Diagnostic odyssey for patients with acid sphingomyelinase deficiency (ASMD): Exploring the potential indicators of diagnosis using quantitative and qualitative data.

Acid sphingomyelinase deficiency (ASMD) is a rare, progressive, and potentially fatal lysosomal storage disease. This two-part international study aimed to understand physician, patient, and caregivers' experiences during the ASMD diagnostic journey. Qualitative interviews were conducted with patients with ASMD type B or A/B, caregivers (for patients <18 years), and physicians (January 2018-May 2019). A quantitative patient chart review was then performed by physicians (1-3 charts per physician) (April to May 2020). Overall, 12 physicians and 27 patients (self-reported, n = 11; caregiver-reported, n = 16) completed qualitative interviews. Symptoms first presented at approximately 2 years, with physician visits 2 months-1 year later. On average, diagnosis took 3 years and average age at diagnosis was 5 years. During childhood, all patients reported abdominal enlargement and 67% had respiratory issues. Adult patients frequently reported fatigue (64%) and heart problems (36%). In the quantitative study, 86 physicians reviewed 193 ASMD patient charts. At initial presentation, most patients reported abdominal enlargement (pediatric, 55%; adolescents/adults, 39%). Time to diagnosis ranged 0-10 years for patients with ASMD type A/B or type B, and most patients (85%) received an incorrect initial diagnosis. Diagnosis of ASMD can be challenging, and is often delayed due to disease heterogeneity and misdiagnoses.

Assessment of health state utilities associated with adult and pediatric acid sphingomyelinase deficiency (ASMD).

INTRODUCTION: Acid sphingomyelinase deficiency (ASMD) type B is a rare genetic disorder leading to enlargement of the spleen and liver, pulmonary dysfunction, and other symptoms. Cost-utility analyses are often conducted to quantify the value of new treatments, and these analyses require health state utilities. Therefore, the purpose of this study was to estimate utilities associated with varying levels of severity of adult and pediatric ASMD type B. METHODS: Seven adult and seven child health state vignettes describing ASMD were developed based on published literature, clinical trial results, and interviews with clinicians, patients with ASMD, and parents of children with ASMD. The health states were valued in time trade-off interviews with adult general population respondents in the UK. RESULTS: Interviews were completed with 202 participants (50.0% female; mean age = 41.3 years). The health state representing ASMD without impairment had the highest mean utility for both the adult and child health states (0.92/0.94), and severe ASMD had the lowest mean utility (0.33/0.45). Every child health state had a significantly greater utility than the corresponding adult health state. Differences between adult/child paired states ranged from 0.02 to 0.13. Subgroup analyses explored the impact of parenting status on valuation of child health states. DISCUSSION: Greater severity of ASMD was associated with lower mean utility. Results have implications for valuation of pediatric health states. The resulting utilities may be useful in cost-utility modeling estimating the value of treatment for ASMD.

A retrospective study of morbidity and mortality of chronic acid sphingomyelinase deficiency in Germany.

BACKGROUND: Acid sphingomyelinase deficiency (ASMD) is a rare, progressive, potentially fatal lysosomal storage disease that exhibits a broad spectrum of clinical phenotypes. There is a need to expand the knowledge of disease mortality and morbidity in Germany because of limited information on survival analysis in patients with chronic ASMD (type B or type A/B). METHODS: This observational, multicentre, retrospective cohort study was conducted using medical records of patients with the first symptom onset/diagnosis of ASMD type B or type A/B between 1st January 1990 and 31st July 2021 from four German medical centres. Eligible medical records were abstracted to collect data on demographic characteristics, medical history, hospitalisation, mortality, and causes of death from disease onset to the last follow-up/death. Survival outcomes were estimated using the Kaplan-Meier analysis. Standardised mortality ratio (SMR) was also explored. RESULTS: This study included 33 chart records of patients with ASMD type B (n = 24) and type A/B (n = 9), with a median (interquartile range [IQR]) age of 8.0 [3.0-20.0] years and 1.0 [1.0-2.0] years, respectively, at diagnosis. The commonly reported manifestations were related to spleen (100.0%), liver (93.9%), and respiratory (77.4%) abnormalities. Nine deaths were reported at a median [IQR] age of 17.0 [5.0-25.0] years, with 66.7% of overall patients deceased at less than 18 years of age; the median [IQR] age at death for patients with ASMD type B (n = 4) and type A/B (n = 5) was 31.0 [11.0-55.0] and 9.0 [4.0-18.0] years, respectively. All deaths were ASMD-related and primarily caused by liver or respiratory failures or severe progressive neurodegeneration (two patients with ASMD type A/B). The median (95% confidence interval [CI]) overall survival age since birth was 45.4 (17.5-65.0) years. Additionally, an SMR [95% CI] analysis (21.6 [9.8-38.0]) showed that age-specific deaths in the ASMD population were 21.6 times more frequent than that in the general German population. CONCLUSIONS: This study highlights considerable morbidity and mortality associated with ASMD type B and type A/B in Germany. It further emphasises the importance of effective therapy for chronic ASMD to reduce disease complications.

