Social cognition, emotion-regulation and social competence in classical galactosemia patients without intellectual disability

Objective: Classical galactosemia (CG) is an inborn error of galactose metabolism. Many CG-patients suffer from long-Term complications including poor cognitive functioning. There are indications of social dysfunction but limited evidence in the literature. Therefore, this study aims to improve our understanding of social competence in CG by investigating social cognition, neurocognition and emotion-regulation. Methods: A comprehensive (neuro)psychological test battery including self-and proxy questionnaires was administered to CG-patients without intellectual disability. Social cognition was assessed by facial emotion recognition, Theory of Mind and self-reported empathy. Standardized results were compared to normative data of the general population. Results: Data of 23 patients (aged 8-52) were included in the study. On a group-level, CG-patients reported satisfaction with social roles and no social dysfunction despite the self-report of lower social skills. They showed deficits on all aspects of social cognition on both performance tests (emotion-recognition and Theory of Mind) and self-report questionnaires (empathy). Adults had a lower social participation than the general population. Parents reported lower social functioning, less adaptive emotion-regulation and communication difficulties in their children. Individual differences in scores were present. Conclusion: This study shows that CG patients without intellectual disability are satisfied with their social competence, especially social functioning. Nevertheless, deficits in social cognition are present in a large proportion of CG-patients. Due to the large variability in scores and discrepancies between self-and proxy-report, an individually tailored, comprehensive neuropsychological assessment including social cognition is advised in all CG-patients. Treatment plans need to be customized to the individual patient.</p

Crystal clear cerebral ultrasound images mimicking acute asphyxia in an infant with primary hyperoxaluria

Genetic deficiencies in enzymes involved in glyoxylate metabolism lead to primary hyperoxaluria (PH) type I, typically characterized by deposition of oxalate crystals in kidneys. A 2-month-old infant was admitted, and was diagnosed with renal failure. Abdominal ultrasound images revealed enlarged and hyperechoic kidneys. Additionally, on cerebral ultrasound (CUS) hyperechoic changes of thalami and basal ganglia were noted, reminiscent of perinatal hypoxic-ischemic brain damage. However, MRI of the brain did not show any abnormal signal intensities compatible with asphyxia. The hyperechoic appearance of deep grey matter, in particular putamen, was therefore not due to asphyxiated brain damage but seemed related to the deposition of oxalate salts. Moreover, macular crystals were detected at ophthalmoscopy. Our case report shows the potential of US imaging to detect deposition of crystals not only in kidneys but also in brain mimicking, perinatal asphyxia

Crystal clear cerebral ultrasound images mimicking acute asphyxia in an infant with primary hyperoxaluria

Genetic deficiencies in enzymes involved in glyoxylate metabolism lead to primary hyperoxaluria (PH) type I, typically characterized by deposition of oxalate crystals in kidneys. A 2-month-old infant was admitted, and was diagnosed with renal failure. Abdominal ultrasound images revealed enlarged and hyperechoic kidneys. Additionally, on cerebral ultrasound (CUS) hyperechoic changes of thalami and basal ganglia were noted, reminiscent of perinatal hypoxic-ischemic brain damage. However, MRI of the brain did not show any abnormal signal intensities compatible with asphyxia. The hyperechoic appearance of deep grey matter, in particular putamen, was therefore not due to asphyxiated brain damage but seemed related to the deposition of oxalate salts. Moreover, macular crystals were detected at ophthalmoscopy. Our case report shows the potential of US imaging to detect deposition of crystals not only in kidneys but also in brain mimicking, perinatal asphyxia

Social cognition, emotion-regulation and social competence in classical galactosemia patients without intellectual disability

Objective: Classical galactosemia (CG) is an inborn error of galactose metabolism. Many CG-patients suffer from long-Term complications including poor cognitive functioning. There are indications of social dysfunction but limited evidence in the literature. Therefore, this study aims to improve our understanding of social competence in CG by investigating social cognition, neurocognition and emotion-regulation. Methods: A comprehensive (neuro)psychological test battery including self-and proxy questionnaires was administered to CG-patients without intellectual disability. Social cognition was assessed by facial emotion recognition, Theory of Mind and self-reported empathy. Standardized results were compared to normative data of the general population. Results: Data of 23 patients (aged 8-52) were included in the study. On a group-level, CG-patients reported satisfaction with social roles and no social dysfunction despite the self-report of lower social skills. They showed deficits on all aspects of social cognition on both performance tests (emotion-recognition and Theory of Mind) and self-report questionnaires (empathy). Adults had a lower social participation than the general population. Parents reported lower social functioning, less adaptive emotion-regulation and communication difficulties in their children. Individual differences in scores were present. Conclusion: This study shows that CG patients without intellectual disability are satisfied with their social competence, especially social functioning. Nevertheless, deficits in social cognition are present in a large proportion of CG-patients. Due to the large variability in scores and discrepancies between self-and proxy-report, an individually tailored, comprehensive neuropsychological assessment including social cognition is advised in all CG-patients. Treatment plans need to be customized to the individual patient.</p

