Preconception expanded carrier screening: Impact of information presented by text or video on genetic knowledge and attitudes.

Preconception expanded carrier screening (ECS) aims to identify couples with an increased risk of having a child with an autosomal recessive (AR) disorder before pregnancy, thereby enabling reproductive choices. Genetic knowledge and experiential knowledge both influence the uptake of ECS. As people in the general public often lack such knowledge, it is essential to provide appropriate and understandable information when offering ECS. This study investigated the effect of an educational video, compared to an educational text, on the knowledge and attitudes toward preconception ECS in the general population. Both the text and video consisted of a brief educational summary on AR inheritance and on the type of disorders included in ECS, with the progressive neurodegenerative condition mucopolysaccharidosis type III (MPS III) as an example. Participants in the reproductive age were invited in collaboration with a research agency. Respondents (N = 789) were offered an educational video prior to completing an online questionnaire that examined genetic knowledge, the perceived severity of MPS III, perceived risk, and attitudes toward ECS. Outcomes were compared to reference data collected previously in which respondents had been offered an educational text (N = 781). We first again studied the attitudes toward ECS in a smaller educational text group (N = 266) in order to assess whether attitudes had changed over time due to increased media coverage on ECS, which did not reveal any significant changes. Respondents who were offered the video had a better genetic knowledge, perceived MPS III as more severe, perceived their risks higher and were more likely to participate in ECS compared to those who were offered text. Online video may well be used as supportive tool to the genetic counseling process, creating more knowledge on ECS and severe genetic disorders included in preconception screening panels.

Attitudes of the general population towards preconception expanded carrier screening for autosomal recessive disorders including inborn errors of metabolism.

BACKGROUND: A substantial number of severely debilitating and often ultimately fatal inborn errors of metabolism (IEMs) still lack an effective disease-modifying treatment. Informing couples before a pregnancy about an increased risk of having a child with an inherited disorder is now feasible by preconception expanded carrier screening (ECS). While knowledge about carrier status enhances reproductive autonomy, it may also result in ethical dilemmas. The purpose of this study was to assess the attitudes of the general Dutch population towards preconception ECS and to investigate which factors influence these attitudes. METHODS: Data collection was carried out in collaboration with a market research agency. In total, 1188 Dutch individuals of reproductive age (18-45 years) were invited by email to complete an online ECS questionnaire in 2016. Prior to the start of the questionnaire, a written explanation of the concepts of autosomal recessive (AR) inheritance, carrier status and ECS was presented. RESULTS: The questionnaire was completed by 781 individuals (65.7%), of whom 31% indicated they would take an ECS test themselves. In addition, 55% agreed that ECS should be offered to all prospective parents. The most frequently selected argument in favor of ECS (47.2%) was that participants want to spare a child from a life with a severe hereditary disorder. The reason most often mentioned not to participate in ECS (48%) was that participants reported not having a hereditary disorder in the family. The majority preferred receiving individual test results above a couple-based disclosure method in which participants receive the carrier status results only when they are a carrier couple of the same disorder. Participants with religious beliefs were less likely to participate in ECS, whereas participants who were considering a (future) pregnancy were more likely to participate. CONCLUSION: Our study demonstrates an overall positive attitude among participants of reproductive age in the general Dutch population towards preconception ECS. A striking misconception is that many of the participants believe that ECS is of interest only for those with a positive family history of one of the hereditary disorders. This finding emphasizes the importance of providing understandable, balanced information and education to the general public regarding the concepts of inheritance when presenting the option of carrier screening. Our results provide valuable insights that can be used in the debate about the responsible implementation of preconception ECS for AR disorders, including IEMs.

Cardiac disease in mucopolysaccharidosis type III.

Mucopolysaccharidosis type III (MPS III; Sanfilippo disease) is primarily characterized by neurocognitive decline with limited somatic disease. Only few reports addressed cardiac disease (CD) in MPS III. We investigated the prevalence of CD in a relatively large cohort of patients. In this cross-sectional study, extensive echocardiographic studies were performed in 30 MPS III patients (16 patients <18 years), all without clinical symptoms of CD. Results were compared to data from matched controls. The mean global longitudinal strain on speckle-tracking echocardiography (STE) was impaired in both pediatric and adult patients vs controls (resp. -18.4% vs -20.7%; mean difference 2.25, 95% CI 0.61-3.89, P = 0.009 and -16.9% vs -19.5%; mean difference 2.64, 95% CI 0.78-4.49, P = 0.007), indicating early systolic dysfunction. Left ventricle ejection fraction (LVEF) was normal in pediatric patients and (slightly) impaired in adult patients vs controls (48.7% vs 55.8%, P = 0.002). Tissue Doppler imaging (TDI) showed significantly slower early diastolic velocities (e') compared to controls indicative for diastolic dysfunction. Furthermore, mitral and aortic valve abnormalities were prevalent (43% and 33% of patients, respectively). Finally, 15.6% of the patients had a first-degree atrioventricular block on electrocardiography (ECG). The impaired STE reveals early, subclinical LV dysfunction which is supported by results of TDI. In addition, mild valvular disease and ECG abnormalities are prevalent. The lowered LVEF in adult patients suggests that the LV dysfunction is progressive, and may ultimately lead to clinical myocardial disease when patients live longer due to an effective disease-modifying treatment of which a number of options are now in clinical trials.

