Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
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Advances in Clinical and Experimental Medicine

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doi: 10.17219/acem/193696

Publication type: research letter

Language: English

License: Creative Commons Attribution 3.0 Unported (CC BY 3.0)

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Lipiński P, Ługowska A, Tylki-Szymańska A. Chronic acid sphingomyelinase deficiency diagnosed in infancy/childhood in Polish patients: 2024 update [published online as ahead of print on October 23, 2024]. Adv Clin Exp Med. 2024. doi:10.17219/acem/193696

Chronic acid sphingomyelinase deficiency diagnosed in infancy/childhood in Polish patients: 2024 update

Patryk Lipiński1,A,B,C,D,E,F, Agnieszka Ługowska2,B,C, Anna Tylki-Szymańska3,B,C,E

1 Institute of Clinical Sciences, Maria Skłodowska-Curie Medical Academy, Warsaw, Poland

2 Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland

3 Department of Pediatrics, Nutrition and Metabolic Diseases, The Children’s Memorial Health Institute, Warsaw, Poland

Graphical abstract


Graphical abstracts

Abstract

Background. Acid sphingomyelinase deficiency (ASMD) is an autosomal recessive lysosomal storage disease (LSD) associated with biallelic pathogenic variants in the sphingomyelin phosphodiesterase 1 (SMPD1) gene.

Objectives. The aim of this study was to provide the 2024 update on chronic visceral and neurovisceral ASMD diagnosed in the infancy/childhood in Polish patients.

Materials and methods. All the patients diagnosed in the pediatric age (0–18 years) with ASMD, both chronic neurovisceral and visceral type, and then systematically followed up, were enrolled into the study.

Results. A total number of 7 patients were enrolled into the study. Four patients were previously reported. Two patients were newly recognized with ASMD – 1 with chronic visceral and 1 with chronic neurovisceral ASMD. Splenomegaly was noted in all the patients while a mild liver enlargement was observed in 4 of 7 patients. All patients presented with decreased high-density lipoprotein cholesterol (HDL-C) and decreased serum 25-hydroxy-vitamin D concentration while almost all (6 of 7) with hypercholesterolemia. Cherry-red spot was observed in 5 of 7 patients, including 1 patient with neurovisceral type. Seven various SMPD1 gene variants were identified and missense variants were the most common types of genetic lesions, comprising 71% of all alleles. In all the screened patients, lyso-sphingomyelin (lyso-SM) in dried blood spot (DBS) was found elevated; however, the greater values were observed for patients with chronic neurovisceral type.

Conclusions. Chronic acid sphingomyelinase deficiency (ASMD) is a slowly progressive disease. Pediatric ASMD is characterized by spleno-hepatomegaly, dyslipidemia (with decreased HDL-C as the most characteristic) and infiltrative (interstitial) lung disease. Both visceral and neurovisceral chronic ASMD patients could present with cherry-red spot. Both acid spingomyelinase activity and lyso-spingomyelin concentration in DBS should be regarded as a first-tier screening method into ASMD.

Key words: children, lysosomal storage disease, acid sphingomyelinase deficiency, lyso-spingomyelin, dried blood spot

Background

Acid sphingomyelinase deficiency (ASMD), due to biallelic pathogenic variants in the sphingomyelin phosphodiesterase 1 (SMPD1) gene (MIM *607608), is an autosomal recessive lysosomal storage disease (LSD) associated with accumulation of lysosomal sphingomyelin.1

The original Niemann–Pick type A (MIM # 257200) disease is currently classified as the infantile neurovisceral ASMD, while Niemann–Pick type B (# 607616) disease is referred to as the chronic visceral type, and Niemann–Pick type A/B as the chronic neurovisceral type.2, 3 Infantile neurovisceral ASMD constitutes a neuronopathic (neurodegenerative), rapidly progressing, and fatal disorder while chronic visceral ASMD is a non-neuronopathic, slowly progressive and visceral disorder.2, 3 Infants with neurovisceral ASMD typically present with delayed psychomotor development followed by its regression (clinically noted in the 2nd 6 months of life). Neurological features are accompanied by massive hepatosplenomegaly, failure to thrive, and recurrent respiratory tract infections. Patients with visceral ASMD do not present neurological features, but the somatic phenotype is very heterogeneous. The most common signs and symptoms include hepatosplenomegaly (sometimes associated with thrombocytopenia), elevated serum transaminases (mildly-to-moderately), dyslipidemia, and interstitial lung disease (based on radiological features). An intermediate neurological phenotype (slowly progressive neurological disease) with somatic (visceral) manifestations similar to type B, underlines the chronic neurovisceral ASMD.2, 3, 4 In this group of ASMD patients, the onset of neurological symptoms occurs later in life than in patients with infantile neurovisceral form, but is usually noted in childhood. The most commonly reported symptoms include a mild hypotonia and/or hyporeflexia.

