Nadia Ali

Neurocognition across the spectrum of mucopolysaccharidosis type I: Age, severity, and treatment.

OBJECTIVESnPrecise characterization of cognitive outcomes and factors that contribute to cognitive variability will enable better understanding of disease progression and treatment effects in mucopolysaccharidosis type I (MPS I). We examined the effects on cognition of phenotype, genotype, age at evaluation and first treatment, and somatic disease burden.nnnMETHODSnSixty patients with severe MPS IH (Hurler syndrome treated with hematopoietic cell transplant and 29 with attenuated MPS I treated with enzyme replacement therapy), were studied with IQ measures, medical history, genotypes. Sixty-seven patients had volumetric MRI. Subjects were grouped by age and phenotype and MRI and compared to 96 normal controls.nnnRESULTSnPrior to hematopoietic cell transplant, MPS IH patients were all cognitively average, but post-transplant, 59% were below average, but stable. Genotype and age at HCT were associated with cognitive ability. In attenuated MPS I, 40% were below average with genotype and somatic disease burden predicting their cognitive ability. White matter volumes were associated with IQ for controls, but not for MPS I. Gray matter volumes were positively associated with IQ in controls and attenuated MPS I patients, but negatively associated in MPS IH.nnnCONCLUSIONSnCognitive impairment, a major difficulty for many MPS I patients, is associated with genotype, age at treatment and somatic disease burden. IQ association with white matter differed from controls. Many attenuated MPS patients have significant physical and/or cognitive problems and receive insufficient support services. Results provide direction for future clinical trials and better disease management.

Neurocognitive and neuropsychiatric phenotypes associated with the mutation L238Q of the α-L-iduronidase gene in Hurler–Scheie syndrome

UNLABELLEDnThe lysosomal enzyme α-L-iduronidase hydrolyzes terminal iduronic acid from heparan sulfate and dermatan sulfate, and is an essential step in GAG degradation. Mutations of its gene, IDUA, yield a spectrum of mucopolysaccharidosis (MPS) type I clinical disorders. The IDUA mutation, c.712T>A (p.L238Q) was previously noted as a mild mutation. In a longitudinal study of MPS brain structure and function (Lysosomal Disease Network), we found this mutation in 6 of 14 Hurler-Scheie syndrome patients in the age range of 15 to 25 years. We hypothesized that L238Q, when paired with a nonsense mutation, is significantly more severe than other missense-nonsense combinations.nnnMETHODSnOf 6 patients with a L238Q mutation, the L238Q allele was paired with a nonsense mutation in 4 patients, paired with a deletion in 1, and with a splice site mutation in another. This group was compared to 6 Hurler-Scheie patients closely matched in age and mutation type. IQ and other neuropsychological tests were administered as part of the protocol. Medical history was compiled into a Physical Symptom Score (PSS). Assessment of IQ, attention, memory, spatial ability, adaptive function and psychological status were measured.nnnRESULTSnNo group differences were found in mean age at evaluation (17.8 and 19.0 years), duration of ERT, or PSS. By history, all were reported to be average in IQ (4/6 with documentation) in early childhood. All (100%) of the L238Q group had a psychiatric history and sleep problems compared to none (0%) of the comparison group. Significant differences were found in depression and withdrawal on parent report measures. IQ was lower in the L238Q group (mean IQ 74) than the comparison group (mean IQ 95; p<0.016). Attention, memory, and visual-spatial ability scores were also significantly lower. Three occurrences of shunted hydrocephalus, and 4 of cervical cord compression were found in the L238Q group; the comparison group had one occurrence of unshunted hydrocephalus and two of cord compression.nnnDISCUSSIONnThe missense mutation L238Q, when paired with a nonsense mutation, is associated with significant, late-onset brain disease: psychiatric disorder, cognitive deficit, and general decline starting at a later age than in Hurler syndrome with a mutation-related rate of GAG accumulation and its pathologic sequelae. This particular genotype-phenotype may provide insight into the genesis of psychiatric illnesses more broadly. Consideration of methods for early, brain-targeted treatment in these patients might be considered.

Patients' perspectives on newborn screening for later-onset lysosomal storage diseases

Lysosomal storage diseases (LSDs) are an individually rare but collectively common group of hereditary, progressive, multi-systemic disorders. Recent technological advances have brought newborn screening (NBS) for LSDs to attention in the United States. However, many LSD symptoms present in later childhood or adulthood, with a wide spectrum of severity. Because late-onset symptoms stray from the traditional NBS model, healthcare providers have expressed concerns about potential harm to patients and/or their families. In this study, 47 individuals with Fabry disease (FD), 22 with Gaucher disease (GD), and 22 with late-onset Pompe disease (LOPD) were surveyed regarding how their life might have been impacted by NBS. Of the 91 participants, none had symptoms at birth and 42 (46.7%) were symptom-free until adulthood. Over half (52.8%) were diagnosed ≥5years from symptom onset; of these, significantly more had FD (60%) or LOPD (63.6%) than GD (23.8%). However, length of diagnostic odyssey was not significantly correlated with opinion on NBS. Most participants either strongly agreed (45%) or agreed (33.3%) with NBS for their condition, with no significant differences between diseases. Opinions on NBS were correlated with participants opinions on whether NBS would have resulted in better current health, but uncorrelated with disease severity or current life satisfaction. Significantly more participants with FD (42.6%) and LOPD (63.6%) than GD (13.6%) felt they would have greater life satisfaction had they been diagnosed as a newborn (p=0.007). Almost half (41%) of participants would have made different life decisions, including lifestyle, financial, and reproductive decisions. Regarding potential harm, participants were most concerned about insurability and least concerned about removal of childrens autonomy. In conclusion, NBS is highly approved of among individuals with LSDs themselves, as it would significantly eliminate diagnostic odysseys and potentially alter life planning.

