Not just carriers: experiences of X-linked female heterozygotes – 7/21

In this study, researchers distributed a survey to understand the needs and experiences of the X-linked carrier community to improve future recognition, diagnosis, and treatment by bringing X-linked carrier voices together. The results found the need for more knowledgeable healthcare providers and medical information within the X-linked carrier community.

Ultra-Deep DNA Methylation Analysis of X-Linked Genes: GLA and AR as Model Genes – 6/20

In this study, researchers analyzed DNA methylation of the X chromosomes to understand its effect on X chromosome inactivation. They used GLA and AR as model genes, and think that this type of test could predict symptomatic vs. asymptomatic individuals.

X-linked diseases: susceptible females – 4/20

In this study, the researcher explores the relationship between X-inactivation and expression of X-linked diseases in females.

Skewed X-inactivation is common in the general female population – 3/19

In this study, researchers looked at skewed X chromosome inactivation (XCI) in 79 female children and their parents. They found that in over 50% of females, there was skewed XCI.

The Process of Disclosure: Mothers’ Experiences of Communicating X-Linked Carrier Risk Information to At-Risk Daughters – 03/18

Researchers found that although the mother had thought everything was communicated when disclosing carrier status to their daughter, there was often something left out. Seeing a genetic counselor can help alleviate some of these concerns, and offer carrier testing.

Skewed X-inactivation is common among the general female population – 12/18

This paper discusses how X inactivation is skewed in the general population. This is a possible explanation for why female carriers can still experience symptoms of a disorder even though they are heterozygous.

A Large Family with p.Arg554His Mutation in ABCD1: Clinical Features and Genotype/Phenotype Correlation in Female Carriers – 4/21

This paper discusses a specific ALD mutation and its symptoms and onset. They found that in this family, the affected male died in the first decade of life, and females developed lower limb weakness, gait, and hyperreflexia in their forties (usually by 42).

Aging Raises Risk of Women Developing ALD Symptoms or More Severe Disease, Study Says – 11/19

This article summaries a study that found that age was a risk factor for ALD symptoms, and the main determinant of disease severity. Researchers hope to use this as a method of intervention.

Disease progression in women with X-linked adrenoleukodystrophy is slow – 01/19

This study focused on the progression of spinal cord disease in people with ALD. They found that it is detected by the Expanded Disability Status Scale (EDSS), but cannot be used as a primary measure for spinal cord disease because it is below the rate of clinical relevance.

Natural history of a cohort of ABCD1 variant female carriers – 10/18

The researchers did a longitudinal study of 32 carriers. They recorded the ALD Clinical Score every 7 years and found that severity and onset of symptoms increases with age. They also found that the cutoff age for phenoconversion is around 41 y/o.

The Process of Disclosure: Mothers’ Experiences of Communicating X-Linked Carrier Risk Information to At-Risk Daughters – 3/18

X-Linked Adrenoleukodystrophy – 2/18

This review discusses ALD and its presentation in female symptomatic carriers.

Understanding X-linked adrenoleukodystrophy in women – 02/17

This article summarizes the results from the 01/14 paper linked below. They found that 63% of patients studied developed spinal cord damage, 57% had nerve damage, and 28% had an inability to control bowel movements. 88% of patients who had symptoms were over 60.

The genetic landscape of X-linked adrenoleukodystrophy – 03/15

This paper summaries the inheritance, mutations, modifier genes, and diagnostic methods of ALD.

X-linked adrenoleukodystrophy in women: a cross-sectional cohort study – 01/14

The researchers aimed to characterize the neurological symptoms in all X linked carriers (both symptomatic and non-symptomatic). They also wanted to determine if symptoms were due to X inactivation. They found that 63% of patients studied developed spinal cord damage, 57% had nerve damage, and 28% had an inability to control bowel movements. 88% of patients who had symptoms were over 60. They did not find an association with X inactivation and symptoms.

X-linked adrenoleukodystrophy in heterozygous female patients: women are not just carriers – 07/12

This study characterized carriers into categories of severity of symptoms. Three of nine women studied had similar symptoms to males, with neurological regression and white matter abnormalities. Four had a less severe phenotype, with spastic paraperisis as the main symptom. Finally, the least severe group still had cramps and discomfort when walking long distances.

