- Variants in NGLY1 lead to intellectual disability, myoclonus epilepsy, sensorimotor axonal polyneuropathy and mitochondrial dysfunction. [Journal Article]Clin Genet 2020CG
- NGLY1 encodes the enzyme N-glycanase that is involved in the degradation of glycoproteins as part of the endoplasmatic reticulum-associated degradation pathway. Variants in this gene have been described to cause a multisystem disease characterized by neuromotor impairment, neuropathy, intellectual disability, and dysmorphic features. Here, we describe four patients with pathogenic variants in NGL…
NGLY1 encodes the enzyme N-glycanase that is involved in the degradation of glycoproteins as part of the endoplasmatic reticulum-associated degradation pathway. Variants in this gene have been described to cause a multisystem disease characterized by neuromotor impairment, neuropathy, intellectual disability, and dysmorphic features. Here, we describe four patients with pathogenic variants in NGLY1. As the clinical features and laboratory results of the patients suggested a multisystem mitochondrial disease, a muscle biopsy had been performed. Biochemical analysis in muscle showed a strongly reduced ATP production rate in all patients, while individual OXPHOS enzyme activities varied from normal to reduced. No causative variants in any mitochondrial disease genes were found using mtDNA analysis and whole exome sequencing. In all four patients, variants in NGLY1 were identified, including two unreported variants (c.849T>G (p.(Cys283Trp)) and c.1067A>G (p.(Glu356Gly)). Western blot analysis of N-glycanase in muscle and fibroblasts showed a complete absence of N-glycanase. One patient showed a decreased basal and maximal oxygen consumption rates in fibroblasts. Mitochondrial morphofunction fibroblast analysis showed patient specific differences when compared to control cell lines. In conclusion, variants in NGLY1 affect mitochondrial energy metabolism which in turn might contribute to the clinical disease course. This article is protected by copyright. All rights reserved.
- Muscular, Ocular and Brain Involvement Associated with a De Novo 11q13.2q14.1 Duplication: Contribution to the Differential Diagnosis of Muscle-Eye-Brain Congenital Muscular Dystrophy. [Journal Article]J Neuromuscul Dis 2019JN
- Muscular weakness and hypotonia may be associated with multisystem involvement giving rise to complex phenotypes, many of which are uncharacterized. We report a patient presenting with congenital hypotonia and severe ocular and brain abnormalities, evoking a Muscle Eye Brain disease (MEB). She had global muscular weakness, hypotonia and amyotrophy, joint hyperlaxity, kyphoscoliosis, respiratory i…
Muscular weakness and hypotonia may be associated with multisystem involvement giving rise to complex phenotypes, many of which are uncharacterized. We report a patient presenting with congenital hypotonia and severe ocular and brain abnormalities, evoking a Muscle Eye Brain disease (MEB). She had global muscular weakness, hypotonia and amyotrophy, joint hyperlaxity, kyphoscoliosis, respiratory insufficiency, dysmorphic features and severe intellectual disability. Brain MRI showed cortical atrophy and hypoplasia of the corpus callosum. Normal CK levels, non-progressive course and absence of dystrophic features or α-dystroglycan abnormalities on the muscle biopsy were not typical of MEB. CGH array identified a large de novo duplication in chromosome 11, including regions partially duplicated in three other patients with common clinical features. This report adds to the differential diagnosis of complex phenotypes characterized by muscular, ocular and CNS involvement and highlights the potential contribution of still unrecognized chromosomal abnormalities to these phenotypes.
- ASC-1 Is a Cell Cycle Regulator Associated with Severe and Mild Forms of Myopathy. [Journal Article]Ann Neurol 2020; 87(2):217-232AN
- CONCLUSIONS: Our results expand the phenotypical and molecular spectrum of TRIP4-associated disease to include mild adult forms with or without cardiomyopathy, associate ASC-1 depletion with isolated primary muscle involvement, and establish TRIP4 as a causative gene for several congenital muscle diseases, including nemaline, core, centronuclear, and cytoplasmic-body myopathies. They also identify ASC-1 as a novel cell cycle regulator with a key role in cell proliferation, and underline transcriptional coregulation defects as a novel pathophysiological mechanism. ANN NEUROL 2020;87:217-232.
- Disordered eating attitudes correlate with body dissatisfaction among Kuwaiti male college students. [Journal Article]J Eat Disord 2019; 7:37JE
- CONCLUSIONS: The high proportion of disordered eating attitudes among Kuwaiti college men was associated with high levels of body image dissatisfaction in relation to both body fat and muscularity. High levels of eating disorder symptoms were also linked to obesity.
