Cause of death in patients with chronic visceral and chronic ...

YMGME-06044; No. of pages: 8; 4C: Molecular Genetics and Metabolism xxx (2016) xxx–xxx

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Research article

Cause of death in patients with chronic visceral and chronic neurovisceral acid sphingomyelinase deficiency (Niemann-Pick disease type B and B variant): Literature review and report of new cases David Cassiman a, Seymour Packman b, Bruno Bembi c, Hadhami Ben Turkia d, Moeenaldeen Al-Sayed e, Manuel Schiff f, Jackie Imrie g, Paulina Mabe h, Tsutomu Takahashi i, Karl Eugen Mengel j, Roberto Giugliani k, Gerald F. Cox l,⁎ a

Metabolic Center, University of Leuven, Leuven, Belgium University of California San Francisco, San Francisco, CA, United States c Academic Medical Centre Hospital of Udine, Udine, Italy d La Rabta Hospital, Tunis, Tunisia e King Faisal Specialist Hospital& Research Center, Riyadh, Saudi Arabia f University of Paris-Diderot, APHP and INSERM U1141, Reference Center for Inborn Errors of Metabolism, Robert-Debré Hospital, Paris, France g Niemann-Pick Disease Group (UK), Tyne and Wear, UK h Hospital Dr. Exequiel González Cortés, Santiago, Chile i Akita University School of Medicine, Akita, Japan j Villa Metabolica, Center of Pediatric and Adolescents Medicine, University Medical Center, Mainz, Germany k Medical Genetics Service, HCPA, Dep. Genetics, UFRGS and INAGEMP, Porto Alegre, Brazil l Clinical Development, Sanofi Genzyme, Cambridge, MA, United States b

a r t i c l e

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Article history: Received 9 March 2016 Received in revised form 4 May 2016 Accepted 5 May 2016 Available online xxxx Keywords: Acid sphingomyelinase deficiency Niemann-Pick disease Liver failure Respiratory failure

a b s t r a c t Background: Acid sphingomyelinase deficiency (ASMD), [Niemann-Pick Disease Types A and B (NPD A and B)], is an inherited metabolic disorder resulting from deficiency of the lysosomal enzyme acid sphingomyelinase. Accumulation of sphingomyelin in hepatocytes, reticuloendothelial cells, and in some cases neurons, results in a progressive multisystem disease that encompasses a broad clinical spectrum of neurological and visceral involvement, including: infantile neurovisceral ASMD (NPD A) that is uniformly fatal by 3 years of age; chronic neurovisceral ASMD (intermediate NPD A/B; NPD B variant) that has later symptom onset and slower neurological and visceral disease progression; and chronic visceral ASMD (NPD B) that lacks neurological symptoms but has significant disease-related morbidities in multiple organ systems. The purpose of this study was to characterize disease-related morbidities and causes of death in patients with the chronic visceral and chronic neurovisceral forms of ASMD. Methods: Data for 85 patients who had died or received liver transplant were collected by treating physicians (n = 27), or abstracted from previously published case studies (n = 58). Ages at symptom onset, diagnosis, and death; cause of death; organ involvement, and morbidity were analyzed. Results: Common disease-related morbidities included splenomegaly (96.6%), hepatomegaly (91.4%), liver dysfunction (82.6%), and pulmonary disease (75.0%). The overall leading causes of death were respiratory failure and liver failure (27.7% each) irrespective of age. For patients with chronic neurovisceral ASMD (31.8%), progression of neurodegenerative disease was a leading cause of death along with respiratory disease (both 23.1%) and liver disease (19.2%). Patients with chronic neurovisceral disease died at younger ages than those with chronic visceral disease (median age at death 8 vs. 23.5 years). Conclusions: The analysis emphasizes that treatment goals for patients with chronic visceral and chronic neurovisceral ASMD should include reducing splenomegaly and improving liver function and respiratory status, with the ultimate goal of decreasing serious morbidity and mortality. © 2016 Published by Elsevier Inc.

1. Introduction ⁎ Corresponding author at: Sanofi Genzyme, 500 Kendall Street, Cambridge, MA 02142, United States. E-mail address: [email protected] (G.F. Cox).

Acid sphingomyelinase deficiency (ASMD), commonly known as Niemann-Pick disease Types A and B (NPD A and B), is a rare lysosomal storage disorder whose birth prevalence is estimated to be 0.4–0.6/

http://dx.doi.org/10.1016/j.ymgme.2016.05.001 1096-7192/© 2016 Published by Elsevier Inc.