Adrenoleukodystrophy in female heterozygotes: Underrecognized and undertreated – 02/12

This review walks through the heterozygous phenotype of symptomatic carriers, neurophysiologic studies, neuroimaging, physical impairments and disability, other X linked diseases, the impact of a diagnosis, and current and emerging therapies for carriers of ALD.

Effect of heterozygous pathogenic COL4A3 or COL4A4 variants on patients with X-linked Alport syndrome – 3/19

In this paper, researchers used next generation sequencing to study males and female carriers with Alport syndrome. THey found that the heterozygous pathogenic variant COL4A3 or COL4A4 make Alport symptoms such as proteinuria more serious.

De novo X-linked Alport syndrome in a 3-year-old girl – 7/19

In this paper, researchers diagnosed a three year old female with Alport syndrome. She had a de novo mutation in the COL4A5 gene.

A case study of choroideremia carrier-Use of multri-spectral imagine in highlighting clinical features – 01/16

This article highlights a personal story from Christina, and discusses the clinical implications of females being treated just as carriers instead of patients.

Choroideremia: Effect of age on visual acuity in patients and female carriers – 11/11

Researchers found the average age of carriers with visual acuity symptoms was 36.4 years, but that there was no relationship with age and symptom onset or severity.

Christianson Syndrome – 1/18

In this review, researchers discuss the clinical characteristics,  diagnosis, and management of this disorder. They discuss how Christianson Syndrome manifests in carriers as behavioral issues or mild intellectual disability.

Skewed X-inactivation in a Female Carrier with X-linked Chronic Granulomatous Disease – 8/19

In this case study, researchers reported on a 38 year old Mexican female that had juvenile onset XL-CGD. They found that she had a de novo mutation and extremely skewed X chromosome inactivation.

Clinical Manifestations in Carriers of X-Linked Chronic Granulomatous Disease in Mexico – 4/19

In this study, researchers characterized carrier symptoms of Mexican XL-CGD, and found that carriers may have an even higher risk of autoimmune disease than previously thought.

Health-Related Quality of Life and Emotional Health in X-Linked Carriers of Chronic Granulomatous Disease in the United Kingdom – 2/19

In this paper, researchers studied the quality of life in X linked carriers of CGD. They  found that over 40% experienced some form of anxiety, and this correlated with depression, lower self esteem, joint or bowel symptoms, and fatigue.

Considerations in the Diagnosis of Chronic Granulomatous Disease – 5/18

In this review, researchers discuss challenges and considerations in diagnosis of CGD. They talk about how autoimmune disorders seem to be more robust in female carriers, and the challenges that come with diagnosing a female.

Health-Related Quality of Life and Emotional Health in X-Linked Carriers of Chronic Granulomatous Disease in the United Kingdom – 03/19

Researchers found that XL-CGD patients have a reduced quality of life, joint and bowel symptoms, and higher levels of fatigue. They believe that carriers should be considered as patients so that their symptoms can be managed.

X-linked carriers of x-linked granulomatous disease: illness, lyonization, and stability – 05/17

Researchers studied the X inactivation pattern in women with XL-CGD. They found that women with CGD-type infections had a lower level of X inactivation compared to women with less severe symptoms. They concluded that the carrier state itself should be considered an autoimmunity.

Aberrant cell segregation in the craniofacial primordium and the emergence of facial dysmorphology in craniofrontonasal syndrome – 2/20

This paper discusses the mechanism behind craniofacial dysmorphology. They generated heterozygous mice (with mutations similar to those of carriers). They found that the mutation regulated cell segregation, causing the differences in face shapes. They also note that heterozygous females are more severely affected than hemizygous males.

Onset mechanism of a female patient with Dent disease 2 – 7/20

In this paper, researchers identified the first female patient with Dent-2 disease. They used DNA and RNA expression tests to confirm that alternate splicing was occurring, and that there was skewed X chromosome inactivation.

X-Linked Dystonia-Parkinsonism – 2/18

In this review, researchers discuss presentation of XDP, including diagnosis and treatments. They also point out that females with the TAF1/DYT3 haplotype are at a small risk for developing symptoms.

