bims-meglyc 2023-10-01 papers

Mol Syndromol. 2023 Aug;14(4): 322-330

DPAGT1-CDG: Report of Two New Pediatric Patients and Brief Review of the Literature.

Özlem Özsoy, Tayfun Cinleti, Çağatay Günay, Gamze Sarıkaya Uzan, Mehmet Can Yeşilmen, Hanns Lochmüller, Rita Horvath, Uluç Yiş, Yavuz Oktay, Semra Hiz Kurul.

Introduction: Congenital glycosylation disorders are multisystem diseases with heterogeneous clinical manifestations caused by defects in the synthesis of the glycan moiety of glycoproteins or glycolipids or the binding of glycans to proteins and lipids. DPAGT1 (UDP-GlcNAc: dolichol phosphate N-acetylglucosamine-1-phosphotransferase) is an initiating protein in the biosynthetic pathway of dolichol-linked oligosaccharides required for protein N-glycosylation. Pathogenic variants in DPAGT1 (UDP-GlcNAc: dolichol phosphate N-acetylglucosamine-1-phosphotransferase) gene cause a rare type of congenital glycosylation disorder called DPAGT1-CDG (formerly CDG-Ij) (OMIM #608093). It is a rare autosomal recessive disease or a milder version with congenital myasthenic syndrome known as DPAGT1-CMS. A severe disease course with hypotonia, cataracts, skeletal deformities, resistant epilepsy, intellectual disability, global developmental delay, premature death has been described in most patients with DPAGT1-CDG.
Patient Presentation: We describe two patients with variants in the DPAGT1 gene: an 8-month-old boy with a homozygous, missense DPAGT1:c.339T>G (p.Phe113Leu) novel variant and a 13-year-old female patient with compound heterozygous variants, DPAGT1:c.466C>T (p.Arg156Cys, R156C) and DPAGT1:c.161+5G>A. While the 8-month-old patient was diagnosed with congenital cataract at the age of 1 month, had dysmorphic findings, and epilepsy, clinical symptoms in the other patient appeared later but with more prominent muscle weakness, behavioral disorder, dysmorphic findings, and no epilepsy.
Discussion: Cholinesterase inhibitor therapy was found to be effective in patients against muscle weakness, supporting DPAGT1 deficiency as the underlying etiology. We started pyridostigmine treatment in our patient with more pronounced muscle weakness, and we saw its benefit. We aimed to present our patients diagnosed with DPAGT1-CDG due to different variants in the same gene and different clinical presentations, treatment and to compare them with other patients in the literature.

Keywords: Congenital disorders of glycosylation; DPAGT1 gene; Dysmorphic facial features; Epilepsy; Muscle weakness

DOI: https://doi.org/10.1159/000529494

Hum Mol Genet. 2023 Sep 26. pii: ddad164. [Epub ahead of print]

Identification of a muscle-specific isoform of VMA21 as a potent actor in X-linked myopathy with excessive autophagy pathogenesis.

Ilaria Cocchiararo, Olivia Cattaneo, Jayasimman Rajendran, Florent Chabry, Mélanie Cornut, Hadrien Soldati, Anne Bigot, Kamel Mamchaoui, Sara Gibertini, Axelle Bouche, Daniel J Ham, Thomas Laumonier, Alexandre Prola, Perrine Castets.

Defective lysosomal acidification is responsible for a large range of multi-systemic disorders associated with impaired autophagy. Diseases caused by mutations in the VMA21 gene stand as exceptions, specifically affecting skeletal muscle (X-linked Myopathy with Excessive Autophagy, XMEA) or liver (Congenital Disorder of Glycosylation). VMA21 chaperones vacuolar (v-) ATPase assembly, which is ubiquitously required for proper lysosomal acidification. The reason VMA21 deficiencies affect specific, but divergent tissues remains unknown. Here, we show that VMA21 encodes a yet-unreported long protein isoform, in addition to the previously described short isoform, which we name VMA21-120 and VMA21-101, respectively. In contrast to the ubiquitous pattern of VMA21-101, VMA21-120 was predominantly expressed in skeletal muscle, and rapidly up-regulated upon differentiation of mouse and human muscle precursors. Accordingly, VMA21-120 accumulated during development, regeneration and denervation of mouse skeletal muscle. In contrast, neither induction nor blockade of autophagy, in vitro and in vivo, strongly affected VMA21 isoform expression. Interestingly, VMA21-101 and VMA21-120 both localized to the sarcoplasmic reticulum of muscle cells, and interacted with the v-ATPase. While VMA21 deficiency impairs autophagy, VMA21-101 or VMA21-120 overexpression had limited impact on autophagic flux in muscle cells. Importantly, XMEA-associated mutations lead to both VMA21-101 deficiency and loss of VMA21-120 expression. These results provide important insights into the clinical diversity of VMA21-related diseases and uncover a muscle-specific VMA21 isoform that potently contributes to XMEA pathogenesis.

