Early and lethal neurodegeneration with myasthenic and myopathic features

Schorling, David; Rost, S.; Lefeber, Dirk; Brady, Lauren; Müller, C. R.; Korinthenberg, Rudolf; Tarnopolsky, Mark A.; Bönnemann, Carsten G.; Rodenburg, Richard J.; Bugiani, Marianna; Beytia, M.; Krüger, Marcus; Knaap, Marjo van der; Kirschner, Janbernd

doi:10.1212/wnl.0000000000004234

Cited by 20 publications

(22 citation statements)

References 19 publications

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“…Epilepsy is a common finding in patients with glycosylation deficiencies, with a wide spectrum of severity and semiology (Freeze et al 2015). Severe epilepsy, often beginning as Ohtahara syndrome (early infantile epileptic encephalopathy) or West syndrome (hypsarrhythmia, clinical spasms, and developmental arrest) and sometimes developing into multifocal hard-to-treat epilepsy, has been reported for many CDG types, including ALG1-CDG (Fiumara et al 2016;Barba et al 2016), ALG3-CDG (Fiumara et al 2016;Barba et al 2016), ALG6-CDG (Fiumara et al 2016), ALG13-CDG (Hamici et al 2017), ALG14-CDG (Schorling et al 2017), DPM2-CDG (Fiumara et al 2016), DOLK-CDG (Helander et al 2013), RFT1-CDG (Barba et al 2016), SLC35A2-CDG (Ng et al 2013), and SLC35A3-CDG (Marini et al 2017). In the published cohort of DPAGT1-CDG patients including this report, 4/24 patients have had the diagnosis West syndrome, and 9 more have a definitive diagnosis of epilepsy, whereas only 3 were negated to have epilepsy.…”

Section: Discussionmentioning

confidence: 99%

DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical and Genetic Description of 11 New Patients

Underhill

Palm

et al. 2018

JIMD Reports

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Pathogenic mutations in DPAGT1 cause a rare type of a congenital disorder of glycosylation termed DPAGT1-CDG or, alternatively, a milder version with only myasthenia known as DPAGT1-CMS. Fourteen disease-causing mutations in 28 patients from 10 families have previously been reported to cause the systemic form, DPAGT1-CDG. We here report on another 11 patients from 8 families and add 10 new mutations. Most patients have a very severe disease course, where common findings are pronounced muscular hypotonia, intractable epilepsy, global developmental delay/intellectual disability, and early death. We also present data on three affected females that are young adults and have a somewhat milder, stable disease. Our findings expand both the molecular and clinical knowledge of previously published data but also widen the phenotypic spectrum of DPAGT1-CDG.

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Section: Discussionmentioning

confidence: 99%

DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical and Genetic Description of 11 New Patients

Underhill

Palm

et al. 2018

JIMD Reports

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“…Recently, mutations in ALG14 were also found in five patients with a rapidly progressive and early lethal CDG phenotype. Severe hypotonia and contractures were present from birth, which temporarily improved with pyridostigmine treatment …”

Section: Clinical Presentation Of Lg‐cms Patientsmentioning

confidence: 99%

Clinical and research strategies for limb‐girdle congenital myasthenic syndromes

O’Connor

Töpf

Zahedi

et al. 2018

Annals of the New York Academy of Sciences

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Congenital myasthenic syndromes (CMS) are a group of rare disorders that cause fatigable muscle weakness due to defective signal transmission at the neuromuscular junction, a specialized synapse between peripheral motor neurons and their target muscle fibers. There are now over 30 causative genes that have been reported for CMS. Of these, there are 10 that are associated with a limb-girdle pattern of muscle weakness and are thus classed as LG-CMS. Next-generation sequencing and advanced methods of data sharing are likely to uncover further genes that are associated with similar clinical phenotypes, contributing to better diagnosis and effective treatment of LG-CMS patients. This review highlights clinical and pathological hallmarks of LG-CMS in relation to the underlying genetic defects and pathways. Tailored animal and cell models are essential to elucidate the exact function and pathomechanisms at the neuromuscular synapse that underlie LG-CMS. The integration of genomics and proteomics data derived from these models and patients reveals new and often unexpected insights that are relevant beyond the rare genetic disorder of LG-CMS and may extend to the functioning of mammalian synapses in health and disease more generally.

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“…Interestingly, this is also true for the ALG13-specific binding partner, ALG14, where biallelic variants cause both congenital myasthenic syndrome-15 (ALG14-CMS) and also a disorder characterized as an early lethal neurodegeneration with myasthenic and myopathic features. 38,39 While ALG13 and ALG14 are both ubiquitously expressed proteins, it is possible that deficiencies in either could cause a tissue-specific disorder. This has for example been seen with a few CDG types that primarily affect the liver (eg, MPI-CDG, TMEM199-CDG, CDCC115-CDG, ATP6AP1-CDG).…”

Section: Discussionmentioning

confidence: 99%

Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions

Ng¹,

Eklund²,

Shiryaev³

et al. 2020

J of Inher Metab Disea

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Asparagine-linked glycosylation 13 homolog (ALG13) encodes a nonredundant, highly conserved, X-linked uridine diphosphate (UDP)-Nacetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N-linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13-CDG. Twenty-four previously reported ALG13-CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13-CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13-deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We

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Early and lethal neurodegeneration with myasthenic and myopathic features

Cited by 20 publications

References 19 publications

DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical and Genetic Description of 11 New Patients

DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical and Genetic Description of 11 New Patients

Clinical and research strategies for limb‐girdle congenital myasthenic syndromes

Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions

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