bims-meglyc 2023-11-19 papers

Genet Med. 2023 Nov 10. pii: S1098-3600(23)01043-2. [Epub ahead of print] 101027

Neurological manifestations in PMM2-congenital disorders of glycosylation (PMM2-CDG): Insights into clinico-radiological characteristics, recommendations for follow-up and future directions.

Karthik Muthusamy, Judit M Perez-Ortiz, Anna N Ligezka, Ruqaiah Altassan, Christin Johnsen, Matthew J Schultz, Marc C Patterson, Eva Morava.

PURPOSE: In the absence of prospective data on neurological symptoms, disease outcome, or guidelines for system specific management in PMM2-CDG, we aimed to collect and review natural history data.METHODS: Fifty-one molecularly confirmed individuals with PMM2-CDG enrolled in the FCDGC natural history study were reviewed. In addition, we prospectively reviewed a smaller cohort of these individuals with PMM2-CDG on off-label acetazolamide treatment.
RESULTS: Mean age at diagnosis was 28.04 months. Developmental delay is a constant phenotype. Neurological manifestation included ataxia (90.2%), myopathy (82.4%), seizures (56.9%), neuropathy (52.9%), microcephaly (19.1%), extrapyramidal symptoms (27.5%), stroke-like episodes (SLE) (15.7%) and spasticity (13.7%). Progressive cerebellar atrophy is the characteristic neuroimaging finding. Additionally, supratentorial white matter changes were noted in adult age. No correlation was observed between the seizure severity and SLE risk, though all patients with SLE have had seizures in the past. "Off label" acetazolamide therapy in a smaller sub-cohort resulted in improvement in speech fluency but did not show statistically significant improvement in objective ataxia scores.
CONCLUSION: Clinical and radiological findings suggest both neurodevelopmental and neurodegenerative pathophysiology. Seizures may manifest at any age and are responsive to levetiracetam monotherapy in most cases. Febrile seizure is the most common trigger for SLEs. Acetazolamide is well tolerated.

Keywords: Congenital Disorders of Glycosylation; PMM2-CDG; Phosphomannomutase 2 enzyme; Stroke like episode (SLE); acetazolamide

DOI: https://doi.org/10.1016/j.gim.2023.101027

bioRxiv. 2023 Oct 27. pii: 2023.10.27.564441. [Epub ahead of print]

Drosophila models of PIGA-CDG mirror patient phenotypes.

Holly J Thorpe, Katie G Owings, Miriam C Aziz, Madelyn Haller, Emily Coelho, Clement Y Chow.

Mutations in the phosphatidylinositol glycan biosynthesis class A (PIGA) gene cause a rare, X-linked recessive congenital disorder of glycosylation (CDG). PIGA-CDG is characterized by seizures, intellectual and developmental delay, and congenital malformations. The PIGA gene encodes an enzyme involved in the first step of GPI anchor biosynthesis. There are over 100 GPI anchored proteins that attach to the cell surface and are involved in cell signaling, immunity, and adhesion. Little is known about the pathophysiology of PIGA-CDG. Here we describe the first Drosophila model of PIGA-CDG and demonstrate that loss of PIG-A function in Drosophila accurately models the human disease. As expected, complete loss of PIG-A function is larval lethal. Heterozygous null animals appear healthy, but when challenged, have a seizure phenotype similar to what is observed in patients. To identify the cell-type specific contributions to disease, we generated neuron- and glia-specific knockdown of PIG-A . Neuron-specific knockdown resulted in reduced lifespan and a number of neurological phenotypes, but no seizure phenotype. Glia-knockdown also reduced lifespan and, notably, resulted in a very strong seizure phenotype. RNAseq analyses demonstrated that there are fundamentally different molecular processes that are disrupted when PIG-A function is eliminated in different cell types. In particular, loss of PIG-A in neurons resulted in upregulation of glycolysis, but loss of PIG-A in glia resulted in upregulation of protein translation machinery. Here we demonstrate that Drosophila is a good model of PIGA-CDG and provide new data resources for future study of PIGA-CDG and other GPI anchor disorders.Article Summary: PIGA-CDG is a rare genetic disorder. In order to study this rare disease, we generated and characterized several Drosophila models of PIGA-CDG. These models faithfully recapitulate different patient phenotypes, including movement disorder and seizures. Drosophila is a good model for PIGA-CDG and other GPI anchor disorders.