In December 2020, enzyme replacement therapy (ERT) with recombinant human ASM (olipudase alfa) was approved by the European Medicines Agency (EMA) for the treatment of the non-neurological manifestations of ASMD.5 Enzyme replacement therapy has become available in Poland since April 2024 (as part of a drug program financed by the National Health Fund). The eligibility criteria for children with ASMD in the drug program, in addition to those included in the EMA registration, include the need for a spleen volume that is at least 5 times the normal volume as measured by a magnetic resonance imaging (MRI) scan.

Objectives

In 2018, we published a single-center study comprising 16 patients (both children and adults) with chronic visceral ASMD (formerly known as Niemann–Pick type B) who were diagnosed and followed up at the Children’s Memorial Health Institute (Warsaw, Poland).6 Since then, several novel patients, including 2 children, have been diagnosed. In April 2024, an enzyme replacement therapy with olipudase alfa became available for patients with ASMD in Poland.

The aim of this study was to provide the 2024 update on chronic visceral and neurovisceral ASMD diagnosed in the infancy/childhood in Polish patients.

Patients and methods

Study design, setting and participants

All the patients diagnosed in the pediatric age (0–18 years) with ASMD, both chronic neurovisceral and visceral type, and then systematically followed up, were enrolled into the study. A retrospective chart review of the patients’ medical records was performed.

Variables: ASM activity, SMPD1 gene sequencing and biomarkers

Acid sphingomyelinase deficiency was diagnosed through the demonstration of reduced ASM activity in peripheral blood leukocytes or dried blood spot (DBS) and confirmed by identification of SMPD1 pathogenic variants. Acid sphingomyelinase activity in leukocytes was measured with the 2-N-hexadecanoylamino-4-nitrophenylphosphorylcholine as a substrate.7 Chitotriosidase (ChT) activity was measured in plasma samples using a spectrofluorometric method as presented by Hollak et al.8 Dried blood spot tests were performed as suggested by the producer (ARCHIMED Life Science GmbH, Vienna, Austria). ARCHIMEDlife laboratory has been certified with ISO 15189 (Medical Laboratory* – Clinical Chemistry to Genetics), ISO 9000 (Quality Management System), ISO 13485 (Medical Devices – IVD Development and Production) and GLP-lab certificate fully integrated for clinical studies. According to the laboratory information, the sample was analyzed as previously described.9

Results

A total number of 7 patients (3 men and 4 women) were enrolled into the study. The characteristics of individual patients are presented in Table 1. Four patients were previously reported.6 Two patients were newly recognized with ASMD – 1 with chronic visceral type (Patient (Pt) 3) and 1 with chronic neurovisceral type (Pt 2). The last patient (Pt 6) was not previously (2018 year) reported due to a diagnosis of chronic neurovisceral type of ASMD.

Three patients from 1 family were of Romani descent (currently living in foster care) and were diagnosed through family screening (at 12 months, 1.5 years and 5 years of age, respectively) – 2 older brothers had died (the primary cause of death was not related to ASMD).6 Four other patients were of Polish origin and were diagnosed at 12 months, 2.5 years, 5 years, and 3 years of age, respectively. Six of the 7 patients underwent routine clinical evaluation. Follow-up of the study patients ranged from 1 to 42 years.