Please cite this article as: D. Cassiman, et al., Cause of death in patients with chronic visceral and chronic neurovisceral acid sphingomyelinase deficiency (Niemann-Pick disease ..., Mol. Genet. Metab. (2016), http://dx.doi.org/10.1016/j.ymgme.2016.05.001

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D. Cassiman et al. / Molecular Genetics and Metabolism xxx (2016) xxx–xxx

100,000 [1]. Deficiency of the lysosomal enzyme acid sphingomyelinase results in the progressive accumulation of sphingomyelin within hepatocytes, reticuloendothelial cells, and in severe cases, neurons [2]. ASMD exhibits a continuous clinical spectrum of presentations and outcomes, but for historical reasons has been categorized into distinctive phenotypes [3]. At the most severe end of the spectrum, patients with infantile neurovisceral ASMD (NPD A) have little to no residual ASM activity, onset in early infancy of rapidly progressive systemic manifestations and neurodegeneration, failure-to-thrive, and death by 3 years of age [4]. In contrast, at the least severe end of the spectrum, patients with chronic visceral ASMD (NPD B) have a variable age of onset ranging from infancy to adulthood and slowly progressive visceral disease manifestations without neurodegeneration. More recently, cases of chronic neurovisceral ASMD (also known as intermediate NPD A/B or NPD B variant) have been reported in between these two historical phenotypes [5] [6] with later symptom onset, slower neurological and visceral disease progression, and prolonged survival that distinguishes it from infantile neurovisceral ASMD. Systemic manifestations of chronic visceral ASMD include hepatosplenomegaly, liver dysfunction, interstitial lung disease, thrombocytopenia, anemia, an atherogenic lipid profile, and bone disease. Patients with chronic visceral ASMD may have a normal lifespan; however, premature deaths from respiratory infections or insufficiency, cirrhosis, and hemorrhage, including splenic rupture, have been reported [7–9]. Mortality rates determined from 1999 to 2004 were higher for ASMD patients b5 years of age compared to those 5 years of age or older [10]. In a single-center natural history study conducted in the United States involving 103 patients with chronic visceral or chronic neurovisceral ASMD followed from 1992 to 2012, the overall mortality rate was 17% (19% in patients b 21 years of age), and the median age of death was 17 years [7]. These data indicate that pediatric patients are particularly at risk for early death. With the exception of two single-center natural history studies reporting on the causes of death in 18 patients in the United States [7] and 5 patients in The Netherlands and Belgium [9] with chronic forms of ASMD, the majority of published reports of death in patients with these phenotypes have been limited to single case reports. In order to better understand the disease course leading to death in patients with chronic forms of ASMD, we analyzed published as well as new cases for causes of death and related morbidities. 2. Methods Information from new cases of deceased patients was collected from clinical records by treating physicians and included age at death, cause of death, race/ethnicity, sex, age at diagnosis, age at symptom onset, spleen status, liver disease status including liver enzyme levels, clotting factors and biopsy results, genotype, cardiac changes, organ involvement at time of death, neurologic involvement, ophthalmologic involvement, and concomitant medications. Information on liver transplanted patients was also collected since it is assumed that these patients would have died without the intervention. Patients with chronic neurovisceral ASMD were identified based on the presence of neurological symptoms, and in most cases, ophthalmologic involvement (i.e., presence of macular cherry red spot). 2.1. Published cases The following terms were used to search for ASMD cases the PubMed database from 1966 to September 30, 2015: (Niemann-pick OR Niemann pick OR acid sphingomyelinase deficiency) and (Type B OR intermediate OR variant OR A/B) with filters for case reports, clinical trials, and review articles. The search yielded 351 publications that were screened for descriptions of patient deaths or liver transplant. Cases identified as Type A or Type C, or where no cause of death was listed for cases with chronic forms of ASMD, were omitted. Cases whose

