Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism, caused by a CGG expansion to greater than 200 repeats in the promoter region of FMR1 on the bottom of the X chromosome. A subgroup of individuals with FXS experience hyperphagia, lack of satiation after meals and severe obesity, this subgroup is referred to have the Prader-Willi phenotype of FXS. Prader-Willi syndrome is one of the most common genetic severe obesity disorders known and it is caused by the lack of the paternal 15q11–13 region. Affected individuals suffer from hyperphagia, lack of satiation, intellectual disability, and behavioral problems. Children with fragile X syndrome Prader-Willi phenotye and those with Prader Willi syndrome have clinical and molecular similarities reviewed here which will impact new treatment options for both disorders.
Fragile X syndrome (FXS); Prader-Willi phenotype; FMR1 gene; Hyperphagia; Autism; IGF-1; Growth hormone
The grey zone (GZ; 45–54 CGG repeats in the FMR1 gene) is considered a normal allele, however several studies have found a high frequency of GZ in movement disordered populations. Here, we describe neurological features of FXTAS in two carriers of GZ alleles, although FXTAS has been defined as occurring only in premutation carriers (55–200 CGG repeats). Both patients had family members who had the premutation and were diagnosed with FXTAS. The presence of relatively high GZ alleles with elevated FMR1-mRNA combined with a family history of FXTAS that may represent a facilitating genetic background for FXTAS are the factors that led to the presence of FXTAS in these individuals with a GZ allele. Further research into clinical involvement of GZ alleles is recommended and the definition of FXTAS may requires revision.
ataxia; FMR1-mRNA; FXTAS; grey zone; premutation; tremor
We examined whether females with the fragile X-associated tremor ataxia syndrome (FXTAS) and non-FXTAS premutation carriers have electrophysiological signs of underlying peripheral neuropathy.
Nerve conduction studies (NCS) were performed on 19 women with FXTAS, 20 non- FXTAS carriers, and 26 age-matched controls. The results were compared to existing data on corresponding male carriers.
Women with FXTAS and non-FXTAS carriers had reduced sensory nerve action potential amplitudes. Also, there was a strong trend for reduced compound muscle action potential amplitudes observed in women with FXTAS, but not in non-FXTAS carriers. No significant slowing of nerve conduction velocities, prolongation of F-wave latencies, or associations with molecular measures was observed.
This study suggests an underlying axonal neuropathy in women with FXTAS. However, in comparison to men with FXTAS, the NCS abnormalities in women were less severe, possibly due to the effect of a normal X-chromosome.
nerve conduction studies; fragile X premutation; FXTAS; fragile X-associated tremor ataxia syndrome; FMR1
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, and is the leading single-gene cause of autism spectrum disorders. It is due to a loss of the fragile X mental retardation protein, which leads to molecular, behavioral, and cognitive deficits in these patients. Improvements in our understanding of its pathophysiology have led to the development of numerous targeted treatments in FXS as highlighted by metabotropic glutamate receptor antagonists and gamma-Aminobutyric acid receptor modulators. This review will summarize relevant pre-clinical data and results from clinical trials in human subjects with FXS. It will also highlight upcoming studies and future directions for clinical trials as well.
Fragile X syndrome; targeted treatments; clinical trials
This study examined the relationship between the Fragile X premutation and Restless Legs Syndrome (RLS). Demographic, medical history and survey responses related to sleep were collected from 213 participants (127 carriers and 86 age matched controls). Subjects were asked about the presence of the four formal diagnostic criteria for RLS. Individuals with the premutation were 1.9 times as likely to meet criteria for RLS (95% CI 1.1–3.2, p=0.025) as controls. Premutation carriers with RLS also experienced significantly worse symptoms than matched controls with adjusted mean scores of 15.1±8.8 vs. 7.9±4.4 respectively on the International Restless Legs Scale. As markers for domains of sleep disturbance, all subjects completed the Epworth Sleepiness Scale, the Insomnia Severity Index and the Pittsburgh Sleep Quality Index. Premutation carriers demonstrated significantly more pathology on these tests except for the Epworth Sleepiness Scale where there was a trend towards increased daytime sleepiness in carriers. RLS joins a host of other conditions that should be carefully screened for in those carrying the Fragile X premutation and sleep should be a focus for clinicians providing care to them.
