Muscle weakness in children with neurofibromatosis type 1

Cornett, Kayla; North, Klaus; Rose, Kristy; Burns, Joshua

doi:10.1111/dmcn.12777

Cited by 24 publications

(32 citation statements)

References 18 publications

(32 reference statements)

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“…This suggests that loss of Nf1 does not induce muscle atrophy at a specific time point, but rather that NF1-associated muscle weakness is a continuous process of decreased hypertrophic growth beginning in childhood. Indeed, muscle weakness and decreased muscle CSA are already seen in pediatric patients [7,8]. In Nf1 Myf5 mice predominantly fast (type 2) fibers are affected.…”

Section: Discussionmentioning

confidence: 99%

“…The musculoskeletal system is often affected in NF1 patients, with scoliosis, long bone dysplasia and osteoporosis being a main cause of considerable morbidity [2]. Furthermore, pronounced reduction of muscle size and muscle weakness has been reported in NF1 patients [3][4][5][6][7][8], and has also been described as general feature in RASopathies, i.e. disease traits with mutations in RAS pathway components, [9,10].…”

Section: Introductionmentioning

confidence: 99%

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Cell autonomous requirement of Neurofibromin (Nf1) for postnatal muscle hypertrophic growth and metabolic homeostasis

Wei

Franke

Ost

et al. 2020

Preprint

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BackgroundNeurofibromatosis type 1 (NF1) is a multi-organ disease caused by mutations in Neurofibromin (NF1).Amongst other features, NF1 patients frequently show reduced muscle mass and strength, impairing patients' mobility and increasing the risk of fall. The role of Nf1 in muscle and the cause for the NF1associated myopathy is mostly unknown. MethodsTo dissect the function of Nf1 in muscle, we created muscle-specific knockout mouse models for Nf1, inactivating Nf1 in the prenatal myogenic lineage either under the Lbx1 promoter or under the Myf5 promoter. Mice were analyzed during pre-and postnatal myogenesis and muscle growth. ResultsNf1 Lbx1 and Nf1 Myf5 animals showed only mild defects in prenatal myogenesis. Nf1 Lbx1 animals were perinatally lethal, while Nf1 Myf5 animals survived only up to approx. 25 weeks. A comprehensive phenotypic characterization of Nf1 Myf5 animals showed decreased postnatal growth, reduced muscle size, and fast fiber atrophy. Proteome and transcriptome analysis of muscle tissue indicated decreased protein synthesis and increased proteasomal degradation, and decreased glycolytic and increased oxidative activity in muscle tissue. High-resolution respirometry confirmed enhanced oxidative metabolism in Nf1 Myf5 muscles, which was concomitant to a fiber type shift from type 2B to type 2A and type 1. Moreover, Nf1 Myf5 muscles showed hallmarks of decreased activation of mTORC1 and increased expression of atrogenes. Remarkably, loss of Nf1 promoted a robust activation of AMPK with a gene expression profile indicative of increased fatty acid catabolism. Additionally, we observed a strong induction of genes encoding catabolic cytokines in muscle Nf1 Myf5 animals, in line with a drastic reduction of white, but not brown adipose tissue. ConclusionsOur results demonstrate a cell-autonomous role for Nf1 in myogenic cells during postnatal muscle growth required for metabolic and proteostatic homeostasis. Furthermore, Nf1 deficiency in muscle drives cross-tissue communication and mobilization of lipid reserves.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cell autonomous requirement of Neurofibromin (Nf1) for postnatal muscle hypertrophic growth and metabolic homeostasis

Wei

Franke

Ost

et al. 2020

Preprint

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“…Two studies with conflicting results have assessed strength in children with NF1. 4,5 Cornett et al 6 extend the research by increasing the number of upper and lower extremity muscle groups assessed. Seven upper extremity and eight lower extremity movements were assessed using a hand-held dynamometer.…”

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confidence: 99%

“…However, thermal dose is a function not just of the temperature but also of the duration and frequency of exposures. 6 Retrospective ascertainment of the duration and frequency, along with highest temperature attained, is difficult and often results in missing data points or unreliable estimates.…”

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confidence: 99%

Studying the effects of maternal febrile exposures on neurological outcomes in offspring: conceptual and methodological issues

