Angelman syndrome — insights into a rare neurogenetic disorder

Buiting, Karin; Williams, Charles A.; Horsthemke, Bernhard

doi:10.1038/nrneurol.2016.133

Cited by 289 publications

(282 citation statements)

References 109 publications

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“…However, as the healthy father had the identical genetic and biochemical phenotype and further studies in the index patient showed signs unusual for DPD deficiency, additional studies were performed that finally demonstrated AS. Characteristic signs of AS such as microcephaly, delayed development and characteristic EEG features were encountered in the patient (Buiting et al 2016).…”

Section: Discussionmentioning

confidence: 99%

“…A deletion of the maternal allele of chromosome 15q11.2-13-1 causative for AS was identified (Fig. 3) (Buiting et al 2016).…”

Section: Case Reportmentioning

confidence: 99%

“…In 75% of cases, an interstitial deletion of the maternal part of the chromosome is causative. Genomic imprinting defects, paternal uniparenteral disomy of chromosome 15 and intragenic mutations or deletions of UBE3A gene have also been reported as causes for AS (Buiting et al 2016).…”

Section: Introductionmentioning

confidence: 99%

“…The EEG changes in AS encompass three quite distinctive main patterns: rhythmic high amplitude 2-3 Hz activity predominantly over the frontal regions; rhythmic high amplitude 4-6 Hz activity or 4-5 Hz spike waves over the parietooccipital regions after eye closure. These patterns may appear isolated or in various combinations and often evolve over time in affected individuals (Buiting et al 2016;Boyd et al 1988). The major characteristic in AS is, however, neither the MRI nor the EEG but development and behaviour, which can be characterised as severe intellectual disability, absence of speech, paroxysmal periods of laughter, sleeping disturbances including reversal of the day-night rhythm, and extreme hyperactivity which can result in uncontrolled movements due to ataxia.…”

Section: Introductionmentioning

confidence: 99%

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Dihydropyrimidine Dehydrogenase Deficiency: Metabolic Disease or Biochemical Phenotype?

et al. 2017

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Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disorder of pyrimidine metabolism that impairs the first step of uracil und thymine degradation. The spectrum of clinical presentations in subjects with the full biochemical phenotype of DPD deficiency ranges from asymptomatic individuals to severely affected patients suffering from seizures, microcephaly, muscular hypotonia, developmental delay and eye abnormalities.We report on a boy with intellectual disability, significant impairment of speech development, highly active epileptiform discharges on EEG, microcephaly and impaired gross-motor development. This clinical presentation triggered metabolic workup that demonstrated the biochemical phenotype of DPD deficiency, which was confirmed by enzymatic and molecular genetic studies. The patient proved to be homozygous for a novel c.2059-22T>G mutation which resulted in an in-frame insertion of 21 base pairs (c.2059-21_c.2059-1) of intron 16 of DPYD.Family investigation showed that the asymptomatic father was also homozygous for the same mutation and enzymatic and biochemical findings were similar to his severely affected son. When the child deteriorated clinically, exome sequencing was initiated under the hypothesis that DPD deficiency did not explain the phenotype completely. A deletion of the maternal allele on chromosome 15q11.2-13-1 was identified allowing the diagnosis of Angelman syndrome (AS). This diagnosis explains the patient's clinical presentation sufficiently; the influence of DPD deficiency on the phenotype, however, remains uncertain.

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Section: Discussionmentioning

confidence: 99%

“…A deletion of the maternal allele of chromosome 15q11.2-13-1 causative for AS was identified (Fig. 3) (Buiting et al 2016).…”

Section: Case Reportmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dihydropyrimidine Dehydrogenase Deficiency: Metabolic Disease or Biochemical Phenotype?

et al. 2017

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“…Leptin and other adipokines are ideal candidates for such signalling molecules. Microcephaly, a number of neurological disorders, including intellectual and speech deficiencies, behavioural and sleep abnormalities and epilepsy Buiting et al, 2016 Prader-Willi syndrome (PWS, OMIM 176270)…”