patient histories included death or liver transplant were identified in 18 publications [5,7,9,11–25], and information on age at death or transplant, cause of death, race/ethnicity, sex, age at diagnosis, age at symptom onset, organ involvement, genotype, and morbidity was extracted. 2.2. Causes of death The primary causes of death were categorized by major organ system disease or major disease complication as follows: bleeding/hemorrhage, cancer, cardiac, liver, multiple organ failure, progressive neurodegeneration, respiratory, and other. 2.3. Statistical analysis Data are displayed as mean and standard deviation and/or median and range for continuous variables and as frequency and percentage for categorical variables. The percentages of patients with disease-related morbidities were compared by ASMD phenotype using Fisher's Exact Test. Ages at symptom-onset, diagnosis, and death were compared by ASMD phenotype using one-way analysis of variance. P-values b 0.05 were considered statistically significant. 3. Results Information was collected on 85 patients with chronic forms of ASMD, which included 78 deceased patients and 7 patients who underwent liver transplantation (as these patients were in terminal liver failure). Of these, 27 cases are newly reported, and information on 58 cases was extracted from the literature. Geographic origin was available for 62 patients, and the majority were from Europe/Eastern Europe (n = 36, 58%), followed by the Middle East/Africa, (n = 11, 18%), Asia (n = 9, 14.5%), and South America (n = 6, 9.7%). Patient characteristics are summarized in Table 1 and are stratified by outcome (death or liver transplant) and by phenotype (chronic visceral or chronic neurovisceral ASMD). The majority of cases were classified with chronic visceral disease (68.2%), and were female (61.5%). Information regarding confirmatory diagnostic assay was available for 61 cases with the majority of cases having confirmatory enzyme assay (55/61, 90.2%). Six cases (9.8%) had confirmatory molecular analysis or histology in the absence of enzyme assay results. Median age at first symptom onset for all patients was 0.8 years (range 0–60 years), and median age at diagnosis was 2.0 years (range 0.2–78 years). Median age at death or liver transplant was 18 years (range 0.58–78 years). Patients (n = 7) ranged in age from 4 to 39 years at the time of liver transplantation, and all but 1 had chronic visceral ASMD. Median ages at key time points, and other patient characteristics were similar for deceased patients and those receiving liver transplants. Compared to patients with chronic visceral ASMD, the median ages of patients with chronic neurovisceral ASMD were lower at first symptom onset (0.5 vs. 1.25 years), diagnosis (1.7 vs. 5 years), and death/liver transplant (8 vs. 23.5 years). The distribution of age at death by age at symptom onset is shown in Fig. 1A for 45 patients with available data. All of the patients who died before age 40 had symptom onset before age 8 (n = 35), whereas all of the patients who died after age 40 developed symptoms after age 15 (n = 10). These data are mirrored by the distribution of age at death by age at diagnosis for 55 patients with available data shown in Fig. 1B, which shows that the majority of patients dying in childhood through mid-adulthood (before age 40) were diagnosed before the age of 10. Genotypes for SMPD1 mutations were available for 40 patients (24 with chronic visceral ASMD and 16 with chronic neurovisceral ASMD). Individual mutations and genotypes were very heterogeneous. Most genotypes consisted of homozygous or compound heterozygous missense mutations, and the majority were distinct when stratified by phenotype. The most common mutations (nomenclature based the Human



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Table 1 Demographics and clinical characteristics data are summarized for 27 cases previously unpublished and 58 cases identified from the following references: [5,7,9,11–25] Number of patients with available data is indicated by n. Patient demographics and characteristics

Deceased patients N = 78

Liver transplant patients N=7

All patients N = 85

Sex, N (%) Female Male Phenotype, N (%) Chronic visceral AMSD Chronic neurovisceral ASMD ASMD confirmation, N (%) Enzyme assay (with or without molecular analysis) Molecular or histology (without enzyme assay) Age at first symptom onset Mean ± SD Median (range) Chronic visceral ASMD Mean ± SD Median (range) Chronic neurovisceral ASMD Mean ± SD Median (range) Age at diagnosis Mean ± SD Median (range) Chronic visceral ASMD Mean ± SD Median (range) Chronic neurovisceral ASMD Mean ± SD Median (range) Age at death/liver transplant (all) Mean ± SD Median (range) Chronic visceral ASMD Mean ± SD Median (range) Chronic neurovisceral ASMD Mean ± SD Median (range) Splenectomy N (%)

n = 60 37 (61.7) 23 (38.3) n = 78 52 (66.7) 26 (33.3) n = 58 53 (91.4) 5 (8.6) n = 48 8.97 ± 16.44 1 (0, 60) n = 31 13.47 ± 19.47 1.13 (0, 60) n = 17 0.96 ± 1.41 0.5 (0.08, 6) n = 57 13.30 ± 20.03 2.75 (0.17, 78) n = 38 18.83 ± 22.54 5 (0.5, 78) n = 19 1.81 ± 2.62 0.92 (0.08, 11) n = 78 25.41 ± 22.43 17 (0.58, 78) n = 52 32.92 ± 23.67 23.5 (0.58, 72) n = 26 10.28 ± 7.54 8.5 (2, 32) n = 64 11 (17.2)

