Increased Resting Metabolic Rate in Girls with Rett Syndrome Compared to Girls with Developmental Disabilities

Platte, Petra; Jaschke, H; Herbert, C; Gc, Korenke

doi:10.1055/s-0031-1287841

Cited by 9 publications

(7 citation statements)

References 15 publications

(17 reference statements)

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“…Altered energy balance and metabolic measures have been observed in human RTT females (26)(27)(28). While dietary energy intake and fecal fat loss did not differ between RTT and controls, metabolic rates during sleep and quiet awake were significantly lower (26) and morning levels of leptin and adiponectin were elevated in RTT (17).…”

Section: Discussionmentioning

confidence: 89%

“…Metabolic dysfunctions are observed in RTT patients and mouse models, but whether these are consequences of inflammation or more directly mediated by MECP2, mutation is currently unknown. While RTT girls are generally not obese, perhaps due to the inability to self-feed, they have elevated morning leptin and adiponectin serum levels (17) as well as alterations in energy balance (26)(27)(28). Furthermore, RTT has significant commonalities with mitochondrial disorders, including elevated lactate and pyruvate in blood and cerebral spinal fluid (29), as well as markers of oxidative damage (30) that are also seen in mouse models (31,32).…”

Section: Introductionmentioning

confidence: 99%

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MeCP2 isoform e1 mutant mice recapitulate motor and metabolic phenotypes of Rett syndrome

Ciernia

Yasui

Pride

et al. 2018

Human Molecular Genetics

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Mutations in the X-linked gene MECP2 cause the majority of Rett syndrome (RTT) cases. Two differentially spliced isoforms of exons 1 and 2 (MeCP2-e1 and MeCP2-e2) contribute to the diverse functions of MeCP2, but only mutations in exon 1, not exon 2, are observed in RTT. We previously described an isoform-specific MeCP2-e1-deficient male mouse model of a human RTT mutation that lacks MeCP2-e1 while preserving expression of MeCP2-e2. However, RTT patients are heterozygous females that exhibit delayed and progressive symptom onset beginning in late infancy, including neurologic as well as metabolic, immune, respiratory and gastrointestinal phenotypes. Consequently, we conducted a longitudinal assessment of symptom development in MeCP2-e1 mutant females and males. A delayed and progressive onset of motor impairments was observed in both female and male MeCP2-e1 mutant mice, including hind limb clasping and motor deficits in gait and balance. Because these motor impairments were significantly impacted by age-dependent increases in body weight, we also investigated metabolic phenotypes at an early stage of disease progression. Both male and female MeCP2-e1 mutants exhibited significantly increased body fat compared to sex-matched wild-type littermates prior to weight differences. Mecp2e1-/y males exhibited significant metabolic phenotypes of hypoactivity, decreased energy expenditure, increased respiratory exchange ratio, but decreased food intake compared to wild-type. Untargeted analysis of lipid metabolites demonstrated a distinguishable profile in MeCP2-e1 female mutant liver characterized by increased triglycerides. Together, these results demonstrate that MeCP2-e1 mutation in mice of both sexes recapitulates early and progressive metabolic and motor phenotypes of human RTT.

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Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

MeCP2 isoform e1 mutant mice recapitulate motor and metabolic phenotypes of Rett syndrome

Ciernia

Yasui

Pride

et al. 2018

Human Molecular Genetics

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“…32 We found that despite persistent microcephaly, preserved somatic growth occurs in 45% of girls with RTT and is associated with better development and lower seizure, scoliosis, and RTT behavior burden, contradicting dogma that "proportional" microcephaly conveys a protective effect. The resting metabolic rate is higher in patients with RTT than in those with other developmental disabilities, 33 and intensive nutritional therapy improves growth outcomes. These findings suggest both that growth is an important outcome for clinical trials and that improved nutrition could moderate the association between growth and development.…”

