A Clinically Severe Variant of β-Mannosidosis, Presenting with Neonatal Onset Epilepsy with Subsequent Evolution of Hydrocephalus

Broomfield, Alexander; Gunny, R; Ali, Imran; Vellodi, Ashok; Prabhakar, P

doi:10.1007/8904_2013_227

Cited by 10 publications

(9 citation statements)

References 20 publications

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“…Furthermore, two sequence variants found in ruminants are suggested to abolish the β-mannosidase enzyme activity, resulting in the severe neurodegenerative phenotype (Leipprandt et al 1996, 1999). Comparing patients reported in the literature, no clear genotype–phenotype correlation could be shown in humans (Bedilu et al 2002; Broomfield et al 2013), and variability is suggested to be due to the involvement of other genetic and environmental factors (Gort et al 2006; Riise Stensland et al 2008; Lovell et al 2014). However, comparative structural bioinformatics analyses of inherited mutations reported in MANBA until 2011 indicated the existence of genotype–phenotype correlation in β-mannosidosis (Huynh et al 2011).…”

Section: Discussionmentioning

confidence: 79%

“…So far, to our knowledge, only 22 cases of β-mannosidosis in 18 families from a range of ethnic backgrounds have been reported since the disease was first described in 1986 (Cooper et al 1986; Wenger et al 1986). The disease has a highly variable clinical presentation (Bedilu et al 2002; Riise Stensland et al 2008) including intellectual disability/developmental delay, behavioral disturbance, recurrent infections, hearing loss, and severe neurological phenotypes such as epileptic encephalopathy, hydrocephalus, and spinocerebellar ataxia (Sedel et al 2006; Labauge et al 2009; Broomfield et al 2013). Dysmorphic traits have been reported (Poenaru et al 1992; Labauge et al 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Common symptoms include various degrees of developmental delay, behavioral disturbances, hearing loss, and frequent infections (Wenger et al 1986). Angiokeratomas, facial and skeletal dysmorphic features, hypotonia, peripheral neuropathy, and seizures have also been reported in some of the patients (Cooper et al 1991; Cherian 2004; Broomfield et al 2013). Several of these symptoms are typical for glycoproteinoses.…”

Section: Introductionmentioning

confidence: 91%

“…MANBA is located on Chromosome 4q24 and encodes an 879-amino acid lysosomal protein (Alkhayat et al 1998). So far, only 22 cases of β-mannosidose from 18 families have been reported in humans (Riise Stensland et al 2008; Labauge et al 2009; Broomfield et al 2013). Disease-causing variants include both null mutations (splice, nonsense, small frameshift deletions/insertions) and missense mutations (Riise Stensland et al 2008; Labauge et al 2009; Broomfield et al 2013).…”

Section: Introductionmentioning

confidence: 99%

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β-Mannosidosis caused by a novel homozygous intragenic inverted duplication in MANBA

Blomqvist

Smeland

Lindgren

et al. 2019

Cold Spring Harb Mol Case Stud

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β-Mannosidosis is a lysosomal storage disorder characterized by accumulation of disaccharides due to deficiency of the lysosomal enzyme β-mannosidase. The disease is caused by mutations in MANBA and is extremely rare in humans. Although the clinical presentation is heterogeneous, common symptoms include various degrees of developmental delay, behavioral disturbances, hearing loss, and frequent infections. We report a 15-yr-old girl presenting with mild intellectual disability, sensorineural hearing loss, severe behavioral disturbances, dysmorphic traits, and evolving angiokeratomas. Copy-number variation analysis of next-generation sequencing (NGS) data indicated increased coverage in exons 8–11 of MANBA . Low β-mannosidase activity (1 µkatal/kg protein, refv 25–40) established the diagnosis of β-mannosidosis. Whole-genome sequencing (WGS) and cDNA analysis revealed a novel homozygous intragenic inverted duplication in MANBA, where a 13.1-kb region between introns 7 and 11 was duplicated and inserted in an inverted orientation, creating a 67-base nonduplicated gap at the insertion point. Both junctions showed microhomology regions. The inverted duplication resulted in exon skipping of exons 8–9 or 8–10. Our report highlights the importance of copy-number variation analysis of data from NGS and in particular the power of WGS in the identification and characterization of copy-number variants.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