Female Patients and Their Doctors Must be More Aware of Fabry Symptoms, Treatment, Study Says – 04/19

This article discusses the importance of seeing women as patients instead of just carriers. They talk about the problems with the treatment of patients, including the lack of enzyme replacement therapy available.​

Clinical profile of women diagnosed with Fabry disease not receiving enzyme replacement therapy – 10/18

The researchers aimed to clinically profile women who have been diagnosed with Fabry. They studied 46 carriers and found that the median onset of symptoms occurs at 35.5 years of age, 67% had at least one symptom of Fabry, and enzyme replacement therapy was only offered to one patient.

Nationwide screening for Fabry disease in unselected stroke patients – 12/21

In this paper, researchers screened stroke patients for Fabry disease. They found that in 14 carriers, 11 had strokes that were ischemic, two had strokes that were a transient ischemic attack, and one had an intracerebral hemorrhage stroke.

X Chromosome Inactivation in Carriers of Fabry Disease: Review and Meta-Analysis – 7/21

In this paper, researchers summarize the clinical findings of female carriers of Fabry disease. They explain that 70% of carriers get symptoms, and include the distribution to specific symptoms in section 2. Finally, they discuss a meta-analysis of skewed X chromosome inactivation (XCI), where they found a positive correlation between severity and skewed XCI.

DNA methylation impact on Fabry disease – 2/21

In this review, researchers discuss not only skewed X chromosome inactivation, but also DNA methylation of the promoter of the GLA gene and its impact on disease symptoms. The goal of this review is to encourage future research and development of technology for predicting if carriers will develop symptoms for early intervention.

The Ckd. Qld fabRy Epidemiology (aCQuiRE) study protocol: identifying the prevalence of Fabry disease amongst patients with kidney disease in Queensland, Australia – 2/20

This study protocol discusses how researchers will study the correlation of FD in male and female patients with chronic kidney disease. 

A case of female Fabry disease revealed by renal biopsy – 2/20

In this paper, researchers found that a renal biopsy was able to detect Fabry disease in a 69 year old female patient. They also confirmed the diagnosis with biochemical and genetic analysis. 

Elevated Lyso-Gb3 Suggests the R118C GLA Mutation Is a Pathological Fabry Variant – 12/18

In this paper, researchers identified a new variant for Fabry disease, R118C. They believe that this variant will cause milder symptoms, however patients with this variant should be considered for risk factor management.

Long-Term Effects of Enzyme Replacement Therapy for Anderson-Fabry Disease – 11/18

In this paper, researchers looked at the effect of long term Enzyme Replacement Therapy (ERT). They found that in heterozygous patients (or female carriers), left ventricular hypertrophy and myocardial dysfunction continued while using ERT. On the contrary, there was prevention of disease progression in homozygotes.

Women with bleeding disorders – 05/18

This article explains how carriers have a clotting factor that is around 50% of non carriers. This makes hemophilia carriers more likely to bleed during pregnancy, and after giving birth. The article explains management of pregnancy, and pathways of care.

​​Females with FVIII and FIX deficiency have reduced joint range of motion – 08/14

Researchers confirmed their hypothesis that hemophilia carriers have a reduced joint range of motion. However, they need to determine if a decrease in range of motion correlates with joint bleeding.

Molecular Mechanisms of Skewed X-Chromosome Inactivation in Female Hemophilia Patients—Lessons from Wide Genome Analyses – 8/21

In this study, X chromosome inactivation (XCI) was studied in female carriers with hemophilia. Using PCR, they first determined if X chromosome inactivation was skewed. Then, they used whole exome sequencing (WES) to further study the patients whose XCI was skewed. They found additional pathogenic mutations on the non-hemophilic chromosome, suggesting that skewed XCI could be caused by negative selection against the non-hemophilic chromosome.

Hemophilia A and C in a female: The first case report in literature – 8/21

This paper identifies the first female to have two different coagulation factors, and was diagnosed with both Hemophilia A and C. This case highlights the importance of considering X-linked Hemophilia in female hemorrhage patients.