DOI: https://doi.org/10.1101/2023.10.27.564441

Hepatology. 2023 Nov 17.

Genetic landscape of pediatric acute liver failure of indeterminate origin.

Dominic Lenz, Lea D Schlieben, Masaru Shimura, Alyssa Bianzano, Dmitrii Smirnov, Robert Kopajtich, Riccardo Berutti, Rüdiger Adam, Denise Aldrian, Ivo Baric, Ulrich Baumann, Neslihan Eksi Bozbulut, Melanie Brugger, Theresa Brunet, Philip Bufler, Birutė Burnytė, Pier Luigi Calvo, Ellen Crushell, Buket Dalgıç, Anibh M Das, Antal Dezsőfi, Felix Distelmaier, Alexander Fichtner, Peter Freisinger, Sven F Garbade, Harald Gaspar, Louise Goujon, Nedim Hadzic, Steffen Hartleif, Bianca Hegen, Maja Hempel, Stephan Henning, Andre Hoerning, Roderick Houwen, Joanne Hughes, Raffaele Iorio, Katarzyna Iwanicka-Pronicka, Martin Jankofsky, Norman Junge, Ino Kanavaki, Aydan Kansu, Sonja Kaspar, Simone Kathemann, Deidre Kelly, Ceyda Tuna Kırsaçlıoğlu, Birgit Knoppke, Martina Kohl, Heike Kölbel, Stefan Kölker, Vassiliki Konstantopoulou, Tatiana Krylova, Zarife Kuloğlu, Alice Kuster, Martin W Laass, Elke Lainka, Eberhard Lurz, Hanna Mandel, Katharina Mayerhanser, Johannes A Mayr, Patrick McKiernan, Patricia McLean, Valerie McLin, Karine Mention, Hanna Müller, Laurent Pasquier, Martin Pavlov, Natalia Pechatnikova, Bianca Peters, Danijela Petković Ramadža, Dorota Piekutowska-Abramczuk, Denisa Pilic, Sanjay Rajwal, Nathalie Rock, Agnès Roetig, René Santer, Wilfried Schenk, Natalia Semenova, Christiane Sokollik, Ekkehard Sturm, Robert W Taylor, Eva Tschiedel, Vaidotas Urbonas, Roser Urreizti, Jan Vermehren, Jerry Vockley, Georg-Friedrich Vogel, Matias Wagner, Wendy van der Woerd, Saskia B Wortmann, Ekaterina Zakharova, Georg Friedrich Hoffmann, Thomas Meitinger, Kei Murayama, Christian Staufner, Holger Prokisch.

BACKGROUND AIMS: Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, main causes are viral infections (12-16%) and inherited metabolic diseases (14-28%). Yet, in up to 50% of cases the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition.METHODS: With this international, multicenter observational study, patients (0-18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed.
RESULTS: In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF (RALF). WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (46%), and in children with RALF (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8) and DGUOK (n=7) were the most frequent findings. When categorizing, most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%) and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplants.
CONCLUSION: This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics.

DOI: https://doi.org/10.1097/HEP.0000000000000684

Brain. 2023 Nov 10. pii: awad380. [Epub ahead of print]

Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders.

