The natural history of classic galactosemia: lessons from the GalNet registry

Rubio-Gozalbo, M. Estela; Haskovic, Minela; Bosch, Annet M.; Burnytė, Birutė; Coelho, Ana Daniela; Cassiman, David; Couce, María L.; Dawson, Charlotte; Demirbas, Didem; Derks, Terry G J; Eyskens, François; Forga, María; Grünewald, Stéphanie; Häberle, Johannes; Hochuli, Michel; Hubert, Arnaud; Huidekoper, Hidde H.; Janeiro, Patrícia; Kotzka, Jörg; Knerr, Ina; Labrune, Philippe; Landau, Yuval; Langendonk, Janneke G.; Möslinger, Dorothea; Müller‐Wieland, Dirk; Murphy, Elaine; Õunap, Katrin; Ramadža, Danijela Petković; Rivera, Isabel; Scholl‐Buergi, Sabine; Stępień, Karolina M.; Thijs, Abel; Tran, Christel; Vara, Roshni; Visser, Gepke; Vos, Rein; Vries, Maaike de; Waisbren, Susan E.; Welsink‐Karssies, Mendy M.; Wortmann, Saskia B.; Gautschi, Matthias; Treacy, Eileen P.; Berry, Gerard T.

doi:10.1186/s13023-019-1047-z

Cited by 108 publications

(171 citation statements)

References 49 publications

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“…The Galactosaemia Consortium (GalNet) Registry outcome study [9] has recently demonstrated that 80% of females (of n = 164) have primary ovarian insufficiency which is consistent with other studies [4,5,6,7,8,26,27].…”

Section: Introductionsupporting

confidence: 79%

“…Restriction of galactose is life-saving in the neonate and improves the neonatal intoxication manifestations of feeding difficulties, failure to thrive, sepsis, hepatocellular damage, renal tubulopathy, and cataracts. Affected individuals develop long term complications affecting the central nervous system, bone density/metabolism, and primary ovarian insufficiency and subfertility in females despite dietary galactose restriction [4,5,6,7,8,9]. Primary ovarian insufficiency in CG, first described in 1978 [10] with ovarian follicular depletion is reported in at least 80% of females [9].…”

Section: Introductionmentioning

confidence: 99%

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Insights into the Pathophysiology of Infertility in Females with Classical Galactosaemia

Abidin

Treacy

2019

IJMS

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Classical galactosaemia (CG) (OMIM 230400) is a rare inborn error of galactose metabolism caused by the deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT, EC 2.7.7.12). Primary ovarian insufficiency (POI) is the most common long-term complication experienced by females with CG, presenting with hypergonadotrophic hypoestrogenic infertility affecting at least 80% of females despite new-born screening and lifelong galactose dietary restriction. In this review, we describe the hypothesized pathophysiology of POI from CG, implications of timing of the ovarian dysfunction, and the new horizons and future prospects for treatments and fertility preservation.

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Section: Introductionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Insights into the Pathophysiology of Infertility in Females with Classical Galactosaemia

Abidin

Treacy

2019

IJMS

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“…Based on these findings, the incidence of CG is estimated to be 1:52 800 in the Netherlands ( Welling et al , 2017 b ). Despite an early diagnosis by NBS and treatment with a galactose-restricted diet, patients are at risk to develop long-term complications of the central nervous system, such as abnormalities in motor and speech development, cognitive impairment and movement disorders (MDs) and ovarian insufficiency in females ( Bosch, 2006 ; Hughes et al , 2009 ; Waisbren et al , 2012 ; Coss et al , 2013 ; Rubio-Gozalbo et al , 2019 ). There is a broad spectrum of clinical manifestations ranging from fully normal to severely impaired, even within families with identical mutations ( Fridovich-Keil and Walter, 2008 ; Hughes et al , 2009 ).…”

Section: Introductionmentioning

confidence: 99%

Deep phenotyping classical galactosemia: clinical outcomes and biochemical markers

Welsink‐Karssies

Ferdinandusse

Geurtsen

et al. 2020

Brain Communications

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Early diagnosis and dietary treatment do not prevent long-term complications, which mostly affect the central nervous system in classical galactosemia patients. The clinical outcome of patients is highly variable, and there is an urgent need for prognostic biomarkers. The aim of this study was first to increase knowledge on the natural history of classical galactosemia by studying a cohort of patients with varying geno- and phenotypes and second to study the association between clinical outcomes and two possible prognostic biomarkers. In addition, the association between abnormalities on brain MRI and clinical outcomes was investigated. Classical galactosemia patients visiting the galactosemia expertise outpatient clinic of the Amsterdam University Medical Centre were evaluated according to the International Classical Galactosemia guideline with the addition of an examination by a neurologist, serum immunoglobulin G N-glycan profiling and a brain MRI. The biomarkers of interest were galactose-1-phosphate levels and N-glycan profiles, and the clinical outcomes studied were intellectual outcome and the presence or absence of movement disorders and/or primary ovarian insufficiency. Data of 56 classical galactosemia patients are reported. The intellectual outcome ranged from 45 to 103 (mean 77 ± 14) and was <85 in 62%. Movement disorders were found in 17 (47%) of the 36 tested patients. In females aged 12 years and older, primary ovarian insufficiency was diagnosed in 12 (71%) of the 17 patients. Significant differences in N-glycan peaks were found between controls and patients. However, no significant differences in either N-glycans or galactose-1-phosphate levels were found between patients with a poor (intellectual outcome < 85) and normal intellectual outcome (intellectual outcome ≥ 85), and with or without movement disorders or primary ovarian insufficiency. The variant patients detected by newborn screening, with previously unknown geno- and phenotypes and currently no long-term complications, demonstrated significantly lower galactose-1-phospate levels than classical patients (P < 0.0005). Qualitative analysis of the MRI’s demonstrated brain abnormalities in 18 of the 21 patients, more severely in patients with a lower intellectual outcome and/or with movement disorders. This study demonstrates a large variability in clinical outcome, which varies from a below average intelligence, movement disorders and in females primary ovarian insufficiency to a normal clinical outcome. In our cohort of classical galactosemia patients, galactose-1-phosphate levels and N-glycan variations were not associated with clinical outcomes, but galactose-1-phosphate levels did differentiate between classical and variant patients detected by newborn screening. The correlation between brain abnormalities and clinical outcome should be further investigated by quantitative analysis of the MR images. The variability in clinical outcome necessitates individual and standardized evaluation of all classical galactosemia patients.

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“…The international network for the galactosemias (GalNet), established in 2012, has developed an online registry (https:// ecrf.ctcm.nl/macro/) that includes patients with the different galactosemias from several countries as described in Rubio-Gozalbo et al 19 It was established in accordance with Good Clinical Practice and following General Data Protection Regulation. The local ethics committee of the coordinating center (Maastricht University Medical Center) approved the study (application number METC 13-4-121.6/ab), which was subsequently approved by participating partners.…”

Section: Ethics Statementmentioning

confidence: 99%

Galactokinase deficiency: lessons from the GalNet registry

Rubio‐Gozalbo

Derks

Meyer³

et al. 2021

Genetics in Medicine

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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.

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The natural history of classic galactosemia: lessons from the GalNet registry

Cited by 108 publications

References 49 publications

Insights into the Pathophysiology of Infertility in Females with Classical Galactosaemia

Insights into the Pathophysiology of Infertility in Females with Classical Galactosaemia

Deep phenotyping classical galactosemia: clinical outcomes and biochemical markers

Galactokinase deficiency: lessons from the GalNet registry

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