Caregiver-reported impact on quality of life and disease burden in patients diagnosed with metachromatic leukodystrophy: Results of an online survey and a qualitative interview
adolescent; adult; biomedical technology assessment; bone marrow transplantation; Caregiver; child; clinical article; conference abstract; controlled study; disease burden; enzyme replacement; European Quality of Life 5 Dimensions questionnaire; female; follow up; France; Germany; human; human tissue; infant; institutional review; interview; investment; juvenile; male; metachromatic leukodystrophy; multicenter study; palliative therapy; patient advocacy; patient care; preliminary data; quality of life; recall; sample size; wellbeing
Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal disorder caused by a deficiency of the enzyme arylsulfatase A (ARSA). Symptoms include motor decline, developmental regression, decreased intellectual capabilities, and behavioural/psychiatric abnormalities. Until now, little data exists on the burden of illness of MLD for patients and their caregivers. This multinational study aims to quantify caregiver-reported impacts across several key domains including symptoms, treatment burden, time investment, social & emotional well-being, and professional and financial impact. Data were collected using a 45 min web survey and follow-up interview. The survey incorporated the PedsQLTM, a well-validated QoL measure for adolescents and children, and other questions specifically designed to measure the resource use relevant for MLD families based on a majority recall period of 4 weeks. The EQ-5D was also administered to capture the impact of MLD on caregivers (health disutilities). Extensive validation of the survey was conducted through feedback from clinical experts (US and France), and MLD patient advocacy groups (US and UK). This study was approved by an independent Institutional Review Board. Respondents were recruited from the US, UK, France, and Germany, representing a mix of families based on onset types (late infantile, juvenile, adult) and treatment received (supportive/palliative care, bone marrow transplant, enzyme replacement therapy). Due to the rarity of the disease, this study has no upper limit on sample size and is actively recruiting to December 2019 with a sample of >=30 respondents. Preliminary results based on current available data indicate that there is significant burden of MLD on patients and their caregivers, with some degree of variability depending on onset type. This multinational study enhances our understanding of the burden of disease of MLD, which ultimately should improve patient care and assist in the health technology assessment (HTA) of interventions for MLD.
Pang F; Shapovalov Y; Howie K; Wilds A; Calcagni C; Walz M
Molecular Genetics and Metabolism
2020
Article information provided for research and reference use only. PedPalASCNET does not hold any rights over the resource listed here. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.ymgme.2019.11.329" target="_blank" rel="noreferrer noopener">10.1016/j.ymgme.2019.11.329</a>
Quantifying behaviors of children with Sanfilippo syndrome: The Sanfilippo Behavior Rating Scale
Medicine; amygdala volume; autism; Behavior phenotype; Behavior rating scale; Endocrinology & Metabolism; Genetics & Heredity; kluver; management; mucopolysaccharidosis type iiia; MPSIII; Research & Experimental; Sanfilippo Syndrome; behavioral problems; trajectory; characteristics
The Sanfilippo Behavior Rating Scale (SBRS), a 68 item questionnaire, has been developed to assess the behavioral phenotype of children with Sanfilippo syndrome and its progression overtime. Fifteen scales rate orality, movement/activity, attention/self-control, emotional function including anger and fear, and social interaction. Items within scales intercorrelate; measures of internal consistency are adequate. Twelve scales are grouped into 4 abnormality clusters: Movement, Lack of fear, Social/emotional and Executive Dysfunction. A Loess age-trajectory analysis showed that Lack of Fear, Social/Emotional and Executive Dysfunction increased steadily with age; Orality and Mood/Anger/Aggression leveled off. Movement peaked around 6 years, then declined as children's excessive/purposeless actions stopped. Compared with standard scales, SBRS Movement was appropriately associated with the Vineland Motor scale; SBRS Lack of Fear had significant associations with the Autism Diagnostic Observation Schedule (ADOS), indicating a symptom overlap between Sanfilippo syndrome and autism. This suggests that reduced fearfulness may be the most salient/sensitive SBRS marker of disease progression. Volumetric MRI showed that increased Lack of Fear was significantly associated with reduced amygdala volume, consistent with our hypothesis that the behavior seen in Sanfilippo syndrome is a variant of Kluver-Bucy syndrome. Hippocampal volume loss had twice the effect on Social-Emotional Dysfunction as amygdala loss, consistent with a hippocampal role in attachment and social emotions. In conclusion, the SBRS assesses the Sanfilippo behavioral phenotype; it can measure behavior change that accompanies disease progression and/or results from treatment (C) 2015 Elsevier Inc. All rights reserved.
