A qualitative study to explore the burden of disease in activated phosphoinositide 3-kinase delta syndrome (APDS).

BACKGROUND: Activated phosphoinositide 3-kinase delta syndrome (APDS) is an ultra-rare primary immunodeficiency, with only 256 cases reported globally. This study aimed to explore the disease burden of APDS from the perspective of individuals with APDS and their caregivers. METHODS: Qualitative interviews were conducted with healthcare providers (HCPs), individuals with APDS and caregivers, to explore the symptoms and health-related quality of life (HRQoL) impact of APDS. Some individuals and caregivers also completed a narrative account exercise. All interviews were audio recorded and transcribed. Data were analysed using thematic analysis and saturation was recorded. RESULTS: Semi-structured qualitative interviews were conducted with healthcare providers (HCPs), individuals with APDS and caregivers. Individuals and caregivers had the option of completing a narrative account exercise. Six HCPs participated in an interview. Seven participants completed the narrative account exercise (N = 5 caregivers and N = 2 individuals with APDS) and 12 took part in an interview (N = 4 caregivers and N = 8 individuals with APDS). Themes identified from HCPs interviews included symptoms, clinical manifestations, HRQoL impacts and treatments/management of APDS. The narrative account exercise identified similar themes, but with the addition to the journey to diagnosis. These themes were explored during the individual/caregiver interviews. Reported clinical manifestations and symptoms of APDS included susceptibility to infections, lymphoproliferation, gastrointestinal (GI) disorders, fatigue, bodily pain, and breathing difficulties. HRQoL impacts of living with APDS included negative impacts to daily activities, including work, education and social and leisure activities, physical functioning, as well as emotional well-being, such as concern for the future, and interpersonal relationships. Impacts to caregiver HRQoL included negative impacts to physical health, work, emotional well-being, interpersonal relationships and family life and holidays. The management of APDS included the use of healthcare services and medications including immunoglobulin replacement therapy (IRT), rapamycin, prophylactic antibiotics, leniolisib, as well as medical procedures due to complications. CONCLUSIONS: APDS has a high disease burden and there is an unmet need for licensed, more targeted treatments which modify disease progression. This study was the first to describe the day-to-day experience and HRQoL impact of APDS from the perspective of individuals living with the condition, caregivers and treating physicians.

Aarskog-Scott syndrome: clinical and molecular characterisation of a family with the coexistence of a novel FGD1 mutation and 16p13.11-p12.3 microduplication.

Aarskog-Scott syndrome (AAS), also known as facio-genital dysplasia or faciodigitogenital syndrome, is a rare genetic disorder clinically characterised by facial, limb and genitalanomalies. Although also autosomal dominance and recessive patterns have been reported, up to now, only an X linked form associated to mutations of the FGD1 gene has been recognised as causative for this syndrome.In this case report, we describe a large Italian family in which three members across three generations show classical features of the syndrome. The youngest patient, the proband, and his mother were both molecularly studied and characterised for the not previously reported variant c.1828C>T (p. Arg610*) in the FGD1 gene but with the classic phenotype of AAS. Additionally, both the proband and his mother present a 2.5 Mb 16p13.11-p12.3 microduplication, a genetic variant still unclear for the phenotypic consequences: the co-occurrence of the two rare conditions is discussed for the possible clinical significance.

Exploring the Burden of X-Linked Hypophosphataemia: An Opportunistic Qualitative Study of Patient Statements Generated During a Technology Appraisal.

