Long-term follow-up and novel genotype-phenotype analysis of monozygotic twins with ATP1A3 mutation in Alternating Hemiplegia of Childhood-2

Pavone, Piero; Pappalardo, Xena Giada; Incorpora, Gemma; Falsaperla, Raffaele; Marino, Simona Domenica; Corsello, Giovanni; Parano, Enrico; Ruggieri, Martino

doi:10.1016/j.ejmg.2020.103957

Cited by 12 publications

(11 citation statements)

References 23 publications

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“…However, the combination of the reciprocal translocation with the 3 rare variants of TMPRSS9 (2 of which were considered to be deleterious in predictive databases) could probably explained the spermatogenesis phenotype. These observations strengthen the “two genetic defects” hypothesis for spermatogenesis failure, as has been seen for several other pathologies [ 34 ].…”

Section: Discussionsupporting

confidence: 87%

Azoospermia and reciprocal translocations: should whole-exome sequencing be recommended?

Ghieh

Barbotin

Prasivoravong

et al. 2021

Basic Clin. Androl.

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Background Although chromosome rearrangements are responsible for spermatogenesis failure, their impact depends greatly on the chromosomes involved. At present, karyotyping and Y chromosome microdeletion screening are the first-line genetic tests for patients with non-obstructive azoospermia. Although it is generally acknowledged that X or Y chromosome rearrangements lead to meiotic arrest and thus rule out any chance of sperm retrieval after a testicular biopsy, we currently lack markers for the likelihood of testicular sperm extraction (TESE) in patients with other chromosome rearrangements. Results We investigated the use of a single nucleotide polymorphism comparative genome hybridization array (SNP-CGH) and whole-exome sequencing (WES) for two patients with non-obstructive azoospermia and testicular meiotic arrest, a reciprocal translocation: t(X;21) and t(20;22), and an unsuccessful TESE. No additional gene defects were identified for the t(X;21) carrier - suggesting that t(X;21) alone damages spermatogenesis. In contrast, the highly consanguineous t(20;22) carrier had two deleterious homozygous variants in the TMPRSS9 gene; these might have contributed to testicular meiotic arrest. Genetic defect was confirmed with Sanger sequencing and immunohistochemical assessments on testicular tissue sections. Conclusions Firstly, TMPRSS9 gene defects might impact spermatogenesis. Secondly, as a function of the chromosome breakpoints for azoospermic patients with chromosome rearrangements, provision of the best possible genetic counselling means that genetic testing should not be limited to karyotyping. Given the risks associated with TESE, it is essential to perform WES - especially for consanguineous patients.

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Section: Discussionsupporting

confidence: 87%

Azoospermia and reciprocal translocations: should whole-exome sequencing be recommended?

Ghieh

Barbotin

Prasivoravong

et al. 2021

Basic Clin. Androl.

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“…The clinical features and course of the disorder was rather similar in both girls but one of whom exhibited milder manifestations as regards the frequency and the intensity of the AHC episodes, in both of twins the ID was mild. A wider clinical manifestation of the twins has been previously reported [12]. The clinical onset started in their rst few months of life with paroxysmal events bath-induced lasted two years.…”

Section: Case Reportsmentioning

confidence: 68%

“…The candidate gene approach identi ed in twin girls a pathogenic variant p.Asn773Ser of ATP1A3 gene (rs606231437) associated with AHC-2 (Table 2) [12]. In the siblings, WES analysis found no mutations in ATP1A3 and ATP1A2 genes, identi ying three potentially pathogenic missense variants of GRIN2A, SCN1B and KCNQ2 genes in the asymptomatic father and the eldest son (Table 1), while in the youngest son was detected only the GRIN2A variant.…”

Section: Resultsmentioning

confidence: 99%

Alternating Hemiplegia of Childhood, neurological comorbidities, intrafamilial variability: case-reports and literature review.