Hashmi¹

2015

Develop Med Child Neuro

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This commentary is on the original article by Holst et al. on pages 725-732 of this issue.Over the last quarter of a century, numerous reports on adverse outcomes associated with maternal febrile exposures have been published. Although results have been inconsistent, the general trend is suggestive of a harmful effect -a hypothesis supported by earlier animal and human studies. Furthermore, the central nervous system (CNS) seems especially susceptible to the detrimental effects of such fever. 1,2However, most of the studies which have assessed the effects of maternal febrile exposure on offspring are limited to outcomes that are evident at birth or shortly after. Few have evaluated longer-term developmental effects, including those reporting an association between maternal fever and developmental delay 3 or poor academic performance. 4In their study, Holst et al. 5 add to this body of knowledge by evaluating motor development in children in relation to in utero febrile exposure.The biological plausibility of an effect of thermal exposure during pregnancy on subsequent development is supported by studies on the offspring of guinea pigs that were exposed to hyperthermia.1 These offspring demonstrated significant reductions in brain stem and cerebellar size, and also displayed learning deficits proportional to the reductions in their brain weight. As with many biological systems, one would assume that if maternal fever caused physical changes in the CNS, then a dose-response relationship may exist. However, Holst et al. 5 failed to identify such an association, thus replicating a trend reported in a recent systematic review.2 Holst et al. stated that this suggests that it is not the fever but the underlying causes of the fever that might be the harmful exposure.Although possible, this assumption fails to consider limitations in design and the heterogeneity of the exposures and effects that are often reported. For instance, data on febrile episodes are usually ascertained in a retrospective fashion (regardless of any prospective recruitment and/or follow-up that may be part of the study design). Therefore, data on the dose or 'severity' of the exposure, often reported in terms of the 'highest temperature recorded', may suffer from recall bias. However, thermal dose is a function not just of the temperature but also of the duration and frequency of exposures.6 Retrospective ascertainment of the duration and frequency, along with highest temperature attained, is difficult and often results in missing data points or unreliable estimates.There are also other issues to consider. When, during embryogenesis, did the febrile exposure occur? What about effect modification caused by antipyretic use? If medications were used during pregnancy, were there any unintended long-term harmful effects of these on the offspring? What role do other factors, such as vitamin use, cigarette smoke, or infective agents, play? Are there compensatory mechanisms that hinder the observation of any effects that are temporally too removed from the...

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“…Two studies with conflicting results have assessed strength in children with NF1 . Cornett et al . extend the research by increasing the number of upper and lower extremity muscle groups assessed.…”

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confidence: 99%

Are muscles weaker in children with neurofibromatosis type 1?

D’Astous

Johnson

2015

Develop Med Child Neuro

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The difficulty in assessing strength in children arises from limitations in the measurement instrument and changes that occur during growth and maturation. Therefore, research on the presence of muscle weakness in children with neurofibromatosis type 1 (NF1) continues to remain inconclusive. The criterion standard for measuring muscle strength is an isokinetic system. Isokinetic dynamometry is an accurate measure of muscle torque; however, the equipment is designed for adults and is not feasible for young children without adaptations to the machine for limb length. Additionally, the velocity of the device significantly influences the results and testing must be done at a variety of speeds. Hand-held dynamometers are frequently used to measure isometric strength and there are published normative values for children 1 in relation to age and sex. Macfarlane et al.2 recommended computing torque values to account for differences in limb lengths in children of varying heights. MacWilliams et al.3 recommended a regression equation to account for anthropometric and maturational differences using seven variables that influence strength in children (age, sex, height, weight, ideal weight, body mass index [BMI], and standard BMI).Two studies with conflicting results have assessed strength in children with NF1. 4,5 Cornett et al. 6 extend the research by increasing the number of upper and lower extremity muscle groups assessed. Seven upper extremity and eight lower extremity movements were assessed using a hand-held dynamometer. The authors evaluated differences between 30 children aged 4 to 16 years with a diagnosis of NF1 and 30 age-, sex-, height-, and weightmatched controls. Children with NF1 were significantly weaker in all muscle groups. The percent difference graph clearly portrays a picture of weakness with the mean of all muscle groups below zero difference and with elbow flexors, hip flexors, hip abductors, and ankle plantar flexors showing greater than À30% difference. There are limitations in the study design and data analysis that may have influenced the results. The control group was 3.9cm taller than the NF1 group and the increase in lever arm length may have contributed to strength differences. Additionally, children were not matched for pubertal stage. Muscle hypertrophy and subsequent strength increases occur during puberty.

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Muscle weakness in children with neurofibromatosis type 1

Cited by 24 publications

References 18 publications

Cell autonomous requirement of Neurofibromin (Nf1) for postnatal muscle hypertrophic growth and metabolic homeostasis

Cell autonomous requirement of Neurofibromin (Nf1) for postnatal muscle hypertrophic growth and metabolic homeostasis

Studying the effects of maternal febrile exposures on neurological outcomes in offspring: conceptual and methodological issues

Are muscles weaker in children with neurofibromatosis type 1?

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