n=5 3 (60) 2 (40) n=7 4 (85.7) 1 (14.3) n=3 2 (66.6) 1 (33.4) n=3 0.94 ± 0.65 0.75 (0.42, 1.7) n=2 1.21 ± 0.65 1.21 (0.75, 1.67) n=1 0.42 0.42 n=4 6.56 ± 7.10 4.92 (0.42, 16) n=3 8.61 ± 7.10 8 (1.83, 16) n=1 0.42 0.42 n=7 21.28 ± 11.16 22 (4, 39) n=6 24.17 ± 8.93 23.5 (12, 39) n=1 4 4 n=5 1 (20)

n = 65 40 (61.5) 25 (38.5) n = 85 58 (68.2) 27 (31.8) n = 61 55 (90.2) 6 (9.8) n = 51 8.34 ± 13.35 0.83 (0, 60) n = 33 12.38 ± 15.89 1.25 (0, 60) n = 18 0.94 ± 1.22 0.5 (0.08, 6.0) n = 61 12.73 ± 17.42 2 (0.17, 78) n = 41 18.09 ± 20.15 5 (0.5, 78) n = 20 1.74 ± 2.32 0.71 (0.17, 11) n = 85 25.03 ± 21.78 18 (0.58, 78) n = 58 32.01 ± 22.70 23.5 (0.58, 78) n = 27 10.05 ± 7.5 8 (2, 32) n = 69 12 (17.4)

Genome Variation Society reference sequence, NP_000534.3) in patients with chronic visceral ASMD were p.R610del [4 homozygous (16.7%) and 3 compound heterozygous (12.5%)], followed by p.A359D (4 homozygous, 16.7%), whereas the most common mutation in patients with chronic neurovisceral ASMD was p.Q274R [1 homozygous (6.3%) and 4 heterozygous (25%)]. 3.1. Disease-related morbidity Associated morbidities are shown in Table 2 for all patients with available data. History of splenomegaly (96.6%), hepatomegaly (91.4%), liver dysfunction (82.6%), pulmonary disease (75.0%), thrombocytopenia (68.6%), and anemia (66.7%) were the most common disease manifestations. When stratified by phenotype, there was a higher frequency of neurological (P b 0.0001) and ophthalmologic (P = 0.032) involvement, as expected, in patients with chronic neurovisceral AMSD. In addition, patients with chronic neurovisceral ASMD appeared to have a higher frequency of cardiac involvement, but the data are limited. Neurological manifestations were more frequent in patients who were 18 years of age or younger at time of death or liver transplant (P = 0.048). 3.2. Primary causes of death Primary causes of death for all patients are shown in Fig. 2A. Respiratory failure and liver disease were the two most common causes of death/liver transplant overall (27.7% each). Other causes of death

(cancer, multiple organ failure, cardiac, bleeding, and severe progressive neurodegeneration) occurred between 4 and 10% each. Results were similar in males and females (data not shown). Causes of death were similar in pediatric and adult patients (Fig. 2C) with minor exceptions as discussed in greater detail below. Causes of death by age at symptom onset and by age at death are shown in Fig. 2B and 2C, respectively. Death from liver disease or respiratory disease (28.2% each) accounted for the majority of deaths in patients with symptom onset 18 years of age or younger, followed by progression of neurodegenerative disease (15.4%). In patients with symptom onset after 18 years of age, death from respiratory issues (44.4%) was the primary cause followed by bleeding and cardiac issues (22.2% each). There were no deaths from neurologic issues or liver disease in patients with symptom onset in adulthood, although one patient with missing data for age at symptom onset died of liver disease at 67 years of age. Cause of death stratified by disease phenotype is shown in Fig. 2D. The primary causes of death in patients with chronic visceral ASMD were respiratory (32.1%) and liver (26.4%) disease, which together accounted for the majority of deaths. By definition, there were no deaths due to neurodegenerative disease in patients with chronic visceral ASMD. For patients with chronic neurovisceral ASMD, respiratory disease (23.1%), neurodegeneration (23.1%), and liver disease (19.2%) were the primary causes of death. Deaths resulting from respiratory, liver, and bleeding issues occurred with similar frequencies in patients dying in childhood or adulthood (Fig. 2C). In contrast, deaths from cardiac disease or cancer