- StatPearls: Body Image Distortion [BOOK]StatPearls Publishing: Treasure Island (FL)BOOK
- Body image is the subjective picture of individuals of their own body, irrespective of how their body actually looks. Body image is a complex construct comprising thoughts, feelings, evaluations, and behaviors related to one’s body. Body image misperception is common in the general population and is also a core component of several serious diseases, including body dysmorphic disorder, an…
Body image is the subjective picture of individuals of their own body, irrespective of how their body actually looks. Body image is a complex construct comprising thoughts, feelings, evaluations, and behaviors related to one’s body. Body image misperception is common in the general population and is also a core component of several serious diseases, including body dysmorphic disorder, anorexia nervosa, and bulimia nervosa. Distortions in body image are unpleasant and can have tragic results. Poor body image can affect physical and psychological health and can influence self-esteem, mood, competence, social functioning, and occupational functioning. The understanding of the neurotypical distortions in healthy cognition and perceptual distortions in clinical conditions is essential to address body image concerns and enable suffering individuals to lead more contented and productive lives. In this activity, we outline the role of body image in psychological and physical functioning and describe features of various body image-related conditions and disorders. Historical Perspective Early in the 1900s, there were considerable efforts by neurologists to understand unusual forms of body perception reported by patients with brain injury, or phantom limb experience in amputees. The early concepts of body image indeed were rooted in neuropathology. Head, in 1920, first defined body image as a unity of past experiences created in the cerebral sensory cortex. Schilder, who was a neurologist, proposed a biopsychosocial approach to body image, highlighting the need to examine its neurological, psychological, and sociocultural components. Newell noted that body image is dynamic and changes with age, mood, or even clothing. Krueger suggested that body image is the representation of identity derived from both external and internal body experiences. Definition What is body image, and why is it important? Body image is one of the components of personal identity. Body image is the figure that one has on their anthropometric measurements, contours, and shape of the body; and also the feelings correlated to these factors that affect the satisfaction with the body or specific parts of the body. Indeed, body image represents how we think, feel, perceive, and behave regarding our bodies. Body image is a multidimensional concept. The complexity of body image can be appreciated by looking at its components. These components apply to people with healthy and unhealthy perceptions of their bodies and include: Cognitive: thoughts and beliefs about the body. Perceptual: how people perceive the size and shape of their body and body parts. Affective: feelings about the body. Behavioral: the actions that people perform to check on, tend to, alter, or conceal their body. Related but different terms are often used interchangeably in the literature concerning the state of consciousness in which there is an altered body image perception, including body image distortion, body image misperception, body image disturbance, negative body image, altered body image, and body dissatisfaction. The problem of variable terms is intensified by the fact that some studies focus on psychiatric or medical patients, some deal with nonpatients, and others deal with both groups. Body image distortion is a multidimensional symptom, comprising various components of body image. Components that most widely accepted are the cognitive, the perceptive, and the affective. The cognitive component is from thoughts and beliefs concerning body shape and appearance, and the mental representation of the body. The perceptive component involves the identification and estimation of the body, and it indicates the accuracy of the individuals' evaluation of their body size, shape, and weight compared to their actual proportions. Finally, the affective component includes feelings that individuals develop towards their body and satisfaction or dissatisfaction of individuals about their body. Thereupon, body image disturbance can manifest as disturbance of percept (i.e., distortion) and concept (i.e., body dissatisfaction). Perceptual disturbance involves the failure to evaluate the size of one’s body accurately. Body dissatisfaction includes attitudinal or affective perception of one’s body and negative feelings and cognitions. Body image disturbances are thought to also manifest on a behavioral level, such as body avoidance, body checking, or dieting. Negative body image characteristically demonstrates a dissatisfaction of body or body parts, preoccupation with appearance, and engaging in behaviors such as frequent mirror checking, self-weighing, or avoidance of public situations. Negative body image often gets measured as body dissatisfaction. Body dissatisfaction is attributable to a discrepancy between the perception of body image and its idealized image. Body Image Development There are some debates as to when body image development begins. Price believes that primitive sense of body image originates in the uterus with spontaneous movements of the fetus and corresponding feedback from sensory and proprioceptive input. Body image is a learned phenomenon from experiences during both pre-natal and post-natal development in which cross-cortical connections and mirror neurons play prominent roles. Complex interactions between neurophysiological, socio-cultural, and cognitive factors contribute to body image development and maintenance. Different factors such as gender, fashion, peer groups, educational and familial influences, evolving socialization, and physical alterations (hair growth, acne, breast development, menstruation) put children into unknown territory with vulnerable body images. Primary socialization takes place early in life, and a sense of self-recognition is assumed to develop by the age of two. Children in the toddler years become aware of their gender. They also discover social norms, such as competitiveness and athleticism for men (strong legs, muscles, large arms), and beauty or smallness for females (glossy hair, perfect skin, tiny waist, no hips). When children become aware of their body appearance, they attempt to manipulate their parents to receive admiration and approval. This need for approval