INTRODUCTION: Capturing the patient experience of living with a rare disease such as X-linked hypophosphataemia (XLH) is critical for a holistic understanding of the burden of a disease. The complexity of the disease coupled with the limited population makes elicitation of the patient burden methodologically challenging. This study used qualitative information direct from patient and caregiver statements to assess the burden of XLH. METHODS: A thematic analysis was conducted on statements received during a National Institute for Health and Care Excellence (NICE) online public open consultation from 15 June to 6 July 2018. Researchers and clinical experts generated themes and codes based on expected aspects of XLH burden. Statements were independently coded by two reviewers, adding additional codes as required, and analysed by frequency and co-reporting across age groups. RESULTS: The majority of responses were submitted from UK-based patients with some from the USA and Australia, and the statements related to children, adolescents and adults. The findings suggest that the greatest burden experienced by children is associated with conventional therapy, co-reported with dosing regimen, adherence, distress and pain. During adolescence, the burden becomes increasingly complex and multi-factorial, with an increasing psychological burden. In adults, conventional therapy co-reported with bone deformity and orthopaedic surgery, as well as pain, mobility, fatigue and dental problems, featured highly. DISCUSSION: Whilst our study was opportunistic in nature, it has highlighted the clear and distinctive evolution of the burden of XLH, transitioning from being therapy-oriented in childhood to multi-factorial in adolescence, and finally to adulthood with its high impact on need for other interventions, function and mobility. This qualitative thematic analysis enhances the understanding of the symptom and treatment burden of XLH.

Quality of Life of Patients with Wiskott Aldrich Syndrome and X-Linked Thrombocytopenia: a Study of the Primary Immune Deficiency Consortium (PIDTC), Immune Deficiency Foundation, and the Wiskott-Aldrich Foundation.

BACKGROUND: We undertook a study to determine the impact of Wiskott Aldrich Syndrome (WAS) and X-linked thrombocytopenia (XLT) and their therapies upon the health-related quality of life (HRQOL) of patients and their families. MATERIALS AND METHODS: We undertook a survey of patients and their families, who self-identified as having either WAS or XLT. We assessed the PedsQL™ 4.0, the parent proxy form, and the family impact module. These results were compared with normative data from previously published reports. RESULTS: Sixty-eight patients (29 patients completed both the PedsQL™ 4.0 and the parent proxy form; 21 completed only the PedsQL™ 4.0; and 18 completed only the parent proxy form) were included. In contrast to patient-reported outcomes, parents of patients who had a bone marrow transplant (BMT) reported that their children had better QOL scores compared with those who did not (82.6 vs. 73.3, p = 0.023). The QOL of patients vs. previously published normative data showed decreases in patient scores for psychosocial health (72.62 vs. 86.58, p = < 0.001), emotional functioning (69.91 vs. 82.64, p = < 0.001), social functioning (77.55 vs. 91.56, p = < 0.001), and school functioning (70.46 vs. 85.67, p = < 0.001). The family impact study revealed deficits in emotional, social, and cognitive functioning, communication, and worry. CONCLUSION: These results show that patients with WAS/XLT are significantly impacted with respect to QOL. BMT offered a better QOL for patients according to parents, but not as reported by the patients. Future studies should incorporate QOL to provide more data and a better understanding of outcomes for long-term survivors and decision-making regarding BMT.

The recency ratio is related to CSF amyloid beta 1-42 levels in MCI-AD.

OBJECTIVE: As anti-amyloid therapeutic interventions shift from enrolling patients with Alzheimer's disease (AD) dementia to individuals with pre-clinical disease, the need for sensitive measures that allow for non-invasive, fast, disseminable, and cost-effective identification of preclinical status increases in importance. The recency ratio (Rr) is a memory measure that relies on analysis of serial position performance, which has been found to predict cognitive decline and conversion to early mild cognitive impairment (MCI). The aim of this study was to test Rr's sensitivity to cerebrospinal fluid (CSF) levels of the core AD biomarkers in individuals with MCI-AD and controls. METHODS: Baseline data from 126 (110 controls and 16 MCI-AD) participants from the Wisconsin Alzheimer's Disease Research Center were analysed. Partial correlations adjusting for demographics were carried out between CSF measure of amyloid beta (Aß40, Aß42, and the 40/42 ratio) and tau (total and phosphorylated), and memory measures (Rr, delayed recall, and total recall) derived from the Rey's Auditory Verbal Learning Test. RESULTS: Results indicated that Rr was the most sensitive memory score to Aß42 levels in MCI-AD, while no memory score correlated significantly with any biomarker in controls. CONCLUSIONS: This study shows that Rr is a sensitive cognitive index of underlying amyloid ß pathology in MCI-AD.

