Neuroradiologic Phenotyping of Galactosemia: From the Neonatal Form to the Chronic Stage

Rossi‐Espagnet, Maria Camilla; Sudhakar, Sniya; Fontana, Esther Roldán; Longo, Dario Livio; Davison, James; Petengill, A.L.; Bevivino, Elsa; Pacheco, Felipe Torres; Rocha, Antônio José da; Hanagandi, Prasad B.; Soldatelli, Matheus Dorigatti; Mankad, Kshitij; Amaral, Lázaro Luís Faria do

doi:10.3174/ajnr.a7016

Cited by 7 publications

(13 citation statements)

References 18 publications

(27 reference statements)

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“…In vivo elevation of brain galactitol was associated with diffuse white matter abnormalities in a newborn with CG and encephalopathy ( Berry et al, 2001 ). Furthermore, increased T2 signal in white matter and areas of restricted diffusion involving the cortex and deep grey matter nuclei, consistent with cytotoxic edema, was observed in 3 patients during neonatal illness and confirmed galactitol accumulation ( Rossi-Espagnet et al, 2021 ).…”

Section: Proposed Disease Mechanismsmentioning

confidence: 73%

“…Although the aforementioned abnormalities could help explain the neurocognitive profile, the possibility of a coexistent disorder should always be considered, especially in case of unexpected symptoms ( Papachristoforou et al, 2014 ; Neville et al, 2016 ; Boca and Whone, 2017 ; Rossi-Espagnet et al, 2021 ).…”

Section: Clinical Spectrummentioning

confidence: 99%

“…Galactitol excretion in urine can be elevated up to 300 times in patients on diet ( Krabbi et al, 2011 ). Studies have reported galactitol elevations in the brains of neonatal and pediatric CG patients ( Quan-Ma et al, 1966 ; Berry et al, 2001 ; Otaduy et al, 2006 ; Rossi-Espagnet et al, 2021 ). Galactitol is poorly diffusible and highly osmotic, and can lead to cell swelling and brain edema.…”

Section: Proposed Disease Mechanismsmentioning

confidence: 99%

“…It is not clear whether disease-related mechanisms continue to damage structures (striatum/cerebellum) or whether this is the result of a prenatal/perinatal hit with a dying back phenomenon. Vasogenic edema might play a role in the delayed myelination later in life ( Rossi-Espagnet et al, 2021 ). However, disturbances in myelination are also found in children without neonatal illness, suggesting the implication of other disease mechanisms.…”

Section: Time Of Damagementioning

confidence: 99%

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Brain function in classic galactosemia, a galactosemia network (GalNet) members review

Panis,

Vos,

Barić

et al. 2024

Front. Genet.

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Classic galactosemia (CG, OMIM #230400, ORPHA: 79,239) is a hereditary disorder of galactose metabolism that, despite treatment with galactose restriction, affects brain function in 85% of the patients. Problems with cognitive function, neuropsychological/social emotional difficulties, neurological symptoms, and abnormalities in neuroimaging and electrophysiological assessments are frequently reported in this group of patients, with an enormous individual variability. In this review, we describe the role of impaired galactose metabolism on brain dysfunction based on state of the art knowledge. Several proposed disease mechanisms are discussed, as well as the time of damage and potential treatment options. Furthermore, we combine data from longitudinal, cross-sectional and retrospective studies with the observations of specialist teams treating this disease to depict the brain disease course over time. Based on current data and insights, the majority of patients do not exhibit cognitive decline. A subset of patients, often with early onset cerebral and cerebellar volume loss, can nevertheless experience neurological worsening. While a large number of patients with CG suffer from anxiety and depression, the increased complaints about memory loss, anxiety and depression at an older age are likely multifactorial in origin.

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Section: Proposed Disease Mechanismsmentioning

confidence: 73%

Section: Clinical Spectrummentioning

confidence: 99%

Section: Proposed Disease Mechanismsmentioning

confidence: 99%

Section: Time Of Damagementioning

confidence: 99%

See 2 more Smart Citations

Brain function in classic galactosemia, a galactosemia network (GalNet) members review

Panis,

Vos,

Barić

et al. 2024

Front. Genet.