Shapiro E G; Nestrasil I; Ahmed A; Wey A; Rudser K R; Delaney K A; Rumsey R K; Haslett P A J; Whitley C B; Potegal M
Molecular Genetics and Metabolism
2015
Article information provided for research and reference use only. PedPalASCNET does not hold any rights over the resource listed here. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.ymgme.2015.02.008" target="_blank" rel="noreferrer noopener">10.1016/j.ymgme.2015.02.008</a>
A double-blind, placebo-controlled, crossover trial of the selective dopamine D1 receptor antagonist ecopipam in patients with Lesch-Nyhan disease
behavioral problems; Lesch-Nyhan syndrome; pharmacologic intervention; ecopipam; self-injury
Lesch-Nyhan disease (LND) is a genetic disorder that has characteristic metabolic, neurologic, and behavioral features. There are multiple behavioral problems including impulsivity, aggressiveness, and severe recurrent self-injurious behavior (SIB). This last behavior varies considerably across subjects and may encompass self-biting, self-hitting, scratching, head banging, and other injurious actions. Current treatments for SIB involve behavioral extinction, sedatives, physical restraints, and removal of teeth. Because these interventions do not reliably control SIB, better treatments are urgently needed. Animal studies have suggested that D1-dopamine receptor antagonists such as ecopipam may suppress SIB. These observations have led to proposals that such drugs might provide effective treatment for in LND. The current study describes the results of a double-blind, three-period, crossover trial of a single dose of ecopipam in subjects with LND. The study was designed for 20 patients, but it was terminated after recruitment of only 10 patients, because interim analysis revealed unanticipated side effects. These side effects were most likely related to starting with a single large dose without any titration phase. Despite the limited data due to early termination, the drug appeared to reduce SIB in most cases. Subjects who completed the trial were eligible to continue the drug in an open-label extension phase lasting a year, and one patient who elected to continue has maintained a striking reduction in SIB for more than a year with no apparent side effects. These results suggest ecopipam could be a useful treatment for SIB in, but further studies are needed to establish an appropriate dosing regimen.
Khasnavis T; Torres R J; Sommerfeld B; Puig J G; Chipkin R; Jinnah H A
Molecular Genetics and Metabolism
2016
Article information provided for research and reference use only. PedPalASCNET does not hold any rights over the resource listed here. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.ymgme.2016.04.012" target="_blank" rel="noreferrer noopener">10.1016/j.ymgme.2016.04.012</a>
Melatonin ineffective in neuronal ceroid lipofuscinosis patients with fragmented or normal motor activity rhythms recorded by wrist actigraphy
Adolescent; Adult; Antioxidants/tu [Therapeutic Use]; Child; Circadian Rhythm; Dose-Response Relationship; Drug Electrophysiology; Female; Humans; Male; Melatonin/tu [Therapeutic Use]; Neuronal Ceroid-Lipofuscinoses/dt [Drug Therapy]; Sleep Wake Disorders/th [Therapy]; 0 (Antioxidants); JL5DK93RCL (Melatonin); sleep disturbance/disorders; NCL3; pharmacologic intervention; melatonin
Melatonin was tested as a sleeping pill in five patients with neuronal ceroid lipofuscinoses. The single-blind, placebo-controlled study consisted of motor activity recordings, sleep logs, and administration of placebo or melatonin (2.5 or 5 mg). Daily motor activity rhythms were measured by wrist actigraphy during four 7-day periods (baseline, placebo, melatonin 2.5 mg, and melatonin 5 mg). The placebo or melatonin was administered in the evenings for 3 weeks, and the recordings were made during the last week of the 3-week treatment. Sleep logs were kept by the caregivers during the recordings. Based on period analyses, the activity recordings were evaluated to display a normal (24-h) or fragmented rhythm. Three patients had normal motor activity patterns during the baseline recordings, and administration of placebo or melatonin did not affect their rest/activity rhythms. Two patients had abnormally fragmented activity rhythms during the baseline periods, and administration of placebo or melatonin did not induce synchronization. According to the actigraphic data, there were no changes in activity rhythms resulting from administration of melatonin. However, based on the observations, three families reported that melatonin slightly improved the sleep quality of the patients. These controversial findings show the difficulties involved in specifying the role of melatonin in modulating sleep. Thus, we conclude that more evidence is required before the significance of melatonin as a sleeping pill is defined.Copyright 1999 Academic Press.