Qualitative Study of the Patient Experience with Venglustat for Gaucher Disease Type 3 in a Phase 2 Open-Label, Multicenter, Multinational Study (LEAP).

INTRODUCTION: Gaucher disease type 3 (GD3) is a genetic, progressive lysosomal storage disorder characterized by visceral manifestations and chronic neurologic symptoms (e.g., horizontal ophthalmoplegia/supranuclear gaze palsy, ataxia, dystonia). The investigational agent venglustat is being studied in combination with imiglucerase as potential treatment for systemic and neuronopathic manifestations of GD3 in a single-arm, open-label, phase 2 trial (LEAP; N = 11). To understand perceived changes in GD3 symptoms from the perspectives of patients, caregivers, and clinicians, we conducted a qualitative case study of selected LEAP participants. METHODS: Four patients in LEAP (age range, 20-28 years), four of their caregivers, and three clinicians involved in LEAP were interviewed individually by moderators using semi-structured guides. Clinicians' perceptions were based on observation of interviewed patients and those in LEAP who were not interviewed, as well as information provided by other staff involved in LEAP, patients, and caregivers. RESULTS: Reported changes in GD3 symptoms varied among patients and among reporters. Only eye movement was spontaneously mentioned as improved by at least one patient, caregiver, and clinical expert. Symptom improvement also varied in terms of time to improvement. Within the first weeks, improvements were seen in understanding new information or complex instructions, remembering the weekday, eye movement, tremor, and seizures. Changes in alertness, engagement and responsiveness, memory, and concentration appeared after months or a year. Most caregivers and all clinical experts reported greater patient independence (e.g., increased ability to perform activities of daily living or travel independently during the trial) as a perceived treatment effect on a GD3 impact. For one patient who perceived benefits from venglustat therapy, pharmacokinetic analyses during LEAP found low to undetectable venglustat levels in their plasma and cerebrospinal fluid. CONCLUSION: Outcomes from this study provide insights into GD3 symptoms and the early signaling of changes reported during venglustat therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02843035.

Survival of patients with chronic acid sphingomyelinase deficiency (ASMD) in the United States: A retrospective chart review study.

Background: Acid sphingomyelinase deficiency (ASMD), historically known as Niemann-Pick disease type A, A/B, and B, is a rare lysosomal storage pathology with multisystemic clinical manifestations. The aims of this study were to estimate the survival probability in patients in the United States with chronic ASMD (ASMD types B and A/B), and to describe the disease characteristics of these patients. Methods: This observational retrospective study included medical chart records of patients with chronic ASMD with retrievable data abstracted by 69 participating physicians from 25 medical centers in the United States. Included patients had a date of ASMD diagnosis or first presentation to a physician for ASMD symptoms (whichever occurred first) between January 01, 1990, and February 28, 2021. Medical chart records were excluded if patients were diagnosed with ASMD type A. Eligible medical chart records were abstracted to collect demographic, medical and developmental history, and mortality data. Survival outcomes were analyzed using Kaplan-Meier survival analyses from birth until death. Results: The overall study population (N = 110) included 69 patients with ASMD type B, nine with type A/B, and 32 with ASMD "non-type A" (ASMD subtype was unknown, but patients were confirmed as not having ASMD type A). The majority of patients were male with a median age at diagnosis of 3.8 years. Thirty-eight patients died during the study observation period, at a median age of 6.8 years. The median (95% confidence interval) survival age from birth was 21.3 (10.2; 60.4) years. At diagnosis or first presentation, 42.7% patients had ≥1 ASMD-related complication; splenic (30.0%) and hepatobiliary (20.9%) being the most common, and 40.9% required ≥1 medical visit due to complications. Conclusion: Patients with chronic ASMD in the United States have poor survival and significant burden of illness.