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neurovisceral ASMD group (32.1% versus 23.1%, respectively). Fifteen patients had their cause of death listed as respiratory failure/insufficiency, 7 had pneumonia, and 1 had pulmonary embolism. The majority of patients had interstitial lung disease (19/23, 82.6%). Consistent with the morbidity data summary in Table 2, the pertinent histories for patients with terminal liver disease or death from respiratory disease reflect the high frequency of multisystem involvement, such that the majority of patients dying primarily from respiratory disease also had liver failure, and vice versa. Only 1 patient dying from respiratory disease at 1.25 years of age had no other organ involvement identified. 3.3. Other causes of death

Fig. 1. Relationship between age at symptom onset and age at death (2A), or age at diagnosis and age at death (2B) for patients with chronic visceral or chronic neurovisceral ASMD.

occurred primarily in adulthood. As expected, deaths from hematopoietic stem cell transplant complications occurred exclusively in childhood in temporal proximity to the procedure. Among the 23 patients with terminal liver disease, 12 (52.2%) died/ had liver transplantation in childhood (age range 2.5 to 18 years) and 11 (47.8%) died/had transplantation in adulthood (age range 21–67 years). Median age at death was 18 years (range 2.5–67 years). The median age at ASMD symptom onset for patients with terminal liver disease was 0.8 years (range 0.17–5 years), with a median age at ASMD diagnosis of 3 years (range 0.2–67 years). The majority of patients with terminal liver disease had chronic visceral ASMD (17/24, 70.8%). Among the 23 patients with death from respiratory disease, 11 (47.8%) died during childhood (range 0.6–17 years), and 12 (52.2%) died in adulthood. The median age at death was 18 years, with median ages at ASMD symptom onset at 0.6 years and diagnosis at 1.75 years. As with liver disease, the majority of patients with respiratory-related deaths had chronic visceral ASMD (17/23, 73.9%), which accounts for the higher percentage of deaths in this group compared to the chronic

• Eight patients died from bleeding complications, including gastrointestinal/varices bleeding (n = 4), and postoperative hemorrhage, intrathoracic bleeding after injury, subdural hemorrhage, and splenic vein tear (n = 1 each). Deaths due to hemorrhage occurred in patients of all ages (age range 0.9 to 64 years). Four of the 8 patients also had concomitant liver disease. • Six patients who died from heart failure ranged in age from 11 to 65 years. Five were above 18 years of age, and 3 also had respiratory arrest. • Five of 6 patients who received a bone marrow/stem cell transplant died from complications of the procedure. For 2 patients with available data, severe respiratory and liver disease and severe splenomegaly were the indications for the transplant. Death from infection and/ or multi-organ failure followed bone marrow rejection and transplant failure. • Twelve patients who had undergone a total or partial splenectomy died from respiratory disease (n = 4), liver disease (n = 3), bleeding (n = 2), multiple organ failure (n = 1), or complications following bone marrow transplant (n = 1). • Six of 27 (23.1%) patients with chronic neurovisceral ASMD died of neurodegenerative disease at ages ranging from 8 to 32 years. Neurologic decline and seizures, severe psychomotor retardation, dementia, spasticity, and ataxia were among the neurologic symptoms described for these patients. • Five patients died of cancer, including 2 with liver cancer and 1 each with multiple myeloma, chondrosarcoma, and no specific cause listed. All cancer deaths occurred in older adults (range 43 to 65 years) with chronic visceral ASMD. • Three patients with chronic neurovisceral ASMD had “ASMD-related” listed as the cause of death. One patient had severe neurological decline with progressive cirrhosis and varices and died at 5 years of age, while the 2 other patients were described as having fatal visceral storage. One patient had a non ASMD-related cause of death (homicide). • Three patients with multiple organ failure listed as the cause of death had liver, respiratory, and/or cardiac failure listed as contributing factors.

4. Discussion This case series represents the largest analysis of mortality data in patients with chronic forms of ASMD (neurovisceral and visceral), and it is the first analysis of causes of death by age of disease onset. Data were consolidated for the newly described and previously reported cases, and there was no overlap of patients between the two groups. Overall, liver disease and respiratory disease were the leading causes of death in both pediatric and adult patients as well as in patients who experienced onset of symptoms in childhood. Liver disease is known to be a cause of significant morbidity and mortality in chronic ASMD. As part of the screening for entry into the



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Table 2 Morbidities for all patients and stratified by phenotype and age at death/liver transplant. Morbidity

