Newborn screening for homocystinurias: recent recommendations versus current practice

Keller, Reinhold; Chrastina, Petr; Pavlı́ková, Markéta; Gouveia, Sofía; Ribes, Antònia; Kölker, Stefan; Blom, Henk J.; Baumgartner, Matthias R.; Bártl, Josef; Vici, C. Dionisi; Gleich, Florian; Morris, Andrew A. M.; Kožich, Viktor; Huemer, Martina; Barić, Ivo; Ben‐Omran, Tawfeq; Blasco‐Alonso, Javier; Delgado, María Andrea; Carducci, Claudia; Cassanello, Michela; Cerone, R.; Couce, María L.; Crushell, Ellen; Pecellín, Carmen Delgado; Dulín, Elena; Espada, Mercedes; Ferino, Giulio; Fingerhut, Ralph; Jiménez, Inmaculada García; González‐Irazabal, Yolanda; Gramer, Gwendolyn; Fita, María Jesús Juan; Karg, Eszter; Klein, Jeanette; Konstantopoulou, Vassiliki; Marca, Giancarlo la; Leão‐Teles, Elisa; Leuzzi, Vincenzo; Lilliu, Franco; López, Rosa María; Lund, Allan Meldgaard; Mayne, Philip; Meavilla, Silvia; Moat, Stuart; Okun, Jürgen G.; Pasquini, Elisa; Pedrón‐Giner, Consuelo; Rácz, Gábor; Gómez, María Ángeles Ruiz; Vilarinho, Laura; Yahyaoui, Raquel; Tansek, Moja Zerjav; Zetterström, Rolf; Zeyda, Maximilian

doi:10.1007/s10545-018-0213-0

Cited by 3 publications

(17 citation statements)

References 28 publications

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“…A relevant finding of our study was the observation that the four children identified by NBS were the only ones with a DQ within normal range, with a normal brain MRI and lacking epilepsy. This supports previous studies suggesting that an early diagnosis using NBS can allow a better outcome, as it reduces the exposition to offending metabolites and prevents the occurrence of major disease‐related events (eg, hydrocephalus, hemolytic uremic syndrome, pulmonary hypertension) that greatly contribute to long‐term disabilities in cblC defect. It is of interest that children with symptomatic diagnosis in the neonatal age, who had a relatively short exposure to toxic metabolites, still had a lower level of development in all examined abilities when compared to those identified by NBS.…”

Section: Discussionsupporting

confidence: 90%

Early neurodevelopmental characterization in children with cobalamin C/defect

Ricci

Martinelli

Ferrantini

et al. 2020

J of Inher Metab Disea

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Cobalamin C (cblC) defect is the most common inherited disorder of cobalamin metabolism. Developmental delay, behavioral problems, and maculopathy are common, but they have not been systematically investigated. The aim of this study was to define early neurodevelopment in cblC patients and the possible contribution of different factors, such as mode of diagnosis, age at diagnosis, presence of brain lesions and epilepsy. Children up to the age of 4 years with a visual acuity ≥1/10 were evaluated using the Griffiths' Mental Development Scales. Eighteen children were enrolled (age range 12‐48 months). Four were diagnosed by newborn screening (NBS); in the others mean age at diagnosis was 3.5 months (range 0.3‐18 months). Eight had seizures: three in the first year, and five after the second year of life. Fourteen had brain lesions on magnetic resonance imaging (MRI). Neurovisual assessment evidenced low visual acuity (<3/10) in 4/18. NBS diagnosed patients had higher general and subquotients neurodevelopmental scores, normal brain MRI, and no epilepsy. The others showed a progressive reduction of the developmental quotient with age and language impairment, which was evident after 24 months of age. Our findings showed a progressive neurodevelopmental deterioration and a specific fall in language development after 24 months in cblC defect. The presence of brain lesions and epilepsy was associated with a worst neurodevelopmental outcome. NBS, avoiding major disease‐related events and allowing an earlier treatment initiation, appeared to have a protective effect on the development of brain lesions and to promote a more favorable neurodevelopment.

