Psychosocial and supportive care needs of individuals with advanced myeloma.

Purpose: The purpose of this qualitative study is to understand, from the patient's perspective, their experience of living with advanced multiple myeloma, the psychosocial impact, and needs for support in managing and adapting to this illness. Methods: An interpretive descriptive approach was used. Individual semi-structured telephone interviews were conducted with each participant, which focused on eliciting their descriptions of psychosocial issues and concerns, as well as the supports they use for coping with cancer. Transcripts were analyzed using interpretive description, resulting in the generation of common themes that represented the data. Results: The sample comprised twelve adults with a diagnosis of advanced multiple myeloma who had undergone at least three lines of treatment or were transfusion dependent. All participants were receiving ambulatory care for their myeloma in Toronto, Ontario, Canada. Four themes were generated: (1) confusion about the diagnosis and treatment options; (2) challenges in finding relevant information; (3) dealing with the chronicity of treatment side effects; (4) social support as critical for coping with the life-threat of multiple myeloma. Conclusion: Findings suggest that the psychosocial impact of living with advanced multiple myeloma is greatly impacted by one's ability to understand the complexities of the diagnosis and access supports to cope with its physical and emotional consequences. Clinical interventions specifically tailored to meeting the information and support needs of this population are needed.

Delivering multidisciplinary neuromuscular care for children via telehealth.

INTRODUCTION/AIMS: In response to coronavirus disease 2019 (COVID-19) pandemic restrictions int 2020, our face-to-face (F2F) multidisciplinary neuromuscular clinic (NMC) transitioned to widespread use of telehealth (TH). This study aimed to (1) understand parent/guardian, child, and clinician perceptions of TH; (2) examine TH-related changes in clinical activity; and (3) use these findings to inform a future model of care for the NMC. METHODS: A clinical audit was undertaken to examine clinical activity throughout 2018-2020. Online surveys were distributed to clinicians and parents of children attending the NMC via TH in 2020. A working group of clinicians created a checklist to guide a future hybrid model of TH and F2F care. RESULTS: Total clinical activity in 2020 was maintained from previous years; 62.8% of all appointments occurred via TH, and 82.3% of patients attended NMC by TH at least once. Ninety-nine parents (30.6% response rate), 52 children, and 17 clinicians (77% response rate) responded to the survey. All groups reported better interaction when F2F compared to TH. Eighty percent of parents identified advantages of TH and reported lower levels of stress. A lack of "hands-on" physical assessment was identified by parents and clinicians as a TH limitation. Most families (68.1% of parents; 58.8% of children) and all clinicians indicated a preference for a mix of TH and F2F NMC appointments in the future. DISCUSSION: This study has informed a checklist to guide future TH use in a new hybrid model of care. Further investigation is required to assess health impacts of TH use in pediatric neuromuscular care.

Communication about spinal muscular atrophy and genetic risk within families: An Australian pilot study.

AIM: In families with a child diagnosed with spinal muscular atrophy (SMA), siblings who do not have SMA could still be genetic carriers of the condition. This study is the first to explore how siblings of patients with SMA learn about the condition and their genetic risk. METHOD: In-depth, semi-structured interviews were conducted with several parents and unaffected siblings of people with SMA types II and III in Australia. Thematic analysis was performed. RESULTS: Siblings described learning about SMA gradually over time through conversations with their parents and other sources, including the Internet, biology classes and support groups. Parents and unaffected siblings described challenges in family communication due to the emotional intensity associated with having SMA in the family. Most siblings did not report learning from their family how the inheritance of SMA related to their own genetic carrier risk and possible reproductive implications. CONCLUSION: Siblings described their parents as being open and honest in communicating about SMA; however, this study found that communication before the age of understanding abstract concepts, in combination with the emotional intensity of SMA, resulted in gaps in knowledge about SMA.

Nusinersen for SMA: expanded access programme.

