Neurocognitive profiles in MSUD school‐age patients

Bouchereau, Juliette; Leduc-Leballeur, Julie; Pichard, Samia; Imbard, Apolline; Benoist, Jean‐François; Wardé, Marie‐Thérèse Abi; Arnoux, Jean‐Baptiste; Barbier, Valérie; Brassier, Anaïs; Broué, Pierre; Cano, Aline; Chabrol, B.; Damon, G; Guillain, Isabelle; Habarou, Florence; Lamireau, Delphine; Ottolenghi, Chris; Paermentier, Laetitia; Sabourdy, Frédérique; Touati, Guy; Baulny, Hélène Ogier de; Lonlay, Pascale de; Schiff, Manuel

doi:10.1007/s10545-017-0033-7

Cited by 17 publications

(8 citation statements)

References 35 publications

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“…19 In our study, we tested the overall IQ ability (FSIQ). A French study by Bouchereau et al 42 found that some of their group of MSUD patients had verbal abilities that were significantly better developed than their nonverbal/performance skills. Future studies in our own centre would favour early testing of our MSUD cohort to detect any similar issues.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…Moreover, liver transplantation is an effective treatment, which may reduce the progression of brain damage; however, liver transplantation is not sufficient to reverse pre-existing neurological damages (32). Therefore, early treatment of MSUD is essential to allow normal neuronal development (33).…”

Section: Discussionmentioning

confidence: 99%

Paroxysmal spasticity of lower extremities as the initial symptom in two siblings with maple syrup urine disease

et al. 2019

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Maple syrup urine disease (MSUD) is a rare autosomal recessive metabolic disorder caused by mutations in genes that encode subunits of the branched-chain α-ketoacid dehydrogenase (BCKD) complex. Impairment of the BCKD complex results in an abnormal accumulation of branched-chain amino acids and their corresponding branched-chain keto acids in the blood and cerebrospinal fluid, which are neurovirulent and may become life-threatening. An 11-day-old boy was admitted to the hospital with paroxysmal spasticity of lower extremities. Of note, his 10-year-old sister presented similar symptoms during the neonatal period, and her condition was diagnosed as MSUD when she was 1.5 years old. Genetic screening was performed, and the boy and his sister exhibited two novel compound heterozygous mutations in the branched chain keto acid dehydrogenase E1 subunit β (BCKDHB) gene: A substitution from guanine to adenine in the coding region at position 1,076 (c.1,076G>A) in exon 10 and a deletion of a thymine at position 705 (c.705delT) in exon 6. The missense mutation c.1076G>A results in an amino acid substitution from arginine to lysine at position 359 (p.Arg359Lys), whereas the mutation c.705delT results in the replacement of a cysteine at position 235 with a stop codon (p.Cys235Ter). Neither of the BCKDHB alleles in the compound heterozygote patients is able to generate normal E1β subunits, resulting in a possible impairment of the activity of the BCKD complex. In the present study, it was hypothesized that the two novel heterozygous mutations in the BCKDHB gene found in the Chinese family may be responsible for the phenotype of the two siblings with MSUD.

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“…Such treatment is difficult to maintain in the long term and is largely incompatible with a normal quality of life. Further, it does not prevent long-term neurocognitive 5 and psychiatric impairments 6 , the latter affecting roughly 30% of the patients after the age of 20 years 6 . Orthotopic liver transplantation (OLT), was shown as an effective MSUD therapy allowing removal of dietary restrictions, full protection from acute decompensations during illness 7 , 8 , arrest of neurocognitive impairment progression 3 , 9 , prevention of life-threatening cerebral edema 3 , metabolic and clinical stability 9 .…”

Section: Introductionmentioning

confidence: 99%

Neonatal gene therapy achieves sustained disease rescue of maple syrup urine disease in mice

et al. 2022

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Maple 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.

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Neurocognitive profiles in MSUD school‐age patients

Cited by 17 publications

References 35 publications

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

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

Paroxysmal spasticity of lower extremities as the initial symptom in two siblings with maple syrup urine disease

Neonatal gene therapy achieves sustained disease rescue of maple syrup urine disease in mice

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