Restless Legs Syndrome; Fragile X premutation; Sleep; Trinucleotide repeat disorders; Insomnia
The fragile X-associated tremor ataxia syndrome (FXTAS) is caused by the premutation in FMR1 gene. Recent reports of environmental toxins appear to worsen the progression of FXTAS. Here we present a case of male adult with FXTAS and a long history of methadone use. The patient shows a faster progression in both symptoms of disease and MRI changes compared to what is typically seen in FXTAS. There has been no research regarding the role of narcotics in onset, progression, and severity of FXTAS symptoms. However, research has shown that narcotics can have a negative impact on several neurodegenerative diseases, and we hypothesize that in this particular case, methadone may have contributed to a faster progression of FXTAS as well as exacerbating white matter disease through RNA toxicity seen in premutation carriers.
premutation; FMR1 gene; narcotics; methadone; white matter; FXTAS
Automated segmentation is a useful method for studying large brain structures such as the cerebellum and brainstem. However, automated segmentation may lead to inaccuracy and/or undesirable boundary. The goal of the present study was to investigate whether SegAdapter, a machine learning-based method, is useful for automatically correcting large segmentation errors and disagreement in anatomical definition. We further assessed the robustness of the method in handling size of training set, differences in head coil usage, and amount of brain atrophy. High resolution T1-weighted images were acquired from 30 healthy controls scanned with either an 8-channel or 32-channel head coil. Ten patients, who suffered from brain atrophy because of fragile X-associated tremor/ataxia syndrome, were scanned using the 32-channel head coil. The initial segmentations of the cerebellum and brainstem were generated automatically using Freesurfer. Subsequently, Freesurfer’s segmentations were both manually corrected to serve as the gold standard and automatically corrected by SegAdapter. Using only 5 scans in the training set, spatial overlap with manual segmentation in Dice coefficient improved significantly from 0.956 (for Freesurfer segmentation) to 0.978 (for SegAdapter-corrected segmentation) for the cerebellum and from 0.821 to 0.954 for the brainstem. Reducing the training set size to 2 scans only decreased the Dice coefficient ≤0.002 for the cerebellum and ≤ 0.005 for the brainstem compared to the use of training set size of 5 scans in corrective learning. The method was also robust in handling differences between the training set and the test set in head coil usage and the amount of brain atrophy, which reduced spatial overlap only by <0.01. These results suggest that the combination of automated segmentation and corrective learning provides a valuable method for accurate and efficient segmentation of the cerebellum and brainstem, particularly in large-scale neuroimaging studies, and potentially for segmenting other neural regions as well.
This study examined use of a speaker's direction of gaze during word learning by boys with fragile X syndrome (FXS), boys with nonsyndromic autism spectrum disorder (ASD), and typically developing (TD) boys.
A fast-mapping task with follow-in and discrepant labeling conditions was administered. We expected that the use of speaker gaze would lead to participants selecting as the referent of the novel label the object to which they attended in follow-in trials and the object to which the examiner attended in the discrepant labeling trials. Participants were school-aged boys with FXS (n = 18) or ASD (n = 18) matched on age, intelligence quotient, and nonverbal cognition and younger TD boys (n = 18) matched on nonverbal cognition.
All groups performed above chance in both conditions, although the TD boys performed closest to the expected pattern. Boys with FXS performed better during follow-in than in discrepant label trials, whereas TD boys and boys with ASD did equally well in both trial types. The type of trial administered first influenced subsequent responding. Error patterns also distinguished the groups.
The ability to utilize a speaker's gaze during word learning is not as well developed in boys with FXS or nonsyndromic ASD as in TD boys of the same developmental level.
Although males with fragile X syndrome (FXS) are frequently described as demonstrating autism symptomatology, there is much debate regarding whether the behavioral symptoms representing the core domains of autism are the result of the same or different underlying neurological/psychological mechanisms. The present study used a cross-sectional developmental trajectories approach to compare the profiles of autism symptomatology relative to chronological age (CA), nonverbal IQ, and expressive vocabulary ability between individuals with FXS and individuals with nonsyndromic ASD. Results suggest that the onset of autism symptoms and their developmental trajectories in males with FXS differ in important ways as a function of chronological age, nonverbal cognitive ability, and expressive vocabulary relative to males with nonsyndromic ASD. Theoretical and clinical implications are discussed.