Visual functioning in adults with Idiopathic Infantile Nystagmus Syndrome (IINS).

PURPOSE: IINS is associated with mild/moderate visual impairment, strabismus and compensatory head postures (CHP), which can negatively impact quality of life. Standard visual acuity assessments tend to underestimate the effect of IINS on visual functioning. Published evidence on the effect of INS on quality of life is slowly emerging. Our study examines visual functioning of adults with IINS using the National Eye Institute Visual Function Questionairre-25 (VFQ-25). METHODS: 38 participants were recruited to participate in the study. All participants underwent detailed clinical examination, as well as appropriate investigations and were asked to complete the self administered VFQ-25. RESULTS: 35/38 participants completed the questionnaire. The mean age of the population was 35.1 years (range 17-64). Mean overall VFQ-25 score at baseline was 65 (SD 13, range 34-91). Participants specifically demonstrated lowest scores for the impact of IINS on mental health, role limitations and dependency. 26/35 of participants were not driving, either due to sub-normal vision, lack of confidence or difficulties with contrast sensitivity. CONCLUSIONS: IINS can have a greater than expected impact on an individual's quality of life, without necessarily causing markedly reduced visual acuity. Our study showed lowest scores in the domains of mental health and wellbeing. Patients also reported reduced visual functioning in driving, which can impact adversely on employability and independence. Visual functioning questionnaires such as the VFQ-25 may provide more functional information on the impact of nystagmus on an individual's quality of life than objective measures such as high contrast Snellen and/or LogMAR visual acuity.

The Basal Ganglia Striosomes Affect the Modulation of Conflicts by Subliminal Information-Evidence from X-Linked Dystonia Parkinsonism.

Cognitive control is relevant when distracting information induces behavioral conflicts. Such conflicts can be produced consciously and by subliminally processed information. Interestingly, both sources of conflict interact suggesting that they share neural mechanisms. Here, we ask whether conjoint effects between different sources of conflict are modulated by microstructural basal ganglia dysfunction. To this end, we carried out an electroencephalography study and examined event-related potentials (ERPs) including source localization using a combined flanker-subliminal priming task in patients with X-linked dystonia Parkinsonism (XDP) and a group of healthy controls. XDP in its early stages is known to predominantly affect the basal ganglia striosomes. The results suggest that conjoint effects between subliminal and conscious sources of conflicts are modulated by the striosomes and were stronger in XDP patients. The neurophysiological data indicate that this effect is related to modulations in conflict monitoring and response selection (N2 ERP) mechanisms engaging the anterior cingulate cortex. Bottom-up perceptual gating, attentional selection, and motor response activation processes in response to the stimuli (P1, N1, and lateralized readiness potential ERPs) were unaffected. Taken together, these data indicate that striosomes modulate the processing of conscious and subliminal sources of conflict suggesting that microstructural basal ganglia properties are relevant for cognitive control.

Dysfunctions in striatal microstructure can enhance perceptual decision making through deficits in predictive coding.

An important brain function is to predict upcoming events on the basis of extracted regularities of previous inputs. These predictive coding processes can disturb performance in concurrent perceptual decision-making and are known to depend on fronto-striatal circuits. However, it is unknown whether, and if so, to what extent striatal microstructural properties modulate these processes. We addressed this question in a human disease model of striosomal dysfunction, i.e. X-linked dystonia-parkinsonism (XDP), using high-density EEG recordings and source localization. The results show faster and more accurate perceptual decision-making performance during distraction in XDP patients compared to healthy controls. The electrophysiological data show that sensory memory and predictive coding processes reflected by the mismatch negativity related to lateral prefrontal brain regions were weakened in XDP patients and thus induced less cognitive conflict than in controls as reflected by the N2 event-related potential (ERP). Consequently, attentional shifting (P3a ERP) and reorientation processes (RON ERP) were less pronounced in the XDP group. Taken together, these results suggests that striosomal dysfunction is related to predictive coding deficits leading to a better performance in concomitant perceptual decision-making, probably because predictive coding does not interfere with perceptual decision-making processes. These effects may reflect striatal imbalances between the striosomes and the matrix compartment.