BACKGROUND: Spinal muscular atrophy (SMA) is a devastating motor neuron disorder causing progressive muscle weakness and respiratory insufficiency. We present the initial Australian experiences implementing the expanded access programme (EAP) to enable preapproval access to nusinersen, the first disease-modifying therapy, for SMA type 1. METHODS: An Australian multicentre, open-label EAP for nusinersen enrolled patients with infantile-onset SMA type 1 from November 2016 to September 2017. Standard-of-care medical therapy and treatment with intrathecal nusinersen were provided to all patients. Clinical and diagnostic characteristics, molecular genetics, treatment administered, and functional motor outcomes were assessed. RESULTS: A total of 20 patients with SMA type 1 met the inclusion criteria, of whom 16 consented and received nusinersen treatment. Median time to diagnosis from symptom onset was 5.0 months and was correlated with age of onset (r=0.54, P<0.05). Management shifts included proactive nutritional and pulmonary support in all newly diagnosed patients with increased complexity of decision making. Supplemental nutrition with or without nocturnal non-invasive ventilation was implemented during follow-up in new diagnoses with age of onset <3 months and 2 SMN2 copies. CONCLUSIONS: The nusinersen EAP highlights difficulties in achieving early diagnosis and/or prevention, the evolution of optimal clinical care in a time of uncertain prognostication, resource implications and ethical issues in clinical practice for SMA type 1. These challenges are broadly relevant to the realisation of all novel therapeutics in neurological disorders.

Informed decision making and psychosocial outcomes in pregnant and nonpregnant women offered population fragile X carrier screening.

PurposePopulation-based carrier screening for fragile X syndrome (FXS) is still not universally endorsed by professional organizations due to concerns around genetic counseling for complex information and potential for psychosocial harms.MethodsWe determined uptake levels, decision making, and psychosocial impact in a prospective study of pregnant and nonpregnant Australian women offered FXS carrier screening in clinical settings. Women received pretest genetic counseling, and completed questionnaires when deciding and one month later.ResultsOf 1,156 women recruited, 83.1% returned the first questionnaire with 70.6% nonpregnant and 58.8% pregnant women choosing testing (χ2=16.98, P<0.001). Overall, informed choice was high in both nonpregnant (77.4%) and pregnant (72.9%) women (χ2=0.21, P=0.644), and more tested (76.0%) than not-tested (66.7%) women (χ2=6.35, P=0.012) made an informed choice. Measures of depression, stress, and anxiety were similar to population norms for ~85% of women. Decisional conflict and regret were generally low; however, decisional uncertainty and regret were greater in pregnant than nonpregnant women, and not-tested than tested women (uncertainty: χ2=18.51, P<0.001 and χ2=43.11, P<0.001, respectively; regret: χ2=6.61, P<0.037 and χ2=35.54, P<0.001, respectively).ConclusionWe provide evidence to inform guidelines that population FXS carrier screening can be implemented with minimal psychosocial harms following appropriate information and prescreening genetic counseling.

'A short time but a lovely little short time': Bereaved parents' experiences of having a child with spinal muscular atrophy type 1.

AIM: Spinal muscular atrophy (SMA) type 1 is a relatively common, untreatable and invariably fatal neuromuscular disorder of early childhood. Psychosocial care is vital in management of families affected by this disease. There are few studies examining the impact of having a family member with a neuromuscular disorder, and none describing parents' experiences of having a child with SMA type 1. This study explored parents' perspectives of having a child with SMA type 1, from diagnosis to bereavement, in order to inform clinical practice by identifying aspects most meaningful to parents and to aid development of support strategies. METHODS: This qualitative study undertook thematic analysis of 11 in-depth interviews with 13 bereaved parents of children with SMA type 1. RESULTS: While individuals' experiences were unique, common themes emerging from the data include: experiencing shock and anticipatory grief, processing feelings of responsibility and helplessness, experiencing multiple losses including the loss of future reproductive freedom, feeling supported, regaining a sense of control by making decisions about the child's life and death, and finding peace in the dying process. CONCLUSION: These findings highlight the importance of a multidisciplinary approach to the care of such families, including psychosocial support beginning from the time of diagnosis and continuing to bereavement. We suggest areas for further exploration, with a goal to develop family-centred and evidence-based psychosocial care guidelines to complement the current Standards of Care for Spinal Muscular Atrophy.

