Periventricular nodular heterotopia in Smith‐Magenis syndrome

Capra, Valeria; Biancheri, Roberta; Morana, Giovanni; Striano, Pasquale; Novara, Francesca; Ferrero, Giovanni Battista; Boeri, Luca; Celle, Maria Elena; Mancardi, Maria Margherita; Zuffardi, Orsetta; Parrini, Elena; Guerrini, Renzo

doi:10.1002/ajmg.a.36742

Cited by 14 publications

(10 citation statements)

References 33 publications

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“…More details on newly reported patients are available in the Supplementary Clinical Notes and in Supplementary Figure 1. Eight patients, including a mother and her son, both exhibiting bilateral PNH, had already been described in previous publications from our team [9,[12][13][14]. These individuals were included in this study only for the purposes of assessing the prevalence of CNVs in PNH versus other MCDs and for gene enrichment analysis.…”

Section: Clinical Featuresmentioning

confidence: 99%

“…We present clinical and genetic data on 15 patients with PNH carrying pathogenic genomic imbalances, including two parent/proband couples. Eight such patients had been included in previous publications from our team [9,[12][13][14], while seven (five sporadic and two familial) had not been described before (Table 1a, b). We report seven genomic regions (2p11.2q12.1, 4p15, 14q11.2q12, 16p13.…”

Section: Introductionmentioning

confidence: 99%

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Multiple genomic copy number variants associated with periventricular nodular heterotopia indicate extreme genetic heterogeneity

et al. 2019

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Periventricular nodular heterotopia (PNH) is a brain malformation in which nodules of neurons are ectopically retained along the lateral ventricles. Genetic causes include FLNA abnormalities (classical X-linked PNH), rare variants in ARFGEF2, DCHS1, ERMARD, FAT4, INTS8, MAP1B, MCPH1, and NEDD4L, as well as several chromosomal abnormalities. We performed array-CGH in 106 patients with different malformations of cortical development (MCD) and looked for common pathways possibly involved in PNH. Forty-two patients, including two parent/proband couples, exhibited PNH associated or not with other brain abnormalities, 44 had polymicrogyria and 20 had rarer MCDs. We found an enrichment of either large rearrangements or cryptic copy number variants (CNVs) in PNH (15/42, 35.7%) vs polymicrogyria (4/44, 9.1%) (i.e., 5.6 times increased risk for PNH of carrying a pathogenic CNV). CNVs in seven genomic regions (2p11.2q12.1, 4p15, 14q11.2q12, 16p13.3, 19q13.33, 20q13.33, 22q11) represented novel, potentially causative, associations with PNH. Through in silico analysis of genes included in imbalances whose breakpoints were clearly detailed, we detected in 9/12 unrelated patients in our series and in 15/24 previously published patients, a significant (P < 0.05) overrepresentation of genes involved in vesicle-mediated transport. Rare genomic imbalances, either small CNVs or large rearrangements, are cumulatively a frequent cause of PNH. Dysregulation of specific cellular mechanisms might play a key pathogenic role in PNH but it remains to be determined whether this is exerted through single genes or the cumulative dosage effect of more genes. Array-CGH should be considered as a first-line diagnostic test in PNH, especially if sporadic and non-classical.

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Section: Clinical Featuresmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Multiple genomic copy number variants associated with periventricular nodular heterotopia indicate extreme genetic heterogeneity

et al. 2019

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“…However, more recent case reports suggest that CNS abnormalities including migrational and other structural anomalies may be more prevalent in SMS. 34,35 Clinical seizures are seen in up to 20 to 30% of patients but an abnormal electroencephalogram (EEG) is recorded in as many as approximately 50% of the patients undergoing sleep study. 16,19,22 Catamenial seizures (seizures exacerbated by menses) have also been reported.…”

Section: Sleep Disturbances and Neurologic Findingsmentioning

confidence: 99%

Neurodevelopmental Disorders Associated with Abnormal Gene Dosage: Smith–Magenis and Potocki–Lupski Syndromes

Neira‐Fresneda

Potocki

2015

J Pediatr Genet

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Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) are reciprocal contiguous gene syndromes within the well-characterized 17p11.2 region. Approximately 3.6 Mb microduplication of 17p11.2, known as PTLS, represents the mechanistically predicted homologous recombination reciprocal of the SMS microdeletion, both resulting in multiple congenital anomalies. Mouse model studies have revealed that the retinoic acid-inducible 1 gene (RAI1) within the SMS and PTLS critical genomic interval is the dosage-sensitive gene responsible for the major phenotypic features in these disorders. Even though PTLS and SMS share the same genomic region, clinical manifestations and behavioral issues are distinct and in fact some mirror traits may be on opposite ends of a given phenotypic spectrum. We describe the neurobehavioral phenotypes of SMS and PTLS patients during different life phases as well as clinical guidelines for diagnosis and a multidisciplinary approach once diagnosis is confirmed by array comparative genomic hybridization or RAI1 gene sequencing. The main goal is to increase awareness of these rare disorders because an earlier diagnosis will lead to more timely developmental intervention and medical management which will improve clinical outcome.

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“…Other genes have been linked to a phenotype characterized by intractable epilepsy, intellectual disability, facial dysmorphisms, and migrational abnormalities. These include the C6orf70 gene (Conti et al, 2013) and the RAI1 gene, the causative gene of Smith-Magenis syndrome (Capra et al, 2014).…”

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confidence: 99%

Early‐life epileptic encephalopathy secondary to SZT2 pathogenic recessive variants

Venkatesan¹,

Angle²,

Millichap³

2016

Epileptic Disorders

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Advances in genetic testing have led to the identification of increasing numbers of novel gene mutations that underlie infantile‐onset epileptic encephalopathies. Recently, a mutagenesis screen identified a novel gene, SZT2, with no known protein function that has been linked to epileptogenesis in mice. Thus far, two clinical reports have identified children with different recessive mutations in SZT2 and varying clinical phenotypes. One case report described patients with epileptic encephalopathy and the other noted patients with cognitive deficiencies, but normal MRI and no epilepsy. This case report identifies novel mutations (a compound heterozygous frameshift and a nonsense variant) in the SZT2 gene with distinct clinical and radiographic findings relative to those previously reported. Our patient presented with intractable epilepsy at 2 months of age. Seizures were refractory to numerous antiepileptic medications and the patient finally achieved seizure cessation at age 3 years with a combination of divalproex and lamotrigine. Our patient had similar facial dysmorphisms (macrocephaly, high forehead, and down‐slanted palpebral fissures) to a previous case with truncating mutation. While developmental delay and cognitive deficiencies were present, our case had unique MRI findings suggesting migrational abnormalities not previously reported in other cases.

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Periventricular nodular heterotopia in Smith‐Magenis syndrome

Cited by 14 publications

References 33 publications

Multiple genomic copy number variants associated with periventricular nodular heterotopia indicate extreme genetic heterogeneity

Multiple genomic copy number variants associated with periventricular nodular heterotopia indicate extreme genetic heterogeneity

Neurodevelopmental Disorders Associated with Abnormal Gene Dosage: Smith–Magenis and Potocki–Lupski Syndromes

Early‐life epileptic encephalopathy secondary to SZT2 pathogenic recessive variants

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