On the basis on clinical and molecular characteristics, the chronic visceral type of ASMD was diagnosed in 5 patients, while 2 others (Pt 2 and Pt 6) were diagnosed with chronic neurovisceral ASMD. Patient 2 presented with a slightly delayed psychomotor development and based on genetic results – 2 SMPD1 variants (in-trans): c.748A>C (p.Ser250Arg) and c. c.1092-1G>C associated with Niemann–Pick type A disease (Table 2). Patient 6 presented with psychomotor regression since the age of 3 years and developed epilepsy at the age of 6–7 years. He was found to be a homozygote for c.880C>A (p.Gln294Lys) variant associated with the intermediate type.

Splenomegaly was noted in all the patients, while a mild liver enlargement was observed in 4 of 7 patients at the time of ASMD diagnosis. A gradual enlargement of both organs, spleen and liver, was observed during clinical monitoring (Table 1). Elevated serum aspartate aminotransferase (AST) was observed in 6 of 7 patients while elevated serum alanine aminotransferase (ALT) was observed in 3 of 7 patients at the time of diagnosis. The value of serum transaminases was found to be several-fold above the upper limit of normal values (Table 1). A decrease (to normalization) of serum transaminases was observed during follow-up.

Only 1 patient (Pt 2 with chronic neurovisceral type) presented with thrombocytopenia (defined as platelets below 150,000/µL) at the time of diagnosis. Two other patients (Pt 6 with chronic neurovisceral type and Pt 7 with chronic visceral type) developed thrombocytopenia at the age of 10 years and 35 years, respectively.

Elevated total serum cholesterol and LDL cholesterol as well as triglycerides were noted in 6 of 7 patients, while decreased HDL cholesterol was observed in all patients. Decreased serum 25-hydroxyvitamin D concentrations were also observed in all patients (Table 1). Cherry-red spot was described in 5 of 7 patients at the time of ASMD diagnosis, including 1 patient with neurovisceral type.

All patients were diagnosed with interstitial lung disease by chest X-ray or computed tomography (CT). Except for frequent respiratory tract infections in infancy/early childhood reported in all patients, no clinical consequences (normal spirometry in all 3 diagnosed patients) of pulmonary macrophage involvement in childhood/adolescence were observed. The last patient (Pt 7), who was followed for almost 42 years, was diagnosed with restrictive lung disease at 20 years of age.

Data on ASM activity were available for all (7) patients (5 in peripheral blood leukocytes and 2 in DBS). In case of 1 patient (Pt 6), ASM activity in leukocytes was found normal; however, due to strong clinical suspicion (and excluding Gaucher disease; GD), the final diagnosis of ASMD was established by molecular analysis of the SMPD1 gene. This patient was found to be heterozygous for Q292K SMPD1 variant (and deletion on the 2nd allele). Seven various SMPD1 gene variants (Table 2) were identified in the study group, and missense variants were the most common types of genetic lesions, comprising 71% of all alleles.

At the time of diagnosis, the lyso-sphingomyelin (lyso-SM) value in DBS was available only for 2 patients, while 6 patients underwent follow-up assessment (Table 1). In all patients with ASMD, lyso-SM was found elevated, however, the greater values were observed in patients with chronic neurovisceral type.

Chitotriosidase activity in serum was available for all 6 patients, however, in 4 of them subsequent analyses were performed. It decreased in 2 of them and increased in 2 others (neurovisceral type).

Discussion

The paper described the 2024 update on ASMD in Poland from pediatric perspective. It provides a clinical, biochemical and molecular characteristics of 7 Polish patients with chronic visceral and neurovisceral ASMD who were diagnosed in the infancy/childhood and systematically followed up.

With the growing awareness of rare diseases, including inherited metabolic diseases (IMD), and the greater availability of diagnostic methods, including routine assessment of lyso-spingolipids as biomarkers in LSD, but most importantly next-generation sequencing (NGS) technology, new patients with known diseases and novel diseases are being discovered.10 Only last year (2023), 2 pediatric patients with chronic ASMD were diagnosed in Poland. This is of great importance in the context of enzyme replacement therapy that has only recently become available in Poland.

The clinical and biochemical features of the presented cohort of pediatric patients with ASMD are consistent with those reported in the literature. Children with ASMD typically present with hepatosplenomegaly accompanied by elevated serum transaminases, dyslipidemia and radiological features of interstitial lung disease.