Rare homozygous disease-associated sequence variants in children with spinal muscular atrophy: a phenotypic description and review of the literature.

5q-associated spinal muscular atrophy (SMA) is the most common autosomal recessive neurological disease. Depletion in functional SMN protein leads to dysfunction and irreversible degeneration of the motor neurons. Over 95 % of individuals with SMA have homozygous exon 7 deletions in the SMN1 gene. Most of the remaining 4-5 % are compound heterozygous for deletion and a disease-associated sequence variant in the non-deleted allele. Individuals with SMA due to bi-allelic SMN1 sequence variants have rarely been reported. Data regarding their clinical phenotype, disease progression, outcome and treatment response are sparse. This study describes six individuals from three families, all with homozygous sequence variants in SMN1, and four of whom received treatment with disease-modifying therapies. We also describe the challenges faced during the diagnostic process and intrafamilial phenotypic variability observed between siblings.

5q31.3 Microdeletion syndrome: clinical and molecular characterization of two further cases.

The 5q31.3 microdeletion syndrome has recently emerged as a distinct clinical entity, and we report two new patients with de novo deletions of this region, bringing the total to seven. Similarly to previously reported cases, the phenotype of our patients is characterized by marked hypotonia, apnea, developmental delay, and feeding difficulties. Both patients had abnormal movements which did not correlate with epileptiform activity on electroencephalogram (EEG). Developmental brain changes on neuroimaging consisted of abnormalities predominantly affecting the white matter and frontal lobes. The 5q31.3 deleted regions overlap those of previously reported cases, and allow further refinement of the shortest region of overlap to 101 kb, including only three genes. Of these, the purine-rich element binding protein A (PURA) gene has an established role in brain development, and we propose that haploinsufficiency for this gene is primarily responsible for the neurodevelopmental features observed.

Phenotypic variability of distal 22q11.2 copy number abnormalities.

The availability of microarray technology has led to the recent recognition of copy number abnormalities of distal chromosome 22q11.2 that are distinct from the better-characterized deletions and duplications of the proximal region. This report describes five unrelated individuals with copy number abnormalities affecting distal chromosome 22q11.2. We report on novel phenotypic features including diaphragmatic hernia and uterine didelphys associated with the distal microdeletion syndrome; and frontomedial polymicrogyria and callosal agenesis associated with the distal microduplication syndrome. We describe the third distal chromosome 22q11.2 microdeletion patient with Goldenhar syndrome. Patients with distal chromosome 22q11.2 copy number abnormalities exhibit inter- and intra-familial phenotypic variability, and challenge our ability to draw meaningful genotype-phenotype correlations.

Generating an iPSC line (with isogenic control) from the PBMCs of an ACTA1 (p.Gly148Asp) nemaline myopathy patient.

To produce an in vitro model of nemaline myopathy, we reprogrammed the peripheral blood mononuclear cells (PBMCs) of a patient with a heterozygous p.Gly148Asp mutation in exon 3 of the ACTA1 gene to iPSCs. Using CRISPR/Cas9 gene editing we corrected the mutation to generate an isogenic control line. Both the mutant and control show a normal karyotype, express pluripotency markers and could differentiae into the three cell states that represent embryonic germ layers (endoderm, mesoderm and neuroectoderm) and the dermomyotome (precursor of skeletal muscle). When differentiated these cell lines will be used to explore disease mechanisms and evaluate novel therapeutics.

Novel quantitative trait loci for central corneal thickness identified by candidate gene analysis of osteogenesis imperfecta genes.