Analysis of urinary oligosaccharide excretion patterns by UHPLC/HRAM mass spectrometry for screening of lysosomal storage disorders

Oligosaccharidoses, sphingolipidoses and mucolipidoses are lysosomal storage disorders (LSDs) in which defective breakdown of glycan-side chains of glycosylated proteins and glycolipids leads to the accumulation of incompletely degraded oligosaccharides within lysosomes. In metabolic laboratories, these disorders are commonly diagnosed by thin-layer chromatography (TLC) but more recently also mass spectrometry-based approaches have been published. To expand the possibilities to screen for these diseases, we developed an ultra-high-performance liquid chromatography (UHPLC) with a high-resolution accurate mass (HRAM) mass spectrometry (MS) screening platform, together with an open-source iterative bioinformatics pipeline. This pipeline generates comprehensive biomarker profiles and allows for extensive quality control (QC) monitoring. Using this platform, we were able to identify α-mannosidosis, β-mannosidosis, α-N-acetylgalactosaminidase deficiency, sialidosis, galactosialidosis, fucosidosis, aspartylglucosaminuria, GM1 gangliosidosis, GM2 gangliosidosis (M. Sandhoff) and mucolipidosis II/III in patient samples. Aberrant urinary oligosaccharide excretions were also detected for other disorders, including NGLY1 congenital disorder of deglycosylation, sialic acid storage disease, MPS type IV B and GSD II (Pompe disease). For the latter disorder, we identified heptahexose (Hex7), as a potential urinary biomarker, in addition to glucose tetrasaccharide (Glc4), for the diagnosis and monitoring of young onset cases of Pompe disease. Occasionally, so-called “neonate” biomarker profiles were observed in young patients, which were probably due to nutrition. Our UHPLC/HRAM-MS screening platform can easily be adopted in biochemical laboratories and allows for simple and robust screening and straightforward interpretation of the screening results to detect disorders in which aberrant oligosaccharides accumulate

Effect of Anti-Iduronate 2-Sulfatase Antibodies in Patients with Mucopolysaccharidosis Type II Treated with Enzyme Replacement Therapy

Objective To assess the relationship between anti-Iduronate 2-sulfatase (IDS) antibodies, IDS genotypes, phenotypes and their impact in patients with enzyme replacement therapy (ERT)-treated Mucopolysaccharidosis type II. Study design Dutch patients treated with ERT were analyzed in this observational cohort study. Antibody titers were determined by enzyme-linked immunosorbent assay. Neutralizing effects were measured in fibroblasts. Pharmacokinetic analysis of ERT was combined with immunoprecipitation. Urinary glycosaminoglycans were measured using mass spectrometry and dimethylmethylene blue. Results Eight of 17 patients (47%) developed anti-IDS antibodies. Three patients with the severe, neuronopathic phenotype, two of whom did not express IDS protein, showed sustained antibodies for up to 10 years of ERT. Titers of 1:5120 or greater inhibited cellular IDS uptake and/or intracellular activity in vitro. In 1 patient who was neuronopathic with a titer of 1:20 480, pharmacokinetic analysis showed that all plasma recombinant IDS was antibody bound. This finding was not the case in 2 patients who were not neuronopathic with a titer of 1:1280 or less. Patients with sustained antibody titers showed increased urinary glycosaminoglycan levels compared with patients with nonsustained or no-low titers. Conclusions Patients with the neuronopathic form and lack of IDS protein expression were most at risk to develop sustained anti-IDS antibody titers, which inhibited IDS uptake and/or activity in vitro, and the efficacy of ERT in patients by lowering urinary glycosaminoglycan levels. (J Pediatr 2022;248:100-7)

Hip disease in Mucopolysaccharidoses and Mucolipidoses: A review of mechanisms, interventions and future perspectives

The hips are frequently involved in inheritable diseases which affect the bones. The clinical and radiological presentation of these diseases may be very similar to common hip disorders as developmental dysplasia of the hip, osteoarthritis and avascular necrosis, so the diagnosis may be easily overlooked and treatment may be suboptimal. Mucopolysaccharidosis (MPS) and Mucolipidosis (ML II and III) are lysosomal storage disorders with multisystemic involvement. Characteristic skeletal abnormalities, known as dysostosis multiplex, are common in MPS and ML and originate from intra-lysosomal storage of glycosaminoglycans in cells of the cartilage, bones and ligaments. The hip joint is severely affected in MPS and ML. Hip pathology results in limitations in mobility and pain from young age, and negatively affects quality of life. In order to better understand the underlying process that causes hip disease in MPS and ML, this review first describes the normal physiological (embryonic) hip joint development, including the interplay between the acetabulum and the femoral head. In the second part the factors contributing to altered hip morphology and function in MPS and ML are discussed, such as abnormal development of the pelvic- and femoral bones (which results in altered biomechanical forces) and inflammation. In the last part of this review therapeutic options and future perspectives are addressed

