Genotype–phenotype correlation of 33 patients with maple syrup urine disease

Khalifa, Ola; Imtiaz, Faiqa; Ramzan, Khushnooda; Zaki, Osama K.; Gamal, Radwa; El-Baik, Lina; Rihan, Shaimaa; Salam, Ehab; Abdul-Mawgoud, Rehab; Hassan, Magdy M.; Hassan, Nahla S.; Saleh, Eman M.; Seoudi, Dina M.; Moustafa, Amr Soliman

doi:10.1002/ajmg.a.61806

Cited by 9 publications

(4 citation statements)

References 36 publications

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“…In terms of genetic variants detected, the proportion of patients with biallelic variants in BCKDHB is much larger than the reported in the Mennonite population (Strauss et al, 2020). Malaysian, Egyptian and Brazilian populations also show a predominance of biallelic variants in BCKDHB, being associated with 45-55% MSUD cases (Ali & Ngu, 2018;Khalifa et al, 2020;Margutti et al, 2020). Nevertheless, our population shows an even higher frequency of these variants.…”

Section: Discussioncontrasting

confidence: 61%

Maple syrup urine disease: Characteristics of diagnosis and treatment in 45 patients in Chile

Medina

Castro

Falcón

et al. 2021

American J of Med Genetics Pt C

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Maple urine syrup disease (MSUD) is an autosomal recessive disorder characterized by deficient activity of the branched-chain alpha ketoacid dehydrogenase (BCKAD) enzymatic complex due to biallelic variants in the alpha (BCKDHA) or beta (BCKDHB) subunits or the acyltransferase component (DBT). Treatment consists in leucine (LEU), isoleucine (ILE), and valine (VAL) (branched-chain amino acids) dietary restriction and strict metabolic control. to determine the characteristics of the Chilean cohort with MSUD currently in follow-up at Instituto de Nutrici on y Tecnología de los Alimentos, during the 1990-2017 period Retrospective analytical study in 45 MSUD cases. Measured: biochemical parameters (LEU, ILE, and VAL), anthropometric evaluation, and neurocognitive development. In 18 cases undergoing genetic study were analyzed according to the gene and protein location, number of affected alleles, and type of posttranslational modification affected. Then, 45 patients with MSUD diagnosis were identified during the period: 37 were alive at the time of the study. Average diagnosis age was 71 ± 231 days. Average serum diagnosis LEU concentrations: 1.463 ± 854.1 μmol/L, VAL 550 ± 598 μmol/L and ILE 454 ± 458 μmol/L. BCKDHB variants explain 89% cases, while BCKDHA and DBT variants explain 5.5% of cases each. Variants p.Thr338Ile in BCKDHA, p.Pro240Thr and p.Ser342Asn in BCKDHB have not been previously reported in literature. Average serum follow-up LEU concentrations were 252.7 ± 16.9 μmol/L in the <5 years group and 299 ± 123.2 μmol/L in ≥5 years. Most cases presented some degree of developmental delay. Early diagnosis and treatment is essential to improve the long-term prognosis. Frequent blood LEU measurements are required to optimize metabolic control and to establish relationships between different aspects analyzed.

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Section: Discussioncontrasting

confidence: 61%

Maple syrup urine disease: Characteristics of diagnosis and treatment in 45 patients in Chile

Medina

Castro

Falcón

et al. 2021

American J of Med Genetics Pt C

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“…Unlike other cohorts, such as the old order Mennonites and Filipino cohorts, the Irish cohort is genetically quite heterogeneous, including genotypes which had not been hitherto reported. Additionally when compared to other recent cohort studies conducted in Spain, Egypt and Brazil where a large burden of disease was attributable to consanguinity (22.7%‐88% of patients described), 19‐21 there was limited evidence of consanguinity, although one included family (n = 2) were of Irish‐Traveller descent which as previously described has a low level of genetic heterogeneity 22 …”

Section: Discussionmentioning

confidence: 72%

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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“…The clinical manifestations of patients with DBT gene variant are relatively mild, but in this study, two classical patients who carried DBT homozygous mutations, both with neonatal onset and death, were classic MUSD patients. A previous study reported that a classical patient with the c.1291C>T (p.R431*) homozygous mutation died at six months (Khalifa et al, 2020). The report indicated that another patient who carried the c.1291C>T (p.R431*) homozygous mutation was diagnosed four days after birth with feeding difficulties and seizure symptoms, diagnosed as MSUD (Abiri et al, 2019).…”

Section: Discussionmentioning

confidence: 98%

Identification of gene mutations in six Chinese patients with maple syrup urine disease

Mao²,

Yang³

et al. 2023

Front. Genet.

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Background: Maple syrup urine disease (MSUD) is a rare autosomal recessive amino acid metabolic disease. This study is to identify the pathogenic genetic factors of six cases of MUSD and evaluates the application value of high-throughput sequencing technology in the early diagnosis of MUSD.Methods: Clinical examination was carried out for patients and used blood tandem mass spectrometry (MS/MS), urine gas chromatography-mass spectrometry (GC/MS), and the application of high-throughput sequencing technology for detection. Validate candidate mutations by polymerase chain reaction (PCR)—Sanger sequencing technology. Bioinformatics software analyzed the variants’ pathogenicity. Using Swiss PDB Viewer software to predict the effect of mutation on the structure of BCKDHA and BCKDHB proteins.Result: A total of six MSUD patients were diagnosed, including four males and two females. Nine variants were found in three genes of six MSUD families by high-throughput sequencing, including four missense mutations: c.659C>T(p.A220V), c.818C>T(p.T273I), c.1134C>G(p.D378E), and c.1006G>A(p.G336S); two non-sense mutations: c.1291C>T(p.R431*) and c.331C>T(p.R111*); three deletion mutations: c.550delT (p.S184Pfs*46), c.718delC (p.P240Lfs*14), and c.795delG (p.N266Tfs*64). Sanger sequencing’s results were consistent with the high-throughput sequencing. The bioinformatics software revealed that the mutations were harmful, and the prediction results of Swiss PDB Viewer suggest that variation affects protein conformation.Conclusion: This study identified nine pathogenic variants in the BCKDHA, BCKDHB, and DBT genes in six MSUD families, including two novel pathogenic variants in the BCKDHB gene, which enriched the genetic mutational spectrum of the disease. High-throughput sequencing is essential for the MSUD’s differential diagnosis, early treatment, and prenatal diagnosis.

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Genotype–phenotype correlation of 33 patients with maple syrup urine disease

Cited by 9 publications

References 36 publications

Maple syrup urine disease: Characteristics of diagnosis and treatment in 45 patients in Chile

Maple syrup urine disease: Characteristics of diagnosis and treatment in 45 patients in Chile

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

Identification of gene mutations in six Chinese patients with maple syrup urine disease

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