Maternal mosaicism underlies the inheritance of a rare germline AKT3 variant which is responsible for megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome in two Roma half-siblings

Szalai, Renáta; Melegh, Béla; Till, Ágnes; Ripszám, Réka; Csábí, Györgyi; Acharya, Anushree; Schrauwen, Isabelle; Leal, Suzanne M.; Komoly, Sámuel; Kosztolányi, György; Hadzsiev, Kinga

doi:10.1016/j.yexmp.2020.104471

Cited by 6 publications

(16 citation statements)

References 32 publications

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“…Table 2 shows conditions associated with megacephaly, polymicrogyria, and congenital hydrocephalus. Polydactyly is related to numerous conditions, so we decided to exclude polydactyly from the table [1][2][3][4][5].…”

Section: Components Of the Syndromementioning

confidence: 99%

“…In table 3 we present some cases which highlight the clinical variation of the syndrome [3,4,[11][12][13][14][15].…”

Section: Clinical Variation Of the Syndromementioning

confidence: 99%

“…The RAC-alpha serine/threonine-protein kinase (AKT) gene is located on chromosome 1 and encodes for a serine/threonine kinase, which it is mainly expressed in the central nervous system [ 4 ]. AKT is part of a PI3K-AKT-mTOR pathway and is important in cell growth, metabolism, brain development, synaptic plasticity, neurodevelopment, and cancer formation [ 3 , 4 ]. Most cases occur due to a mutation in the PIKT-AKT pathway.…”

Section: Introductionmentioning

confidence: 99%

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Megalencephaly Polymicrogyria Polydactyly Hydrocephalus (MPPH): A Case Report and Review of Literature

Ortíz¹,

Ruxmohan²,

Khurana³

et al. 2021

Cureus

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Megacephaly polymicrogyria, polydactyly, hydrocephalus (MPPH) is an extremely rare condition caused by a defect in the AKT3, CCND2, or PIKR2 genes. Although the prevalence of the syndrome is very low, there is a significant clinical and radiological variation in the syndrome. We present a case with MPPH admitted to the hospital due to an increase in seizure frequency. The patient had a history of cerebral palsy, global developmental delay, spasticity, and hypoglycemic episodes. MRI findings revealed ventriculomegaly, polymicrogyria, abnormal encephalon, and pachygyria. The addition of clobazam and alprazolam diminished the seizures' frequency and the patient's spasticity, respectively. To highlight the clinical and radiological variation of the syndrome, we review cases of MPPH with clinical and radiological variants. Pachygyria and cerebral palsy are new associations not previously described before in MPPH. Pachygyria and cerebral palsy could be worsening the seizures and the global delay in this patient. Hypoglycemic episodes are probably related to the AKT3 gene, promoting more glucose consumption. Spasticity is most probably related to an upper motor sign due to the patient's cerebral palsy. This case highlights the clinical and radiological variation of the syndrome. More cases of MPPH need to be described to consolidate the knowledge and have a better understanding of the clinical and radiological variation of the syndrome.

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Section: Components Of the Syndromementioning

confidence: 99%

“…In table 3 we present some cases which highlight the clinical variation of the syndrome [3,4,[11][12][13][14][15].…”

Section: Clinical Variation Of the Syndromementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Megalencephaly Polymicrogyria Polydactyly Hydrocephalus (MPPH): A Case Report and Review of Literature

Ortíz¹,

Ruxmohan²,

Khurana³

et al. 2021

Cureus

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“…One such syndrome, megalencephaly polydactyly polymicrogyria hydrocephalus (MPPH) syndrome was first described in five patients in 2004 (Mirzaa et al, 2004) and has subsequently been reported in only a small number of additional patients (Colombani et al, 2006;Garavelli et al, 2007;Osterling et al, 2011;Pisano et al, 2008;Tohyama et al, 2007;Tore et al, 2009Riviere et al, 2012;Szalai et al, 2020). MPPH features early overgrowth of brain more than somatic tissues, cortical brain malformations (including polymicrogyria), and distal limb anomalies including polydactyly.…”

mentioning

confidence: 99%

“…Molecular diagnosis of MPPH hinges on identifying a heterozygous germline variant in AKT3, CCND2, or PIK3R2 genes (Lee et al, 2012;Lindhurst et al, 2012;Mirzaa et al, 2014;Riviere et al, 2012). There have also been reports of mosaicism in patients with somatic variants in PIK3R2 (Mirzaa, 2016;Szalai et al, 2020).…”

mentioning

confidence: 99%

Medulloblastoma in the setting of megalencephaly polymicrogyria polydactyly hydrocephalus

Hadzipasic

Karsten

Olson

et al. 2021

American J of Med Genetics Pt A

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The somatic p.T81dup variant in AKT3 gene underlies a mild cerebral phenotype and expands the spectrum including capillary malformation and lateralized overgrowth

Luca

Piglionica

Bagnulo

et al. 2023

Genes Chromosomes & Cancer

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Heterozygous germline or somatic variants in AKT3 gene can cause isolated malformations of cortical development (MCDs) such as focal cortical dysplasia, megalencephaly (MEG), Hemimegalencephaly (HME), dysplastic megalencephaly, and syndromic forms like megalencephaly‐polymicrogyria‐polydactyly‐hydrocephalus syndrome, and megalencephaly‐capillary malformation syndrome. This report describes a new case of HME and capillary malformation caused by a somatic AKT3 variant that differs from the common p.E17K variant described in literature. The patient's skin biopsy from the angiomatous region revealed an heterozygous likely pathogenic variant AKT3:c.241_243dup, p.(T81dup) that may affect the binding domain and downstream pathways. Compared to previously reported cases with a common E17K mosaic variant, the phenotype is milder and patients showed segmental overgrowth, an uncommon characteristic in AKT3 variant cases. These findings suggest that the severity of the disease may be influenced not only by the level of mosaicism but also by the type of variant. This report expands the phenotypic spectrum associated with AKT3 variants and highlights the importance of genomic analysis in patients with capillary malformation and MCDs.

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Maternal mosaicism underlies the inheritance of a rare germline AKT3 variant which is responsible for megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome in two Roma half-siblings

Cited by 6 publications

References 32 publications

Megalencephaly Polymicrogyria Polydactyly Hydrocephalus (MPPH): A Case Report and Review of Literature

Megalencephaly Polymicrogyria Polydactyly Hydrocephalus (MPPH): A Case Report and Review of Literature

Medulloblastoma in the setting of megalencephaly polymicrogyria polydactyly hydrocephalus

The somatic p.T81dup variant in AKT3 gene underlies a mild cerebral phenotype and expands the spectrum including capillary malformation and lateralized overgrowth

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