Gray and white matter are both affected in classical galactosemia: An explorative study on the association between neuroimaging and clinical outcome

Background: Classical Galactosemia (CG) is an inherited disorder of galactose metabolism caused by a deficiency of the galactose-1-phosphate uridylyltransferase (GALT) enzyme resulting in neurocognitive complications. As in many Inborn Errors of Metabolism, the metabolic pathway of CG is well-defined, but the pathophysiology and high variability in clinical outcome are poorly understood. The aim of this study was to investigate structural changes of the brain of CG patients on MRI and their association with clinical outcome. Methods: In this prospective cohort study an MRI protocol was developed to evaluate gray matter (GM) and white matter (WM) volume of the cerebrum and cerebellum, WM hyperintensity volume, WM microstructure and myelin content with the use of conventional MRI techniques, diffusion tensor imaging (DTI) and quantitative T1 mapping. The association between several neuroimaging parameters and both neurological and intellectual outcome was investigated. Results: Twenty-one patients with CG (median age 22 years, range 8–47) and 24 controls (median age 30, range 16–52) were included. Compared to controls, the WM of CG patients was lower in volume and the microstructure of WM was impaired both in the whole brain and corticospinal tract (CST) and the lower R1 values of WM, GM and the CST were indicative of less myelin. The volume of WM lesions were comparable between patients and controls. The 9/16 patients with a poor neurological outcome (defined as the presence of a tremor and/or dystonia), demonstrated a lower WM volume, an impaired WM microstructure and lower R1 values of the WM indicative of less myelin content compared to 7/16 patients without movement disorders. In 15/21 patients with a poor intellectual outcome (defined as an IQ < 85) both GM and WM were affected with a lower cerebral and cerebellar WM and GM volume compared to 6/21 patients with an IQ ≥ 85. Both the severity of the tremor (as indicated by the Tremor Rating Scale) and IQ (as continuous measure) were associated with several neuroimaging parameters such as GM volume, WM volume, CSF volume, WM microstructure parameters and R1 values of GM and WM. Conclusion: In this explorative study performed in patients with Classical Galactosemia, not only WM but also GM pathology was found, with more severe brain abnormalities on MRI in patients with a poor neurological and intellectual outcome. The finding that structural changes of the brain were associated with the severity of long-term complications indicates that quantitative MRI techniques could be of use to explain neurological and cognitive dysfunction as part of the disease spectrum. Based on the clinical outcome of patients, the absence of widespread WM lesions and the finding that both GM and WM are affected, CG could be primarily a GM disease with secondary damage to the WM as a result of neuronal degeneration. To investigate this further the course of GM and WM should be evaluated in longitudinal research, which could also clarify if CG is a neurodegenerative disease

A long term follow-up study of the development of hip disease in Mucopolysaccharidosis type VI

Hip problems in Mucopolysaccharidosis type VI (MPS VI) lead to severe disability. Lacic of data on the course of hip disease in MPS VI make decisions regarding necessity, timing and type of surgical intervention difficult. We therefore studied the development of hip pathology in MPS VI patients over time. Data were collected as part of a prospective follow-up study. Standardized supine AP pelvis and frog leg lateral radiographs of both hips were performed yearly or every 2 years. Image assessment was performed quantitatively (angle measurements) and qualitatively (hip morphology). Clinical burden of hip disease was evaluated by physical examination, six minute walking test (6MWT) and a questionnaire assessing pain, wheelchair-dependency and walking distance. A total of 157 pelvic radiographs of 14 ERT treated MPS VI patients were evaluated. Age at first image ranged from 2.0 to 21.1 years. Median follow up duration was 6.8 years. In all patients, even in the youngest, the acetabulum and os ilium were dysplastic. Coverage of the femoral head by the acetabulum improved over time, but remained insufficient. While the femoral head appeared normal in the radiographs at young age, the ossification pattern became abnormal in all patients over time. In all patients the distance covered in the 6MWT was reduced (median Z scores -3.3). Twelve patients had a waddling gait. Four patients were partially wheelchair-dependent and ten patients had limitations in their maximum walking distance. In conclusion, clinically significant hip abnormalities develop in all MPS VI patients from very early in life, starting with deformities of the os ilium and acetabulum. Femoral head abnormalities occur later, most likely due to altered mechanical forces in combination with epiphyseal abnormalities due to glycosaminoglycan storage. The final shape and angle of the femoral head differs significantly between individual MPS VI patients and is difficult to predict. (C) 2017 Elsevier Inc. All rights reserve