Limited data to evaluate real-world effectiveness of enzyme replacement therapy for mucopolysaccharidosis type I.

Orphan medicinal products (OMPs) are often authorized based on pivotal phase II and III trials that do not always meet high quality criteria. Laronidase is an example of an OMP used for treatment of mucopolysaccharidosis I (MPS I). One randomized controlled trial demonstrated efficacy on several somatic symptoms. However, effectiveness in the real-world setting remains to be determined. We performed a systematic review to evaluate the effectiveness of enzyme replacement therapy (ERT) on clinically relevant outcomes in MPS I. A search in OVID MEDLINE and OVID EMBASE was performed. Postmarketing studies including MPS I patients treated with ERT and reporting data on any of 19 predefined clinical outcome measures obtained before the start of ERT and at follow-up were eligible. Three scenarios were used to define effectiveness of ERT. The first scenario (A) assumes that improvement is essential, while the second scenario (B) also includes stabilization of signs and symptoms. The third scenario (C) defines failure of therapy. Twenty case series were included. The criteria indicating effectiveness (A), were met for four of 19 outcome measures while the criteria, indicating unclear effectiveness (B) were met for five of 19. For one of 19 nonverifiable data were reported and for nine of 19 no overall conclusions could be drawn (ambiguous results). Real-world effectiveness of laronidase is extremely difficult to assess, 15 years after marketing authorization. This is partially due to insufficient natural history data. We recommend the conduct of rigorous and independent postmarketing studies including core outcome sets for OMPs, enforced by marketing and/or reimbursing authorities aiming to demonstrate real-world effectiveness within a reasonable time frame.

Prediction of phenotypic severity in mucopolysaccharidosis type IIIA.

OBJECTIVE: Mucopolysaccharidosis IIIA or Sanfilippo disease type A is a progressive neurodegenerative disorder presenting in early childhood, caused by an inherited deficiency of the lysosomal hydrolase sulfamidase. New missense mutations, for which genotype-phenotype correlations are currently unknown, are frequently reported, hampering early prediction of phenotypic severity and efficacy assessment of new disease-modifying treatments. We aimed to design a method to determine phenotypic severity early in the disease course. METHODS: Fifty-three patients were included for whom skin fibroblasts and data on disease course and mutation analysis were available. Patients were phenotypically characterized on clinical data as rapidly progressing or slowly progressing. Sulfamidase activity was measured in fibroblasts cultured at 37 °C and at 30 °C. RESULTS: Sulfamidase activity in fibroblasts from patients homozygous or compound heterozygous for a combination of known severe mutations remained below the limit of quantification under both culture conditions. In contrast, sulfamidase activity in fibroblasts from patients homozygous or compound heterozygous for a known mild mutation increased above the limit of quantification when cultured at 30 °C. With division on the basis of the patients' phenotype, fibroblasts from slowly progressing patients could be separated from rapidly progressing patients by increase in sulfamidase activity when cultured at 30 °C (p < 0.001, sensitivity = 96%, specificity = 93%). INTERPRETATION: Phenotypic severity strongly correlates with the potential to increase sulfamidase activity in fibroblasts cultured at 30 °C, allowing reliable distinction between patients with rapidly progressing or slowly progressing phenotypes. This method may provide an essential tool for assessment of treatment effects and for health care and life planning decisions. Ann Neurol 2017;82:686-696.

Attitudes of relatives of mucopolysaccharidosis type III patients toward preconception expanded carrier screening.

