Molecular basis of intermittent maple syrup urine disease: novel mutations in the E2 gene of the branched-chain α-keto acid dehydrogenase complex

Abstract Objectives To report two novel mutations in the BCKDHB gene with Maple syrup urine disease (MSUD) and compare their data with 52 cases of MSUD reported in the available Chinese literature. Methods Clinical data of a case of a newborn with MSUD was retrospectively studied. Literatures on MSUD in the local medical journals from January 1990 till December 2019 in China were reviewed. Results Two novel BCKDHB mutations c.90_91insCTGGCGCGGGG (p.Phe35TrpfsTer41) and c.80_90del (p.Ala32PhefsTer48) were identified. We found a total of 52 cases of MSUD reports so far. A total of 49 cases had the symptom of poor feeding (94.2%), 50 cases showed poor responses to stimulation (96.2%), 21 cases had odor of maple syrup (40.3%), 29 cases had seizures (55.7%), and 13 cases had respiratory failure (25.0%). The average of the blood ammonia was 127.2 ± 75.0 μmol/L. A total of 18 cases reported the gene testing, among of them 9 cases of BCKDHA mutations, 6 cases of BCKDHB mutations, and 2 cases of DBT mutations. A total of 13 cases (25%) were treated with mechanical ventilation, 50 cases (96.2%) with protein-restricted diet and l-carnitine, 29 cases with thiamine, and only 2 cases were treated with blood purification. Finally, 19 patients (36.5%) were died, 21 cases (40.4%) were improved after treatments. Conclusions The clinical phenotype of neonatal MSUD in China belongs to the classical type currently. Suspected patients should have blood or urine branched-chain amino acid levels tested and brain MRI as early as possible to enable early diagnosis, thus improvement in prognosis.

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Four novel mutations of the BCKDHA, BCKDHB and DBT genes in Iranian patients with maple syrup urine disease

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2017-0305 ◽

2018 ◽

Vol 31 (2) ◽

pp. 205-212 ◽

Cited By ~ 2

Author(s):

Monica Zeynalzadeh ◽

Alireza Tafazoli ◽

Azadeh Aarabi ◽

Morteza Moghaddassian ◽

Farah Ashrafzadeh ◽

...

Keyword(s):

Maple Syrup Urine Disease ◽

Energy Levels ◽

Clinical Manifestations ◽

Autosomal Recessive Disorder ◽

Strong Correlations ◽

Novel Mutations ◽

Maple Syrup ◽

Urine Disease ◽

Branched Chain ◽

Ketoacid Dehydrogenase

Abstract Background: Maple syrup urine disease (MSUD) is a rare metabolic autosomal recessive disorder caused by dysfunction of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex. Mutations in the BCKDHA, BCKDHB and DBT genes are responsible for MSUD. The current study analyzed seven Iranian MSUD patients genetically and explored probable correlations between their genotype and phenotype. Methods: The panel of genes, including BCKDHA, BCKDHB and DBT, was evaluated, using routine the polymerase chain reaction (PCR)-sequencing method. In addition, protein modeling (homology and threading modeling) of the deduced novel mutations was performed. The resulting structures were then analyzed, using state-of-the-art bioinformatics tools to better understand the structural and functional effects caused by mutations. Results: Seven mutations were detected in seven patients, including four novel pathogenic mutations in BCKDHA (c.1198delA, c.629C>T), BCKDHB (c.652C>T) and DBT (c.1150A>G) genes. Molecular modeling of the novel mutations revealed clear changes in the molecular energy levels and stereochemical traits of the modeled proteins, which may be indicative of strong correlations with the functional modifications of the genes. Structural deficiencies were compatible with the observed phenotypes. Conclusions: Any type of MSUD can show heterogeneous clinical manifestations in different ethnic groups. Comprehensive molecular investigations would be necessary for differential diagnosis.

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Branched Chain Amino Acids Induce Apoptosis in Neural Cells without Mitochondrial Membrane Depolarization or Cytochromec Release: Implications for Neurological Impairment Associated with Maple Syrup Urine Disease

Molecular Biology of the Cell ◽

10.1091/mbc.11.5.1919 ◽

2000 ◽

Vol 11 (5) ◽

pp. 1919-1932 ◽

Cited By ~ 82

Author(s):

Philippe Jouvet ◽

Pierre Rustin ◽

Deanna L. Taylor ◽

Jennifer M. Pocock ◽

Ursula Felderhoff-Mueser ◽

...

Keyword(s):

Amino Acids ◽

Cytochrome C ◽

Maple Syrup Urine Disease ◽

Mitochondrial Membrane ◽

Branched Chain Amino Acids ◽

Keto Acid ◽

Maple Syrup ◽

Mitochondrial Membrane Depolarization ◽

Urine Disease ◽

Branched Chain

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.

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