X-linked ichthyosis (steroid sulfatase deficiency) is associated with increased risk of attention deficit hyperactivity disorder, autism and social communication deficits

Kent, Lindsey; Emerton, Jane; Bhadravathi, Vishu; Weisblatt, Emma; Pasco, Greg; Willatt, Lionel; McMahon, Robert C.; Yates, John R.

doi:10.1136/jmg.2008.057729

Cited by 140 publications

(129 citation statements)

References 29 publications

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“…In all five informative families, segregation analysis showed paternal transmission of the affected X-chromosome to the XLI carrier daughter. Taken together, these findings indicate that the STS The presence of low-copy repeat regions on either side of the STS gene has been shown to be responsible for the recurrent microdeletion (Yen et al, 1990) seen in STS deficiency, with common breakpoints being seen in a significant proportion of patients (Saeki et al, 1998;Aviram-Goldring et al, 2000;Kent et al, 2008). The deletion mapping in our patients was consistent with results of previous studies.…”

Section: Molecular Analysissupporting

confidence: 82%

“…With a high incidence and the ability to identify most, if not all cases, prenatally, the condition will be detected in approximately 1 in 3000 pregnancies undergoing second trimester maternal serum screening for Down syndrome which incorporates the measurement of uE3. Although a recent publication (Kent et al, 2008) suggests an increased risk of ADHD in boys with isolated STS deficiency, the risk of developmental disability (defined as IQ less than 70) or autism is not increased unless the STS deficiency is part of a contiguous gene deletion syndrome. Although this latter association is well established in the literature, our study is the first prenatal series to estimate the risk of contiguous gene deletion syndrome to be 8.3% in the context of a prenatally diagnosed sporadic case of STS deficiency (n = 12).…”

Section: Molecular Analysismentioning

confidence: 99%

“…A small percentage of affected boys are born with undescended testes (Ballabio and Shapiro, 2001). In a very recent publication, Kent et al (2008) described an association between STS deficiency and attention deficit hyperactivity disorder (ADHD). Sporadic cases of STS deficiency with additional features due to a deletion of contiguous genes have also been reported (Ballabio et al, 1989;Bick et al 1989;Klink et al,1994;Muroya et al, 1996;Weissörtel R et al, *Correspondence to: Sylvie Langlois, Medical Genetics, University of British Columbia, C234, 4500 Oak Street, Vancouver, BC, Canada V6H 3N1.…”

Section: Introductionmentioning

confidence: 99%

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Steroid sulfatase deficiency and contiguous gene deletion syndrome amongst pregnant patients with low serum unconjugated estriols

et al. 2009

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ObjectiveTo ascertain all prenatally diagnosed cases of Steroid Sulfatase (STS) deficiency in British Columbia between August 2002 and July 2007 to determine the incidence of this condition, the clinical and laboratory findings, and the risk of a contiguous gene deletion syndrome.MethodsWe reviewed the medical records of these patients to obtain detailed information about the maternal serum screening results, family history, investigations performed, and outcome of the pregnancy.ResultsThirty pregnant patients were found to have a male fetus/infant with STS deficiency, giving a minimal estimated incidence of this condition of approximately 1 in 1513 males. In twenty nine cases, this condition was isolated. One patient was found to have a contiguous gene deletion syndrome. In cases of sporadic STS deficiency diagnosed prenatally, the frequency of contiguous gene deletion syndrome in this study was 1 out of 12 (8.3%).ConclusionThe clinical, cytogenetic and molecular data on this series of prenatally diagnosed cases of STS deficiency indicates that this is a common condition and in cases with no family history, the risk of contiguous gene deletion syndrome is significant, and warrants additional molecular genetic investigations of the mother and/or fetus. Copyright © 2009 John Wiley & Sons, Ltd.

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Section: Molecular Analysissupporting

confidence: 82%

Section: Molecular Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Steroid sulfatase deficiency and contiguous gene deletion syndrome amongst pregnant patients with low serum unconjugated estriols

et al. 2009

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“…Although individuals with this deletion usually show normal development, some also present with intellectual disability and susceptibility to ADHD, autism and social communication deficits. 18,19 Therefore, we cannot exclude the fact that, besides ichthyosis, this deletion additionally contributes to the developmental and behavior phenotype. One should note that the mother of the patient carries the same deletion without features of ichthyosis.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction and organic aciduria in five patients carrying mutations in the Ras-MAPK pathway