Fragile X mental retardation 1 (FMR1) premutation associated phenotypes have been explored extensively since the molecular mechanism emerged involving elevated FMR1 messenger ribonucleic acid (mRNA) levels. Lowered fragile X mental retardation protein (FMRP) can also occur which may have an additive effect to the high levels of mRNA leading to neurodevelopmental problems and psychopathology. This paper was aimed to review psychosis and catatonia in premutation carriers, express the role of elevated FMR1 mRNA and lowered FMRP in the phenotype of carriers and present a case of psychosis and catatonia in a carrier. This case also demonstrates additional genetic and environmental factors which may also affect the phenotype. We review the literature and report an exemplary case of a 25 year old male premutation carrier with elevated FMR1 mRNA, low FMRP, a cytochrome P450 family 2 subfamily D polypeptide 6 (CYP2D6)*2xN mutation and a perinatal insult. This patient developed an autism spectrum disorder, psychosis, catatonia with subsequent cognitive decline after electro-convulsive therapy (ECT) for his catatonia. He had a premutation of 72 CGG repeat in FMR1, FMR1 mRNA level that was over 2.4 times normal and FMRP level at 18% of normal, and additionally, a CYP2D6 allelic variant which leads to ultrarapid metabolism (UM) of medication. There is an overlapping pathophysiological mechanism of catatonia and fragile X-associated premutation phenotypes including autism and psychosis. This case demonstrates the shared phenotype and the overlap of the pathophysiological mechanisms that can influence the intervention. Multiple genetic and environmental hits can lead to more significant involvement in premutation carriers.
Catatonia; fragile X syndrome; premutation; psychosis
Alcohol use disorders (AUDs) have been reported in a limited number of individuals with cognitive impairment but rarely in those with fragile X syndrome (FXS). However, in Colombia, culturally, alcohol consumption is very common. Here, we report eight cases of patients with FXS who have frequent alcohol consumption in Ricaurte, Colombia. Some of these patients have also used tobacco and illegal substances, including cocaine, which use has not been previously reported in those with FXS. Alcohol and substance use dependence is associated with exacerbation of their behavioral problems, such as increased impulsivity and aggression, as well as of medical problems such as an increased frequency of seizures.
Alcohol use disorders; fragile X syndrome
The fragile X mental retardation 1 gene, which codes for the fragile X mental retardation 1 protein, usually has 5 to 40 CGG repeats in the 5′ untranslated promoter. The full mutation is the almost always the cause of fragile X syndrome (FXS). The prevalence of FXS is about 1 in 4,000 to 1 in 7,000 in the general population although the prevalence varies in different regions of the world. FXS is the most common inherited cause of intellectual disability and autism. The understanding of the neurobiology of FXS has led to many targeted treatments, but none have cured this disorder. The treatment of the medical problems and associated behaviors remain the most useful intervention for children with FXS. In this review, we focus on the non-pharmacological and pharmacological management of medical and behavioral problems associated with FXS as well as current recommendations for follow-up and surveillance.
Fragile X syndrome; Autism Spectrum Disorder; Intellectual Disability; developmental delay; premutation; clinical management; clinical guidelines; treatment; medical problems; FMR1; FMRP
Cognitive and behavioral correlates of molecular variations related to the FMR1 gene have been studied rather extensively, but research about the long-term outcome in individuals with fragile X spectrum disorders remains sparse. In this review, we present an overview of aging research and recent findings in regard to cellular and clinical manifestations of aging in fragile X syndrome, and the FMR1 premutation.
fragile X syndrome; aging; neurodegeneration; FMRP
Parkinsonian features have been used as a minor diagnostic criterion for fragile X-associated tremor/ataxia syndrome (FXTAS). However, prior studies have examined parkinsonism (defined as having bradykinesia with at least rest tremor or postural instability) mostly in premutation carriers without a diagnosis of FXTAS. The current study was intended to elaborate this important aspect of the FXTAS spectrum, and to quantify the relationships between parkinsonism, FXTAS clinical staging and genetic/molecular measures.
Thirty eight (38) FXTAS patients and 10 age-matched normal controls underwent a detailed neurological examination that included all but one item (i.e. rigidity) of the motor section of the Unified Parkinson’s Disease Rating Scale (UPDRS).