Acid sphingomyelinase deficiency in France: a retrospective survival study.

BACKGROUND: Acid sphingomyelinase deficiency (ASMD) or Niemann-Pick disease types A, A/B, and B is a progressive, life-limiting, autosomal recessive disorder caused by sphingomyelin phosphodiesterase 1 (SMPD1) gene mutations. There is a need to increase the understanding of morbidity and mortality across children to adults diagnosed with ASMD. METHODS: This observational retrospective survey analysed medical records of patients with ASMD with retrievable data from 27 hospitals in France, diagnosed/followed up between 1st January 1990 and 31st December 2020. Eligible records were abstracted to collect demographic, medical/developmental history, and mortality data. Survival outcomes were estimated from birth until death using Kaplan-Meier survival analyses; standardised mortality ratio (SMR) was also explored. RESULTS: A total of 118 medical records of patients with ASMD (type B [n = 94], type A [n = 15], and type A/B [n = 9]) were assessed. The majority of patients were males (63.6%); the median [range] age at diagnosis was 8.0 [1.0-18.0] months (type A), 1.0 [0-3] year (type A/B), and 5.5 [0-73] years (type B). Overall, 30 patients were deceased at the study completion date; the median [range] age at death for patients with ASMD type A (n = 14) was 1 [0-3.6] year, type A/B (n = 6) was 8.5 [3.0-30.9] years, and type B (n = 10) was 57.6 [3.4-74.1] years. The median [95% confidence interval (CI)] survival age from birth in patients with ASMD type A and type A/B was 2.0 [1.8-2.7] years and 11.4 [5.5-18.5] years, respectively. Survival analysis in ASMD type B was explored using SMR [95% CI] analysis (3.5 [1.6-5.9]), which showed that age-specific deaths in the ASMD type B population were 3.5 times more frequent than those in the general French population. The causes of death were mostly severe progressive neurodegeneration (type A: 16.7%), cancer (type B: 16.7%), or unspecified (across groups: 33.3%). CONCLUSIONS: This study illustrated a substantial burden of illness with high mortality rates in patients with ASMD, including adults with ASMD type B, in France.

Natural history of acid sphingomyelinase deficiency among European patients during childhood and adolescence: A retrospective observational study.

Acid sphingomyelinase deficiency (ASMD) is a rare, lysosomal storage disease with limited evidence on its natural history. This retrospective, medical record abstraction study aimed to characterize the natural history of ASMD (types B and A/B) during childhood and adolescence. Recruiting sites were European centers (i.e., France, Germany, Italy, and the United Kingdom) from the ASCEND-Peds trial (NCT02292654); these sites were targeted because of the rarity of ASMD and specialized care provided at these centers. The study population comprised ASMD trial patients (before exposure to treatment) and ASMD non-trial participants who were managed at the same trial sites. Overall, 18 patients were included (11 trials; 7 non-trials; median [Q1; Q3] age at ASMD diagnosis: 2.5 [1.0; 4.0] years). Median follow-up duration was 10.0 years. Frequently reported medical conditions were hepatobiliary (17 [94.4%]) and blood and lymphatic system disorders (16 [88.9%]). Adenoidectomy (3 [16.7%]) was the most commonly reported surgical procedure; gastroenteritis (5 [27.8%]) was the most frequently reported infection, and epistaxis (6 [33.3%]) was the most commonly reported bleeding event. Abnormal spleen (16 [88.9%]) and liver (15 [83.3%]) size and respiratory function (8 [44.4%]) were commonly reported during physical examination. Overall, 11 (61.1%) patients were hospitalized; 6 (33.3%) patients had emergency room visits. Findings were consistent with published literature and support the current understanding of natural history of ASMD.