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      International clinical guideline for the management of classical galactosemia: diagnosis, treatment, and follow-up

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          Classical galactosemia (CG) is an inborn error of galactose metabolism. Evidence-based guidelines for the treatment and follow-up of CG are currently lacking, and treatment and follow-up have been demonstrated to vary worldwide. To provide patients around the world the same state-of-the-art in care, members of The Galactosemia Network (GalNet) developed an evidence-based and internationally applicable guideline for the diagnosis, treatment, and follow-up of CG. The guideline was developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. A systematic review of the literature was performed, after key questions were formulated during an initial GalNet meeting. The first author and one of the working group experts conducted data-extraction. All experts were involved in data-extraction. Quality of the body of evidence was evaluated and recommendations were formulated. Whenever possible recommendations were evidence-based, if not they were based on expert opinion. Consensus was reached by multiple conference calls, consensus rounds via e-mail and a final consensus meeting. Recommendations addressing diagnosis, dietary treatment, biochemical monitoring, and follow-up of clinical complications were formulated. For all recommendations but one, full consensus was reached. A 93 % consensus was reached on the recommendation addressing age at start of bone density screening. During the development of this guideline, gaps of knowledge were identified in most fields of interest, foremost in the fields of treatment and follow-up.

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          The online version of this article (doi:10.1007/s10545-016-9990-5) contains supplementary material, which is available to authorized users.

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          Combination of enzyme analysis, allele-specific PCR and sequencing to detect mutations in the GALT gene.

          Newborn screening can identify patients with classical galactosaemia, and their diagnosis needs to be confirmed with assay of the activity of galactose-1-phosphate uridyltransferase (GALT). Unfortunately, in many cases the results can be ambiguous and further testing is required. Here we report a combination of biochemical analysis of GALT enzyme activity and mutation analysis of the most common mutations in the corresponding gene. Samples (n = 243) submitted for confirmatory testing for classical galactosaemia were analysed simultaneously for GALT enzyme activity and allele-specific PCR/fragment analysis for seven mutations and two polymorphisms in the GALT gene (mutations IVS2-2A>G, p.S135L, p.T138M, p.L195P, p.K285N, p.Q188R, p.Y209C; polymorphisms p.N314D, p.L218L). Mutation detection accorded with biochemical analysis in 93% of samples. Subsequently, a total of 34 samples with either discordant results between the above methods or low enzyme activity were fully sequenced, identifying previously reported pathogenic mutations and seven novel variations (p.P185H, p.R201C, p.E220K, p.R223S, p.I278N, p.L289F and p.L218X) in the GALT gene. This approach further increased concordance between genetic and biochemical analysis to 99% of all alleles tested. Our results indicate that DNA testing can help to verify biochemical enzymatic data and improve distinction of borderline enzyme activities where a patient may still benefit from treatment.

            Author and article information

            J Inherit Metab Dis
            J. Inherit. Metab. Dis
            Journal of Inherited Metabolic Disease
            Springer Netherlands (Dordrecht )
            17 November 2016
            17 November 2016
            : 40
            : 2
            : 171-176
            [1 ]ISNI 0000000404654431, GRID grid.5650.6, Department of Pediatrics, Emma Children’s Hospital, , Academic Medical Center, ; Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
            [2 ]ISNI 0000 0001 0690 7621, GRID grid.413957.d, Section of Clinical Genetics and Metabolism, Inherited Metabolic Disease Nutrition Department, , University of Colorado–Denver School of Medicine, The Children’s Hospital Colorado, ; Aurora, CO USA
            [3 ]ISNI 000000041936754X, GRID grid.38142.3c, Division of Genetics and Genomics, Boston Children’s Hospital, , Harvard Medical School, ; Boston, MA USA
            [4 ]GRID grid.66859.34, , Broad Institute of MIT and Harvard, ; Cambridge, MA USA
            [5 ]ISNI 0000 0004 1757 3470, GRID grid.5608.b, Department of Pediatrics, Metabolic Unit, University Hospital, , University of Padova, ; Padova, Italy
            [6 ]ISNI 0000 0004 0626 3418, GRID grid.411414.5, Department of Metabolic Disorders in Children, , Antwerp University Hospital UZA, ; Edegem, Belgium
            [7 ]ISNI 0000 0001 0726 5157, GRID grid.5734.5, University Children’s Hospital, Pediatric Endocrinology, Diabetes and Metabolism, and Institute of Clinical Chemistry, Inselspital, , University of Bern, ; Bern, Switzerland
            [8 ]ISNI 0000000121901201, GRID grid.83440.3b, Metabolic Unit, Great Ormond Street Hospital and Institute of Child Health, , University College London, ; London, UK
            [9 ]ISNI 0000 0004 0514 6607, GRID grid.411466.0, National Centre for Inherited Metabolic Disorders, , Temple St. Children’s University Hospital, ; Dublin, Ireland
            [10 ]ISNI 0000 0000 9454 4367, GRID grid.413738.a, Department of Pediatrics, APHP, , Hopital Antoine Béclère, ; Cedex Clamart, France
            [11 ]ISNI 0000000404654431, GRID grid.5650.6, Pediatric Clinical Research Office, Emma Children’s Hospital, , Academic Medical Center, ; Amsterdam, The Netherlands
            [12 ]ISNI 0000 0004 0399 7272, GRID grid.415246.0, , Birmingham Children’s Hospital, ; Steelhouse Lane, Birmingham, UK
            [13 ]ISNI 0000 0004 0612 2631, GRID grid.436283.8, Charles Dent Metabolic Unit, , National Hospital for Neurology and Neurosurgery, ; Queen Square, London, UK
            [14 ]Medical Advisory Panel, Galactosemia Support Group UK, West Midlands, UK
            [15 ]ISNI 0000 0001 0943 7661, GRID grid.10939.32, Department of Pediatrics, , University of Tartu, ; Tartu, Estonia
            [16 ]ISNI 0000 0001 0585 7044, GRID grid.412269.a, Department of Genetics, , Tartu University Hospital, ; Tartu, Estonia
            [17 ]ISNI 0000 0001 2157 6568, GRID grid.30064.31, Department of Speech and Hearing Sciences, , Washington State University, ; Spokane, WA USA
            [18 ]GRID grid.412966.e, Department of Pediatrics and Laboratory Genetic Metabolic Diseases, , Maastricht University Medical Centre, ; Maastricht, The Netherlands
            [19 ]Department of Gynecology and Obstetrics, School of Medicine, Emory University, Atlanta, Georgia
            [20 ]ISNI 0000 0001 0481 6099, GRID grid.5012.6, Department of Cognitive Neuroscience, , Maastricht University, ; Maastricht, The Netherlands
            [21 ]ISNI 0000 0004 0488 8430, GRID grid.411596.e, National Centre for Inherited Metabolic Disorders, , Temple St. Children’s University Hospital and Mater Misericordiae University Hospital, ; Dublin, Ireland
            [22 ]ISNI 0000 0000 9758 5690, GRID grid.5288.7, Department of Molecular and Medical Genetics, School of Medicine, , Oregon Health and Science University, ; Portland, OR USA
            [23 ]ISNI 0000 0004 0378 8438, GRID grid.2515.3, Division of Genetics and Genomics, , Boston Children’s Hospital and Harvard Medical School, ; Boston, MA USA
            Author notes

            Communicated by: Georg Hoffmann

            © The Author(s) 2016

            Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

            Funded by: FundRef, Nederlandse Organisatie voor Wetenschappelijk Onderzoek;
            Funded by: US Galactosemia Foundation
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