Galactokinase deficiency: lessons from the GalNet registry.,Genetics in Medicine

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Galactokinase deficiency: lessons from the GalNet registry.
Genetics in Medicine ( IF 6.6 ) Pub Date : 2020-08-18 , DOI: 10.1038/s41436-020-00942-9
M Estela Rubio-Gozalbo ₁ , Britt Derks ₁ , Anibh Martin Das ₂ , Uta Meyer ₂ , Dorothea Möslinger ₃ , M Luz Couce ₄ , Aurélie Empain ₅ , Can Ficicioglu ₆ , Natalia Juliá Palacios ₇ , Mariela M De Los Santos De Pelegrin ₇ , Isabel A Rivera ₈ , Sabine Scholl-Bürgi ₉ , Annet M Bosch ₁₀ , David Cassiman ₁₁ , Didem Demirbas ₁₂ , Matthias Gautschi ₁₃ , Ina Knerr ₁₄ , Philippe Labrune _{15,

16} , Anastasia Skouma ₁₇ , Patrick Verloo ₁₈ , Saskia B Wortmann _{19,

20} , Eileen P Treacy ₂₁ , David J Timson ₂₂ , Gerard T Berry ₁₂

Affiliation

Department of Pediatrics and Clinical Genetics, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
Clinic for Paediatric Kidney-, Liver- and Metabolic Diseases, Hannover, Germany.
Department for Pediatrics and Adolescent Medicine, Inborn Errors of Metabolism, Medical University of Vienna, Vienna, Austria.
Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, S. Neonatology, Department of Pediatrics, University and Hospital Clínico Universitario de Santiago de Compostela, CIBERER, Health Research Institute of Santiago de Compostela (IDIS), MetabERN: European Reference Network for Rare Hereditary Metabolic Disorders, Santiago de Compostela, Spain.
Department of Pediatrics, Queen Fabiola Children's University Hospital, Metabolic Centre ULB-VUB, Brussels, Belgium.
Department of Metabolic Disease Program, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Metabolic Unit. Departments of Neurology and Gastroenterology-Nutrition. IPR (Institut Pediàtric de Recerca), CIBERER and MetabERN. Hospital Sant Joan de Déu, Barcelona, Spain.
Research Institute for Medicines (iMed.ULisboa), and Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
Department of Pediatrics, Medical University of Innsbruck, Innsbruck, Austria.
Amsterdam UMC, University of Amsterdam, Pediatric Metabolic Diseases, Emma Children's Hospital, Amsterdam, Netherlands.
Metabolic Center, Department of Gastroenterology-Hepatology, Leuven University Hospitals and KU Leuven, Leuven, Belgium.
Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Pediatrics and Institute of Clinical Chemistry, Inselspital, University Hospital Bern, Bern, Switzerland.
National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin, Ireland.
APHP, HUPS, Hôpital Antoine Béclère, Centre de Référence Maladies Héréditaires Hépatiques, Clamart, France.
Université Paris Sud-Paris Saclay, and INSERM U, Paris, France.
Institute of Child Health, Institouto Ygeias Paidiou (ICH), Thivon 1 & Papadiamantopoulou, Athens, Greece.
Division of Child Neurology and Metabolism, Department of Pediatrics, Ghent University Hospital, Ghent, Belgium.
University Children's Hospital, Parcelsus Medical University (PMU), Salzburg, Austria.
Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Amalia Children's Hospital, Radboudumc, Nijmegen, The Netherlands.
National Centre for Inherited Metabolic Disorders-Adult Services, Mater Misericordiae University Hospital, Dublin, Ireland.
School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, UK.

Purpose

Galactokinase (GALK1) deficiency is a rare hereditary galactose metabolism disorder. Beyond cataract, the phenotypic spectrum is questionable. Data from affected patients included in the Galactosemias Network registry were collected to better characterize the phenotype.

Methods

Observational study collecting medical data of 53 not previously reported GALK1 deficient patients from 17 centers in 11 countries from December 2014 to April 2020.

Results

Neonatal or childhood cataract was reported in 15 and 4 patients respectively. The occurrence of neonatal hypoglycemia and infection were comparable with the general population, whereas bleeding diathesis (8.1% versus 2.17–5.9%) and encephalopathy (3.9% versus 0.3%) were reported more often. Elevated transaminases were seen in 25.5%. Cognitive delay was reported in 5 patients. Urinary galactitol was elevated in all patients at diagnosis; five showed unexpected Gal-1-P increase. Most patients showed enzyme activities ≤1%. Eleven different genotypes were described, including six unpublished variants. The majority was homozygous for NM_000154.1:c.82C>A (p.Pro28Thr). Thirty-five patients were diagnosed following newborn screening, which was clearly beneficial.

Conclusion

The phenotype of GALK1 deficiency may include neonatal elevation of transaminases, bleeding diathesis, and encephalopathy in addition to cataract. Potential complications beyond the neonatal period are not systematically surveyed and a better delineation is needed.

中文翻译：

半乳糖激酶缺乏症：GalNet 注册表的经验教训。

目的

半乳糖激酶（GALK1）缺乏症是一种罕见的遗传性半乳糖代谢障碍。除了白内障，表型谱也值得怀疑。收集了来自半乳糖血症网络注册表中受影响患者的数据，以更好地表征表型。

方法

观察性研究收集了 2014 年 12 月至 2020 年 4 月期间来自 11 个国家的 17 个中心的 53 名先前未报告的 GALK1 缺陷患者的医学数据。

结果

分别有 15 名和 4 名患者报告了新生儿或儿童白内障。新生儿低血糖和感染的发生率与一般人群相当，而出血素质（8.1% 对 2.17-5.9%）和脑病（3.9% 对 0.3%）的报道较多。25.5% 的患者出现转氨酶升高。5 例患者报告认知延迟。诊断时所有患者的尿半乳糖醇均升高；五个显示出意外的 Gal-1-P 增加。大多数患者显示酶活性≤1%。描述了 11 种不同的基因型，包括 6 种未发表的变体。大多数是 NM_000154.1:c.82C>A (p.Pro28Thr) 的纯合子。新生儿筛查后诊断出 35 名患者，这显然是有益的。