Rauan Kaiyrzhanov, Aboulfazl Rad, Sheng-Jia Lin, Aida Bertoli-Avella, Wouter W Kallemeijn, Annie Godwin, Maha S Zaki, Kevin Huang, Tracy Lau, Cassidy Petree, Stephanie Efthymiou, Ehsan Ghayoor Karimiani, Maja Hempel, Elizabeth A Normand, Sabine Rudnik-Schöneborn, Ulrich A Schatz, Marc P Baggelaar, Muhammad Ilyas, Tipu Sultan, Javeria Raza Alvi, Manizha Ganieva, Ben Fowler, Ruxandra Aanicai, Gulsen Akay Tayfun, Abdulaziz Al Saman, Abdulrahman Alswaid, Nafise Amiri, Nilufar Asilova, Vorasuk Shotelersuk, Patra Yeetong, Matloob Azam, Meisam Babaei, Gholamreza Bahrami Monajemi, Pouria Mohammadi, Saeed Samie, Selina Husna Banu, Jorge Pinto Basto, Fanny Kortüm, Mislen Bauer, Peter Bauer, Christian Beetz, Masoud Garshasbi, Awatif Hameed Issa, Wafaa Eyaid, Hind Ahmed, Narges Hashemi, Kazem Hassanpour, Isabella Herman, Sherozjon Ibrohimov, Ban A Abdul-Majeed, Maria Imdad, Maksudjon Isrofilov, Qassem Kaiyal, Suliman Khan, Brian Kirmse, Janet Koster, Charles Marques Lourenço, Tadahiro Mitani, Oana Moldovan, David Murphy, Maryam Najafi, Davut Pehlivan, Maria Eugenia Rocha, Vincenzo Salpietro, Miriam Schmidts, Adel Shalata, Mohammad Mahroum, Jawabreh Kassem Talbeya, Robert W Taylor, Dayana Vazquez, Annalisa Vetro, Hans R Waterham, Mashaya Zaman, Tina A Schrader, Wendy K Chung, Renzo Guerrini, James R Lupski, Joseph Gleeson, Mohnish Suri, Yalda Jamshidi, Kailash P Bhatia, Barbara Vona, Michael Schrader, Mariasavina Severino, Matthew Guille, Edward W Tate, Gaurav K Varshney, Henry Houlden, Reza Maroofian.

The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins, and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Utilizing exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with YnMyr chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), with ages ranging from 1 to 50 years old, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%), and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%), and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%), and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each), as well as hypertrophy of the clava (24%) were common neuroimaging findings. acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism, and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localisation and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-Myristoylation was similarly affected in acbd6-deficient zebrafish and Xenopus tropicalis models, including Fus, Marcks, and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders.

Keywords: ACBD6 ; N-myristoylation; ataxia; dystonia; neudegeneration; parkinsonism

DOI: https://doi.org/10.1093/brain/awad380

Prenat Diagn. 2023 Nov 13.

Intrauterine enzyme replacement therapies for lysosomal storage disorders: Current developments and promising future prospects.

Akos Herzeg, Beltran Borges, Billie R Lianoglou, Juan Gonzalez-Velez, Emma Canepa, Dane Munar, Sarah P Young, Deeksha Bali, Michel H Gelb, Pranesh Chakraborty, Priya S Kishnani, Paul Harmatz, Jennifer L Cohen, Tippi C MacKenzie.

Lysosomal storage disorders (LSDs) are a group of monogenic condition, with many characterized by an enzyme deficiency leading to the accumulation of an undegraded substrate within the lysosomes. For those LSDs, postnatal enzyme replacement therapy (ERT) represents the standard of care, but this treatment has limitations when administered only postnatally because, at that point, prenatal disease sequelae may be irreversible. Furthermore, most forms of ERT, specifically those administered systemically, are currently unable to access certain tissues, such as the central nervous system (CNS), and furthermore, may initiate an immune response. In utero enzyme replacement therapy (IUERT) is a novel approach to address these challenges evaluated in a first-in-human clinical trial for IUERT in LSDs (NCT04532047). IUERT has numerous advantages: in-utero intervention may prevent early pathology; the CNS can be accessed before the blood-brain barrier forms; and the unique fetal immune system enables exposure to new proteins with the potential to prevent an immune response and may induce sustained tolerance. However, there are challenges and limitations for any fetal procedure that involves two patients. This article reviews the current state of IUERT for LSDs, including its advantages, limitations, and potential future directions for definitive therapies.

DOI: https://doi.org/10.1002/pd.6460