bims-meglyc 2025-01-26 papers

Issue of 2025–01–26
seven papers selected by
Silvia Radenkovic, UMC Utrecht

Clin Case Rep. 2025 Jan;13(1): e70027

Pediatric Anesthetic Management of a Patient With an ALG-13 Gene Mutation, a Rare Congenital Disorder of Glycosylation.

Esha Thakkar, John A Iasiello, Sunny R Cai, Adrienne Hutton.

Congenital disorders of glycosylation are rare and present a challenge in management due to interactions with intraoperative medications. We present safe and successful anesthetic management of a pediatric patient with an ALG-13 gene mutation.

Keywords: ALG‐13 mutation; congenital disorders of glycosylation; malignant hyperthermia; pediatric anesthesia; pharmacology

DOI: https://doi.org/10.1002/ccr3.70027

Mol Genet Metab. 2025 Jan 15. pii: S1096-7192(25)00015-0. [Epub ahead of print]144(3): 109024

Rare disorders, big challenges: Special issue on congenital disorders of glycosylation.

Peter Witters, Carlos R Ferreira.

DOI: https://doi.org/10.1016/j.ymgme.2025.109024

J Investig Med High Impact Case Rep. 2025 Jan-Dec;13:13 23247096251313731

A Case of Rafiq Syndrome (MAN1B1-CDG) in a Palestinian Child, With Brief Literature Review of 44 Cases.

Reema Iskafi, Bahaa AbuRahmeh, Roa'a Aljuneidi, Hidaya AlShweiki, Siraj Abdelnabi, Anas Abukhalaf, Bara' Maraqa.

Rafiq syndrome, MAN1B1-CDG, was described in 2010 and associated with genetic mutation in MAN1B1 gene in 2011. The disorder follows an autosomal recessive pattern of inheritance and typically presents with specific facial dysmorphism, intellectual disability, developmental delay, obesity, and hypotonia. The syndrome belongs to a group of metabolic disorders called Congenital Glycosylation Disorders (CGD). In this study, we discuss a 5-year-old male from Palestine who presented with developmental delay, hypotonia, characteristic facial dysmorphisms, impulsive behaviors, inability to speak, cryptorchidism, and other manifestations. This constellation of manifestations raised suspicion of a genetic disorder, prompting whole exome sequencing (WES), which revealed the presence of a homozygous likely pathogenic variant in the MAN1B1 gene (c.1976T>G)(p.Phe659Cys). We also reviewed all previously documented cases and compared the clinical features among them. After reviewing the family pedigree and its suspected cases, we found that the 2 most frequent features among them are intellectual disability and facial dysmorphism, whereas the least frequent one is truncal obesity. We discussed the importance of providing genetic counseling to parents of children with this and other rare, autosomal recessive disorders to prevent new cases from appearing.

Keywords: MAN1B1 mutation; Rafiq syndrome; case report; intellectual disability; truncal obesity

DOI: https://doi.org/10.1177/23247096251313731

Neurol Sci. 2025 Jan 20.

First case report of effective and safe application of cannabidiol to treat concurrent ALG3-CDG and Lennox-Gastaut Syndrome.

Seok-Jin Lee, Ji-Hoon Na, Hyunjoo Lee, Young-Mock Lee.

This study presents the first reported case of a Korean patient with Alpha-1,3-Mannosyltransferase-Congenital Disorder of Glycosylation (ALG3-CDG), characterized by a novel maternally inherited missense mutation and a previously reported paternally inherited nonsense mutation. The patient exhibited typical ALG3-CDG manifestations, including developmental delays, epilepsy, and multisystem involvement, alongside a diagnosis of Lennox-Gastaut Syndrome (LGS). Cannabidiol therapy, combined with dietary management, led to seizure freedom for over 13 months, significant EEG improvement, and enhanced developmental outcomes. This case underscores the potential of cannabidiol as a promising treatment strategy for patients with ALG3-CDG and refractory epilepsy, broadening therapeutic perspectives for this rare disorder.

Keywords: ALG3-CDG; Cannabidiol; Epilepsy; Lennox-Gastaut Syndrome

DOI: https://doi.org/10.1007/s10072-025-08004-1

Int Med Case Rep J. 2025 ;18 111-116

X-Linked Autism Type 9 Caused by a Hemizygote Pathogenic Variant in the TMLHE Gene: Etiological Diagnosis in an Adult Male with Moderate Intellectual Disability.

Willem M A Verhoeven, Rolph Pfundt, Udo F H Engelke, Leo A J Kluijtmans, Jos I M Egger.

Introduction: Levocarnitine is essential for brain functioning and fatty acid metabolism and stems largely from dietary sources. The Epsilon-Trimethyllysine Hydroxylase (TMLHE) gene encodes the enzyme N-Trimethyllysine hydroxylase (TMLH) which catalyses the first step in the biosynthesis of carnitine. Lack of TMLH enzyme activity is associated with developmental delay and autistic behaviours described as X-linked recessive autism, type 6 (OMIM#300872).
Patient and Methods: Here, an institutionalized adult male patient with intellectual disability, autism, and challenging behaviours is presented in whom genetic analysis disclosed a novel pathogenic variant in the TMLHE gene. Extensive somatic, neurological, psychiatric, and neuropsychological investigations were performed next to examination of hematological and biochemical parameters including plasma carnitine status. Also, Whole Exome Sequencing (WES) and Next-Generation Metabolic Screening (NGMS) were performed.
Results: Moderate intellectual disability along with obsessive and aggressive behaviour in the context of autism spectrum disorders was established as well as symptoms from the catatonic spectrum. With WES, a novel variant in the TMHLE gene was identified and using NGMS, increased concentration of trimethyllysine and decreased concentration of γ-butyrobetaine were found resulting in a significantly decreased BB/TML ratio, confirming the pathogenicity of this variant.
Conclusion: X-linked autism type 6 is characterized by moderate intellectual disability and symptoms from the autism spectrum in the absence of any dysmorphisms. To prevent regressive autistic episodes in young children, it is highly recommended to consider next-generation sequencing techniques as the first step in the differential diagnostic process of autism.