Treatment of Depression in Adults with Fabry Disease

Fabry disease (FD) is a genetic X-linked, multisystemic, progressive lysosomal storage disorder (LSD). Depression has emerged as a disease complication, with prevalence estimates ranging from 15 to 62%. This is a pilot study examining the effects of psychological counseling for depression in FD on depression, adaptive functioning (AF), quality of life (QOL), and subjective pain experience. Telecounseling was also piloted, as it has beneficial effects in other chronic diseases which make in-person counseling problematic. Subjects completed 6xa0months of in-person or telecounseling with the same health psychologist, followed by 6xa0months without counseling. Self-report measures of depression, AF, QOL, and subjective pain were completed every 3xa0months. All subjects experienced improvements in depression, which were sustained during the follow-up period. Improvements in depression were correlated with improvements in mental health QOL and subjective pain severity, while improvements in mental health QOL were correlated with improvements in AF. While statistical comparison between counseling modes was not possible with the given sample size, relevant observations were noted. Recommendations for future research include replication of results with a larger sample size and a longer counseling period. The use of video counseling may be beneficial. In conclusion, the present pilot study supports the efficacy of psychological treatment for depression in people with FD, highlighting the importance of having health psychologists housed in LSD treatment centers, rather than specialty psychology/psychiatry settings, to increase participation and decrease potential obstacles to access due to perceived stigma.

Newborn screening for Pompe disease: impact on families

Pompe disease (PD) is an autosomal recessive lysosomal storage disorder causing progressive glycogen accumulation in muscles, with variability in age of onset and severity. For infantile-onset PD (IOPD), initiation of early treatment can be life-saving; however, current newborn screening (NBS) technology cannot distinguish IOPD from late-onset PD (LOPD) without clinical workup. Therefore, families of LOPD infants diagnosed by NBS may now spend years or even decades aware of their illness before symptoms appear, creating a pre-symptomatic awareness phase with which the medical community has little experience. The present study examines the effects of receiving a positive NBS result for PD on families. In-depth qualitative interviews were conducted with mothers of nine children (three IOPD and six LOPD) diagnosed via NBS, exploring their experiences, understanding of PD, how they are coping, and what impact diagnosis is having on family life. Interviews were coded using MaxQDA v.12 and analyzed for thematic trends. While overall opinion of NBS was favorable, it is clear many of the concerns anticipated by HCPs, patients, and families regarding NBS for late-onset LSDs are being realized to varying degrees; LOPD families are becoming patients-in-waiting. Increased fear/anxiety and living with uncertainty (regarding diagnosis, their children’s future, and when to start treatment) were predominant themes, with all families voicing considerable emotional reactions and varied social and healthcare support concerns. Coping strategies and psychosocial challenges are interpreted using Rolland & Williams’ Family Systems Genetic Illness model. Recommendations for improvement in delivery of service, as well as families’ advice for future parents and HCPs, are discussed.

Caregiver Quality of Life with Tyrosinemia Type 1

Tyrosinemia type I (HT1) is an inborn error of metabolism (IEM). Current management guidelines include lifelong specialized diet and use of the orphan drug, nitisinone. This study explores the quality of life (QOL) of caregivers of children with HT1. Caregivers for 26 children with HT1 completed a questionnaire (TYR-QOL) adapted to this patient population from an existing validated QOL questionnaire (PKU-QOL). Responses were analyzed via domain scores, based on predetermined scoring guidelines. Results suggest HT1 has a moderate overall impact on caregiver QOL, with emotional aspects of the disease having the greatest impact. HT1 diet and specialized formula also had an impact on caregiver QOL, with the vast majority feeling guilt if their child’s diet and specialized formula plan were not followed. Management of nitisinone did not impact caregiver QOL. Results were compared to the phenylketonuria (PKU) population. Domain scores for the emotional, practical, social, and overall impact on QOL were higher for HT1 than for mild PKU, indicating a greater impact on QOL. Domain scores for practical and social aspects were similarly higher for HT1 than for classic PKU, though emotional and overall impacts were comparable. This is the first questionnaire to assess QOL in caregivers of children with HT1. Results can be used to better understand psychosocial implications of HT1 and assist healthcare professionals in addressing treatment issues.