Brief Report: Systematic Review of Rett Syndrome in Males

Reichow, Brian; George-Puskar, Annie; Lutz, Tara M.; Smith, I.; Volkmar, Fred R.

doi:10.1007/s10803-015-2519-1

Cited by 55 publications

(38 citation statements)

References 57 publications

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“…In XY males, however, mutations in MECP2 result in fatal neonatal encephalopathy due to the x-linked nature of the disease, or, rarely, a more classical RTT presentation (47–49). Paralleling findings in humans, Mecp2 ZFN/y rats became symptomatic within weeks of birth and died early, all findings that are corroborated by earlier reports in various mouse models (10–12,20–22,37,50,51).…”

Section: Discussionmentioning

confidence: 99%

MeCP2 deficiency results in robust Rett-like behavioural and motor deficits in male and female rats

et al. 2016

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Since the identification of MECP2 as the causative gene in the majority of Rett Syndrome (RTT) cases, transgenic mouse models have played a critical role in our understanding of this disease. The use of additional mammalian RTT models offers the promise of further elucidating critical early mechanisms of disease as well as providing new avenues for translational studies. We have identified significant abnormalities in growth as well as motor and behavioural function in a novel zinc-finger nuclease model of RTT utilizing both male and female rats throughout development. Male rats lacking MeCP2 (Mecp2ZFN/y) were noticeably symptomatic as early as postnatal day 21, with most dying by postnatal day 55, while females lacking one copy of Mecp2 (Mecp2ZFN/+) displayed a more protracted disease course. Brain weights of Mecp2ZFN/y and Mecp2ZFN/+ rats were significantly reduced by postnatal day 14 and 21, respectively. Early motor and breathing abnormalities were apparent in Mecp2ZFN/y rats, whereas Mecp2ZFN/+ rats displayed functional irregularities later in development. The large size of this species will provide profound advantages in the identification of early disease mechanisms and the development of appropriately timed therapeutics. The current study establishes a foundational basis for the continued utilization of this rat model in future RTT research.

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Section: Discussionmentioning

confidence: 99%

MeCP2 deficiency results in robust Rett-like behavioural and motor deficits in male and female rats

et al. 2016

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“…Nonetheless, the misperception among those not familiar with RTT that males with MECP2 mutations do not survive pregnancy or die within the first year of life unless afforded ventilatory support has been repeated in the published literature on animal models [Chen, Y.et al 2017]. Further, the suggestion that RTT occurs in males despite not meeting the established consensus criteria, or even having a duplication in MECP2 , is still evident [Reichow, B.et al 2015]. …”

Section: Introductionmentioning

confidence: 99%

The array of clinical phenotypes of males with mutations in Methyl‐CpG binding protein 2

Neul

Benke

Marsh

et al. 2018

American J of Med Genetics Pt B

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Mutations in the X-linked gene MECP2 are associated with a severe neurodevelopmental disorder, Rett syndrome, primarily in girls. It had been suspected that mutations in MECP2 led to embryonic lethality in males, however such males have been reported. To enhance understanding of the phenotypic spectrum present in these individuals, we identified thirty males with MECP2 mutations in the RTT Natural History Study databases. A wide phenotypic spectrum was observed, ranging from severe neonatal encephalopathy to cognitive impairment. Two males with a somatic mutation in MECP2 had classic RTT. Of the remaining 28 subjects, 16 had RTT-causing MECP2 mutations, 9 with mutations that are not seen in females with RTT but are likely pathogenic, and 3 with uncertain variants. Two subjects with RTT-causing mutations were previously diagnosed as having atypical RTT; however, careful review of the clinical history determined that an additional 12/28 subjects met criteria for atypical RTT, but with more severe clinical presentation and course, and less distinctive RTT features, than females with RTT, leading to the designation of a new diagnostic entity, Male RTT Encephalopathy. Increased awareness of the clinical spectrum and widespread comprehensive genomic testing in boys with neurodevelopmental problems will lead to improved identification.

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“…RTT is a neurodevelopmental disorder that manifests in young girls with an incidence of about 1: 10,000 female live births [1]. Although initial reports suggested exclusivity of RTT in females, due to the fact that in males the mutation was often embryonic lethal, males with milder mutations can survive and at present 57 cases of RTT have been reported in males [2]. The clinical picture presents with a constellation of neurological symptoms ranging from anxiety, replacement of meaningful hand movements with repetitive stereotypies, seizures, neurogenic apnoea, breathing abnormalities and a prominent delay or absence in speech [3] but also less prominent non-neurological pathologies such as osteopenia, scoliosis, gastrointestinal disorders, and a general retardation in growth [3].…”

Section: Introductionmentioning

confidence: 99%

Paradoxical physiological responses to propranolol in a Rett syndrome patient: a case report

et al. 2016

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BackgroundRett Syndrome (RTT), caused by a loss-of-function in the epigenetic modulator: X-linked methyl-CpG binding protein 2 (MeCP2), is a pervasive neurological disorder characterized by compromised brain functions, anxiety, severe mental retardation, language and learning disabilities, repetitive stereotyped hand movements and developmental regression. An imbalance in the sympathetic and the parasympathetic nervous system (dysautonomia) and the resulting autonomic storms is a frequent occurrence in patients with RTT. The prototypical beta blocker propranolol has been used to manage sympathetic hyperactivity in patients with RTT.Case presentationA 13 year old girl with RTT was referred to the Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust. Her clinical picture included disordered breathing with concomitant hyperventilation and apnoea, epilepsy, scoliosis, no QT prolongation (QT/QTc [372/467 ms on automated electrocardiogram [ECG], but manually calculated to be 440 ms]), no cardiac abnormalities (PR interval: 104 ms, QRS duration: 78 ms), and generalised anxiety disorder (ICD-10-CM Diagnosis Code F41.1). She was also constipated and was fed via percutaneous endoscopic gastrostomy (PEG). To manage the dysautonomia, propranolol was given (5 mg and 10 mg) and in parallel her physiological parameters, including heart rate, skin temperature and skin transpiration, were monitored continuously for 24 h as she went about her activities of daily living. Whilst her skin temperature increased and skin transpiration decreased, unexpectedly there was a significant paradoxical increase in the patient’s average heart rate following propranolol treatment.ConclusionHere, we present a unique case of a paradoxical increase in heart rate response following propranolol treatment for managing dysautonomia in a child with RTT. Further studies are warranted to better understand the underlying dysautonomia in patients with RTT and the impact this might have on treatment strategies in rare disorders such as RTT.

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Brief Report: Systematic Review of Rett Syndrome in Males

Cited by 55 publications

References 57 publications

MeCP2 deficiency results in robust Rett-like behavioural and motor deficits in male and female rats

MeCP2 deficiency results in robust Rett-like behavioural and motor deficits in male and female rats

The array of clinical phenotypes of males with mutations in Methyl‐CpG binding protein 2

Paradoxical physiological responses to propranolol in a Rett syndrome patient: a case report

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