Keywords: TMLHE; autism; contextual neuropsychology; epsilon-trimethyllysine hydroxylase gene; intellectual disability; levocarnitine; psychopathology

DOI: https://doi.org/10.2147/IMCRJ.S506204

bioRxiv. 2025 Jan 10. pii: 2025.01.10.632366. [Epub ahead of print]

A zebrafish model of nicotinamide adenine dinucleotide (NAD+) deficiency-derived congenital disorders.

Visakuo Tsurho, Carla Gilliland, Jessica Ensing, Elizabeth Vansickle, Nathan J Lanning, Paul R Mark, Stephanie Grainger.

Congenital NAD deficiency disorder (CNDD) is a multisystem condition in which cardiac, renal, vertebral, and limb anomalies are most common, but anomalies in all organ systems have been identified. Patients with this condition have biallelic pathogenic variants involving genes in the nicotinamide adenine dinucleotide (NAD+) synthesis pathway leading to decreased systemic NAD+ levels. CNDD anomalies mimic the clinical features described in vertebral-anal-cardiac-tracheoesophageal fistula-renal-limb (VACTERL) association raising the possibility that CNDD and VACTERL association possess similar underlying causes. However, the mechanism by which NAD+ deficiency causes CNDD developmental anomalies has not been determined, nor has NAD+ deficiency been definitively linked to VACTERL association. Therefore, additional animal models amenable to detailed observation of embryonic development are needed to address the causes and progression of congenital anomalies in both CNDD and VACTERL association. Here, we describe a zebrafish model of NAD+ disruption to begin to model CNDD and VACTERL association phenotypes, assessing developmental anomalies in real-time. Treatment of zebrafish embryos with 2-amino-1,3,4-thiadiazole (ATDA), a teratogen known to disrupt NAD+ metabolism, resulted in neural tube, craniofacial, cardiac, and tail defects. These defects were rescued by the administration of nicotinamide (NAM) in a dose-dependent manner. Our work establishes zebrafish as a useful model for investigating the mechanistic causes and developmental dynamics of CNDD and VACTERL association. Further, as VACTERL association has been linked to teratogens, our zebrafish model provides a platform to assess these agents.

Keywords: 2-Amino-1,3,4-thiadiazole (ATDA); birth defects; congenital NAD deficiency disorder (CNDD); nicotinamide (NAM); nicotinamide adenine dinucleotide (NAD+); vertebral-anal-cardiac-tracheoesophageal fistula-renal-limb (VACTERL) association; zebrafish

DOI: https://doi.org/10.1101/2025.01.10.632366

Int J Neonatal Screen. 2024 Dec 28. pii: 1. [Epub ahead of print]11(1):

Newborn Screening by DNA-First: Systematic Evaluation of the Eligibility of Inherited Metabolic Disorders Based on Treatability.

Abigail Veldman, Birgit Sikkema-Raddatz, Terry G J Derks, Clara D M van Karnebeek, M B Gea Kiewiet, Margaretha F Mulder, Marcel R Nelen, M Estela Rubio-Gozalbo, Richard J Sinke, Monique G de Sain-van der Velden, Gepke Visser, Maaike C de Vries, Dineke Westra, Monique Williams, Ron A Wevers, M Rebecca Heiner-Fokkema, Francjan J van Spronsen.

The biomarker-based Dutch Newborn Screening (NBS) panel (as of 2024) comprises 19 inherited metabolic disorders (IMDs). With the use of next-generation sequencing (NGS) as a first-tier screen, NBS could expand to include IMDs that lack a reliable biochemical footprint in dried blood spots, while also reducing secondary findings. To be eligible for inclusion in NBS, an IMD needs to fulfill the Wilson and Jungner criteria, with treatability being one of the most important criteria. In this study, we aimed to identify IMDs eligible for DNA-first NBS when considering only treatability in the context of NBS as a prerequisite. First, three independent reviewers performed a systematic literature review of the 1459 genotypic IMDs and their causative gene(s), as described in the International Classification of Inherited Metabolic Disorders (dated 1 February 2021), applying 16 criteria to exclude non-treatable disorders. Eligible disorders were then discussed in three online meetings with a project group of clinical laboratory geneticists, medical laboratory specialists specialized in IMD, and pediatricians with expertise in IMDs. Based on treatability, we identified 100 genes, causing 95 IMDs, as eligible for NBS, including 42 causal genes for the IMDs in the current biomarker-based NBS. The other 58 genes are primarily associated with treatable defects in amino acid metabolism and fatty acid oxidation. Other IMDs were excluded, most often because of insufficient literature. As the evaluation of treatability was not straightforward, we recommend the development of standardized treatability scores for the inclusion of IMDs in NBS.

Keywords: Wilson and Jungner criteria; genetics-first; heel prick; inborn errors of metabolism; inherited metabolic disease; newborn screening; next-generation sequencing; treatability

DOI: https://doi.org/10.3390/ijns11010001