Pavone¹,

Pappalardo²,

Mustafa³

et al. 2021

Preprint

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BACKGROUND Alternating Hemiplegia of Childhood (AHC) is an uncommon and complex disorder characterized by age of onset before 18 months, recurrent hemiplegia of one or either sides of the body or quadriplegia. Neurological comorbidities observed in two couples of AHC affected children are here reported together with data drawn by literature review. Results of genetic analysis obtained in the probands are also discussed. Developmental delay, epilepsy, tonic or dystonic spells, nystagmus and autonomic manifestations are frequently reported. AHC is mainly caused by mutations in ATP1A3 gene, and to a lesser extent in ATP1A2 gene.CASE PRESENTATION Clinical and genetic findings of a couple of twins and a couple of siblings affected by AHC from two different Italian families were deeply examined. Intrafamilial clinical variability was shown in the present cases. A pathogenic variant rs606231437 in ATP1A3 gene was detected in twins. For the affected siblings of family 2, the genetic results showed that the older brother and the healthy father shared a novel variant of GRIN2A (c.3175T>A) gene, and two missense mutations in SCNIB (rs150721582) and KCNQ2 (rs771211103) genes. In the younger brother was found only the GRIN2A variant.CONCLUSIONS Developmental delay, epileptic seizures and motor dysfunction are features frequently associated to paroxysmal hemiplegic attacks. Hemiplegic episode is only a sign even if the most remarkable of several neurological comorbidities in AHC carriers. The comparison of molecular analysis among the four probands brings out how the genetic framework is not recurrent, but may result from an unexpected greater genetic heterogeneity.

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“…The clinical features and course of the disorder was rather similar in both girls but one of whom exhibited milder manifestations as regards the frequency and the intensity of the AHC episodes, in both of twins the ID was mild. A wider clinical manifestation of the twins has been previously reported [8]. The clinical onset started in their rst few months of life with paroxysmal events bath-induced lasted two years.…”

Section: Patient Information Of Family (Twin Pair)mentioning

confidence: 68%

“…The candidate gene approach identi ed in twin girls a pathogenic variant p.Asn773Ser of ATP1A3 gene (rs606231437) associated with AHC-2 ( Table 2) [8]. In the siblings, WES analysis found no mutations in ATP1A3 and ATP1A2 genes, identi ying three potentially pathogenic missense variants of GRIN2A, SCN1B and KCNQ2 genes in the affected children and their father ( Table 2).…”

Section: Resultsmentioning

confidence: 99%

Alternating Hemiplegia of Childhood and Neurological Comorbidities. Variable Intrafamilial Clinical Features.

Pavone

Pappalardo

Mustafa

et al. 2020

Preprint

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BACKGROUND Alternating Hemiplegia of Childhood (AHC) is an uncommon and complex disorder characterized by age of onset before 18 months, recurrent hemiplegia of one or either sides of the body or quadriplegia. Developmental delay, epilepsy, tonic or dystonic spells, nystagmus and autonomic manifestations are frequently reported manifestations. AHC is mainly caused by mutations in ATP1A3 gene, and to a lesser extent in ATP1A2 gene.CASE PRESENTATION Clinical and genetic findings of a couple of twins and a couple of siblings affected by AHC from two different Italian families were deeply examined. Intrafamilial clinical variability was shown in the present cases. A pathogenic variant rs606231437 in ATP1A3 gene was detected in twins, while in one of the siblings was found a novel variant of GRIN2A (c.3175T>A) gene, shared by the other brother who also had a variant in SCN1B (c.632G>A) and KCNQ2 (c.1870G>A) genes.CONCLUSIONS Developmental delay, epileptic seizures and motor dysfunction are features frequently associated to paroxysmal hemiplegic attacks. Hemiplegic episode is only a sign even if the most remarkable of several neurological comorbidities in AHC carriers. Therefore, we suggest that the view of the disorder should be greatly changed to the term “AHC spectrum disorder". The comparison of molecular analysis among the four probands brings out how the genetic framework is not recurrent, but may result from an unexpected greater genetic heterogeneity, such as seen in siblings carrying a new set of gene variants implicated in channelopathies likely to be eligible as further risk factors for AHC.

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Long-term follow-up and novel genotype-phenotype analysis of monozygotic twins with ATP1A3 mutation in Alternating Hemiplegia of Childhood-2

Cited by 12 publications

References 23 publications

Azoospermia and reciprocal translocations: should whole-exome sequencing be recommended?

Azoospermia and reciprocal translocations: should whole-exome sequencing be recommended?

Alternating Hemiplegia of Childhood, neurological comorbidities, intrafamilial variability: case-reports and literature review.

Alternating Hemiplegia of Childhood and Neurological Comorbidities. Variable Intrafamilial Clinical Features.

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