The FXTAS patient group displayed substantially higher prevalence of parkinsonian features including body bradykinesia (57%) and rest tremor (26%), compared to the control group. Furthermore, parkinsonism was identified in 29% of FXTAS patients. Across all patients, body bradykinesia scores significantly correlated with FXTAS clinical stage, FMR1 mRNA level, and ataxic gait of cerebellar origin, while postural instability was associated with intention tremor.
Parkinsonian features in FXTAS appear to be characterized as bradykinesia concurrent with cerebellar gait ataxia, postural instability accompanied by intention tremor, and frequent rest tremor, representing distinctive patterns that highlight the need for further clinical studies including genetic testing for the FMR1 premutation. The association between FMR1 mRNA level and bradykinesia implicates pathophysiological mechanisms which may link FMR1 mRNA toxicity, dopamine deficiency and parkinsonism in FXTAS.
Fragile X premutation; Parkinsonism; Bradykinesia; FMR1 mRNA
Symptoms of autism are frequent in males with fragile X syndrome (FXS), but it is not clear whether symptom profiles differ from those of nonsyndromic ASD. Using individual item scores from the Autism Diagnostic Inventory-Revised (ADI-R), we examined which current symptoms of autism differed in boys with FXS relative to same-aged boys diagnosed with nonsyndromic ASD. In addition, different subsamples of participants were matched on autism diagnostic status and severity of autism symptoms. Between-group comparisons revealed that boys with FXS showed significantly less impairment in Social Smiling than did age-, diagnostic, and severity-matched boys with nonsyndromic ASD. Severity-matched boys with FXS showed more impairment in Complex Mannerisms than did boys with nonsyndromic ASD. Behavioral differences between FXS and nonsyndromic ASD may be of theoretical importance in understanding the causes and correlates of ASD in FXS and in developing and implementing appropriate treatments.
Fragile X Syndrome (FXS) is a trinucleotide repeat disorder that results in the silencing of the Fragile X Mental Retardation 1 gene (FMR1), leading to a lack of the FMR1 protein (FMRP). FMRP is an mRNA-binding protein that regulates the translation of hundreds of mRNAs important for synaptic plasticity. Several of these pathways have been identified and have guided the development of targeted treatments for FXS. Here we present evidence that serotonin is dysregulated in FXS and treatment with the selective serotonin reuptake inhibitor (SSRI) sertraline may be beneficial for individuals with FXS, particularly in early childhood.
Fragile X Syndrome; fragile X mental retardation protein; selective serotonin reuptake inhibitors; sertraline
A debilitating late-onset disorder of the premutation in the FMR1 gene is the neurodegenerative disorder fragile X-associated tremor ataxia syndrome (FXTAS). We report two patients with FXTAS who have a history of substance abuse (opiates, alcohol, and cocaine) which may have exacerbated their rapid neurological deterioration with FXTAS. There has been no case report regarding the role of substance abuse in onset, progression, and severity of FXTAS symptoms. However, research has shown that substance abuse can have a negative impact on several neurodegenerative diseases, and we propose that in these cases, substance abuse contributed to a faster progression of FXTAS as well as exacerbated white matter disease.
Substance abuse; neurological deterioration; FXTAS; premutation; opiates
Approximately 40% of males with the fragile X premutation develop fragile X-associated tremor/ataxia syndrome after age 50. Although the thalamus and basal ganglia play a crucial role in movement disorders, their involvement in fragile X premutation carriers has not been systematically investigated.
The current study characterized structural abnormalities associated with fragile X premutation carriers (with and without fragile X-associated tremor/ataxia syndrome) in the thalamus, caudate nucleus, putamen, and globus pallidus using T1-weighted and diffusion tensor imaging.
Male premutation carriers with fragile X-associated tremor/ataxia syndrome showed significant volume atrophy and diffusion-weighted signal loss in all 4 structures compared to the control group. They also exhibited volume atrophy and diffusion-weighted signal loss in the thalamus and striatum compared to the premutation carriers without fragile X-associated tremor/ataxia syndrome. Importantly, many of the measurements exhibited robust correlations with symptom severity, with volume and DWI measurements displaying negative correlations and fractional anisotropy measurements displaying positive correlations.