A new hemophilia carrier nomenclature to define hemophilia in women and girls: Communication from the SSC of the ISTH – 7/21

Recently, the International Society on Thrombosis and Haemostasis has defined different categories of hemophilia carriers in effort to reduce hampering of diagnosis. They are based on the FVIII/IX levels, and are as follows: mild, moderate or severe (FVIII/IX >.05 and <.4 IU/ml, .01-.05 IU/ml, and <.01 IU/ml). 

X Chromosome inactivation: a modifier of factor VIII and IX plasma levels and bleeding phenotype in Haemophilia carriers – 10/20

In this paper, researchers were looking to find the correlation between skewed X chromosome inactivation (XCI) and FVIII and FIX levels, and bleeding symptoms. They found that low levels of FVIII and FIX and high XCI caused more symptoms than those with a high FVIII and FIX levels and low XCI. 

Skewed Inactivation of X Chromosome: A Cause of Hemophilia Manifestation in Carrier Females – 10/20

This review discusses the literature so far about symptomatic carriers of Hemophilia. It talks about implications for being undiagnosed, and different treatments.

Bone health in symptomatic carriers of haemophilia A: a protocol for a multicentre prospective matched-cohort study – 12/19

This paper suggests a protocol to study the bone mineral density levels of hemophilia carriers vs. non hemophilia participants. They plan to match 40 symptomatic carriers with 40 non carriers from two hospitals in Canada. Results will then be compared using a regression model.

Total hip arthroplasty for a woman with hemophilia A -case report – 5/19

In this paper, researchers discussed the importance of diagnosing female carriers with hemophilia. A Japanese patient who was diagnosed with hemophilia A was able to have a total hip replacement by using blood product coagulation factor VIII.

No evidence for preferential X-chromosome inactivation as the main cause of divergent phenotypes in sisters with X-linked hypohidrotic ectodermal dysplasia – 2/21

In the study, the researchers aimed to determine whether or not skewed X chromosome inactivation (XCI) caused the symptom differences between individuals with the same variant of the EDA gene. They studied sisters, but found that there was no significant difference in XCI, and that phenotypic variability must be due to something else.

Medical and neurobehavioural phenotypes in carriers of X-linked ichthyosis-associated genetic deletions in the UK Biobank – 03/20

Researchers compared the phenotypes of males and females with steroid sulfatase (STS) deletions. They found that both males and females have decreased performance on the Fluid Intelligence Test. Females have a smaller right putamen and left nucleus accumbens.

Behavioural and psychiatric phenotypes in female carriers of genetic mutations associated with X-linked ichthyosis – 02/19

Researchers surveyed female carriers who were postpartum and non-postpartum to males. They found that ​females experience many of the same symptoms as males, including increased rates of developmental and mood disorders, inattention, and impulsiveness. They also saw increased levels of postpartum mental illness in female carriers relative to controls.

Novel clinical and genetic insight into CXorf56-associated intellectual disability – 3/20

In this paper, researchers studied three female carriers and six males with XLID. They found that skewed X chromosome inactivation (XCI) was shown in blood samples of symptomatic females.

Two novel PCDH19 mutations in Russian patients with epilepsy with intellectual disability limited to females: a case report – 10/20

In this study, researchers looked at two cases of epilepsy in patients who had Epileptic encephalopathy, early infantile (EIEE). They found that heterozygous females could be at risk due to X inactivation status, but that hemizygous males are not affected.

A de novo variant in the X-linked gene CNKSR2 is associated with seizures and mild intellectual disability in a female patient – 10/19

Researchers found a de novo nonsense mutation in the CNKSR2 gene in a female carrier with seizures and XLID. There was also skewed X chromosome inactivation.

Spectrum of X-linked intellectual disabilities and psychiatric symptoms in a family harbouring a Xp22.12 microduplication encompassing the RPS6KA3 gene – 3/19

In this paper, microduplications of the X chromosome gene RPS6KA3. They studied a family, and found that four female carriers had mild intellectual disability and major depression.

A Novel Nonsense Mutation of PHF6 in a Female with Extended Phenotypes of Borjeson-Forssman-Lehmann Syndrome – 11/19

In this paper, researchers found a heterozygous mutation nonsense in a female who was diagnosed with Borjeson-Forssman-Lehmann syndrome. They also found that she had skewed X chromosome inactivation (XCI), and so did her unaffected mother.