Chronic visceral AMSD N = 58

Chronic neurovisceral ASMD N = 27

Death or liver transplant ≤18 years N = 43

Death or liver transplant N18 years N = 42

n = 59 57 (96.6) n = 58 53 (91.4) n = 46 38 (82.6) n = 68 51 (75.0) n = 35 24 (68.6) n = 33 22 (66.7) n = 43 20 (46.5)

n = 40 38 (95.0) n = 39 34 (87.2) n = 35 28 (80.0) n = 48 38 (79.2) n = 27 20 (74.1) n = 26 18 (69.2) n = 27 9 (33.3)

n = 31 29 (93.5) n = 31 29 (93.5) n = 23 19 (82.6) n = 36 27 (75.0) n = 20 13 (65.0) n = 17 10 (58.8) n = 22 13 (59.1)

n = 28 28 (100.0) n = 27 24 (88.9) n = 23 19 (82.6) n = 32 24 (75.0) n = 15 11 (73.3) n = 16 12 (75.0) n = 21 7 (33.3)

n = 59 25 (42.4) n = 78 23 (29.5)

n = 51 20 (39.2) n = 51 8 (15.7)

n = 19 19 (100.0) n = 19 19 (100.0) n = 11 10 (90.9) n = 20 13 (65.0) n=8 4 (50.0) n=7 4 (57.1) n = 16 11 (68.8) P = 0.032 n=8 5 (62.5) n = 27 15 (55.6) P b 0.0001

n = 31 10 (32.3) n = 40 16 (40.0) P = 0.048

n = 28 15 (53.6) n = 38 7 (18.4)

All patients N = 85 N (%)

History of splenomegaly Hepatomegaly Liver dysfunction Pulmonary Thrombocytopenia Anemia Ophthalmologic

Cardiac Neurologic


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Phase 1a study of olipudase alfa (recombinant human acid sphingomyelinase), liver biopsy revealed that nearly all (88%, 15/17) of the adult patients had some degree of hepatic fibrosis, including 2 with previously undiagnosed cirrhosis [26]. Fibrosis is a result of hepatocyte cell death, which is believed to be related to the large amount of sphingomyelin and secondary cholesterol storage within hepatocyte lysosomes. ASMD and a related sphingolipidosis, Gaucher disease, are both characterized by hepatomegaly and massive infiltration of macrophages into the sinusoidal spaces. These macrophages also accumulate stored sphingolipids and are histologically transformed into foam cells (ASMD) or Gaucher cells (Gaucher disease). Only ASMD, however, shows significant hepatocyte storage of sphingolipids, most likely as a result of different rates of flux of these two distinct sphingolipids (glucosylceramide in Gaucher disease and sphingomyelin in ASMD) through the liver. Liver failure is a common cause of death in ASMD, but is rarely reported in Gaucher disease. Liver disease as a primary cause of death in patients with ASMD has previously been reported in a single-center natural history study conducted in the United States [7]. Our analysis of patients who died from liver disease or had liver transplants provides additional evidence that a subset of patients with onset of symptoms in childhood are at increased risk for early liver failure. Death due to liver disease was equally frequent in pediatric and adult patients, and all but 1 adult patient died before the age of 45. Liver disease was also a common comorbidity in patients whose primary causes of death were listed as respiratory, cardiac, bleeding, or multiple organ failure. Death from respiratory failure also occurred with similar frequency in pediatric and adult patients. The majority of adult patients with ASMD have been found to have interstitial lung disease by radiographic methods [27]. The pathophysiology of pulmonary disease involves the accumulation of lipid-laden macrophages in the alveolar spaces and septa, bronchial walls, and pleura, resulting in progressive restriction of lung volumes and impaired gas exchange [28] [7]. An inflammatory component that drives the recruitment of macrophages to the lung may also be a factor as observed in the ASM knockout mouse model [3]. Pulmonary involvement is part of the multisystem manifestation of sphingomyelin storage [29], and lung-only involvement has been reported in adult ASMD patients [30]. All patients dying from respiratory failure in our analysis also had multiple organ involvement, with the exception of 1 adult patient with no history of hepatosplenomegaly. Treatment options for pulmonary involvement in ASMD are limited. Regular patient assessments include monitoring pulmonary function and supplemental oxygen use for symptomatic pulmonary disease [3]. There have been reports of pulmonary lavage for severe pulmonary symptoms in ASMD patients, but any benefit appears to be temporary, as inflammatory cells repopulate the airways and alveoli over time [17,31]. One patient in our analysis had undergone pulmonary lavage 6 months before dying from respiratory failure [17]. Plasma lipid abnormalities are common in patients with ASMD. Lipid profiles show that HDL cholesterol levels are decreased whereas LDL-C, VLDL-C, and triglyceride levels are increased, all of which are thought to contribute to an increased risk for atherosclerotic disease in patients with chronic visceral ASMD [11,32]. In our series, 6 patients died from heart failure, which was a leading cause of death in patients with symptom onset in adulthood. However, no lipid profile data were analyzed and any relationship between hyperlipidemia and cardiac deaths in our series is speculative. Cardiac comorbidities were common, and occurred in 43% of patients. Hemorrhage was also a leading cause of death in patients with chronic visceral ASMD, and resulted from injury, postoperative hemorrhage, splenic vein tear, and gastrointestinal bleeding/varices bleeding. Hemorrhage-associated deaths occurred with similar frequency in