Hätönen T; Kirveskari E; Heiskala H; Sainio K; Laakso M L; Santavuori P
Molecular Genetics and Metabolism
1999
Article information provided for research and reference use only. PedPalASCNET does not hold any rights over the resource listed here. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1006/mgme.1999.2815" target="_blank" rel="noreferrer noopener">10.1006/mgme.1999.2815</a>
Hospitalizations for mitochondrial disease across the lifespan in the U.S
Hospitalization/sn [Statistics & Numerical Data]; Mitochondrial Diseases/ep [Epidemiology]; Adolescent; Adult; Child; Cost of Illness; Cross-Sectional Studies; Databases; Factual; Female; Health Services Research; Hospital Mortality; Hospitalization/ec [Economics]; Humans; Infant; Longitudinal Studies; Male; Middle Aged; Mitochondrial Diseases/ec [Economics]; Mitochondrial Diseases/mo [Mortality]; Preschool; United States/ep [Epidemiology]; Young Adult
IMPORTANCE: Mitochondrial disease is being diagnosed with increasing frequency. Although children with mitochondrial disease often have severe, life-limiting illnesses, many survive into adulthood. There is, however, limited information about the impact of mitochondrial disease on healthcare utilization in the U.S. across the lifespan., OBJECTIVES: To describe the characteristics of inpatient hospitalizations related to mitochondrial disease in the U.S., to identify patient-level clinical factors associated with in-hospital mortality, and to estimate the burden of hospitalizations on individual patients., DESIGN: Cross-sectional and longitudinal observational studies., SETTING: U.S. hospitals., PARTICIPANTS: Individuals with hospital discharges included in the triennial Healthcare Cost and Utilization Project (HCUP) Kids Inpatient Database (KID) and the National Inpatient Sample (NIS) in 2012 (cross-sectional analysis); individuals with hospital discharges included in the HCUP California State Inpatient Database from 2007 to 2011, inclusive (longitudinal analysis)., EXPOSURE: Hospital discharge associated with a diagnosis of mitochondrial disease., MAIN OUTCOME MEASURES: Total number and rate of hospitalizations for individuals with mitochondrial disease (International Classification of Diseases, 9th revision, Clinical Modification code 277.87, disorder of mitochondrial metabolism); in-hospital mortality., RESULTS: In the 2012, there were approximately 3200 inpatient pediatric hospitalizations (1.9 per 100,000 population) and 2000 inpatient adult hospitalizations (0.8 per 100,000 population) for mitochondrial disease in the U.S., with associated direct medical costs of $113million. In-hospital mortality rates were 2.4% for children and 3.0% for adults, far exceeding population averages. Higher socioeconomic status was associated with both having a diagnosis of mitochondrial disease and with higher in-hospital mortality. From 2007 to 2011 in California, 495 individuals had at least one admission with a diagnosis of mitochondrial disease. Patients had a median of 1.1 hospitalizations (IQI, 0.6-2.2) per calendar year of follow-up; infants under 2y were hospitalized more frequently than other age groups. Over up to five years of follow up, 9.9% of participants with any hospitalization for mitochondrial disease were noted to have an in-hospital death., CONCLUSIONS AND RELEVANCE: Hospitalizations for pediatric and adult mitochondrial diseases are associated with serious illnesses, substantial costs, and significant patient time. Identification of opportunities to prevent or shorten such hospitalizations should be the focus of future studies.Copyright © 2017 Elsevier Inc. All rights reserved.
