A novel <scp><i>ALG14</i></scp> missense variant in an alive child with myopathy, epilepsy, and progressive cerebral atrophy

Palombo, Flavia; Piccolo, Benedetta; Saccani, Elena; Fiorini, Claudio; Capristo, Mariantonietta; Caporali, Leonardo; Pisani, Francesco; Carelli, Valerio

doi:10.1002/ajmg.a.62153

Cited by 3 publications

(5 citation statements)

References 11 publications

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“…Patients with a truncation variant (p.Arg104*) also show a mild disease course (Cossins et al, 2013), while those associated with point mutations show a more severe disease course (Palombo et al, 2021;Schorling et al, 2017). In patients 1 and 2, we found a previously unreported, novel variant closer to the C-terminus (Figure 1e).…”

Section: Discussionmentioning

confidence: 68%

“…The mechanisms by which CMS, MEPCA, and CDG caused by ALG14 pathogenic variants lead to delayed myelination and abnormal brain formation are currently unknown. ALG14 is ubiquitously expressed, including in the central nervous system, and glycosylation of α-dystroglycan is important for brain development (Chan et al, 2010;Palombo et al, 2021). It is highly likely that the abnormal glycosylation caused by the ALG14 pathological mutation is directly related to the central nervous system abnormalities, but organ-specific functional analysis using mouse model or induced pluripotent stem cell is necessary.…”

Section: Discussionmentioning

confidence: 99%

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The longest reported sibling survivors of a severe form of congenital myasthenic syndrome with the ALG14 pathogenic variant

Katata

Uneoka

Saijyo

et al. 2021

American J of Med Genetics Pt A

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Congenital myasthenic syndromes (CMS) is a group of diseases that causes abnormalities at the neuromuscular junction owing to genetic anomalies. The pathogenic variant in ALG14 results in a severe pathological form of CMS causing end-plate acetylcholine receptor deficiency. Here, we report the cases of two siblings with CMS associated with a novel variant in ALG14. Immediately after birth, they showed hypotonia and multiple joint contractures with low Apgar scores. Ptosis, low-set ears, and high-arched palate were noted. Deep tendon reflexes were symmetrical. They showed worsening swallowing and respiratory problems; hence, nasal feeding and tracheotomy were performed. Cranial magnetic resonance imaging scans revealed delayed myelination and cerebral atrophy. Exome sequencing indicated that the siblings had novel compound heterozygous missense variants, c.590T>G (p.Val197Gly) and c.433G>A (p.Gly145Arg), in exon 4 of ALG14. Repetitive nerve stimulation test showed an abnormal decrease in compound muscle action potential. After treatment with pyridostigmine, the time off the respirator increased. Their epileptic seizures were well controlled by anti-epileptic drugs. Their clinical course is stable even now at the ages of 5 and 2 years, making them the longest reported survivors of a severe form of CMS with the ALG14 variant thus far.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

The longest reported sibling survivors of a severe form of congenital myasthenic syndrome with the ALG14 pathogenic variant

Katata

Uneoka

Saijyo

et al. 2021

American J of Med Genetics Pt A

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“…To date, a total of sixteen ALG13-CDG and nine ALG14-CDG missense mutations have been identified from patients ( de Ligt et al, 2012 ; Timal et al, 2012 ; Esposito et al, 2013 ; Judith et al, 2013 ; Smith-Packard et al, 2015 ; Dimassi et al, 2016 ; Kobayashi et al, 2016 ; Bastaki et al, 2017 ; Hamici et al, 2017 ; Schorling et al, 2017 ; Kvarnung et al, 2018 ; Ng et al, 2020 ; Alsharhan et al, 2021 ; Datta et al, 2021 ; Palombo et al, 2021 ; Gang et al, 2022 ; Katata et al, 2022 ). Among these ALG13-CDG mutations, eight are located in the N-terminal region of ALG13 that is shared by isoform 1 and 2 ( Figure 5A ), while the remaining seven mutations are located in regions unique to ALG13-iso1, and only one mutation is located in short C-terminal of isoform 2 (data not shown).…”

Section: Resultsmentioning

confidence: 99%

An in vitro assay for enzymatic studies on human ALG13/14 heterodimeric UDP-N-acetylglucosamine transferase

Wang

Chen

et al. 2022

Front. Cell Dev. Biol.