Osteogenesis imperfecta (OI) is a rare connective tissue disorder caused by mutations in the type I collagen genes, COL1A1 and COL1A2, and is characterised by low bone mass and bone fragility. In this study, we explored the relationship between type 1 collagen genes and the quantitative trait central corneal thickness (CCT). CCT was measured in a cohort of 28 Australian type I OI patients and mean CCT was found to be significantly lower compared to a normal population (P < 0.001). We then investigated CCT and corneal collagen fibril diameter and density in a mouse model of OI with a col1a2 mutation. Mean CCT was significantly lower in mutant mice (P = 0.002), as was corneal collagen fibril diameter (P = 0.034), whilst collagen fibril density was significantly greater in mutants (P = 0.034). Finally, we conducted a genetic study to determine whether common single nucleotide polymorphisms (SNPs) in COL1A1 and COL1A2 are associated with CCT variation in the normal human population. Polymorphism rs2696297 (P = 0.003) in COL1A1 and a three SNP haplotype in COL1A2 (P = 0.007) were all significantly associated with normal CCT variation. These data implicate type 1 collagen in the determination of CCT in both OI patients and normal individuals. This provides the first evidence of quantitative trait loci that influence CCT in a normal population and has potential implications for investigating genes involved in glaucoma pathogenesis, a common eye disease in which the severity and progression is influenced by CCT.

False Negative Carrier Screening in Spinal Muscular Atrophy.

We describe a case of spinal muscular atrophy diagnosed in an infant despite previous parental carrier testing suggesting low risk of the disease. This case report explains how this situation arose and illustrates that clinicians need to perform diagnostic testing in children where clinical suspicion for spinal muscular atrophy is high, regardless of the result of previous parental carrier testing, because of the risk of false negative results.

Clinical and Molecular Differences between 4-Year-Old Monozygous Male Twins Mosaic for Normal, Premutation and Fragile X Full Mutation Alleles.

: This study describes monozygotic (MZ) male twins with fragile X syndrome (FXS), mosaic for normal size (NS: <44 CGGs), premutation (PM: 55­199 CGG) and full mutation (FM alleles ≥ 200) alleles, with autism. At 4 years of age chromosomal microarray confirmed monozygosity with both twins showing an XY sex complement. Normal size (30 CGG), PM (99 CGG) and FM (388­1632 CGGs) alleles were detected in Twin 1 (T1) by standard polymerase chain reaction (PCR) and Southern blot testing, while only PM (99 CGG) and FM (672­1025) alleles were identified in Twin 2 (T2). At ~5 years, T2 had greater intellectual impairments with a full scale IQ (FSIQ) of 55 and verbal IQ (VIQ) of 59, compared to FSIQ of 62 and VIQ of 78 for T1. This was consistent with the quantitative FMR1 methylation testing, revealing 10% higher methylation at 80% for T2; suggesting that less active unmethylated alleles were present in T2 as compared to T1. AmplideX methylation PCR also identified partial methylation, including an unmethylated NS allele in T2, undetected by standard testing. In conclusion, this report demonstrates significant differences in intellectual functioning between the MZ twins mosaic for NS, PM and FM alleles with partial FMR1 promoter methylation.

Consumer contribution to the delivery of genetic health services.

Clinical genetics services have been the focus of evaluation and guidelines since the 1970s. In this study we used consumer satisfaction as the evaluative measure with the aim being to seek feedback from consumers of a genetics service to inform quality measures for client-centered genetic services. In the first phase of the study issues were identified by consumers and health professionals around delivering genetics services and the priorities ranked into five themes: expectations, information, respect, privacy and logistics. These themes then formed the basis of a questionnaire that was distributed to consumers of a genetics service in Victoria, Australia. Three hundred ninety-seven out of 821 questionnaires were completed (49.8% response rate). More than 85% of consumers were satisfied in the theme of expectations, with the only issue being waiting times for genetic test results (68.6% satisfied). Over 83% of consumers were satisfied with the information received from the genetics service. The matter of interruptions during appointments was the only area in the theme of respect that rated less than 80% satisfactory (79.1%). In relation to privacy, consumers rated over 95% satisfaction. Logistics was the theme where satisfaction was lowest with ratings of less than 75% for issues such as availability of public transport to the clinic, parking and wheelchair access. Consumer satisfaction was related to the information received before and after consultations and also to the attitudes and behaviors of health professionals. These findings have implications for genetics services both in Australia and internationally and recommendations from the findings are outlined.

