The most recurrent monogenic disorders that overlap with the phenotype of Rett syndrome

Vidal, Silvia M.; Brandi, Nuria; Pacheco, Paola; Maynou, Joan; Fernàndez, Guerau; Xiol, Clara; Pascual‐Alonso, Ainhoa; Pineda, Merçè; Armstrong, Judith

doi:10.1016/j.ejpn.2019.04.006

Cited by 28 publications

(28 citation statements)

References 48 publications

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“…Due to the considerable overlap of clinical symptoms of RTT patients, especially those who are MECP2 ‐mutation‐negative, with other neurodevelopment disorders, it can be challenging to establish a precise genetic diagnosis. However, recent advances in next‐generation sequencing (NGS) have identified pathogenic variants in a growing list of genes known to cause intellectual disability, severe epilepsy and/or autistic behaviors where some individuals appear to have an RTT‐like clinical picture, thus providing a definitive genetic diagnosis for patients and “closure” for affected families (Cogliati et al, 2019; Henriksen, Ravn, Paus, von Tetzchner, & Skjeldal, 2018; Iwama et al, 2019; Schonewolf‐Greulich et al, 2019; Vidal et al, 2019; Yoo et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A ( KIF1A )

et al. 2020

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Defects in the motor domain of kinesin family member 1A (KIF1A), a neuron‐specific ATP‐dependent anterograde axonal transporter of synaptic cargo, are well‐recognized to cause a spectrum of neurological conditions, commonly known as KIF1A‐associated neurological disorders (KAND). Here, we report one mutation‐negative female with classic Rett syndrome (RTT) harboring a de novo heterozygous novel variant [NP_001230937.1:p.(Asp248Glu)] in the highly conserved motor domain of KIF1A. In addition, three individuals with severe neurodevelopmental disorder along with clinical features overlapping with KAND are also reported carrying de novo heterozygous novel [NP_001230937.1:p.(Cys92Arg) and p.(Pro305Leu)] or previously reported [NP_001230937.1:p.(Thr99Met)] variants in KIF1A. In silico tools predicted these variants to be likely pathogenic, and 3D molecular modeling predicted defective ATP hydrolysis and/or microtubule binding. Using the neurite tip accumulation assay, we demonstrated that all novel KIF1A variants significantly reduced the ability of the motor domain of KIF1A to accumulate along the neurite lengths of differentiated SH‐SY5Y cells. In vitro microtubule gliding assays showed significantly reduced velocities for the variant p.(Asp248Glu) and reduced microtubule binding for the p.(Cys92Arg) and p.(Pro305Leu) variants, suggesting a decreased ability of KIF1A to move along microtubules. Thus, this study further expanded the phenotypic characteristics of KAND individuals with pathogenic variants in the KIF1A motor domain to include clinical features commonly seen in RTT individuals.

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Section: Introductionmentioning

confidence: 99%

Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A ( KIF1A )

et al. 2020

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“…A novel SCN2A mutation has been recently associated early-onset epileptic encephalopathy with the Rett-like features, 47 and also in a Spanish cohort of 437 patients with the Rett or Rettlike phenotypes, SCN2A gene mutations has been described in six patients. 72 A recent report described two members of a Chinese family harboring an SCN2A mutation and having juvenile-onset myoclonus. A 21-year-old male proband suffered from frequent myoclonus at 11 years old with subsequent progressive ataxia, while his elder maternal half-sister also experienced myoclonus.…”

Section: Encephalopathy With Neonatal/early Infantile Epilepsymentioning

confidence: 99%

SCN2A and Its Related Epileptic Phenotypes

Sullo

Pasquetti

Patanè

et al. 2021

Journal of Pediatric Neurology

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Epilepsies due to SCN2A mutations can present with a broad range of phenotypes that are still not fully understood. Clinical characteristics of SNC2A-related epilepsy may vary from neonatal benign epilepsy to early-onset epileptic encephalopathy, including Ohtahara syndrome and West syndrome, and epileptic encephalopathies occurring at later ages (usually within the first 10 years of life). Some patient may present with intellectual disability and/or autism or movement disorders and without epilepsy. The heterogeneity of the phenotypes associated to such genetic mutations does not always allow the clinician to address his suspect on this gene. For this reason, diagnosis is usually made after a multiple gene panel examination through next generation sequencing (NGS) or after whole exome sequencing (WES) or whole genome sequencing (WGS). Subsequently, confirmation by Sanger sequencing can be obtained. Mutations in SCN2A are inherited as an autosomal dominant trait. Most individuals diagnosed with SCN2A–benign familial neonatal-infantile seizures (BFNIS) have an affected parent; however, hypothetically, a child may present SCN2A-BNFNIS as the result of a de novo pathogenic variant. Almost all individuals with SCN2A and severe epileptic encephalopathies have a de novo pathogenic variant. SNC2A-related epilepsies have not shown a clear genotype–phenotype correlation; in some cases, a same variant may lead to different presentations even within the same family and this could be due to other genetic factors or to environmental causes. There is no “standardized” treatment for SCN2A-related epilepsy, as it varies in relation to the clinical presentation and the phenotype of the patient, according to its own gene mutation. Treatment is based mainly on antiepileptic drugs, which include classic wide-spectrum drugs, such as valproic acid, levetiracetam, and lamotrigine. However, specific agents, which act directly modulating the sodium channels activity (phenytoin, carbamazepine, oxcarbamazepine, lamotrigine, and zonisamide), have shown positive result, as other sodium channel blockers (lidocaine and mexiletine) or even other drugs with different targets (phenobarbital).

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“…A Rett-like presentation was previously reported in 8 patients with KCNQ2 encephalopathy. 4 , 5 Two of these patients carried the c.637C>T (p. Arg213Trp) variant, which involves the same region as the c.628C>T variant. One of them presented with neonatal seizures, global developmental delay, a lack of speech, and hand stereotypies.…”

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confidence: 99%

“…One of them presented with neonatal seizures, global developmental delay, a lack of speech, and hand stereotypies. 4 , 5 …”

mentioning

confidence: 99%

KCNQ2 encephalopathy manifesting with Rett-like features

et al. 2020

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The most recurrent monogenic disorders that overlap with the phenotype of Rett syndrome

Cited by 28 publications

References 48 publications

Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A ( KIF1A )

Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A ( KIF1A )

SCN2A and Its Related Epileptic Phenotypes

KCNQ2 encephalopathy manifesting with Rett-like features

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