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The second step of eukaryotic lipid-linked oligosaccharide (LLO) biosynthesis is catalyzed by the conserved ALG13/ALG14 heterodimeric UDP-N-acetylglucosamine transferase (GnTase). In humans, mutations in ALG13 or ALG14 lead to severe neurological disorders with a multisystem phenotype, known as ALG13/14-CDG (congenital disorders of glycosylation). How these mutations relate to disease is unknown because to date, a reliable GnTase assay for studying the ALG13/14 complex is lacking. Here we describe the development of a liquid chromatography/mass spectrometry-based quantitative GnTase assay using chemically synthesized GlcNAc-pyrophosphate-dolichol as the acceptor and purified human ALG13/14 dimeric enzyme. This assay enabled us to demonstrate that in contrast to the literature, only the shorter human ALG13 isoform 2, but not the longer isoform 1 forms a functional complex with ALG14 that participates in LLO synthesis. The longer ALG13 isoform 1 does not form a complex with ALG14 and therefore lacks GnTase activity. Importantly, we further established a quantitative assay for GnTase activities of ALG13- and ALG14-CDG variant alleles, demonstrating that GnTase deficiency is the cause of ALG13/14-CDG phenotypes.

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“…ALG2 -CMS has been reported in 9 patients in 4 pedigrees since 2013 [ 24 , 401 ]. ALG14 -CMS has been reported in 12 patients in 7 pedigrees since 2013 [ 24 , 402 , 403 , 404 , 405 ]. In muscle biopsy of a patient with GFPT1 -CMS, glycogen storage was observed, and glycogen storage disease was considered [ 406 ].…”

Section: Thirty-five Genes In 14 Groups Of Cmsmentioning

confidence: 99%

“…In muscle biopsy of a patient with GFPT1 -CMS, glycogen storage was observed, and glycogen storage disease was considered [ 406 ]. In 12 patients with ALG14 -CMS, 10 patients had epilepsy [ 402 , 403 , 404 , 405 ], and 2 had severe intellectual disability [ 403 ].…”

Section: Thirty-five Genes In 14 Groups Of Cmsmentioning

confidence: 99%

Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes—A Comprehensive Review

Ohno

Ohkawara

Shen

et al. 2023

IJMS

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Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by impaired neuromuscular signal transmission due to germline pathogenic variants in genes expressed at the neuromuscular junction (NMJ). A total of 35 genes have been reported in CMS (AGRN, ALG14, ALG2, CHAT, CHD8, CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, COL13A1, COLQ, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MUSK, MYO9A, PLEC, PREPL, PURA, RAPSN, RPH3A, SCN4A, SLC18A3, SLC25A1, SLC5A7, SNAP25, SYT2, TOR1AIP1, UNC13A, VAMP1). The 35 genes can be classified into 14 groups according to the pathomechanical, clinical, and therapeutic features of CMS patients. Measurement of compound muscle action potentials elicited by repetitive nerve stimulation is required to diagnose CMS. Clinical and electrophysiological features are not sufficient to identify a defective molecule, and genetic studies are always required for accurate diagnosis. From a pharmacological point of view, cholinesterase inhibitors are effective in most groups of CMS, but are contraindicated in some groups of CMS. Similarly, ephedrine, salbutamol (albuterol), amifampridine are effective in most but not all groups of CMS. This review extensively covers pathomechanical and clinical features of CMS by citing 442 relevant articles.

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A novel ALG14 missense variant in an alive child with myopathy, epilepsy, and progressive cerebral atrophy

Cited by 3 publications

References 11 publications

The longest reported sibling survivors of a severe form of congenital myasthenic syndrome with the ALG14 pathogenic variant

The longest reported sibling survivors of a severe form of congenital myasthenic syndrome with the ALG14 pathogenic variant

An in vitro assay for enzymatic studies on human ALG13/14 heterodimeric UDP-N-acetylglucosamine transferase

Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes—A Comprehensive Review

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