Based on the data presented and those from the literature, we recommend that all children with splenomegaly (with or without hepatomegaly) of unknown cause should undergo ASM analysis. Thrombocytopenia was not a frequent abnormality in chronic ASMD as opposed to GD, in which it is usually found in almost all patients.11 The characteristic feature of pediatric patients with ASMD, especially in infancy and early childhood, is elevated serum transaminases activity, with a tendency to normalize in older children. The exact cause of normalization of serum transaminases is not known; however, progression to hepatic fibrosis is observed in the natural history of liver disease in ASMD.12 Dyslipidemia was also found to be a unique biochemical feature of chronic ASMD; however, the similar pattern is observed in lysosomal acid lipase deficiency.11, 13 A quite interesting abnormality was a decreased 25-hydroxy-vitamin D level found in all patients with ASMD. It is a well-known phenomenon observed in GD patients (and other LSD), with no exact explanation.14 Radiographic evidence of infiltrative (interstitial) lung disease was noted in all children with chronic ASMD. Besides frequent respiratory tract infections in early childhood, no other clinical symptoms of pulmonary disease were observed in childhood/adolescence. However, based on the long-term follow-up of 1 study patient (child), there is a risk for restrictive lung disease development in adulthood.

The presence of macular cherry-red spot was noted in both visceral and neurovisceral chronic ASMD patients. This observation is noteworthy since it was believed that the presence of cherry-red spot is associated with a neurological phenotype.15

The gold standard in the diagnosis of ASMD was (and still is) a method based on measuring acid sphingomyelinase (ASM) activity in peripheral blood leukocytes followed by SMPD1 gene sequencing. Recently, a DBS test is in common use, utilizing the same diagnostic protocol with addition of biomarkers (lyso-sphingolipids) assessment.9 In 2010, lyso-glucosylceramide (lyso-Gb1), a newly introduced biomarker, was expected to provide breakthrough into GD field.16 An alternative metabolic pathway favored in state of β-glucocerebrosidase deficiency has been identified, where loads of Gb1 undergo deacylation due to an acid ceramidase activity, producing glucosylsphingosine (lyso-Gb1). The quantification of a de-acylated form of sphingomyelin (lyso-SM) and its carboxylated counterpart (lyso-SM-509) has been shown extremely useful in the diagnosis and monitoring of patients with ASMD and Niemann–Pick disease type C (NPC).17, 18, 19 The combined determination of both, lyso-SM and lyso-SM509 allowed the discrimination of ASMD from NPC, as ASMD patients having elevated levels mainly of lyso-SM, while both ASMD and NPC patients exhibit elevated levels of lysoSM-509.20 However, some adults with attenuated chronic ASMD could present with normal lyso-SM but elevated lyso-SM509 (personal observation). Thus, both these biomarkers should be routinely used as a screening method for ASMD. Unfortunately, lyso-SM509 analysis is not available in Poland, while lyso-SM analysis has been used routinely for about 1 year. Despite the small number of patients and multiple assessments of lyso-SM, there is a noticeable difference between chronic visceral and neurovisceral ASMD patients, with the latter having higher lyso-SM levels.

Increased levels of ChT activity have been reported in several LSD, especially high for GD, due to macrophage activation.21, 22, 23 Mildly elevated ChT activity could be observed in chronic ASMD patients, as presented in our study. This biomarker should not be forgotten due to novel biomarkers development, especially lyso-SM.

The method of collecting and assessing ChT activity is relatively simple and remained the same for over 20 years, which guarantees comparability of results between years.23 For these reasons, it is justly considered as a useful tool for clinical practice and management of GD patients and probably for ASMD.

Limitations

The study was limited by its retrospective nature and a relatively small number of patients, but given the rarity of ASMD, the paper is important in the field of inherited metabolic diseases.

Conclusions

1. Chronic ASMD is a slowly progressive disease.

2. Pediatric ASMD is characterized by spleno-hepatomegaly, dyslipidemia (with decreased HDL cholesterol as the most characteristic) and infiltrative (interstitial) lung disease. Both visceral and neurovisceral chronic ASMD patients may present with cherry-red spot.

