ALG3-CDG (CDG-Id): Clinical, biochemical and molecular findings in two siblings

Riess, Suzi; Reddihough, Dinah; Howell, Katherine; Dagia, Charuta; Jaeken, Jaak; Matthijs, Gert; Yaplito‐Lee, Joy

doi:10.1016/j.ymgme.2013.05.020

Cited by 15 publications

(13 citation statements)

References 9 publications

(34 reference statements)

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“…The neurological picture is associated with dysmorphic features, visual impairment and the possible occurrence of gastrointestinal dysfunction [Riess et al, ]. The siblings reported here presented prenatally with skeletal involvement and MCA.…”

Section: Discussionmentioning

confidence: 96%

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ALG3‐CDG: Report of two siblings with antenatal features carrying homozygous p.Gly96Arg mutation

Lepais

Cheillan

Collardeau-Frachon

et al. 2015

American J of Med Genetics Pt A

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Congenital disorders of glycosylation (CDG) are a group of inborn errors of metabolism presenting with heterogeneous multisystemic clinical manifestations. To date, more than 60 different types of CDG have been reported. ALG3-CDG is very rare, with only nine patients described so far. We report two affected siblings presenting prenatally with skeletal abnormalities associated with dysmorphic features, cerebellar vermis hypoplasia, corpus callosum agenesis, hepatic fibrosis and poor prognosis. This is the first detailed report of an affected fetus including clinical, radiographic and pathological findings. The patients showed some clinical features previously unreported in ALG3-CDG, such as bone dysplasia, cataract, corneal opacities, and pons hypoplasia. Both patients were homozygous for the previously unreported p.Gly96Arg mutation of the ALG3 gene. One patient showed chondrodysplasia punctata (CDP), which has not been previously reported in CDG. An exhaustive genetic and metabolic assessment, performed in order to rule out other possible causes of CDP, showed abnormally raised levels of anti-nuclear antibodies in the mother who, nevertheless, did not show any clinical sign of autoimmune disease during a 7 years follow-up. We speculate that the observed CDP may be explained by the maternal anti-nuclear antibodies; alternatively, a possible link to the underlying metabolic disorder cannot be ruled out. In conclusion, we report the clinical, pathological, biochemical and molecular characterization of two further patients affected by ALG3-CDG, expanding the phenotypic spectrum of this very rare disease.

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Section: Discussionmentioning

confidence: 96%

“…This condition is inherited in an autosomal recessive manner. ALG3‐CDG syndrome is very rare and, to the best of our knowledge, only nine patients have been reported in the literature to date [Stibler et al, ; Körner et al, ; Denecke et al, ; Schollen et al, ; Sun et al, ; Kranz et al, ; Rimella‐Le‐Huu et al, ; Riess et al, ].…”

Section: Introductionmentioning

confidence: 99%

ALG3‐CDG: Report of two siblings with antenatal features carrying homozygous p.Gly96Arg mutation

Lepais

Cheillan

Collardeau-Frachon

et al. 2015

American J of Med Genetics Pt A

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“…Moreover, microcephaly; skeletal malformations, resembling those observed in the present patient; and ophthalmological anomalies were described (Korner et al 1999). Nine patients have been reported (review in Riess et al 2013). They all presented microcephaly, neonatal-onset intractable seizures with multiple patterns (West syndrome, tonic-clonic seizures, or combined types), and various degrees of corpus callosum involvement.…”

Section: Discussionmentioning

confidence: 99%

Electroclinical Features of Early-Onset Epileptic Encephalopathies in Congenital Disorders of Glycosylation (CDGs)

