Twenty novel mutations in BCKDHA , BCKDHB and DBT genes in a cohort of 52 Saudi Arabian patients with maple syrup urine disease

Imtiaz, Faiqa; Al-Mostafa, Abeer; Allam, Rabab; Ramzan, Khushnooda; Tassan, Nada Al; Tahir, Asma; Al‐Numair, Nouf S.; Al‐Hamed, Mohamed H.; Al‐Hassnan, Zuhair N.; Alzaidan, Hamad; Al-Amoudi, Mohammad; Qari, Alya; Balobaid, Ameera; Al-Sayed, Moeenaldeen

doi:10.1016/j.ymgmr.2017.03.006

Cited by 20 publications

(19 citation statements)

References 17 publications

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“…One would suspect that affected individuals in Kuwait have several of the Arabian Peninsula founder mutations. Some of the more commonly reported mutations include: PCCA : p.G117D, p.V681_A706del26, PCCB : p.E331*, p.C381Y [ 19 ], MUT : p.R93H, p.Q37*, p.Y110C, p.Q734* [ 20 ], MSUD: BCKDHA p.N302A, BCKDHB : p.M1?, p.G66R, pT273P, p.G335D, p.G336S [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Incidence of maple syrup urine disease, propionic acidemia, and methylmalonic aciduria from newborn screening data

Gramer

Viall

Summar

2018

Molecular Genetics and Metabolism Reports

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Incidence for the branched-chain intoxication-type disorders, maple syrup urine disease, propionic acidemia and methlymalonic aciduria is dependent on the population screened. Here newborn screening results from three world regions, state screening laboratories in the United States, a region in Germany and Kuwait provides new incidence numbers. Maple syrup urine disease incidence in the United States was calculated to be 1: 220219, in South-West Germany 1: 119573 (Germany nationwide 1:177978), and in Kuwait 1: 59426. Incidence of propionic acidemia alone is calculated to be 1: 242741 in the United States, 1: 284450 in South-West Germany (Germany nationwide 1:202617) and 1:59426 in Kuwait. Incidence of isolated methylmalonic aciduria alone is 1:69354 in the United States, 1:568901 in South-West Germany (Germany nationwide 1:159199) and 1: 19809 in Kuwait. In the United States several newborn screening laboratories combine their results for propionic acidemia and methylmalonic aciduria, and also include combined remethylation disorders in the respective category, resulting in an incidence of 1:50709. Combined evaluation of methylmalonic aciduria, propionic aciduria and combined remethylation disorders results in a similar incidence for Germany of 1:67539. This evaluation of newborn screening incidences reflects some population differences for three intoxication-type metabolic disorders. However, different sample sizes of the populations screened over different time periods, and differences in case definitions for methylmalonic acidurias have to be considered when interpreting these data.

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Section: Discussionmentioning

confidence: 99%

Incidence of maple syrup urine disease, propionic acidemia, and methylmalonic aciduria from newborn screening data

Gramer

Viall

Summar

2018

Molecular Genetics and Metabolism Reports

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“…For another missense mutation, c.818C>T (p.T273I), although it was found in gnomAD database, but it was not detected in homozygous state and the alleles frequency was very low (MAF <1/10,000). Furthermore, a homozygous missense mutation at the same position (p.T273P) has previously been reported in Saudi Arabia patient with intermediate phenotype [ 35 ]. Therefore, this variant can also be considered as a rare in the general population.…”

Section: Discussionmentioning

confidence: 99%

Fourteen new mutations of BCKDHA, BCKDHB and DBT genes associated with maple syrup urine disease (MSUD) in Malaysian population

Ali

Ngu

2018

Molecular Genetics and Metabolism Reports

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Maple syrup urine disease (MSUD) is a rare autosomal recessive metabolic disorder. This disorder is usually caused by mutations in any one of the genes; BCKDHA, BCKDHB and DBT, which represent E1α, E1β and E2 subunits of the branched-chain α-keto acid dehydrogenase (BCKDH) complex, respectively. This study presents the molecular characterization of 31 MSUD patients. Twenty one mutations including 14 new mutations were identified. The BCKDHB gene was the most commonly affected (45.2%) compared to BCKDHA gene (16.1%) and DBT gene (38.7%). In silico webservers predicted all mutations were disease-causing. In addition, structural evaluation disclosed that all new missenses in BCKDHA, BCKDHB and DBT genes affected stability and formation of E1 and E2 subunits. Majority of the patients had neonatal onset MSUD (26 of 31). Meanwhile, the new mutation; c.1196C > G (p.S399C) in DBT gene was noted to be recurrent and found in 9 patients. Conclusion: Our findings have expanded the mutational spectrum of the MSUD and revealed the genetic heterogeneity among Malaysian MSUD patients. We also discovered the p.S399C from DBT gene was noted as a recurrent mutation in Malay community and it suggested the existence of common and unique mutation in Malay population.

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“…All pathogenic variants that have been identified are homozygous or compound heterozygous variants within the same gene. 33 – 35 Genetic testing is essential for a clinical diagnosis of MSUD and to determine which subunit is deficient, which may be helpful in the future for determining individualized therapies. 36 , 37 …”

Section: Medical Managementmentioning

confidence: 99%

Maple syrup urine disease: mechanisms and management

Blackburn¹,

Gass

Vairo³

et al. 2017

TACG

191

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Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by defects in the branched-chain α-ketoacid dehydrogenase complex, which results in elevations of the branched-chain amino acids (BCAAs) in plasma, α-ketoacids in urine, and production of the pathognomonic disease marker, alloisoleucine. The disorder varies in severity and the clinical spectrum is quite broad with five recognized clinical variants that have no known association with genotype. The classic presentation occurs in the neonatal period with developmental delay, failure to thrive, feeding difficulties, and maple syrup odor in the cerumen and urine, and can lead to irreversible neurological complications, including stereotypical movements, metabolic decompensation, and death if left untreated. Treatment consists of dietary restriction of BCAAs and close metabolic monitoring. Clinical outcomes are generally good in patients where treatment is initiated early. Newborn screening for MSUD is now commonplace in the United States and is included on the Recommended Uniform Screening Panel (RUSP). We review this disorder including its presentation, screening and clinical diagnosis, treatment, and other relevant aspects pertaining to the care of patients.

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Twenty novel mutations in BCKDHA , BCKDHB and DBT genes in a cohort of 52 Saudi Arabian patients with maple syrup urine disease

Cited by 20 publications

References 17 publications

Incidence of maple syrup urine disease, propionic acidemia, and methylmalonic aciduria from newborn screening data

Incidence of maple syrup urine disease, propionic acidemia, and methylmalonic aciduria from newborn screening data

Fourteen new mutations of BCKDHA, BCKDHB and DBT genes associated with maple syrup urine disease (MSUD) in Malaysian population

Maple syrup urine disease: mechanisms and management

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