Using record linkage and manual follow-up to evaluate the Victorian maternal serum screening quadruple test for Down's syndrome, trisomy 18 and neural tube defects.

OBJECTIVES: The Genetic Health Services Victoria maternal serum screening (MSS) quadruple test has been available to pregnant women in Victoria since 1996. The objectives of this study were to follow up the pregnancies screened by MSS between July 1998 and June 2000 and to determine the performance characteristics of the test for Down's syndrome, trisomy 18 and neural tube defects (NTDs). METHODS: MSS results were matched to pregnancy outcome information from the Perinatal Data Collection Unit and Birth Defects Register, using automated probabilistic record linkage. For unmatched pregnancies, manual follow-up was carried out by contacting referring doctors and hospitals, resulting in a very high follow-up rate of 99.2% (18,989/19,143). RESULTS: The sensitivity of MSS for Down's syndrome was 85% (23/27-95%CI 72-99%) with a falsepositive rate (FPR) of 6.8% (risk threshold >or= 1 in 250). While using a fixed 5% FPR, the sensitivity for Down's syndrome was slightly lower (78%). The sensitivity for trisomy 18 was 44% (4/9 - 95% CI 12-77%) with a FPR of 0.5% (risk threshold of >or= 1 in 200). 11 of the 15 (73 - 95%CI 51-97%) cases of open NTDs were detected from screening, with a 1% FPR (risk threshold alpha-fetoprotein [AFP] >or=2.5 MoM). All cases of anencephaly had increased AFP levels. CONCLUSION: Probabilistic record linkage and manual follow-up is an efficient method for ascertainment of pregnancy outcomes, with a higher follow-up rate than that reported in similar studies. MSS should remain an available option for all pregnant women in Victoria, with test characteristics comparable with other recent reports of the quadruple test.

X-linked Recessive Distal Myopathy With Hypertrophic Cardiomyopathy Caused by a Novel Mutation in the FHL1 Gene.

FHL1 gene mutations are associated with reducing body myopathy, X-linked myopathy with postural muscle atrophy, scapuloperoneal myopathy, Emery-Dreifuss muscular dystrophy, and isolated hypertrophic cardiomyopathy. We describe a boy with a family history consistent with X-linked distal myopathy/cardiomyopathy. The boy first presented at age 14 years and was found to have distal wasting and weakness. Echocardiogram revealed hypertrophic cardiomyopathy. Muscle biopsy showed a vacuolar pathology with no reducing bodies. Sequencing of FHL1 revealed a novel hemizygous c.764G>C missense mutation in exon 8. This is the first report of a predominantly distal myopathy with hypertrophic cardiomyopathy occurring secondary to an FHL1 mutation.

Community-wide screening for cystic fibrosis carriers could replace newborn screening for the diagnosis of cystic fibrosis.

Most babies with cystic fibrosis (CF) are born to parents who did not know they were carriers until their baby was diagnosed with CF, usually by newborn screening. It is only after the birth of their first child with CF that couples are offered genetic counselling and reproductive choices. Most use this information for prenatal testing of subsequent pregnancies. With the high uptake of first trimester screening for Down syndrome (80% in Victoria) most couples have had screening during the CF affected pregnancy. Yet screening for CF carrier status is available, costs are similar to that for Down syndrome screening and CF carrier screening only ever needs to be done once. Waiting for couples to have a baby with CF before they are identified as carriers denies them choice. A national policy on CF carrier screening in Australia, and determination to equitably fund such a programme, is required.