IQSEC2 and X-linked syndromal intellectual disability.

Despite the recent acceleration in the discovery of genetic risk factors for intellectual disability (ID), the genetic etiology of ID is unknown in approximately half of cases and remains a major frontier of genetics in medicine and psychiatry. The distinction between syndromal and nonsyndromal forms of ID is of great clinical importance, but the boundary between these clinical entities is difficult to ascertain for many genes of interest. ID is more common in men than in women, but the genetic explanation of this sex asymmetry is incompletely understood. This Review systematically examines the reported cases of X-linked ID caused by de novo loss-of-function mutations in the gene IQSEC2. This gene is largely known as a cause of X-linked nonsyndromal ID in male patients. However, depending on the severity of the mutation, the phenotypic spectrum of IQSEC2-related ID can range from the classic X-linked nonsyndromal form of the disease to a severe syndrome that has been reported in the context of de novo mutations only, in both male and female patients. Bioinformatics analysis suggests that truncation of the longer of the two protein isoforms of the gene can be sufficient to lead to the syndrome, which may be caused by the disruption of cell signaling and signal transduction pathways. The clinical features of the syndrome converge on a pattern of global developmental delay, deficits in social communication, stereotypical hand movements, and hypotonia. In addition, many if not all of these patients have seizures, microcephaly, and language regression in addition to delay. We argue that it is clinically appropriate to test for IQSEC2 mutations in male and female patients with this symptom profile but without a known genetic mutation.

Progressive neurodegenerative syndrome in a patient with X-linked agammaglobulinemia receiving intravenous immunoglobulin therapy.

A progressive encephalopathy of unknown etiology has been described in patients with primary immunodeficiency disorders. In this report, we characterize the clinical features of this progressive neurodegenerative dementing disorder in a young man with Bruton agammaglobulinemia, through neuropsychological tests and a video sequence. The clinical course of the encephalopathy seems rather uniform: Cognition, especially frontal lobe function, is affected in the early stages, and some patients develop movement disorders. The syndrome causes severe cognitive and physical disability, and can eventually be fatal. The autoimmunity results from dysregulated immune responses, but the underlying mechanism has not yet been fully explained.

Nonmotor features in sex-linked dystonia parkinsonism.

The natural history of sex-linked dystonia parkinsonism (XDP) has been well documented. However, its nonmotor features have not yet been fully described. We reviewed the available literature on the nonmotor features in XDP. We found five articles involving 79 XDP patients, three of which were on cognition and two on mood (anxiety and depression). There were two case reports showing executive dysfunction. The other paper showed impairments in abstract thinking and motor programming. Two articles were on mood (anxiety and depression). The prevalence of anxiety symptoms was 16.7% and 54.8-92.9% had depressive symptoms. The identification of these nonmotor features should lead to early and appropriate management.

Reduced taste sensitivity in congenital blindness.

Sight is undoubtedly not only important for food identification and selection but also for the modulation of gustatory sensitivity. We can, therefore, assume that taste sensitivity and eating habits are affected by visual deprivation from birth. We measured taste detection and identification thresholds of the 5 basic tastants in 13 congenitally blind and 13 sighted control subjects. Participants also answered several eating habits questionnaires, including the Food Neophobia Scale, the Food Variety Seeking Tendency Scale, the Intuitive Eating Scale, and the Body Awareness Questionnaire. Our behavioral results showed that compared with the normal sighted, blind subjects have increased thresholds for taste detection and taste identification. This finding is at odds with the superior performance of congenitally blind subjects in several tactile, auditory and olfactory tasks. Our psychometric data further indicate that blind subjects more strongly rely on internal hunger and satiety cues, instead of external contextual or emotional cues, to decide when and what to eat. We suggest that the lower taste sensitivity observed in congenitally blind individuals is due to various blindness-related obstacles when shopping for food, cooking and eating out, all of which contribute to underexpose the gustatory system to a larger variety of taste stimuli.