grows upon starting school, exhibiting a need for social acceptance. Cash assumes body image as a learned behavior. Smolak proposes that children mainly focus on appearance in the context of the toys they play with, such as Barbie dolls. As children grow and socialize, they begin comparing themselves with other children, especially concerning appearance (e.g., little children desire to be bigger). By the age of 6, body shape becomes increasingly prominent consideration (especially muscle and weight). Smolak reported that among school children aged 6 to 12 years old, 40–50% demonstrated dissatisfaction with some part of their body size or shape. Adolescence indicates the transition from childhood to adulthood and is associated with physical and social changes. Adolescence is a critical period in body image development. Body image in adolescents is also under the influence of parents. The parent-adolescent relationship has a significant impact on the development of adolescents’ body dissatisfaction. Parents send sociocultural or critical messages and messages about body appearance ideals to their children. When Individuals feel secure regarding their relationships, they are more satisfied with their body and less likely to think in ways that they have to adhere to appearance ideals to receive others’ acceptance. Researches have shown that adolescents with better parent-adolescent relationships are less likely to experience body dissatisfaction. Although in younger children, the influence of families on body image development is more significant than friends, the role of parents decreases as children get older and peer responses become more important than families. Body image in people aged 14 to 27 is greatly affected by their peers. A critical event or series of events such as teasing and rejection may lead to body image misperception. Studies have found that the more frequent being teased about body size and weight while growing up, the more likely to experience body image distortion and body dissatisfaction during adulthood.
- Patient-reported disease burden in oculopharyngeal muscular dystrophy. [Journal Article]Muscle Nerve 2019; 60(6):724-731MN
- There is currently little evidence regarding oculopharyngeal muscular dystrophy (OPMD) disease burden reported by patients. In this study we aim to elicit direct patient input regarding OPMD disease burden.
There is currently little evidence regarding oculopharyngeal muscular dystrophy (OPMD) disease burden reported by patients. In this study we aim to elicit direct patient input regarding OPMD disease burden.
- Assessment and validation of a Spanish version of the Muscle Dysmorphia Disorder Inventory in Argentinian men who exercise: Inventario de Dismorfia Muscular. [Journal Article]Body Image 2019; 31:24-34BI
- Despite an increase in body dissatisfaction and muscularity concerns among Latin American men, there is a paucity of research relating to muscle dysmorphia in this population. In this study we aimed to evaluate, for the first time in Latin America, the factor structure of the Muscle Dysmorphic Disorder Inventory (MDDI; Hildebrandt, Langenbucher, & Schlundt, 2004). A sample of 551 men who exercise…
Despite an increase in body dissatisfaction and muscularity concerns among Latin American men, there is a paucity of research relating to muscle dysmorphia in this population. In this study we aimed to evaluate, for the first time in Latin America, the factor structure of the Muscle Dysmorphic Disorder Inventory (MDDI; Hildebrandt, Langenbucher, & Schlundt, 2004). A sample of 551 men who exercise completed measures of body dissatisfaction, disordered eating, and the MDDI. Exploratory factor analysis in a first split-half sample revealed a 3-factor solution similar to the original version, which was then tested through confirmatory factor analysis (CFA) in a second split-half sample. A re-specified model (allowing for error correlations between Items 10-13 and 11-13) presented adequate fit. Omega coefficients revealed adequate internal consistency (> .80) for the Drive for Size and Functional Impairment subscales. The internal consistency for the Appearance Intolerance subscale was .74 and .72 across subset samples. Associations with body dissatisfaction, disordered eating, body mass index, and frequency of training and rest days are presented as evidence of construct validity. Finally, multi-group CFA indicated that the model was invariant across type of exercise. Overall, these data suggest that the MDDI is suitable for use in Spanish-speaking Latin American male populations.
- Interactions among ryanodine receptor isotypes contribute to muscle fiber type development and function. [Journal Article]Dis Model Mech 2019; 13(2)DM
- Mutations affecting ryanodine receptor (RyR) calcium release channels commonly underlie congenital myopathies. Although these channels are known principally for their essential roles in muscle contractility, mutations in the human RYR1 gene result in a broad spectrum of phenotypes, including muscle weakness, altered proportions of fiber types, anomalous muscle fibers with cores or centrally place…
Mutations affecting ryanodine receptor (RyR) calcium release channels commonly underlie congenital myopathies. Although these channels are known principally for their essential roles in muscle contractility, mutations in the human RYR1 gene result in a broad spectrum of phenotypes, including muscle weakness, altered proportions of fiber types, anomalous muscle fibers with cores or centrally placed nuclei, and dysmorphic craniofacial features. Currently, it is unknown which phenotypes directly reflect requirements for RyRs and which result secondarily to aberrant muscle function. To identify biological processes requiring RyR function, skeletal muscle development was analyzed in zebrafish embryos harboring protein-null mutations. RyR channels contribute to both muscle fiber development and function. Loss of some RyRs had modest effects, altering muscle fiber-type specification in the embryo without compromising viability. In addition, each RyR-encoding gene contributed to normal swimming behavior and muscle function. The RyR channels do not function in a simple additive manner. For example, although isoform RyR1a is sufficient for muscle contraction in the absence of RyR1b, RyR1a normally attenuates the activity of the co-expressed RyR1b channel in slow muscle. RyR3 also acts to modify the functions of other RyR channels. Furthermore, diminished RyR-dependent contractility affects both muscle fiber maturation and craniofacial development. These findings help to explain some of the heterogeneity of phenotypes that accompany RyR1 mutations in humans.