β-Mannosidosis caused by a novel homozygous intragenic inverted duplication in MANBA

Blomqvist

Smeland

Lindgren

et al. 2019

Cold Spring Harb Mol Case Stud

View full text Add to dashboard Cite

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“…The encoded protein localizes to the lysosome where it is the final exoglycosidase in the pathway for N-linked glycoprotein oligosaccharide catabolism. Mutations in this gene cause beta-mannosidosis, including severe forms with neonatal onset epilepsy [ 171 ]. RSC1A1 gene product regulates the neuronal expression of the Na + -D-glucose cotransporter SGLT1, which is increased in the hippocampus during epileptic seizures [ 172 ].…”

Section: Resultsmentioning

confidence: 99%

Community Structure Analysis of Transcriptional Networks Reveals Distinct Molecular Pathways for Early- and Late-Onset Temporal Lobe Epilepsy with Childhood Febrile Seizures

et al. 2015

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Age at epilepsy onset has a broad impact on brain plasticity and epilepsy pathomechanisms. Prolonged febrile seizures in early childhood (FS) constitute an initial precipitating insult (IPI) commonly associated with mesial temporal lobe epilepsy (MTLE). FS-MTLE patients may have early disease onset, i.e. just after the IPI, in early childhood, or late-onset, ranging from mid-adolescence to early adult life. The mechanisms governing early (E) or late (L) disease onset are largely unknown. In order to unveil the molecular pathways underlying E and L subtypes of FS-MTLE we investigated global gene expression in hippocampal CA3 explants of FS-MTLE patients submitted to hippocampectomy. Gene coexpression networks (GCNs) were obtained for the E and L patient groups. A network-based approach for GCN analysis was employed allowing: i) the visualization and analysis of differentially expressed (DE) and complete (CO) - all valid GO annotated transcripts - GCNs for the E and L groups; ii) the study of interactions between all the system’s constituents based on community detection and coarse-grained community structure methods. We found that the E-DE communities with strongest connection weights harbor highly connected genes mainly related to neural excitability and febrile seizures, whereas in L-DE communities these genes are not only involved in network excitability but also playing roles in other epilepsy-related processes. Inversely, in E-CO the strongly connected communities are related to compensatory pathways (seizure inhibition, neuronal survival and responses to stress conditions) while in L-CO these communities harbor several genes related to pro-epileptic effects, seizure-related mechanisms and vulnerability to epilepsy. These results fit the concept, based on fMRI and behavioral studies, that early onset epilepsies, although impacting more severely the hippocampus, are associated to compensatory mechanisms, while in late MTLE development the brain is less able to generate adaptive mechanisms, what has implications for epilepsy management and drug discovery.

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Epilepsy as a Late Complication

Turğut

Turgut

2014

Complications of CSF Shunting in Hydrocephalus

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A Clinically Severe Variant of β-Mannosidosis, Presenting with Neonatal Onset Epilepsy with Subsequent Evolution of Hydrocephalus

Abstract: b-Mannosidosis results from a functional deficiency of the lysosomal enzyme, b-mannosidase.

Cited by 10 publications

References 20 publications

β-Mannosidosis caused by a novel homozygous intragenic inverted duplication in MANBA

β-Mannosidosis caused by a novel homozygous intragenic inverted duplication in MANBA

Community Structure Analysis of Transcriptional Networks Reveals Distinct Molecular Pathways for Early- and Late-Onset Temporal Lobe Epilepsy with Childhood Febrile Seizures

Epilepsy as a Late Complication

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