McCormack SE; Xiao Rui; Kilbaugh TJ; Karlsson M; Ganetzky RD; Cunningham ZZ; Goldstein A; Falk MJ; Damrauer SM
Molecular genetics and metabolism
2017
Article information provided for research and reference use only. PedPalASCNET does not hold any rights over the resource listed here. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.ymgme.2017.04.007" target="_blank" rel="noreferrer noopener">10.1016/j.ymgme.2017.04.007</a>
Clinical and genetic spectrum of Sanfilippo type C (MPS IIIC) disease in The Netherlands
Child; Female; Humans; Male; Adult; Middle Aged; Mutation; Netherlands; Phenotype; adolescent; Preschool; infant; Models; Q3 Literature Search; Age of Onset; DNA Mutational Analysis; Acetyltransferases/chemistry/deficiency/genetics; DNA/genetics; Genotype; Missense; Molecular; Mucopolysaccharidosis III/classification/enzymology/genetics/physiopathology
Mucopolysaccharidosis IIIC (MPS IIIC, Sanfilippo C syndrome) is a lysosomal storage disorder caused by deficiency of the lysosomal enzyme acetyl-CoA:alpha-glucosaminide N-acetyltransferase (HGSNAT). We performed a clinical study on 29 Dutch MPS IIIC patients and determined causative mutations in the recently identified HGSNAT gene. Psychomotor development was reported to be normal in all patients during the first year of life. First clinical signs were usually noted between 1 and 6 years (mean 3.5 years), and consisted of delayed psychomotor development and behavioral problems. Other symptoms included sleeping and hearing problems, recurrent infections, diarrhoea and epilepsy. Two sisters had attenuated disease and did not have symptoms until the third decade. Mean age of death was 34 years (range 25-48). Molecular analysis revealed mutations in both alleles for all patients except one. Altogether 14 different mutations were found: two splice site mutations, one frame shift mutation due to an insertion, three nonsense mutations and eight missense mutations. Two mutations, p.R344C and p.S518F, were frequent among probands of Dutch origin representing 22.0% and 29.3%, respectively, of the mutant alleles. This study demonstrates that MPS IIIC has a milder course than previously reported and that both severity and clinical course are highly variable even between sibs, complicating prediction of the clinical phenotype for individual patients. A clear phenotype-genotype correlation could not be established, except that the mutations p.G262R and p.S539C were only found in two sisters with late-onset disease and presumably convey a mild phenotype.
2008
Ruijter GJ; Valstar MJ; van de Kamp JM; van der Helm RM; Durand S; van Diggelen OP; Wevers RA; Poorthuis BJ; Pshezhetsky AV; Wijburg FA
Molecular Genetics And Metabolism
2008
Article information provided for research and reference use only. PedPalASCNET does not hold any rights over the resource listed here. All rights are retained by the journal listed under publisher and/or the creator(s).
Journal Article
<a href="http://doi.org/10.1016/j.ymgme.2007.09.011" target="_blank" rel="noreferrer">10.1016/j.ymgme.2007.09.011</a>
The Lived Experience Of Parents Of Children With Mucopolysaccharidosis (mps)
Somanadhan Suja; Larkin Philip J
Molecular Genetics And Metabolism
2017
Article information provided for research and reference use only. PedPalASCNET does not hold any rights over the resource listed here. All rights are retained by the journal listed under publisher and/or the creator(s).
10.1016/j.ymgme.2016.11.327