- Isolated Unilateral Cerebellar Hemispheric Dysplasia: A Rare Entity. [Journal Article]Can J Neurol Sci 2019; 46(6):760-761CJ
- A 9-year-old female presented to neurology outpatient department of our hospital with complaints of recurrent generalized tonic-clonic seizures since birth and was being treated with anticonvulsants for the same. Patient also had complaints of giddiness and episodes of momentary loss of consciousness. There was history of twitching of left hemiface and eyelid during infancy, often associated with…
A 9-year-old female presented to neurology outpatient department of our hospital with complaints of recurrent generalized tonic-clonic seizures since birth and was being treated with anticonvulsants for the same. Patient also had complaints of giddiness and episodes of momentary loss of consciousness. There was history of twitching of left hemiface and eyelid during infancy, often associated with deviation of eyes to the left and groaning. The birth history was unremarkable. Family history revealed no known consanguinity. General examination revealed no dysmorphic features. Neurological examination revealed no cognitive deficits/signs to suggest cerebellar pathology. An electroencephalogram was done in view of her recurrent seizures, which was normal. Initial laboratory work-up was normal. The patient then underwent magnetic resonance imaging (MRI) brain, acquired with a 1.5-T unit (Siemens, Erlangen, Germany). MRI brain revealed hemihypertrophy of left cerebellar hemisphere with disorganized architecture, fissural malorientation with individual folia running vertically rather than horizontally with disorganized foliation, abnormal arborization of white matter predominantly involving mid and dorsal surface of left cerebellar hemisphere and a few suspicious areas of abnormal T2-hyperintense signal in subcortical white matter. Right cerebellar hemisphere and cerebellar vermis were normal. Corpus callosum was normal. Cerebral parenchyma was normal in signal intensity pattern with normal gray-white matter differentiation. Ventricular system was normal (Figures 1 and 2). Cerebellar malformations are uncommon and are usually associated with Dandy-Walker continuum, Joubert syndrome, rhombencephalosynapsis, lissencephaly, Fukuyama congenital muscular dystrophy, Walker-Warburg syndrome, muscle-eye-brain disease, congenital cytomegalovirus infection to name a few.1,2 Isolated unilateral cerebellar hemispheric dysplasia is exceedingly rare with only a few cases previously described in English literature. Cerebellar malformations are less adequately understood entity partly because of the complex cerebellar embryology and limited histologic studies of these disorders. Genes expressed in migration and maintenance of the Purkinje cells and/or in the generation and migration of granular cells when mutated will disrupt cerebellar migration and foliation and thus cause cerebellar malformation.3-5 Cerebellum is known to be a centre for motor learning, coordination, and higher cognitive functions. Clinical presentation of cerebellar malformations is highly variable and depends on the degree of cerebellar involvement, presence of associated cerebral involvement and the underlying disorders such as muscular dystrophy if any. Patel and Barkovich suggested an imaging-based classification of cerebellar malformations and classified the malformations broadly into two types, malformations with cerebellar hypoplasia and the ones with cerebellar dysplasia. Each of these was further classified into focal and diffuse.1 Demaerel gave a classification of abnormalities of cerebellar foliation and fissuration.2 Our index case with disorganized architecture, fissural malorientation and disorganized foliation of left cerebellar hemisphere associated with normal cerebellar vermis, corpus callosum, and absence of cerebral malformation falls into Type 2 category as per the classification by Demaerel.2 Treatment depends upon the severity of symptoms and the underlying disorder in case of syndromic malformations. Generally, treatment is symptomatic and supportive. Understanding of the basics of cerebellar embryology, knowledge of the imaging features, and clinical presentation aids in the precise diagnosis of this disorder and its optimal management.
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- Biallelic variants in the transcription factor PAX7 are a new genetic cause of myopathy. [Journal Article]Genet Med 2019; 21(11):2521-2531GM
- CONCLUSIONS: These findings show that biallelic variants in the master transcription factor PAX7 cause a new type of myopathy that specifically affects satellite cell survival.