Section: Figure 1 Height and Weight In Unaffected Children (Orange) Amentioning

confidence: 99%

Growth failure and outcome in Rett syndrome

Tarquinio¹,

Motil²,

Hou³

et al. 2012

Neurology

109

110

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Objectives: Prominent growth failure typifies Rett syndrome (RTT). Our aims were to 1) develop RTT growth charts for clinical and research settings, 2) compare growth in children with RTT with that of unaffected children, and 3) compare growth patterns among RTT genotypes and phenotypes.Methods: A cohort of the RTT Rare Diseases Clinical Research Network observational study participants was recruited, and cross-sectional and longitudinal growth data and comprehensive clinical information were collected. A reliability study confirmed interobserver consistency. Reference curves for height, weight, head circumference, and body mass index (BMI), generated using a semiparametric model with goodness-of-fit tests, were compared with normative values using Student's t test adjusted for multiple comparisons. Genotype and phenotype subgroups were compared using analysis of variance and linear regression.Results: Growth charts for classic and atypical RTT were created from 9,749 observations of 816 female participants. Mean growth in classic RTT decreased below that for the normative population at 1 month for head circumference, 6 months for weight, and 17 months for length. Mean BMI was similar in those with RTT and the normative population. Pubertal increases in height and weight were absent in classic RTT. Classic RTT was associated with more growth failure than atypical RTT. In classic RTT, poor growth was associated with worse development, higher disease severity, and certain MECP2 mutations (pre-C-terminal truncation, large deletion, T158M, R168X, R255X, and R270X). Conclusions:RTT-specific growth references will allow effective screening for disease and treatment monitoring. Growth failure occurs less frequently in girls with RTT with better development, less morbidity typically associated with RTT, and late truncation mutations. Neurology ® 2012;79:1653-1661 GLOSSARY ANOVA ϭ analysis of variance; BMI ϭ body mass index; CSS ϭ Clinical Severity Score; EDF ϭ equivalent degrees of freedom; FDR ϭ false discovery rate; FOC ϭ fronto-occipital head circumference; MBA ϭ Motor Behavioral Assessment; non-RTT ϭ participants possessing MECP2 mutation but without Rett syndrome; RNHS ϭ Rett Natural History Study; RTT ϭ Rett syndrome.Growth failure is a prominent feature in Rett syndrome (RTT); however, no RTT-specific growth charts exist. Many comorbid disorders have an impact on growth in RTT, such as oropharyngeal and gastrointestinal dysfunction, scoliosis, seizures, and osteopenia. The pattern of growth in female patients with RTT trends well below the lowest centile on standard growth references, 1 which fail to differentiate a normal RTT growth pattern from one caused by malnutrition or illness.Disease-specific standards screen for disease [2][3][4][5][6][7][8][9][10][11][12][13] and measure the effect of therapeutic interventions designed to improve nutrition and neurologic function.14,15 With more than 200 mutation sites identified in the methyl-CpG-binding protein 2 gene (MECP2), the clinical severity in RTT var...

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“…After this first sign of growth retardation, poor weight gain and height growth follows in the majority. The pathophysiology behind this global growth retardation remains unclear, but some of it may be explained by an increased resting metabolic rate, in combination with more feeding difficulties in girls with RTT compared to controls with equivalent developmental disorders (Isaacs et al, 2003;Platte et al, 2011).…”

Section: Growthmentioning

confidence: 99%

Genetic and clinical variations in a Norwegian sample diagnosed with Rett syndrome

Henriksen

Breck

Sejersted

et al. 2020

Brain and Development

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Rett syndrome (RTT) is a neurodevelopmental disorder that almost exclusively affects females. Epilepsy is a major clinical feature, but its long-term course in RTT has not been sufficiently explored. This study addresses the development of the epilepsy in adults with RTT. Methods: Available females diagnosed with RTT in Norway were asked to participate. Parents/caregivers were interviewed, the girls/women were examined and their medical records reviewed. Participants were categorized according to age, epilepsy, seizure patterns and mutation severity groups. RTT severity was assessed (epilepsy score excluded). Results: 70 females with classic RTT were included. A presumed pathogenic mutation in MECP2 was found in 96%. The presence of active epilepsy (seizures last five years) was similar in all age groups above the age of ten: 11 (65%) in adolescents (11-20 years), 9 (60%) in young adults (21-30 years) and 14 (67%) in participants above 30 years of age. Tonic-clonic seizures within the last year were present in 55, 67 and 64%, and ≥ weekly seizures occurred in 27, 45 and 50% in the respective age groups. Among participants with active epilepsy, 69% had unremitting seizures, whereas 31% had experienced remissions for more than six months during the last five years. In the oldest group (> 30 years), only 19% had obtained seizure control for > 5 years, and 14% had never experienced seizures. Seizure activity correlated with RTT severity score, whereas the relationship to mutation type remained ambiguous. Conclusion: Epilepsy continues to be a major concern in adults with RTT. Two thirds of women above 30 years of age remained with active epilepsy and 50% of them had seizures at least weekly.

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Increased Resting Metabolic Rate in Girls with Rett Syndrome Compared to Girls with Developmental Disabilities

Cited by 9 publications

References 15 publications

MeCP2 isoform e1 mutant mice recapitulate motor and metabolic phenotypes of Rett syndrome

MeCP2 isoform e1 mutant mice recapitulate motor and metabolic phenotypes of Rett syndrome

Growth failure and outcome in Rett syndrome

Genetic and clinical variations in a Norwegian sample diagnosed with Rett syndrome

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