De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females – 2/18

In this paper, researchers identified new variants of CLCN4 in affected males and females. They also showed that females can be just as affected as males, but it not due to skewed X chromosome inactivation in the blood.

X-Linked intellectual disability: Phenotypical expression in carrier females – 11/19

Researchers found that of those studied, 61% of carriers experienced cognitive phenotypic expression of intellectual disability. Additionally, in 16.6%< X inactivation was skewed consistently, and 37.5% showed variable skewing.

A manifesting female carrier of Duchenne muscular dystrophy: importance of genetics for the dystrophinopathies – 1/23

This study highlights the case of a 55-year-old carrier of Duchenne muscular dystrophy with clinical symptoms. The researchers explain that carriers can experience a range of symptoms, and in rare cases, may present with the full phenotype of Duchenne.

Clinical and genetic characteristics of female dystrophinopathy carriers – 02/19

Researchers identified and studied 78 Duchenne Muscular Dystrophy (DMD) and Becker Muscular Dystrophy (BMD). They found that all 4 of the manifesting carriers identified had duplication mutations. The asymptomatic carriers had deletion mutations (41.89%)  and point mutations (44.59%), but only 13.51% had duplications.

X-Linked Emery-Dreifuss Muscular Dystrophy: Study of X-Chromosome Inactivation and Its Relation with Clinical Phenotypes in Female Carriers – 11/19

Researchers aimed to find the relationship between carrier’s X-Chromosome inactivation (XCI) pattern on lymphocytes and cardiac symptoms. They saw that the XCI pattern was similar in symptomatic vs. asymptomatic carriers. They think that this might be because lymphocytes and cardiac conduction tissue have different embryological origins, or atrial cells were replaced by fibrous tissue.

Female Carriers of Duchenne Muscular Dystrophy – 12/13

Researchers discuss manifesting symptoms of Muscular Dystrophy, including proximal asymmetric muscle weakness, gait problems, myalgia, isolated cardiomyopathy and camptocormia. In the article, they go into insights for diagnosing a female carrier.

Can symptomatic nmDuchenne carriers benefit from treatment with ataluren? Results of 193-month follow-up – 12/21

The researchers followed 4 nmDMD female patients who were treated with ataluren for 193 months. Their labs did not show any abnormalities or adverse clinical effects, and the treatment seemed to improve or at least stabilize their symptoms.

Quantitative Muscle MRI and Clinical Findings in Women With Pathogenic Dystrophin Gene Variants – 9/21

In this study, researchers compared MRI and blood test results of carriers for DMD and normal females. They found that carriers had higher fat fractions, were weaker, and increased levels of blood creatine kinase and myoglobin. 

Cardiac Involvement in Dystrophin-Deficient Females: Current Understanding and Implications for the Treatment of Dystrophinopathies – 6/20

In this review, researchers discuss heart problems for female carriers of DMD and BMD. They also discuss the general clinical manifestation of symptoms in female carriers, and the implications for therapies.

Connexin-43 reduction prevents muscle defects in a mouse model of manifesting Duchenne muscular dystrophy female carriers – 3/20

In this paper, researchers were able to generate a mouse model for carriers of DMD. They then studied the cardiomyopathy features of DMD, and found that connexin-43 was reduced in symptomatic carriers. This leads them to believe that this could lead to remodeling in the heart.

Electrophysiological abnormalities in induced pluripotent stem cell-derived cardiomyocytes generated from Duchenne muscular dystrophy patients – 1/19

In this paper, researchers looked at cardiac abnormalities of one male patient and one female carrier with symptoms of DMD. They found that both males and females have low spontaneous firing rate, arrhythmias, and increased action potential length. Additionally, females experience increased beat rate variability.

X-Linked Emery-Dreifuss Muscular Dystrophy: Study Of X-Chromosome Inactivation and Its Relation with Clinical Phenotypes in Female Carriers – 11/19

In this paper, researchers studied skewed X chromosome activation and cardiac symptoms of Emery-Dreifuss muscular dystrophy. However, they did not find a relationship.