et al. 2010

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Various syndromes of the Ras-mitogen-activated protein kinase (MAPK) pathway, including the Noonan, Cardio-Facio-Cutaneous, LEOPARD and Costello syndromes, share the common features of craniofacial dysmorphisms, heart defect and short stature. In a subgroup of patients, severe muscle hypotonia, central nervous system involvement and failure to thrive occur as well. In this study we report on five children diagnosed initially with classic metabolic and clinical symptoms of an oxidative phosphorylation disorder. Later in the course of the disease, the children presented with characteristic features of Ras-MAPK pathway-related syndromes, leading to the reevaluation of the initial diagnosis. In the five patients, in addition to the oxidative phosphorylation disorder, disease-causing mutations were detected in the Ras-MAPK pathway. Three of the patients also carried a second, mitochondrial genetic alteration, which was asymptomatically present in their healthy relatives. Did we miss the correct diagnosis in the first place or is mitochondrial dysfunction directly related to Ras-MAPK pathway defects? The Ras-MAPK pathway is known to have various targets, including proteins in the mitochondrial membrane influencing mitochondrial morphology and dynamics. Prospective screening of 18 patients with various Ras-MAPK pathway defects detected biochemical signs of disturbed oxidative phosphorylation in three additional children. We concluded that only a specific, metabolically vulnerable sub-population of patients with Ras-MAPK pathway mutations presents with mitochondrial dysfunction and a more severe, early-onset disease. We postulate that patients with Ras-MAPK mutations have an increased susceptibility, but a second metabolic hit is needed to cause the clinical manifestation of mitochondrial dysfunction.

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“…Mice lacking the Sts gene, or given an inhibitor of the enzyme, display attentional deficits relative to wildtype or vehicle‐treated mice manifest as increased omission or commission errors respectively (Davies et al., 2009); interestingly, contrary to expectation, the former groups exhibit enhanced response inhibition relative to wildtype or vehicle‐treated mice (Davies et al., 2014). Somewhat consistent with these mouse data, males lacking a functional STS gene are at increased risk of developing attention deficit hyperactivity disorder (ADHD; particularly the inattentive presentation) but seem to exhibit normal levels of motor impulsivity (Chatterjee, Humby, & Davies, 2016; Kent et al., 2008). In the developing human brain, STS is highly expressed in brain regions important in attention and response control, notably the thalamus and the basal ganglia (Stergiakouli et al., 2011).…”

Section: Introductionmentioning

confidence: 99%

A genetic variant within STS previously associated with inattention in boys with attention deficit hyperactivity disorder is associated with enhanced cognition in healthy adult males

et al. 2017

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IntroductionThe enzyme steroid sulfatase (STS) converts sulfated steroids to their non‐sulfated forms. Deficiency for this enzyme is associated with inattention but preserved response control. The polymorphism rs17268988 within the X‐linked STS gene is associated with inattentive, but not other, symptoms in boys with attention deficit hyperactivity disorder (ADHD).MethodsWe initially tested whether rs17268988 genotype was associated with attention, response control, and underlying aspects of cognition, using questionnaires and neuropsychological tasks, in two independent cohorts of healthy adult males. In an additional analysis based upon existing data, the performance of mice with genetic or pharmacological manipulations of the STS axis under attentionally demanding conditions was investigated.ResultsG‐allele carriers at rs17268988 exhibited reduced reaction time, enhanced attention, and reduced reaction time variability relative to C‐allele carriers. Mice with genetic or pharmacological manipulations of the STS axis were shown to have perturbed reaction time variability.DiscussionOur findings provide additional support for an association between rs17268988 genotype and attention, which may be partially mediated by reaction time variability; they also indicate that, in contrast to the situation in boys with ADHD, in healthy men, the G‐allele at rs17268988 is associated with enhanced cognition. As reaction time variability is a predictor of well‐being, rs17268988 genotype may represent a biomarker for long‐term health.

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X-linked ichthyosis (steroid sulfatase deficiency) is associated with increased risk of attention deficit hyperactivity disorder, autism and social communication deficits

Abstract: STS deficiency may be a risk factor for ADHD with predominantly inattentive symptoms. Boys with XLI and large deletions encompassing STS and NLGN4 are at increased risk of developing autism and related disorders.

Cited by 140 publications

References 29 publications

Steroid sulfatase deficiency and contiguous gene deletion syndrome amongst pregnant patients with low serum unconjugated estriols

Steroid sulfatase deficiency and contiguous gene deletion syndrome amongst pregnant patients with low serum unconjugated estriols

Mitochondrial dysfunction and organic aciduria in five patients carrying mutations in the Ras-MAPK pathway

A genetic variant within STS previously associated with inattention in boys with attention deficit hyperactivity disorder is associated with enhanced cognition in healthy adult males

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