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“…Other findings are presented in Table 2A and Table S5. Some metabolic diseases are known to cause changes in brain images, regardless of whether cholestasis is present 54–75 . The details can be seen in Table 2B and Table S3.…”

Section: Resultsmentioning

confidence: 99%

Brain imaging in children with neonatal cholestatic liver disease: A systematic review

Helt,

Johansen,

Faurholt‐Jepsen

et al. 2024

Acta Paediatrica

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AimTo determine if children with neonatal cholestatic liver disease had concurrent and later findings on brain imaging studies that could be attributed and the cholestasis to contribute to the understanding of the impaired neuropsychological development.MethodsOvid MEDLINE and EMBASE were searched on July 21, 2022, and updated on March 26, 2023. Studies with children under 18 years of age with neonatal cholestasis and a brain scan at the time of diagnosis or later in life were included. Excluded studies were non‐English, non‐human, reviews or conference abstracts. Data were extracted on demographics, brain imaging findings, treatment and outcome. The results were summarised by disease categories. Risk of bias was assessed using JBI critical appraisal tools.ResultsThe search yielded 12 011 reports, of which 1261 underwent full text review and 89 were eligible for inclusion. Haemorrhage was the most common finding, especially in children with bile duct obstruction, including biliary atresia. Some findings were resolved after liver transplantation.ConclusionChildren with neonatal cholestasis had changes in brain imaging, which might play a role in impaired neuropsychological development, but longitudinal clinical research with structured assessment is needed to better qualify the aetiology of the impairment.

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Galactokinase 1 is the source of elevated galactose‐1‐phosphate and cerebrosides are modestly reduced in a mouse model of classic galactosemia

Mangini,

Lawrence,

Lopez

et al. 2024

JIMD Reports

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Classic galactosemia (CG) arises from loss‐of‐function mutations in the Galt gene, which codes for the enzyme galactose‐1‐phosphate uridylyltransferase (GALT), a central component in galactose metabolism. The neonatal fatality associated with CG can be prevented by galactose dietary restriction, but for decades it has been known that limiting galactose intake is not a cure and patients often have lasting complications. Even on a low‐galactose diet, GALT's substrate galactose‐1‐phosphate (Gal1P) is elevated and one hypothesis is that elevated Gal1P is a driver of pathology. Here we show that Gal1P levels were elevated above wildtype (WT) in Galt mutant mice, while mice doubly mutant for Galt and the gene encoding galactokinase 1 (Galk1) had normal Gal1P levels. This indicates that GALK1 is necessary for the elevated Gal1P in CG. Another hypothesis to explain the pathology is that an inability to metabolize galactose leads to diminished or disrupted galactosylation of proteins or lipids. Our studies reveal that levels of a subset of cerebrosides—galactosylceramide 24:1, sulfatide 24:1, and glucosylceramide 24:1—were modestly decreased compared to WT. In contrast, gangliosides were unaltered. The observed reduction in these 24:1 cerebrosides may be relevant to the clinical pathology of CG, since the cerebroside galactosylceramide is an important structural component of myelin, the 24:1 species is the most abundant in myelin, and irregularities in white matter, of which myelin is a constituent, have been observed in patients with CG. Therefore, impaired cerebroside production may be a contributing factor to the brain damage that is a common clinical feature of the human disease.

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Neuroradiologic Phenotyping of Galactosemia: From the Neonatal Form to the Chronic Stage

Cited by 7 publications

References 18 publications

Brain function in classic galactosemia, a galactosemia network (GalNet) members review

Brain function in classic galactosemia, a galactosemia network (GalNet) members review

Brain imaging in children with neonatal cholestatic liver disease: A systematic review

Galactokinase 1 is the source of elevated galactose‐1‐phosphate and cerebrosides are modestly reduced in a mouse model of classic galactosemia

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