3. Both acid spingomyelinase activity and lyso-SM concentration in DBS should be regarded as a first-tier screening method for ASMD.

Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Consent for publication

Not applicable.

Tables


Table 1. Clinical, biochemical and molecular characteristics of the study patients

Patient No.

Genotype

Age [years]

Lyso-SPM [ng/mL] <70

ChT

[nmol/mL/h] <150

Liver length in midclavicular line [mm]

Spleen longitudinal length [mm]

Platelets
[1000/µL] <150

AST [IU/L] <45

ALT [IU/L] <40

TC [mg/dL] <200

LDL-C [mg/dL] <115

HDL-C [mg/dL]

32–63

TG [mg/dL]

44–197

25-OH-D

[ng/mL] >30

1

Hmz;

c.880C>A, p.Gln294Lys

5

490.8

620

100

110

161

48

18

175

123

27

125

24

2

c.748A>C, p.Ser250Arg/

c.1092-1G>C, p.?

1

294.9

960

80

110

121

212

160

235

149

19

331

24

2

813.5

1080

125

165

118

130

150

210

125

17

288

15

3

Hmz;

c.1177T>G, p.Trp393Gly

1

n.a.

36

50

85

255

160

138

220

130

20

350

n.a.

3

n.a.

2048

110

130

300

49

46

208

140

21

230

17

5

279

1540

130

180

236

44

32

213

156

20

182

22

4

Hmz;

c.1177T>G, p.Trp393Gly

1.5

n.a.

n.a.

110

90

330

1,200

580

186

120

9

300

36

3

n.a.

488

120

115

230

470

370

206

138

18

250

24

8

367

360

150

210

153

46

30

219

158

17

220

9

5

Hmz;

c.1177T>G, p.Trp393Gly

5

n.a.

296

100

120

256

77

65

243

145

45

270

12

13

303

n.a.

160

150

259

95

25

220

160

39

106

18

15

378

n.a.

190

180

238

37

23

192

120

34

191

10

6

c.880C>A, p.Gln294Lys/

c.1758_1786del, p.Ala597Profs*7

2.5

n.a.

2000

135

165

191

57

17

121

93

13

75

21

6

n.a.

3500

150

190

162

64

35

128

87

18

113

21

10

756

n.a.

160

200

97

42

39

150

90

17

124

17

7

c.581dup,

p.Ala195Serfs*14/

c.1829_1831del,

p.Arg610del

3

n.a.

n.a.

10 cm below costal margin

5 cm below costal margin

222

38

20

253

n.a.

n.a.

242

n.a.

13

n.a.

n.a.

8 cm below costal margin

10 cm below costal margin

240

35

30

270

n.a.

n.a.

220

n.a.

20

n.a.

908

145

165

180

20

22

n.a.

186

n.a.

162

n.a.

35

n.a.

n.a.

150

180

138

25

30

235

205

20

195

n.a.

45 

309

n.a.

180

180

127

35

30

278

194

25

298

13.4

n.a. – not analyzed; hmz – homozygote; ChT – chitotriosidase; AST – aspartate aminotransferase; ALT – alanine aminotransferase; LDL-C – low-density lipoprotein cholesterol; HDL-C – high-density lipoprotein cholesterol; TC – total cholesterol; TG – triglicerides.
Table 2. SMPD1 variants in the study group according to ClinVar

SMPD1 variant

Molecular consequence

Protein change

Condition

c.1177T>G

missense variant

p.Trp393Gly

Niemann–Pick disease, type B

c.880C>A

missense variant

p.Gln294Lys

Niemann–Pick disease, intermediate, protracted neurovisceral

c.1092-1G>C

splice acceptor

Non applicable

Niemann–Pick disease, type A

c.1785_1786del

frameshift variant

p.Ala597fs

Niemann–Pick disease, type A

c.748A>C

missense variant

p.Ser250Arg

Niemann–Pick disease, type A

c.581dup

frameshift variant

p.Ala195Serfs*14

Niemann–Pick disease, type A; Niemann–Pick disease, type B

c.1829_1831del

inframe deletion

p.Arg610del

Niemann–Pick disease, type B

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