bims-meglyc 2025-01-19 papers

Issue of 2025–01–19
three papers selected by
Silvia Radenkovic, UMC Utrecht

Pediatr Neurol. 2024 Dec 25. pii: S0887-8994(24)00418-1. [Epub ahead of print]164 7-9

Progressive Loss of Cerebral Structures in ALG11-Related Congenital Disorder Glycosylation.

Olivier Fortin, Gilbert Vezina, David M Steinhorn, Sarah B Mulkey.

BACKGROUND: Congenital disorders of glycosylation (CDG) are a group of metabolic disorders related to dysfunctional glycoprotein and glycolipid biosynthesis. ALG11-related CDG is a rare member of this group, characterized by severe neurodevelopmental impairment, progressive microcephaly, sensorineural hearing loss, and epilepsy. The objective of this report is to provide an update on the phenotype and brain magnetic resonance imaging (MRI) at age seven years for a patient initially described in early infancy with fetal brain disruption sequence.
METHODS: We provide an updated detailed clinical description of a seven-year-old male with ALG-11 CDG who underwent brain MRI at age seven years.
RESULTS: Brain MRI at age seven years showed significant disease progression compared to the neonatal brain MRI. There was near complete loss of cerebral hemispheres, severe cerebellar atrophy, and decreased volume of the brainstem. The prior brain MRI (done at six weeks of age) had shown severe supratentorial volume loss but a relatively preserved cerebellum and brainstem at that time.
CONCLUSIONS: Reports on the natural history of rare conditions are important to improve our understanding of these conditions. ALG11-CDG is associated with atrophy and eventual vanishing of supratentorial brain structures, and infratentorial brain structures later in the disease process. The involvement of a pediatric palliative care service is a valuable adjunct to assist with symptom management and family support for these complex progressive conditions.

Keywords: Brain atrophy; Congenital disorders of glycosylation; Fetal neurology; Neurogenetics; Neuroimaging; Palliative care

DOI: https://doi.org/10.1016/j.pediatrneurol.2024.12.009

Mol Genet Metab. 2025 Jan;pii: S1096-7192(24)00891-6. [Epub ahead of print]144(1): 109007

Mitochondrial HMG-CoA synthase deficiency.

Bram Decru, Marine Lys, Kobe Truijens, Nathalie Mercier, Jean Papadopoulos, Daisy Rymen, Dominique Roland, Joseph P Dewulf, Pieter Vermeersch.

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) deficiency is a rare, potentially life-threatening autosomal recessive disorder resulting from mutations in the HMGCS2 gene, leading to impaired ketogenesis. We systematically reviewed the clinical presentations, biochemical and genetic abnormalities in 93 reported cases and 2 new patients diagnosed based on biochemical findings. Reported onset ages ranged from 3 months to 6 years, mostly before the age of 3. Children younger than one year old are more prone to a severe clinical course. In most patients, the initial metabolic decompensation occurs after an episode of gastroenteritis or gastroenteritis-like symptoms. Other commonly observed symptoms during the first clinical episode included poor intake, altered consciousness, dyspnea, seizures and hepatomegaly. Severity was correlated with the number of truncating mutations. Most patients presented with acute metabolic decompensation with hypoglycemia, dicarboxyluria and inadequate ketonuria. Dicarboxylic acid levels were elevated in 54/56 cases. The organic acid 4-hydroxy-6-methyl-2-pyrone (4HMP) was detected in 33/35 urine samples taken during the acute episodes, but typically only retrospectively. The plasma C2/C0 acylcarnitine ratio was abnormal in 16/18 (88.9 %) of acute plasma samples, but only in 2/6 (33 %) of DBS samples. Other metabolites that have been reported are hydroxyhexenoic acid, 3,5-dihydroxyhexanoic (1,5 lactone), glutaric acidand 3-OH-isovaleric acid. Laboratories should look for 4HMP in urinary organic acid analysis and an increased plasma C2/C0 acylcarnitine ratio to facilitate the diagnosis of HMGCS2 deficiency, especially in cases of metabolic decompensation with dicarboxyluria without adequate ketonuria.

Keywords: 4-hydroxy-6-methyl-2-pyrone; HMGCS2; Hypoketotic hypoglycemia; Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase

DOI: https://doi.org/10.1016/j.ymgme.2024.109007

Curr Opin Biotechnol. 2025 Jan 13. pii: S0958-1669(24)00189-7. [Epub ahead of print]92 103253

Engineering organoids as cerebral disease models.

Alexander Geidies, Marija Lj Medar, Hannes M Beyer.

Cerebral organoids pioneered in replicating complex brain tissue architectures in vitro, offering a vast potential for human disease modeling. They enable the in vitro study of human physiological and pathophysiological mechanisms of various neurological diseases and disorders. The trajectory of technological advancements in brain organoid generation and engineering over the past decade indicates that the technology might, in the future, mature into indispensable solutions at the horizon of personalized and regenerative medicine. In this review, we highlight recent advances in the engineering of brain organoids as disease models and discuss some of the challenges and opportunities for future research in this rapidly evolving field.

DOI: https://doi.org/10.1016/j.copbio.2024.103253