patients with symptom onset in childhood and adulthood. Splenomegaly and concomitant thrombocytopenia were present in all patients who died of hemorrhage. Half of the patients also had liver disease/cirrhosis, which is known to have an increased bleeding risk due to altered levels of coagulation factors and natural anticoagulants and profibrinolytics [33]. Among the 6 patients who received bone marrow/stem cell transplants, 5 died from complications of the procedure. This high mortality rate highlights that a risk-benefit analysis is necessary before performing these procedures in patients with chronic ASMD. Splenectomy has also been linked with higher mortality in these patients [7]. Twelve patients had undergone full or partial splenectomy in our case series. The causes of death in these patients varied, and included pneumonia, respiratory, liver and multiple organ failure, hemorrhage, and complications following BMT. In the past, some patients underwent splenectomy to treat severe thrombocytopenia and severe bleeding diatheses, but this practice is discouraged today because of the belief that it may exacerbate the disease. In other lysosomal storage disorders where splenomegaly is a prominent feature, such as Gaucher disease type 1, splenectomized patients have a greater risk of life-threatening pulmonary hypertension and a lower life expectancy as compared with non–splenectomized Gaucher patients [34,35]. Deaths due to cancer occurred in 5 adult patients, including 2 with liver cancer and 1 with multiple myeloma. While it is not known if the cancer deaths are related to ASMD, cirrhosis is a known risk factor for hepatic carcinoma. Patients with Gaucher disease type 1 have an increased risk of cancer in general and multiple myeloma in particular [36]. Recent studies suggest that the lipid substrates that accumulate in Gaucher disease, in particular the deacylated form of glucosylceramide (lyso-glucosylceramide), may cause immune dysregulation and lead to the chronic stimulation of antibody-producing B cells, resulting in the development of polyclonal and monoclonal gammopathies and possibly multiple myeloma [37,38]. Of note, patients with ASMD have been shown to have high plasma levels of the deacylated form of sphingomyelin, lyso-sphingomyelin [39], although it is not known whether this is related to increased cancer risk. Chronic neurovisceral ASMD refers to patients with an intermediate phenotype that includes neurological and retinal abnormalities with milder manifestations and slower progression than in infantile neurovisceral ASMD, but more severe than chronic visceral ASMD [5] [6]. In our series, neurodegenerative disease, liver disease, and respiratory failure contributed similarly to causes of death in patients with chronic neurovisceral ASMD, and their median age at death (8 years) occurred much younger than in patients with chronic visceral ASMD (23.5 years). For many of the patients in our cohort who had neurodegenerative disease listed as a cause of death, the actual events contributing to their deaths are largely unknown, but symptoms included neurologic decline, psychomotor retardation, seizures, dementia, and ataxia. In general, and specifically for patients with available data, death due to neurodegenerative disease commonly involved aspiration pneumonia, cachexia, and malnutrition leading to electrolyte disturbances and arrhythmia, and a therapy-refractory epileptic state. All of these can be considered direct complications of underlying neurodegeneration. Thus, more pronounced visceral disease and the neurodegenerative phenotype contribute to earlier death in these patients. Chronic neurovisceral ASMD is most commonly seen in central Europe and is associated with certain SMPD1 gene mutations, including p.Q294K [5] [6] and p.W393G [40] (nomenclature based the Human Genome Variation Society reference sequence, NP_000534.3). Five of 14 patients with chronic neurovisceral ASMD in our case series were heterozygous or homozygous for p.Q294K. One patient who was heterozygous for the p.Q294K mutation had chronic visceral ASMD, illustrating

Fig. 2. Primary causes of death. Percent of patients dying from different causes overall (A) and stratified by age at symptom onset (B), age at death (C), and ASMD phenotype (D). Transplant complications refer to deaths resulting from complications following bone marrow/stem cell transplant. Among the 4 patients with cause of death as “Other”, 3 causes of death were ASMDrelated, and 1 was not ASMD-related. Patients who received liver transplants are included in the liver disease category. Information on cause of death is missing for 2 patients.