et al. 2015

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Congenital disorders of glycosylation (CDG) are a constantly growing group of genetic defects of glycoprotein and glycolipid glycan synthesis. CDGs are usually multisystem diseases, and in the majority of patients, there is an important neurological involvement comprising psychomotor disability, hypotonia, ataxia, seizures, stroke-like episodes, and peripheral neuropathy. To assess the incidence, among early-onset epileptic encephalopathies (EOEE), of patients with identified congenital disorders of glycosylation (CDG), we made a review of clinical, electrophysiological, and neuroimaging findings of 27 CDG patients focusing on seizure onset, semiology and frequency, response to antiepileptic drugs (AED), and early epileptic manifestations. Epilepsy was uncommon in PMM2-CDG (11%), while it was a main concern in other rare forms. We describe a series of patients with EOEE and genetically confirmed CDG (ALG3-CDG, ALG6-CDG, DPM2-CDG, ALG1-CDG). Epileptic seizures at onset included myoclonic and clonic fits and focal seizures. With time, patients developed recurrent and intractable seizures principally tonic-clonic seizures, infantile spasms, and myoclonic seizures. Electrophysiological correlates included focal and multifocal epileptic discharges, slowed background rhythm, and generalized epileptic activity including burst suppression pattern and status epilepticus. We propose a diagnostic flowchart for the early diagnosis of CDG in patients presenting with EOEE and suggest to perform serum transferrin IEF (or capillary zone electrophoresis) as a first-line screening in early-onset epilepsy.

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“…Unless indicated, these variants were absent in 194 unrelated Pakistani exomes with non-cognitive Mendelian phenotypes and in ~ 1000 unrelated individuals in the GME Variome Project. References per known gene: ALG3 (Riess et al 2013); ASPM (Kousar et al 2010); BCKDK (Novarino et al 2012); CRADD (Di Donato et al 2016; Harel et al 2017); CWF19L1 (Burns et al 2014; Nguyen et al 2016; Evers et al 2016); CYB5R3 (Ewenczyk et al 2008); GAN (Kuhlenbäumer et al 2002; Tazir et al 2009); LRP2 (Vasli et al 2016); MBOAT7 (Johansen et al 2016); MLYCD (Salomons et al 2007); PNKP (Shen et al 2010); SPTBN2 (Lise et al 2012); TUSC3 (Garshasbi et al 2008, 2011; Khan et al 2011; Loddo et al 2013; Al-Amri et al 2016); WDR62 (Wang et al 2017). …”

Section: Figmentioning

confidence: 99%

Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability

Santos‐Cortez

Khan

et al. 2018

Hum Genet

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Identification of Mendelian genes for neurodevelopmental disorders using exome sequencing to study autosomal recessive (AR) consanguineous pedigrees has been highly successful. To identify causal variants for syndromic and non-syndromic intellectual disability (ID), exome sequencing was performed using DNA samples from 22 consanguineous Pakistani families with ARID, of which 21 have additional phenotypes including microcephaly. To aid in variant identification, homozygosity mapping and linkage analysis were performed. DNA samples from affected family member(s) from every pedigree underwent exome sequencing. Identified rare damaging exome variants were tested for co-segregation with ID using Sanger sequencing. For seven ARID families, variants were identified in genes not previously associated with ID, including: EI24, FXR1 and TET3 for which knockout mouse models have brain defects; and CACNG7 and TRAPPC10 where cell studies suggest roles in important neural pathways. For two families, the novel ARID genes CARNMT1 and GARNL3 lie within previously reported ID microdeletion regions. We also observed homozygous variants in two ID candidate genes, GRAMD1B and TBRG1, for which each has been previously reported in a single family. An additional 14 families have homozygous variants in established ID genes, of which 11 variants are novel. All ARID genes have increased expression in specific structures of the developing and adult human brain and 91% of the genes are differentially expressed in utero or during early childhood. The identification of novel ARID candidate genes and variants adds to the knowledge base that is required to further understand human brain function and development.

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ALG3-CDG (CDG-Id): Clinical, biochemical and molecular findings in two siblings

Cited by 15 publications

References 9 publications

ALG3‐CDG: Report of two siblings with antenatal features carrying homozygous p.Gly96Arg mutation

ALG3‐CDG: Report of two siblings with antenatal features carrying homozygous p.Gly96Arg mutation

Electroclinical Features of Early-Onset Epileptic Encephalopathies in Congenital Disorders of Glycosylation (CDGs)

Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability

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