X-linked Aarskog syndrome: report on a novel FGD1 gene mutation. Executive dysfunction as part of the behavioural phenotype.

Aarskog-Scott syndrome [OMIM 100050] is a predominantly X-linked disorder that is phenotypically characterized by short stature, craniofacial dysmorphisms, brachydactyly and urogenital abnormalities. The level of intelligence shows a great variability and no specific behavioural phenotype has been described so far. In about 20 percent ofAarskog families, a mutation in the FGD1 gene located in Xp11.21 can be identified. In the present study, four affected males from the fourth generation of a large Dutch family (published in 1983 by Van de Vooren et al. (41)) are described. A novel FGD1 missense mutation (R402W) at position 1204 (1204C>T) was demonstrated. In the patients, the level of intelligence varied between normal and severely disabled. Their behavioural profile showed, among others, elements of attention deficit hyperactivity disorder, primarily reflected by impaired executive attentional processes that may be sensitive to systematic training.

Reproductive empowerment: the main motivator and outcome of carrier testing.

The aim of this Grounded Theory study was to assess the motivation and outcomes of carrier testing. Qualitative semi-structured interviews were conducted with participants who had undergone carrier testing for autosomal recessive, X-linked conditions and chromosome translocations. Reproductive empowerment emerged as the central phenomenon. A desire to manage risk was the main motivator for carrier testing, and information gathering the main facilitator. Participants were then able to make informed decisions, regain control over their reproductive risk and pass on information to family members. These findings support a patient-reported outcome measure of empowerment currently being developed for genetic services.

Biosocial influences on fraudulent behaviors.

A wealth of empirical research has revealed that antisocial behavioral phenotypes result from genetic and environmental factors working independently and interactively. However, much of this research has focused on traditional forms of antisocial behavior, such as aggression and violence. At the same time, research has been slow to examine whether genetic factors may relate to involvement in fraudulent behaviors. This article addresses this gap in the literature and examines whether a polymorphism in the promoter region of the monoamine oxidase A (MAOA) gene interacts with exposure to delinquent peers to predict variation in fraudulent behaviors. Analysis of male participants from the National Longitudinal Study of Adolescent Health (J. R. Udry, 2003) revealed a statistically significant Gene x Environment interaction in which the high-MAOA activity allele increased the odds of fraudulent behaviors, but only among male participants with a high number of delinquent peers.

Neuropsychological profile of a Filipino gentleman with X-linked dystonia-parkinsonism: a case report of Lubag disease.

X-Linked Dystonia-Parkinsonism (XDP or "Lubag") is a progressive neurodegenerative disorder unique to the Island of Panay in the Philippines. Imaging and autopsy studies have suggested involvement of the caudate and putamen in late stages. Because the clinical presentation of patients with XDP resembles that of patients with Parkinson disease or dystonia, it is reasonable to predict the neuropsychological profile might be similar; however, the neuropsychological profile of a XDP patient has not previously been published. We present the neuropsychological findings of a 67-year-old gentleman with a 10-year history of XDP who presented with parkinsonian and dystonic symptoms. He was evaluated for suitability for deep brain stimulation surgery. Neuropsychological findings demonstrated diffuse impairment involving memory, visuospatial, language, and executive functioning.

The quality of life of children and adolescents with X-linked agammaglobulinemia.

INTRODUCTION: The health-related quality of life in X-linked agammaglobulinemia was investigated in 25 children and adolescents patients through the Italian version of Pediatric Quality of Life Inventory 4.0 Generic Core Scale for patients aged less then 18 years, comparing child perception to that of the parents and the physician's evaluation. The data were compared with the ones of 80 healthy controls and the literature data of a group of patients with rheumatic diseases. DISCUSSION: The agammaglobulinemia subjects perceived a lower global quality of life than the healthy subjects, but significantly higher than the rheumatic diseases controls. The clinical relevance of health-related quality of life assessment in X-linked agammaglobulinemia pediatric patients is discussed.