Emery-Dreifuss Muscular Dystrophy – 8/19

In this review, researchers discuss the diagnosis, management, and genetic counseling for Emery-Dreifuss muscular dystrophy. They mention that heterozygous carriers are at risk for cardiac disease, and muscular dystrophy symptoms.

Manifesting carriers of X-linked myotubular myopathy – 09/20

Researchers studied female carriers for myotubular myopathy for X-Chromosome inactivation and modifier sequences. They found a 4.2 Mb segment of DNA on chromosome 19 that was present in non manifesting carriers, but not manifesting ones. They hypothesized this region to be a protective factor.

X-Linked Myotubular Myopathy – 2/18

In this review, researchers discuss the clinical characteristics, diagnosis, and management of myotubular myopathy. Female carriers may present with respiratory decline or severe muscle weakness.

X-Linked Opitz G/BBB Syndrome – 4/18

In this review, researchers discuss the clinical characteristics, diagnosis, and management of opitz. Female carriers may present with hypertelorism.

Late-Onset Ornithine Transcarbamylase Deficiency and Variable Phenotypes in Vietnamese Females With OTC Mutations – 7/20

In this study, researchers looked at two Vietnamese patients who were suspected of being carriers for OTCD. It is known that female carriers can have late onset symptoms. The case study walks through the diagnosis process, and treatment.

Pelizaeus-Merzbacher disease in female carriers – 10/11

Female carriers can experience neurological symptoms of PMD, usually if the males in the family are mildly affected. This is because in the milder forms, oligodendrocytes do not undergo cell death, and therefore damaged cells survive and cause disease symptoms.

Rare Co-Occurrence of Visual Snow in a Female Carrier With RPGR ORF15-Associated Retinal Disorder – 10/21

Researchers report on a eight year old female carrier who had reduction of visual acuity and attenuation of photoreceptors for at least three years.

The X-linked retinopathies: Physiological insights, pathogenic mechanisms, phenotypic features and novel therapies – 5/21

In this review paper, researchers discuss X-linked retinopathies and female carriers. In section 4.1.5 “Female Carriers,” they summarize the findings from multiple studies about X-linked RPGR. Some of the results include that 40% of female carriers had at least one abnormal test for visual acuity, and that there are four patterns of fundus appearance, which correlated with visual function.

X-Chromosome Inactivation Is a Biomarker of Clinical Severity in Female Carriers of RPGR-Associated X-Linked Retinitis Pigmentosa – 5/20

In this paper, researchers looked at the correlation between skewed X chromosome inactivation (XCI) and disease severity in female carriers. They found that visual symptoms could be predicted by the XCI status in blood and saliva, and found tha skewed XCI was correlated with a more severe phenotype.

X-linked Retinitis Pigmentosa in Japan: Clinical and Genetic Findings in Male Patients and Female Carriers – 3/19

In this paper, researchers studied a Japanese population for RP. They found that 92% of female carriers had electroretinographic abnormalities and 63% had a radial autofluorescent pattern. Additionally, those with myopia had more severe symptoms.

The Spectrum of Structural and Functional Abnormalities in Female Carriers of Pathogenic Variants in the RPGR Gene – 08/18

Researchers found that there is a range of phenotypes for female carriers. In the patients they studied, they found that 58% have retinal pigmentary changes, 40% have visual symptoms, and 23% had complete expression. They believe these individuals may benefit from treatment.

Assessment of Phenotypic Variability Among Female Carriers of X-linked Retinitis Pigmentosa – 02/11

Researchers wanted to assess the phenotypic diversity of carriers. They found a large amount of heterogeneity among the sixty patients they studied, despite comparing the nonsense-mediated decay mutants to the abnormal protein product mutants.

Case Report: Wiskott-Aldrich Syndrome Caused by Extremely Skewed X-Chromosome Inactivation in a Chinese Girl – 8/21

In this paper, a Chinese symptomatic carrier presented with severe skewed X chromosome inactivation (XCI). Researchers believe this is the reason why she developed symptoms, and should be included in genetic counseling.

A novel de novo nonsense mutation in ZC4H2 causes Wieacker-Wolff Syndrome – 12/19

In this paper, researchers identified a de novo nonsense mutation of WWS in a female carrier who had symptoms. Additionally, this patient had skewed X chromosome inactivation.