Preconception expanded carrier screening (ECS) aims to detect carrier couples of autosomal recessive (AR) disorders before pregnancy in order to increase reproductive autonomy of prospective parents. Genetic knowledge and knowledge gained from experience influence decision making on participation in genetic testing and understanding carrier test results. In this study we assessed whether parents and relatives of patients with the severe AR condition mucopolysaccharidosis type III (MPS III), who are expected to have genetic and experiential knowledge, have more positive attitudes toward ECS than the Dutch reference group. Parents of all MPS III patients known to the Dutch expert center were invited to participate and asked to invite first and second degree relatives. The online questionnaire started with an educational text, and assessed attitudes toward ECS, genetic knowledge and perceived MPS III severity. Results were compared with the Dutch population. Parents and relatives of MPS III patients (n = 159) scored higher on the genetic knowledge test and perceived MPS III as more severe compared with the general Dutch population (n = 781). Parents and relatives reported to be more likely to participate in ECS (84.3% and 62.5%, respectively) compared with the public (31%) (p < 0.001). Being a relative of a MPS III patient was the strongest variable in the regression analyses for intended ECS participation. Our results show that genetic knowledge influences ECS decision making. Therefore, appropriate information on ECS and genetic counseling is needed to enable prospective parents from the general population, including relatives of patients with severe hereditary disorders, to make informed decisions.

Psychosocial Functioning in Parents of MPS III Patients.

BACKGROUND: Mucopolysaccharidosis type III (MPS III or Sanfilippo syndrome) is a lysosomal storage disease resulting in progressive neurocognitive decline during childhood and early demise. Its diagnosis may have a great impact on parents, potentially leading to psychosocial problems such as anxiety, depression, parental distress, and posttraumatic stress. METHODS: Twenty-six mothers and 19 fathers of 34 Dutch MPS III patients completed the "Hospital Anxiety and Depression Scale" (HADS), the "Distress Thermometer for Parents" (DT-P), and the "Self-Rating Scale for Posttraumatic Stress Disorders" (SRS-PTSD). Independent-sample T-tests and chi-square tests were used to assess differences between parents of MPS III patients and reference groups regarding anxiety and depression (HADS), distress (DT-P), and posttraumatic stress (SRS-PTSD). RESULTS: Mothers met the criteria for clinically relevant anxiety (50%) and depression (34.6%) more frequently compared to reference mothers (p = 0.001). Fathers more often met the criteria for clinically relevant depression (36.8%) compared to reference fathers (p = 0.022). Clinically relevant distress was highly prevalent in mothers (84.6%) and fathers (68.4%) of MPS III patients compared to reference parents (p < 0.01). Finally, the prevalence of PTSD was strikingly higher in both mothers (26.9%) and fathers (15%) than reported in the general Dutch population (respectively, p < 0.001 and p < 0.05). CONCLUSIONS: We report a clinically relevant impact of parenting an MPS III patient on psychosocial functioning, which is demonstrated by high levels of anxiety, depression, distress, and a remarkably high prevalence of PTSD. Structural monitoring of the psychosocial functioning of MPS III parents is therefore essential and may be beneficial for the whole family.

The attenuated end of the phenotypic spectrum in MPS III: from late-onset stable cognitive impairment to a non-neuronopathic phenotype.

BACKGROUND: The phenotypic spectrum of many rare disorders is much wider than previously considered. Mucopolysaccharidosis type III (Sanfilippo syndrome, MPS III), is a lysosomal storage disorder traditionally considered to be characterized by childhood onset, progressive neurocognitive deterioration with a rapidly or slowly progressing phenotype. The presented MPS III case series demonstrates adult onset phenotypes with mild cognitive impairment or non-neuronopathic phenotypes. METHODS: In this case series all adult MPS III patients with a mild- or non-neuronopathic phenotype, who attend the outpatient clinic of 3 expert centers for lysosomal storage disorders were included. A mild- or non-neuronopathic phenotype was defined as having completed regular secondary education and attaining a level of independency during adulthood, involving either independent living or a paid job. RESULTS: Twelve patients from six families, with a median age at diagnosis of 43 years (range 3-68) were included (11 MPS IIIA, 1 MPS IIIB). In the four index patients symptoms which led to diagnostic studies (whole exome sequencing and metabolomics) resulting in the diagnosis of MPS III; two patients presented with retinal dystrophy, one with hypertrophic cardiomyopathy and one with neurocognitive decline. The other eight patients were diagnosed by family screening. At a median age of 47 years (range 19-74) 9 out of the 12 patients had normal cognitive functions. Nine patients had retinal dystrophy and 8 patients hypertrophic cardiomyopathy. CONCLUSION: We show the very mild end of the phenotypic spectrum of MPS III, ranging from late-onset stable neurocognitive impairment to a fully non-neuronopathic phenotype. Awareness of this phenotype could lead to timely diagnosis and genetic counseling.