Deep phenotyping classical galactosemia: clinical outcomes and biochemical markers

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.

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

“…In the current study, we have replicated our previous findings showing a decrease in galactosylation in CG as demonstrated by significantly increased ratios of G0/G1, G0/G2, and G0/G1/G2 (Table 2B) consistent with the report by Stockmann et al 22 We also report significant increases in the glycans GP4 and 26 and decreases in GP1, 5, 18, and 24 (Table 2A); consistent with findings by Maratha et al and Welsink et al, respectively 23,26 . In this cohort, we also report additional significant peaks (GP2, 4, 8, 12, 19, 20, 22, and 25).…”

“…The long‐term outcomes in treated patients with CG have indicated a high incidence of lower intellectual outcome, and more recently a high percentage of motor symptoms including dystonia and tremor in children and adults 2‐6,26,46 . In parallel with this, a number of studies have indicated gray and white matter changes in MRI scans of the brain in individuals with CG 26,47,48 . It is currently unclear if the white and gray matter changes observed in patients with CG are progressive.…”

“…Applying the circulating IgG N ‐glycan markers to a deep phenotyping study to include IQ as a measure of intelligence, neurological examination assessing motor development, tremor, and speech abnormalities of 56 Dutch CG patients (children and adults), statistically significant differences were noted in specific N ‐glycan peaks between patients and controls. However, specific individual glycan peaks were not found to correlate directly with neurological outcomes 26 …”

Advances and Challenges in Classical Galactosemia. Pathophysiology and Treatment

“…However, treatment does not prevent long-term complications such as premature ovarian failure, neurological manifestations, behavioral alterations, and decreased bone mineral density which have been reported to occur with different degrees of severity [2,11]. Several publications suggest that such complications may appear independent of the age of onset and treatment adherence [2,[11][12][13][14][15][16][17]. Over time, patients may have difficulties in learning and language (verbal dyspraxia and dysarthria), also they frequently develop tremors and, to a lesser extent, ataxia and dystonia [11,14].…”

The Discovery of GALM Deficiency (Type IV Galactosemia) and Newborn Screening System for Galactosemia in Japan

“…Various chronic complications, including cataracts, intellectual/psychiatric disorders, movement disorders, and primary ovarian insufficiency, are also associated to classic galactosemia. Some of these chronic complications may occur despite life-long galactose restriction [ 15 ]. In contrast, cataracts are the only consistent symptom in patients with GALK1 deficiency (type II galactosemia).…”