Section: Energy Homeostasis and Resource Allocation During Pregnancymentioning

confidence: 99%

Genomic imprinting, growth and maternal–fetal interactions

Cassidy

Charalambous

2018

Journal of Experimental Biology

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In the 1980s, mouse nuclear transplantation experiments revealed that both male and female parental genomes are required for successful development to term (McGrath and Solter, 1983; Surani and Barton, 1983). This non-equivalence of parental genomes is because imprinted genes are predominantly expressed from only one parental chromosome. Uniparental inheritance of these genomic regions causes paediatric growth disorders such as Beckwith–Wiedemann and Silver–Russell syndromes (reviewed in Peters, 2014). More than 100 imprinted genes have now been discovered and the functions of many of these genes have been assessed in murine models. The first such genes described were the fetal growth factor insulin-like growth factor 2 (Igf2) and its inhibitor Igf2 receptor (Igf2r) (DeChiara et al., 1991; Lau et al., 1994; Wang et al., 1994). Since then, it has emerged that most imprinted genes modulate fetal growth and resource acquisition in a variety of ways. First, imprinted genes are required for the development of a functional placenta, the organ that mediates the exchange of nutrients between mother and fetus. Second, these genes act in an embryo-autonomous manner to affect the growth rate and organogenesis. Finally, imprinted genes can signal the nutritional status between mother and fetus, and can modulate levels of maternal care. Importantly, many imprinted genes have been shown to affect postnatal growth and energy homeostasis. Given that abnormal birthweight correlates with adverse adult metabolic health, including obesity and cardiovascular disease, it is crucial to understand how the modulation of this dosage-sensitive, epigenetically regulated class of genes can contribute to fetal and postnatal growth, with implications for lifelong health and disease.

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A parent‐of‐origin analysis of paternal genetic variants and increased risk of conotruncal heart defects

Nembhard

Tang

et al. 2018

American J of Med Genetics Pt A

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The association between conotruncal heart defects (CTHDs) and maternal genetic and environmental exposures is well studied. However, little is known about paternal genetic or environmental exposures and risk of CTHDs. We assessed the effect of paternal genetic variants in the folate, homocysteine, and transsulfuration pathways on risk of CTHDs in offspring. We utilized National Birth Defects Prevention Study data to conduct a family-based case only study using 616 live-born infants with CTHDs, born October 1997-August 2008. Maternal, paternal and infant DNA was genotyped using an Illumina® Golden Gate custom single nucleotide polymorphism (SNP) panel. Relative risks (RR) and 95% confidence intervals (CI) from log-linear models determined parent of origin effects for 921 SNPs in 60 candidate genes involved in the folate, homocysteine, and transsulfuration pathways on risk of CTHDs. The risk of CTHD among children who inherited a paternally derived copy of the A allele on GLRX (rs17085159) or the T allele of GLRX (rs12109442) was 0.23 (95%CI: 0.12, 0.42; p = 1.09 × 10 ) and 0.27 (95%CI: 0.14, 0.50; p = 2.06 × 10 ) times the risk among children who inherited a maternal copy of the same allele. The paternally inherited copy of the GSR (rs7818511) A allele had a 0.31 (95%CI: 0.18, 0.53; p = 9.94 × 10 ] risk of CTHD compared to children with the maternal copy of the same allele. The risk of CTHD is less influenced by variants in paternal genes involved in the folate, homocysteine, or transsulfuration pathways than variants in maternal genes in those pathways.

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Angelman syndrome — insights into a rare neurogenetic disorder

Cited by 289 publications

References 109 publications

Dihydropyrimidine Dehydrogenase Deficiency: Metabolic Disease or Biochemical Phenotype?

Dihydropyrimidine Dehydrogenase Deficiency: Metabolic Disease or Biochemical Phenotype?

Genomic imprinting, growth and maternal–fetal interactions

A parent‐of‐origin analysis of paternal genetic variants and increased risk of conotruncal heart defects

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