Movement disorders and nonmotor neuropsychological symptoms in children and adults with classical galactosemia

Kuiper, Anouk; Grünewald, Stéphanie; Murphy, Elaine; Coenen, Maraike A; Eggink, Hendriekje; Zutt, Rodi; Rubio-Gozalbo, M. Estela; Bosch, Annet M.; Williams, Monique; Derks, Terry G J; Lachmann, Robin; Brouwers, Martijn C.G.J.; Janssen, Mirian C. H.; Tijssen, Marina A. J.; Koning, Tom J. de

doi:10.1002/jimd.12054

Cited by 30 publications

(43 citation statements)

References 19 publications

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“…This finding might be explained by the fact that the latter reported on adults only, and it confirms the lower frequency of MDs in children, which has also been reported previously ( Kuiper et al , 2019 ). Interestingly, tremors were more frequently and dystonia less frequently observed in our cohort when compared with previous studies ( Rubio-Agusti et al , 2013 ; Kuiper et al , 2019 ). Unlike other cohorts, ataxia was not found in our patients.…”

Section: Discussionsupporting

confidence: 90%

“…The frequency of long-term complications did not differ between screened and non-screened classical patients. Thus, early diagnosis and initiation of treatment does not explain the differences in clinical outcome, which is in line with previous research ( Fridovich-Keil and Walter, 2008 ; Hughes et al , 2009 ; Kuiper et al , 2019 ). The highly variable clinical outcome spectrum of CG patients and the diversity in genotypes, phenotypes and biochemistry underline the need for predictors of clinical outcome.…”

Section: Discussionsupporting

confidence: 90%

“…The neurological examination revealed MDs in 47% of patients, which is comparable to the results of Kuiper et al (2019) but less frequent than reported by Rubio-Agusti et al (2013) . This finding might be explained by the fact that the latter reported on adults only, and it confirms the lower frequency of MDs in children, which has also been reported previously ( Kuiper et al , 2019 ). Interestingly, tremors were more frequently and dystonia less frequently observed in our cohort when compared with previous studies ( Rubio-Agusti et al , 2013 ; Kuiper et al , 2019 ).…”

Section: Discussionsupporting

confidence: 78%

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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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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 78%

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Deep phenotyping classical galactosemia: clinical outcomes and biochemical markers

Welsink‐Karssies

Ferdinandusse

Geurtsen

et al. 2020

Brain Communications

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“…In other cohorts, severe progressive ataxia and tremor developed in 10–20% of patients despite early diagnosis and dietary therapy (Ridel et al, 2005) and tremor, ataxia, and dysmetria were detected in 12/45 patients aged 4–39 years (Kaufman et al, 1995). In their series of 37 classic galactosemia patients consisting of 19 adults (mean age 32.6 years) and 18 children (mean age 10.7 years), Kuiper et al determined movement disorders in 48.6% using video recordings, and reported that dystonia and tremor were most common in adult patients while myoclonus was predominant in pediatric patients (Kuiper et al, 2019). We observed movement disorders in our patients, ataxia being the most common (11/46, 23%); this rate may increase if the cohort is re‐evaluated at older ages.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms of acute and long‐term complications are still discussed and several hypotheses are presented in the literature: perturbation of glycosylation; endogenous galactose production; and inositol signaling during prenatal galactose intoxication, in combination with long‐term galactose restriction (Bosch, 2006; Maratha et al, 2017; Viggiano et al, 2018). Most studies of long‐term neurological complications have been performed in large patient groups which include children and adults at different ages (Kaufman et al, 1995; Doyle et al, 2010; Kuiper et al, 2019). In this study, early neurological complications of pediatric patients, all carrying the p.gln188arg mutation, were evaluated.…”

Section: Introductionmentioning

confidence: 99%

Early neurological complications in children with classical galactosemia and p.gln188arg mutation

Özgün¹,

Çelik²,

Akdeniz³

et al. 2019

Intl J of Devlp Neuroscience

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Background Despite implementation of a controlled diet, children with classical galactosemia (CG) may develop a variety of developmental and cognitive problems. In this study, we examined the early developmental status of, as well as the neurological and neuroradiological findings for, children with CG. Methods We retrospectively evaluated 46 galactosemia patients who were followed between 2003 and 2017. We included those who exhibited CG and p.gln188arg homozygous mutation without concomitant disease and who had undergone detailed neurological examination, brain magnetic resonance imaging (MRI), and Denver II developmental testing. Results The mean ages at the time of the most recent neurological examination and Denver II testing were 48.5 ± 28.5 months and 34.4 ± 18.2 months, respectively. Developmental delay was defined as developmental age ≥ 20% lower than chronological age. The results were normal in 25 patients and delayed ≥ 20% in least in one domain, primarily in language development, in 21 patients. Brain MRI was abnormal in 22 patients. Conclusions This analysis of the youngest children with the same genetic mutation reported thus far showed that, despite treatment, developmental delays and abnormalities on brain MRI may begin at an early age.

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Pd‐Catalyzed Intermolecular Transthiolation of Ar‐OTf Using Methyl 3‐(Methylthio) Propanoate as a Thiol Surrogate

Pan

Tian

et al. 2021

Eur J Org Chem

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A method for the odorless synthesis of unsymmetrical sulfides via Csp 2 À O and Csp 3 À S bond activation is presented. Using methyl 3-(methylthio) propanoate as a MeSH surrogate, a series of substituted aryl methyl sulfides have been obtained in moderate to good yields. This catalytic protocol can also tolerate methyl 3-(methylthio)propionate derivatives to afford the corresponding aryl sulfides.

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Movement disorders and nonmotor neuropsychological symptoms in children and adults with classical galactosemia

Cited by 30 publications

References 19 publications

Deep phenotyping classical galactosemia: clinical outcomes and biochemical markers

Deep phenotyping classical galactosemia: clinical outcomes and biochemical markers

Early neurological complications in children with classical galactosemia and p.gln188arg mutation

Pd‐Catalyzed Intermolecular Transthiolation of Ar‐OTf Using Methyl 3‐(Methylthio) Propanoate as a Thiol Surrogate

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