The current study demonstrated involvement of all 4 subcortical gray matter structures in fragile X-associated tremor/ataxia syndrome, with significant volume atrophy, and possibly iron deposition indicated by the diffusion-weighted signal loss. The significant correlation between the subcortical measurements and symptom severity suggests the benefits of tracking structural changes in the subcortical gray matter in future longitudinal studies for early detection and disease monitoring.
neurodegeneration; iron dysregulation; genetic disorder; diffusion tensor imaging; diffusion weighted imaging
To investigate the nature of cognitive impairments and underlying brain mechanisms in older female fragile X premutation carriers with and without fragile X-associated tremor/ataxia syndrome (FXTAS).
Extensive neuropsychological testing and cognitive event-related brain potentials (ERPs, particularly, the auditory P300) were examined in 84 female participants: 33 fragile X premutation carriers with FXTAS (mean age = 62.8), 25 premutation carriers without FXTAS (mean age = 55.4) and 26 normal healthy controls (mean age = 59.3).
Both premutation groups exhibited executive dysfunction on the Behavioral Dyscontrol Scale (BDS), with subtle impairments in inhibition and performance monitoring in female carriers without FXTAS, and more substantial deficits in FXTAS women. However, the female carrier group without FXTAS showed more pronounced deficiencies in working memory.
Abnormal ERPs were recorded over the frontal lobes, where FXTAS patients showed both P300 amplitude reduction and latency prolongation, while only decreased frontal P300 amplitudes were found in carriers without FXTAS. These frontal P3 measures correlated with executive function and information processing speed.
The neuropsychological testing and ERP results of the present study provide support for the hypothesis that executive dysfunction is the primary cognitive impairment among older female premutation carriers both with and without FXTAS, although these deficits are relatively mild compared to those in FXTAS males. These findings are consistent with a synergistic effect of the premutation and aging on cognitive impairment among older female fragile X premutation carriers, even in those without FXTAS symptoms.
This report seeks to establish the prevalence of sleep apnea in patients with the FMR1 premutation with and without FXTAS and to determine any correlation between CGG repeat and FMR1 mRNA levels with sleep apnea prevalence. Demographic and medical data from 430 (229 males, 201 females) participants were used in this analysis. Participants included premutation carriers with (n=118) and without FXTAS (n=174) as well as controls without the premutation (n=123). Logistic regression models were employed to estimate the odds ratio of sleep apnea relative to controls, adjusted for age and gender, and also to examine potential association with CGG size and FMR1 mRNA expression level. The observed proportion of sleep apnea in premutation carriers with and without FXTAS and controls are 31.4% (37/118), 8.6% (15/174), and 13.8% (17/123), respectively. The adjusted odds of sleep apnea for premutation carriers with FXTAS is about 3.4 times that compared to controls (odds ratio, OR=3.4, 95% CI 1.8 to 7.4; p=0.001), and similarly relative to premutation carriers without FXTAS (OR=2.9, 95% CI 1.2 to 6.9; p=0.014). The risk of sleep apnea was not different between controls and premutation carriers without FXTAS. The presence of sleep apnea is not associated with CGG repeat numbers nor FMR1 mRNA expression level among premutation carriers. Our data supports a higher prevalence and risk of sleep apnea in patients with FXTAS. We recommend that all patients diagnosed with FXTAS be screened for sleep apnea given the negative and perhaps accelerative impact sleep apnea may have on their FXTAS progression.
sleep apnea; fragile X-associated tremor/ataxia syndrome; trinucleotide repeat diseases; mitochondrial disorders; gait disorders/ataxia
The relative risk of immune-mediated disorders (IMDs) among women carrier of premutation alleles is estimated by a survey for IMDs among 344 carrier women (age 19 to 81 years; mean 46.35 and SD 12.60) and 72 controls (age 18 to 87 years; mean 52.40 and SD 15.40). One hundred fifty four (44.77%) women carrier had at least one IMD, as did 20 controls (27.78%). Among women carrier, autoimmune thyroid disorder was the most common (24.4%), then fibromyalgia (10.2%), irritable bowel syndrome (IBS; 9.9%), Raynaud’s phenomenon (7.6%), rheumatoid arthritis (RA; 3.8%), Sjögren syndrome (2.6%), systemic lupus erythematosus (SLE; 2.03%), multiple sclerosis (1.74%). Of 55 carriers age 40 or older with FXTAS, 72.73% had at least one IMD, compared to 46.54% of those without FXTAS (n=159), and 31.58% of controls (n=57). The estimated odds ratio (OR) for IMD is 2.6 (95% CI 1.2–5.6, p = 0.015) for women with FXTAS relative to those without FXTAS; the likelihood of IMD in carriers without or with FXTAS was also significantly higher than for controls (OR 2.1, 95% CI 1.1–4.2, p = 0.034; OR 5.5, 95% CI 2.4–12.5, p < 0.001 respectively). Similarly, the odds of having an IMD among carriers with FXPOI is about 2.4 times higher when compared to carriers without FXPOI (95% CI 1.1–5.0; p = 0.021). The likelihood of IMD in carriers with or without FXPOI is greater (OR 2.4, 95% CI 1.1–5.0; p = 0.021) compared to that of controls.