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Section: Discussionsupporting

confidence: 90%

Early neurodevelopmental characterization in children with cobalamin C/defect

Ricci

Martinelli

Ferrantini

et al. 2020

J of Inher Metab Disea

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“…It is known that patients with milder forms of inborn errors of Cbl metabolism have been missed by similar screening approaches and so most likely, not all clinically relevant cases of maternal Cbl deficiency in the neonate will be detectable using this algorithm. The post‐analytical tools offered by the Collaborative Laboratory Integrated Reports project seem promising for a general improvement of newborn screening for remethylation disorders.…”

Section: Acquired Cbl Deficienciesmentioning

confidence: 99%

“…Gramer et al proposed second tier Hcy measurement in dried blood spots when first tier testing is abnormal and concluded that neonates with severe Cbl deprivation can be detected without causing unreasonable costs or recall rates 11 . It is known that patients with milder forms of inborn errors of Cbl metabolism have been missed by similar screening approaches 30 and so most likely, not all clinically relevant cases of maternal Cbl deficiency in the neonate will be detectable using this algorithm. The post-analytical tools offered by the Collaborative Laboratory Integrated Reports project seem promising for a general improvement of newborn screening for remethylation disorders 30,31 .…”

Section: Acquired Cbl Deficiencies: Background and Clinical Presentmentioning

confidence: 99%

“…The dose of parenteral OH-Cbl required to keep MMA concentrations in the targeted range needs to be adjusted individually. In selected cases, parenteral OH-Cbl may in part or even completely be replaced by oral Cbl preparations 62 ( (123) μmol/l in Cbl-dependent remethylation disorders and even higher (mean 182 ± 91; median 179 μmol/L) in MTHFR deficiency 71 . In MTHFD1 deficiency normal or moderately elevated (up to 50 μmol/L) tHcy concentrations have been observed 6 .…”

Section: Isolated Cbl-dependent Methylmalonic Acidurias: Treatment mentioning

confidence: 99%

“…Current knowledge, based on the small number of reported cases, suggests that the clinical patterns of cblF and cblJ disease are very similar. Feeding problems and failure to thrive often with onset in the first year accompanied by developmental delay, macrocytic anemia and in single cases pancytopenia, respiratory failure, congenital heart defects and progressive hyperpigmentation or stomatitis have been reported 71,75,81,82 .…”

Section: The Cblf Cblj and Combined Cbld-mmahcy Defectsmentioning

confidence: 99%

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The clinical presentation of cobalamin‐related disorders: From acquired deficiencies to inborn errors of absorption and intracellular pathways

Huemer

Baumgartner

2019

J of Inher Metab Disea

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This review gives an overview of clinical characteristics, treatment and outcome of nutritional and acquired cobalamin (Cbl; synonym: vitamin B12) deficiencies, inborn errors of Cbl absorption and intracellular trafficking, as well as methylenetetrahydrofolate dehydrogenase (MTHFD1) and methylene tetrahydrofolate reductase (MTHFR) deficiencies, which impair Cbl‐dependent remethylation. Acquired and inborn Cbl‐related disorders and MTHFR deficiency cause multisystem, often severe disease. Failure to thrive, neurocognitive or psychiatric symptoms, eye disease, bone marrow alterations, microangiopathy and thromboembolic events are characteristic. The recently identified MTHFD1 defect additionally presents with severe immune deficiency. Deficient Cbl‐dependent enzymes cause reduced methylation capacity and metabolite toxicity. Further net‐effects of perturbed Cbl function or reduced Cbl supply causing oxidative stress, altered cytokine regulation or immune functions are discussed.

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A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase

Sun

Verby

Coté

et al. 2018

Preprint

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Success in precision medicine depends on our ability to determine which rare human genetic variants have functional effects. Classical homocystinuria-characterized by elevated homocyst(e)ine in plasma and urine-is caused by primarily-rare variants in the cystathionine beta-synthase (CBS) gene. About half of patients respond to vitamin B6 therapy. With early detection in newborns, existing therapies are highly effective. Functional CBS variants, especially those that respond to vitamin B6, can be detected based on their ability to restore growth in yeast cells lacking CYS4 (the yeast ortholog of CBS). This assay has previously been carried out only 'reactively' after first observation of a variant in patients. Here we describe a 'proactive' comprehensive missense variant effect map for human CBS. Together, saturation codon-replacement mutagenesis, en masse growth selection at different vitamin B6 levels, and sequencing yielded a 'look-up table' for CBS missense variant function and vitamin B6-remediability in yeast. The CBS variant effect map identified disease variants and predicted both disease severity (r = 0.82) and human clinical response to vitamin B6 (r = 0.89). Thus, highly-multiplexed cell-based assays can yield proactive maps of variant function and patient response to therapy, even for rare variants not previously seen in the clinic.

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Newborn screening for homocystinurias: recent recommendations versus current practice

Cited by 3 publications

References 28 publications

Early neurodevelopmental characterization in children with cobalamin C/defect

Early neurodevelopmental characterization in children with cobalamin C/defect

The clinical presentation of cobalamin‐related disorders: From acquired deficiencies to inborn errors of absorption and intracellular pathways

A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase

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