Keywords: VMA21; XMEA; autophagy; myogenesis; v-ATPase

DOI: https://doi.org/10.1093/hmg/ddad164

Cells. 2023 Sep 19. pii: 2314. [Epub ahead of print]12(18):

Inborn Errors of Metabolism with Ataxia: Current and Future Treatment Options.

Tatiana Bremova-Ertl, Jan Hofmann, Janine Stucki, Anja Vossenkaul, Matthias Gautschi.

A number of hereditary ataxias are caused by inborn errors of metabolism (IEM), most of which are highly heterogeneous in their clinical presentation. Prompt diagnosis is important because disease-specific therapies may be available. In this review, we offer a comprehensive overview of metabolic ataxias summarized by disease, highlighting novel clinical trials and emerging therapies with a particular emphasis on first-in-human gene therapies. We present disease-specific treatments if they exist and review the current evidence for symptomatic treatments of these highly heterogeneous diseases (where cerebellar ataxia is part of their phenotype) that aim to improve the disease burden and enhance quality of life. In general, a multimodal and holistic approach to the treatment of cerebellar ataxia, irrespective of etiology, is necessary to offer the best medical care. Physical therapy and speech and occupational therapy are obligatory. Genetic counseling is essential for making informed decisions about family planning.

Keywords: GM2-gangliosidosis; Niemann-Pick type C; abetalipoproteinemia; acetyl-DL-leucine; acetyl-L-leucine; biomarkers; cerebellar ataxia; cerebrotendinous xanthomatosis; disease-modifying treatment; disorders of carbohydrate metabolism; hereditary metabolic ataxia; inborn error of metabolism; lysosomal storage disorders; metabolic diseases; neurodegeneration; neuroprotection; ocular motor; symptomatic treatment

DOI: https://doi.org/10.3390/cells12182314

World J Exp Med. 2023 Sep 20. 13(4): 59-74

Neurologic orphan diseases: Emerging innovations and role for genetic treatments.

Ivelina P Kioutchoukova, Devon T Foster, Rajvi N Thakkar, Marco A Foreman, Brandon J Burgess, Rebecca M Toms, Eduardo E Molina Valero, Brandon Lucke-Wold.

Orphan diseases are rare diseases that affect less than 200000 individuals within the United States. Most orphan diseases are of neurologic and genetic origin. With the current advances in technology, more funding has been devoted to developing therapeutic agents for patients with these conditions. In our review, we highlight emerging options for patients with neurologic orphan diseases, specifically including diseases resulting in muscular deterioration, epilepsy, seizures, neurodegenerative movement disorders, inhibited cognitive development, neuron deterioration, and tumors. After extensive literature review, gene therapy offers a promising route for the treatment of neurologic orphan diseases. The use of clustered regularly interspaced palindromic repeats/Cas9 has demonstrated positive results in experiments investigating its role in several diseases. Additionally, the use of adeno-associated viral vectors has shown improvement in survival, motor function, and developmental milestones, while also demonstrating reversal of sensory ataxia and cardiomyopathy in Friedreich ataxia patients. Antisense oligonucleotides have also been used in some neurologic orphan diseases with positive outcomes. Mammalian target of rapamycin inhibitors are currently being investigated and have reduced abnormal cell growth, proliferation, and angiogenesis. Emerging innovations and the role of genetic treatments open a new window of opportunity for the treatment of neurologic orphan diseases.

Keywords: Adeno-associated virus; Antisense oligonucleotides; Clustered regularly interspaced palindromic repeats/Cas9; Gene therapy; Neurologic orphan diseases; mTOR inhibitors

DOI: https://doi.org/10.5493/wjem.v13.i4.59