Autoimmune; FXTAS; RNA toxicity; ovarian insufficiency
Minocycline can rescue the dendritic spine and synaptic structural abnormalities in the fragile X knock-out mouse. This is a review and preliminary survey to document side effects and potential outcome measures for minocycline use in the treatment of individuals with fragile X syndrome. We surveyed 50 patients with fragile X syndrome who received minocycline for at least 2 weeks and found that the most common reported side effect is gastrointestinal difficulty, including loss of appetite. The families reported an improvement in language and behavioral areas. Outcome measures in the design of future randomized clinical trials should include both behavioral and language measures. As with any other treatments, we emphasize that randomized clinical trials are needed to determine the efficacy of minocycline in fragile X syndrome.
Fragile X-associated tremor ataxia syndrome (FXTAS) is a late onset neurodegenerative disease that affects carriers of the fragile X premutation. This study seeks to assess hypertension risk and susceptibility in male premutation carriers with FXTAS. Although many symptoms and diagnostic criteria have been identified, hypertension risk has not been examined in this population. Data from 92 premutation carriers without FXTAS, 100 premutation carriers with FXTAS, and 186 controls was collected via patient medical interview. Age-adjusted logistic regression analysis was used to examine the relative odds of hypertension. We observed a significantly elevated odds ratio (OR) of hypertension relative to controls for premutation carriers with FXTAS (OR = 3.22, 95% CI: 1.72–6.04; P = 0.0003) among participants over 40-year old. The age-adjusted estimated odds of hypertension in premutation carriers without FXTAS in the over 40-year-old age group was higher compared to controls (OR = 1.61, 95% CI: 0.82–3.16), but was not statistically significant (P = 0.164). Chronic hypertension contributes to cardiovascular complications, dementia, and increased risk of stroke. Our results indicate that the risk of hypertension is significantly elevated in male premutation carriers with FXTAS compared with carriers without FXTAS and controls. Thus, evaluation of hypertension in patients diagnosed with FXTAS should be a routine part of the treatment monitoring and intervention for this disease.
hypertension; FMR1 premutation; fragile X-associated tremor/ataxia syndrome; autonomic disease
Methylation of the fragile X mental retardation 1 (FMR1) exon 1/intron 1
boundary positioned fragile X related epigenetic element 2 (FREE2), reveals skewed
X-chromosome inactivation (XCI) in fragile X syndrome full mutation (FM: CGG > 200)
females. XCI skewing has been also linked to abnormal X-linked gene expression with the
broader clinical impact for sex chromosome aneuploidies (SCAs). In this study, 10 FREE2
CpG sites were targeted using methylation specific quantitative melt analysis (MS-QMA),
including 3 sites that could not be analysed with previously used EpiTYPER system. The
method was applied for detection of skewed XCI in FM females and in different types of
SCA. We tested venous blood and saliva DNA collected from 107 controls (CGG < 40),
and 148 FM and 90 SCA individuals. MS-QMA identified: (i) most SCAs if combined with a Y
chromosome test; (ii) locus-specific XCI skewing towards the hypomethylated state in FM
females; and (iii) skewed XCI towards the hypermethylated state in SCA with 3 or more X
chromosomes, and in 5% of the 47,XXY individuals. MS-QMA output also showed significant
correlation with the EpiTYPER reference method in FM males and females
(P < 0.0001) and SCAs (P < 0.05). In
conclusion, we demonstrate use of MS-QMA to quantify skewed XCI in two applications with