Abnormal N ‐glycan fucosylation, galactosylation, and sialylation of IgG in adults with classical galactosemia, influence of dietary galactose intake

Abstract 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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Erratum to: A Case of Classical Galactosemia: Identification and Characterization of 3 Distinct Mutations in Galactose-1-Phosphate Uridyl Transferase (GALT) Gene in a Single Family

The Indian Journal of Pediatrics ◽

10.1007/s12098-011-0498-6 ◽

2011 ◽

Vol 78 (7) ◽

pp. 894-894

Author(s):

Ramandeep Singh ◽

Gurjit Kaur ◽

Babu R. Thapa ◽

Rajendra Prasad ◽

Ketan Kulkarni

Keyword(s):

Single Family ◽

Classical Galactosemia ◽

Galt Gene ◽

Identification And Characterization

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Classical galactosemia: neuropsychological and psychosocial functioning beyond intellectual abilities

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-019-1277-0 ◽

2020 ◽

Vol 15 (1) ◽

Cited By ~ 3

Author(s):

Mendy M. Welsink-Karssies ◽

Kim J. Oostrom ◽

Merel E. Hermans ◽

Carla E. M. Hollak ◽

Mirian C. H. Janssen ◽

...

Keyword(s):

Cognitive Functioning ◽

Social Functioning ◽

Internalizing Problems ◽

Psychosocial Functioning ◽

Cognitive Test ◽

Large Variability ◽

Classical Galactosemia ◽

Cognitive Domains ◽

Neuropsychological Profile ◽

Intellectual Abilities

Abstract Background Despite early diagnosis and treatment, Classical Galactosemia (CG) patients frequently develop long-term complications, such as cognitive impairment. Available literature primarily reports on general intellectual abilities and shows a substantially lower Full Scale Intelligence Quotient (FSIQ) in CG patients than in the general population. Both problems in social functioning as well as internalizing problems are often reported in CG patients. The combination of intelligence, cognitive functioning, behavior and social functioning has not been studied systematically in CG patients. Methods To determine if CG patients demonstrate a specific neuropsychological and psychosocial profile, we investigated intelligence, functioning on multiple cognitive domains, behavior and social functioning with a comprehensive neuropsychological test battery and questionnaires (self- and proxy-reported). Results The data of 48 patients, aged 4–47 years are reported. FSIQ ranged from 45 to 103 (mean 77 ± 14). A negative correlation between age and FSIQ was demonstrated (p = 0.037) which resulted directly from the inclusion of four young ‘milder’ patients detected by newborn screening (NBS) with an expected better clinical outcome. Compared to normative data, patients had significantly lower but highly variable scores on all cognitive domains, especially on tests requiring mental speed. In the context of the FSIQ, 43% of the cognitive test results exceeded IQ based expectations. Overall, the patients’ scores on social functioning were in the normal range but internalizing problems were frequently reported. In our cohort, an early initiation of dietary treatment due to NBS or family screening did not result in a more favorable neuropsychological outcome. Conclusions In this study, we demonstrated that as a cohort, CG patients have a below average intelligence and impaired cognitive functioning without a distinctive neuropsychological profile. The effect of age on neurocognitive functioning should be assessed in longitudinal studies. Social functioning was not impaired, but patients may be at risk for internalizing problems. Considering the large variability in cognitive, behavioral and social functioning and the finding that cognitive outcomes may exceed IQ based expectations, an individual evaluation and follow-up is warranted in all CG patients to ensure timely support if needed.

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Correction to: Classical galactosemia: neuropsychological and psychosocial functioning beyond intellectual abilities

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-020-01447-z ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Mendy M. Welsink-Karssies ◽

Kim J. Oostrom ◽

Merel E. Hermans ◽

Carla E. M. Hollak ◽

Mirian C. H. Janssen ◽

...

Keyword(s):

Psychosocial Functioning ◽

Classical Galactosemia ◽

Intellectual Abilities

An amendment to this paper has been published and can be accessed via the original article.

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The endocrine system in treated patients with classical galactosemia

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2006.07.005 ◽

2006 ◽

Vol 89 (4) ◽

pp. 316-322 ◽

Cited By ~ 15

Author(s):

M. Estela Rubio-Gozalbo ◽

Bianca Panis ◽

Luc J.I. Zimmermann ◽

Leo J. Spaapen ◽

P.P.C.A. Menheere

Keyword(s):

Endocrine System ◽

Classical Galactosemia

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Classical galactosemia patients can achieve high IQ scores

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2018-0515 ◽

2019 ◽

Vol 32 (4) ◽

pp. 399-401 ◽

Cited By ~ 2

Author(s):

Konstantinos Iakovou ◽

Yannis Dotsikas ◽

Yannis L. Loukas ◽

Kleopatra H. Schulpis

Keyword(s):

Maternal Care ◽

Intelligence Quotient ◽

Psychomotor Development ◽

Classical Galactosemia ◽

High Intelligence ◽

Iq Scores ◽

University Degree ◽

Very High

Abstract Very recently, it was reported that a patient with classical galactosemia and a very high intelligence quotient (IQ) score obtained a university degree. In the present study, two siblings with classical galactosemia (homozygous for Q188R mutation) received upper normal IQ scores when tested with psychometric tools. Additionally, the same IQ scores were determined in their healthy brother when tested at the same age. It was concluded that patients could achieve upper normal IQ scores when on diet and followed up closely. Family and especially maternal care may ameliorate the psychomotor development.

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