PIGT-CDG, a disorder of the glycosylphosphatidylinositol anchor: description of 13 novel patients and expansion of the clinical characteristics

Bayat, Allan; Knaus, Alexej; Juul, A; Đukić, Dejan; Gardella, Elena; Charzewska, Agnieszka; Clement, Emma; Hjalgrim, Helle; Hoffman-Zacharska, Dorota; Horn, Denise; Horton, Rachel; Hurst, Jane A.; Josifova, Dragana; Larsen, Line H.G.; Lascelles, Karine; Obersztyn, Ewa; Pagnamenta, Alistair T.; Pal, Deb K.; Pendziwiat, Manuela; Ryten, Mina; Taylor, Jenny C.; Vogt, Julie; Weber, Yvonne G.; Krawitz, Peter; Helbig, Ingo; Kini, Usha; Møller, Rikke S.

doi:10.1038/s41436-019-0512-3

Cited by 26 publications

(72 citation statements)

References 35 publications

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“…GPI synthesis and GPI‐anchored protein modification are mediated by at least 29 genes and loss‐of‐function pathogenic variants in 19 of these genes have been described to cause neurological impairments including intellectual disability (ID), developmental delay (DD), epileptic seizures and multiple congenital anomalies . So far, 26 patients with a GPI anchor deficiency due to recessive PIGT variants have been described . The predominant clinical presentation is that of an epileptic encephalopathy including common but subtle craniofacial dysmorphisms and hypotrichosis, profound ID/DD, hypotonia, cortical visual impairment, nystagmus and cortical/cerebellar atrophy .…”

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confidence: 99%

“…So far, 26 patients with a GPI anchor deficiency due to recessive PIGT variants have been described . The predominant clinical presentation is that of an epileptic encephalopathy including common but subtle craniofacial dysmorphisms and hypotrichosis, profound ID/DD, hypotonia, cortical visual impairment, nystagmus and cortical/cerebellar atrophy .…”

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confidence: 99%

“…A brain MRI performed at the age of 12 days revealed delayed myelination and a hypoplastic corpus callosum with no signs of cerebellar atrophy. He died of pneumonia at the age of 11 months (for clinical details, see ).…”

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confidence: 99%

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First report of the neuropathological findings in a patient with leukodystrophy and compound heterozygous variants in the PIGT gene

Larsen

Bayat

Møller

et al. 2019

Neuropathology Appl Neurobio

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confidence: 99%

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confidence: 99%

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First report of the neuropathological findings in a patient with leukodystrophy and compound heterozygous variants in the PIGT gene

Larsen

Bayat

Møller

et al. 2019

Neuropathology Appl Neurobio

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“…Hyperphosphatasia may be seen in those with pathogenic variant(s) in PIGA, PIGO, and PIGV. [80][81][82][83][84][85][86]…”

Section: Inherited Gpi Deficienciesmentioning

confidence: 99%

Metabolic Disorders Presenting with Seizures in the Neonatal Period

Brimble

Ruzhnikov

2020

Semin Neurol

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Metabolic disorders represent rare but often treatable causes of seizures and epilepsy of neonatal onset. As seizures are relatively common in the neonatal period, systemic clues to a specific diagnosis may be lacking or shrouded by acute illness. An important role of the consulting pediatric neurologist is to identify neonates with a possible metabolic or otherwise genetic diagnosis. In this review, the authors describe presenting signs and symptoms, a diagnostic framework, and disorder-specific treatment options for inborn errors of metabolism that may present in the neonatal period. Specific attention is given to the neurologic aspects of each condition, including the electroclinical phenotype and findings on brain imaging. As expedited diagnosis and prompt initiation of available therapies have been demonstrated to result in improved epilepsy and developmental outcomes, this work acts as a framework to guide evaluation when an inherited metabolic disorder is suspected. In addition to informing treatment, a definitive diagnosis allows for appropriate counseling regarding prognosis, any associated screening or preventive measures, and family planning.

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“…Therefore, we applied an approach with higher sensitivity and specificity to analyze genotype-phenotype correlations. Here, we used data from previously published cases 5,25,26 as well as unpublished facial images of individuals with mutations in GPAA1, PIGA, PIGN, PGAP3, and PIGT to compare the facial gestalt to that of individuals with mutations in PIGU (n ¼ 5). We chose PIGA (n ¼ 25), PIGN (n ¼ 15), PIGT (n ¼ 13), PIGV (n ¼ 24), and PGAP3 (n ¼ 25) (unpublished data) as the most prevalent GPIBDs and we chose GPAA1 (n ¼ 5) as another gene of the GPI transamidase complex.…”

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confidence: 99%

Mutations in PIGU Impair the Function of the GPI Transamidase Complex, Causing Severe Intellectual Disability, Epilepsy, and Brain Anomalies

Knaus

Kortüm

Kleefstra

et al. 2019

The American Journal of Human Genetics

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The glycosylphosphatidylinositol (GPI) anchor links over 150 proteins to the cell surface and is present on every cell type. Many of these proteins play crucial roles in neuronal development and function. Mutations in 18 of the 29 genes implicated in the biosynthesis of the GPI anchor have been identified as the cause of GPI biosynthesis deficiencies (GPIBDs) in humans. GPIBDs are associated with intellectual disability and seizures as their cardinal features. An essential component of the GPI transamidase complex is PIGU, along with PIGK, PIGS, PIGT, and GPAA1, all of which link GPI-anchored proteins (GPI-APs) onto the GPI anchor in the endoplasmic reticulum (ER). Here, we report two homozygous missense mutations (c.209T>A [p.Ile70Lys] and c.1149C>A [p.Asn383Lys]) in five individuals from three unrelated families. All individuals presented with global developmental delay, severe-to-profound intellectual disability, muscular hypotonia, seizures, brain anomalies, scoliosis, and mild facial dysmorphism. Using multicolor flow cytometry, we determined a characteristic profile for GPI transamidase deficiency. On granulocytes this profile consisted of reduced cell-surface expression of fluorescein-labeled proaerolysin (FLAER), CD16, and CD24, but not of CD55 and CD59; additionally, B cells showed an increased expression of free GPI anchors determined by T5 antibody. Moreover, computer-assisted facial analysis of different GPIBDs revealed a characteristic facial gestalt shared among individuals with mutations in PIGU and GPAA1. Our findings improve our understanding of the role of the GPI transamidase complex in the development of nervous and skeletal systems and expand the clinical spectrum of disorders belonging to the group of inherited GPI-anchor deficiencies.

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PIGT-CDG, a disorder of the glycosylphosphatidylinositol anchor: description of 13 novel patients and expansion of the clinical characteristics

Cited by 26 publications

References 35 publications

First report of the neuropathological findings in a patient with leukodystrophy and compound heterozygous variants in the PIGT gene

First report of the neuropathological findings in a patient with leukodystrophy and compound heterozygous variants in the PIGT gene

Metabolic Disorders Presenting with Seizures in the Neonatal Period

Mutations in PIGU Impair the Function of the GPI Transamidase Complex, Causing Severe Intellectual Disability, Epilepsy, and Brain Anomalies

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