to an accumulation of BCAAs and BCKAs [ 5 ]. Due to BCAA and BCKA elevations, patients with MSUD can demonstrate acute severe ketoacidosis and neurological symptoms such as apnea, seizures, and coma as well as chronic features such as poor feeding, ataxia, motor delay, and intellectual disability due to amino acid and neurotransmitter imbalances [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, it is unclear how diet therapy affects the biochemistry of the CNS. Patients treated in this manner may still manifest a high burden of neuropsychological symptoms [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…Liver transplantation aims to replace functional BCKDCs in the liver and to thus promote BCAA metabolism in peripheral tissue [ 7 ]. A recent study demonstrated that transplants can restore homeostasis and may arrest neurocognitive effects [ 5 ]. Unfortunately, liver transplantation was not found to improve preexisting impairments and patients are susceptible to postoperative complications and require long-term immunosuppression [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

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Brain Branched-Chain Amino Acids in Maple Syrup Urine Disease: Implications for Neurological Disorders

Jakher

Ahrens‐Nicklas

2020

IJMS

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Maple syrup urine disease (MSUD) is an autosomal recessive disorder caused by decreased activity of the branched-chain α-ketoacid dehydrogenase complex (BCKDC), which catalyzes the irreversible catabolism of branched-chain amino acids (BCAAs). Current management of this BCAA dyshomeostasis consists of dietary restriction of BCAAs and liver transplantation, which aims to partially restore functional BCKDC activity in the periphery. These treatments improve the circulating levels of BCAAs and significantly increase survival rates in MSUD patients. However, significant cognitive and psychiatric morbidities remain. Specifically, patients are at a higher lifetime risk for cognitive impairments, mood and anxiety disorders (depression, anxiety, and panic disorder), and attention deficit disorder. Recent literature suggests that the neurological sequelae may be due to the brain-specific roles of BCAAs. This review will focus on the derangements of BCAAs observed in the brain of MSUD patients and will explore the potential mechanisms driving neurologic dysfunction. Finally, we will discuss recent evidence that implicates the relevance of BCAA metabolism in other neurological disorders. An understanding of the role of BCAAs in the central nervous system may facilitate future identification of novel therapeutic approaches in MSUD and a broad range of neurological disorders.

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Section: Introductionmentioning

confidence: 99%

“…However, it is unclear how diet therapy affects the biochemistry of the CNS. Patients treated in this manner may still manifest a high burden of neuropsychological symptoms [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Brain Branched-Chain Amino Acids in Maple Syrup Urine Disease: Implications for Neurological Disorders

Jakher

Ahrens‐Nicklas

2020

IJMS

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“…The leucine levels at diagnosis were high and are, in the majority of the studied patients, considered critical, and can produce irreversible damage or even death of the patient (30). Leucine can increase rapidly during catabolic states, altering brain chemistry by competing with nine other amino acids for entry into the brain via the facilitative SLC7A5 transporter (37). Branched-chain amino acid transaminase (BCAT1) catalyzes the formation of α-ketoisocaproic acid (αKIC) from leucine and α-ketoglutarate (αKG); αKIC enters brain (via the monocarboxylate transporter) and is neurotoxic at high concentrations (37).…”

Section: Discussionmentioning

confidence: 98%

“…Leucine can increase rapidly during catabolic states, altering brain chemistry by competing with nine other amino acids for entry into the brain via the facilitative SLC7A5 transporter (37). Branched-chain amino acid transaminase (BCAT1) catalyzes the formation of α-ketoisocaproic acid (αKIC) from leucine and α-ketoglutarate (αKG); αKIC enters brain (via the monocarboxylate transporter) and is neurotoxic at high concentrations (37). Elevated tissue αKIC reverses normal ow through BCAT1, depletes tissues of glutamate (a substrate for glutamine and γ-aminobutyric acid -GABA), and indirectly drives ux through glutamate-pyruvate transaminase to form pyruvate from αKG and alanine (37).…”

Section: Discussionmentioning

confidence: 99%

Maple Syrup Urine Disease in Brazilian Patients: Variants and Clinical Phenotype Heterogeneity

Margutti

Silva

Garcia

et al. 2020

Preprint

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Background: Maple syrup urine disease (MSUD) is an autosomal recessive inherited metabolic disease caused by deficient activity of the branched-chain α-keto acid dehydrogenase (BCKD) enzymatic complex. BCKD is a mitochondrial complex encoded by BCKDHA, BCKDHB, DBT, and DLD genes. MSUD is predominantly caused by Variants in BCKDHA, BCKDHB, and DBT genes encoding the E1α, E1β, and E2 subunits of BCKD complex, respectively. The aim of this study was to characterize the genetic basis of MSUD by identifying the point variants in BCKDHA, BCKDHB, and DBT genes in a cohort of Brazilian MSUD patients and to describe their phenotypic heterogeneity. It is a descriptive cross-sectional study with 21 MSUD patients involving molecular genotyping by Sanger sequencing. Results: Eight new variants predicted as pathogenic were found between 30 variants (damaging and non-damaging) identified in the 21 patients analyzed: one in the BCKDHA gene (p.Tyr120Ter); five in the BCKDHB gene (p.Gly131Val, p.Glu146Glnfs*13, p.Phe149Cysfs*9, p.Cys207Phe, and p.Lys211Asn); and two in the DBT gene (p.Glu148Ter and p.Glu417Val). Seventeen pathogenic variants were previously described and five variants showed no pathogenicity according to in silico analysis. Conclusion: Given that most of the patients received late diagnoses, the study results do not allow us to state that the molecular features of MSUD variant phenotypes are predictive of clinical severity.

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The burden of pathogenic variants in clinically actionable genes in a founder population

Lynch

Maloney

Pollin

et al. 2021

American J of Med Genetics Pt A

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Founder populations may be enriched with certain genetic variants of high clinical impact compared to nonfounder populations due to bottleneck events and genetic drift. Using exome sequencing (ES), we quantified the load of pathogenic variants that may be clinically actionable in 6136 apparently healthy adults living in the Lancaster, PA Old Order Amish settlement. We focused on variants in 78 genes deemed clinically actionable by the American College of Medical Genetics and Genomics (ACMG) or Geisinger's MyCode Health Initiative. ES revealed 3191 total variants among these genes including 480 nonsynonymous variants. After quality control and filtering, we applied the ACMG/AMP guidelines for variant interpretation and classified seven variants, across seven genes, as either pathogenic or likely pathogenic. Through genetic drift, all seven variants, are highly enriched in the Amish compared to nonfounder populations. In total, 14.7% of Lancaster Amish individuals carry at least one of these variants, largely explained by the 13% who harbor a copy of a single variant in APOB. Other studies report combined frequencies of pathogenic/likely pathogenic (P/LP) variants in actionable genes between 2.0% and 6.2% in outbred populations. The Amish population harbors fewer actionable variants compared to similarly characterized nonfounder populations but have a higher frequency of each variant identified, offering opportunities for efficient and cost‐effective targeted precision medicine.

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Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes

Cited by 112 publications

References 49 publications

Brain Branched-Chain Amino Acids in Maple Syrup Urine Disease: Implications for Neurological Disorders

Brain Branched-Chain Amino Acids in Maple Syrup Urine Disease: Implications for Neurological Disorders

Maple Syrup Urine Disease in Brazilian Patients: Variants and Clinical Phenotype Heterogeneity

The burden of pathogenic variants in clinically actionable genes in a founder population

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