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Rett syndrome: a neurological disorder with metabolic components.

ABSTRACT: Rett syndrome (RTT) is a neurological disorder caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2), a ubiquitously expressed transcriptional regulator. Despite remarkable scientific progress since its discovery, the mechanism by which MECP2 mutations cause RTT symptoms is largely unknown. Consequently, treatment options for patients are currently limited and centred on symptom relief. Thought to be an entirely neurological disorder, RTT research has focused on the role of MECP2 in the central nervous system. However, the variety of phenotypes identified in Mecp2 mutant mouse models and RTT patients implicate important roles for MeCP2 in peripheral systems. Here, we review the history of RTT, highlighting breakthroughs in the field that have led us to present day. We explore the current evidence supporting metabolic dysfunction as a component of RTT, presenting recent studies that have revealed perturbed lipid metabolism in the brain and peripheral tissues of mouse models and patients. Such findings may have an impact on the quality of life of RTT patients as both dietary and drug intervention can alter lipid metabolism. Ultimately, we conclude that a thorough knowledge of MeCP2's varied functional targets in the brain and body will be required to treat this complex syndrome.

SUBMITTER: Kyle SM

PROVIDER: S-EPMC5830535 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Rett syndrome: a neurological disorder with metabolic components.

Kyle Stephanie M SM Vashi Neeti N Justice Monica J MJ

Open biology 20180201 2

Rett syndrome (RTT) is a neurological disorder caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (<i>MECP2</i>), a ubiquitously expressed transcriptional regulator. Despite remarkable scientific progress since its discovery, the mechanism by which <i>MECP2</i> mutations cause RTT symptoms is largely unknown. Consequently, treatment options for patients are currently limited and centred on symptom relief. Thought to be an entirely neurological disorder, RTT research has focuse ...[more]

PMID: 29445033

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Project description:With the creation of the Somatic Symptom and Related Disorders category of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition in 2013, the functional neurological (symptom) disorder diagnostic criteria underwent transformative changes. These included an emphasis on 'rule-in' physical examination signs/semiological features guiding diagnosis and the removal of a required proximal psychological stressor to be linked to symptoms. In addition, the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition somatization disorder, somatoform pain disorder and undifferentiated somatoform disorder conditions were eliminated and collapsed into the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition somatic symptom disorder diagnosis. With somatic symptom disorder, emphasis was placed on a cognitive-behavioural (psychological) formulation as the basis for diagnosis in individuals reporting distressing bodily symptoms such as pain and/or fatigue; the need for bodily symptoms to be 'medically unexplained' was removed, and the overall utility of this diagnostic criteria remains debated. A consequence of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition restructuring is that the diagnosis of somatization disorder that encompassed individuals with functional neurological (sensorimotor) symptoms and prominent other bodily symptoms, including pain, was eliminated. This change negatively impacts clinical and research efforts because many patients with functional neurological disorder experience pain, supporting that the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition would benefit from an integrated diagnosis at this intersection. We seek to revisit this with modifications, particularly since pain (and a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition somatization disorder comorbidity, more specifically) is associated with poor clinical prognosis in functional neurological disorder. As a first step, we systematically reviewed the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition somatization disorder literature to detail epidemiologic, healthcare utilization, demographic, diagnostic, medical and psychiatric comorbidity, psychosocial, neurobiological and treatment data. Thereafter, we propose a preliminary revision to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition allowing for the specifier functional neurological disorder 'with prominent pain'. To meet this criterion, core functional neurological symptoms (e.g. limb weakness, gait difficulties, seizures, non-dermatomal sensory loss and/or blindness) would have 'rule-in' signs and pain (>6 months) impairing social and/or occupational functioning would also be present. Two optional secondary specifiers assist in characterizing individuals with cognitive-behavioural (psychological) features recognized to amplify or perpetuate pain and documenting if there is a pain-related comorbidity. The specifier of 'with prominent pain' is etiologically neutral, while secondary specifiers provide additional clarification. We advocate for a similar approach to contextualize fatigue and mixed somatic symptoms in functional neurological disorder. While this preliminary proposal requires prospective data and additional discussion, these revisions offer the potential benefit to readily identify important functional neurological disorder subgroups-resulting in diagnostic, treatment and pathophysiology implications.

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Rett syndrome: a neurological disorder with metabolic components.

Publications

Rett syndrome: a neurological disorder with metabolic components.

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