the difficulty in making genotype/phenotype correlations in compound heterozygous patients. This patient's other mutation was p.P188L, which has been associated with less severe disease [41]. As has been previously reported [41], the p.R610del is specific to the chronic visceral ASMD phenotype and is a common mutation in patients of European and North African descent. The strengths of the study include the level of comprehensive information on a large set of ASMD patients, with a novel aspect of the study being the analysis of data from a relatively large number of patients with the chronic neurovisceral form of ASMD. The study has several limitations, however. Being a retrospective design, there is the potential for bias due to missing data, which was minimized by the complete capture of deaths reported by the treating physicians from multiple centers around the world. However, we cannot exclude bias on some of the cases that were identified by literature search due to the target population of the studies. For example, the paper by Gulhan et al. [22] specifically looked at charts of patients with lung involvement, which included only 10 of the 40 patients at this center. Similarly, the paper by Coelho et al. [25] was a report on patients undergoing liver transplants. Collectively, these patients accounted for 3 of the 85 patients in this analysis. In some cases, information was missing in the literature regarding confirmatory assays for ASMD, and for some older studies, the diagnosis of the extracted cases was based on clinical picture and therefore, the description of ASMD subtype may be less robust. However, these missing data do not detract from the major conclusions of the paper on the primary causes of death in patients with chronic ASMD. The estimate of deaths resulting from liver disease is conservative, since other causes of death listed included conditions directly resulting from advanced liver disease (e.g., variceal bleeding and liver cancer). The dataset included only deceased patients and not all patients who had been seen at the clinical sites, and so it was not possible to determine the relative risk of death by age in the ASMD population as a whole. Nevertheless, the occurrence of premature deaths in patients with chronic forms of ASMD was attributable in most cases to disease manifestations in both newly reported cases and as summarized from the literature, and demonstrates that this is a life threatening disorder associated that has significant morbidity and mortality. 5. Conclusions Severe liver disease and respiratory failure were leading causes of death in both pediatric and adult patients with chronic visceral and chronic neurovisceral ASMD. This information emphasizes the need for safe, effective therapy and suggests that the goals of treatment should be to improve liver function and respiratory status, and reduce splenomegaly in order to avoid splenectomy and other disease complications, with the ultimate goal of reducing serious morbidity and mortality. There is currently no disease-specific treatment for ASMD, although enzyme replacement therapy with olipudase alfa is in clinical development [42]. Acknowledgements and disclosures The authors thank Iva Ivanovska Holder, PhD and Bernd-Jan. Sanson, MD, Global medical Affairs, Sanofi Genzyme, for help with data collection, analysis, and critical review of the manuscript. The authors acknowledge Marc Yudkoff, MD, The Children's Hospital of Philadelphia, for data contribution. Sanofi Genzyme was the sponsor and provided support for the design and conduct of the study. Patrice C Ferriola, PhD provided writing assistance and James MacDougall provided assistance with data analyses; both were funded by the study sponsor. J Imrie has received consultancy fees and travel support from Actelion and Orphazyme; KE Mengel has received speakers fees, consultation honoraria, consultancy fees, and travel reimbursements from Sanofi Genzyme, Shire, Biomarin, Actelion, Merck, Alexion and Orphazyme; The Leuven University Hospitals and Leuven University received travel

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reimbursements, speaker fees and research grants on behalf of D Cassiman, from Sanofi Genzyme, Shire and Actelion; P Mabe has received lectures fees from Sanofi Genzyme and Biomarin; M Al-Sayed has received travel support and honoraria from Sanofi Genzyme; B Bembi has received consultancy fees and research grants from Sanofi Genzyme, Shire, and Actelion; R Giugliani has received investigator fees, speaker honoraria, and travel grants from Sanofi Genzyme, Shire, BioMarin, Amicus, Actelion, and Synageva; S Pckman has received research, education, and program support, variously, from Sanofi Genzyme, Shire, Amicus, BioMarin, and Actelion; T Takahashi has received research support from Sanofi Genzyme; G Cox is an employee of Sanofi Genzyme; M Schiff has no competing interests to disclose. References [1] S.D. Kingma, O.A. Bodamer, F.A. Wijburg, Epidemiology and diagnosis of lysosomal storage disorders; challenges of screening, Best Pract. Res. Clin. Endocrinol. Metab. 29 (2015) 145–157. 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