The impact of interstitial lung disease in patients with acid sphingomyelinase deficiency (ASMD) - A case series

Abstract

Background

Lysosomal storage diseases (LSD) are inherited diseases caused by mutations affecting genes encoding the function of lysosomal enzymes. Acid sphingomyelinase deficiency (ASMD) is an ultra-rare, progressive, and often fatal LSD with an estimated prevalence of 1-in-50,000–250,000 individuals. The PrevASMD study established the ASMD prevalence in Spain at 35 patients. Almost all present asymptomatic interstitial lung disease (ILD), since >90 % patients with chronic visceral ASMD have radiographic evidence of ILD.

Objective

This case series aims to emphasize the importance of ASMD in adult and pediatric patients with ILD, and to underline the consideration of pulmonary involvement as a key feature of the multisystemic manifestation of ASMD.

Methods

This case series describes seven adult and pediatric cases of ASMD in Spain. All presented with pulmonary function impairment. Data were collected on clinical presentation, diagnostic workup, pulmonary function tests, imaging studies, and patient outcomes during follow up.

Results

Sphingomyelin accumulation in ASMD leads to multi-systemic disease involving spleen, liver, lungs, bone marrow, and lymph nodes. Almost all patients presented with asymptomatic ILD, but not all of them exhibited respiratory symptoms and not all were referred to pulmonologists. Periodic assessments included pulmonary function testing (forced vital capacity and diffusing capacity for carbon monoxide), O2 saturation, and exercise tolerance testing.

Conclusion

ASMD patients presented with different target organ involvement, with lung involvement contributing significantly to patient morbi-mortality. ASMD diagnostic suspicion among pulmonologists treating ILD is thus crucial, as multidisciplinary monitoring of ILD as a feature of ASMD can ensure its correct management and follow-up.

Highlights

• •ILD is a key but often underrecognized ASMD feature requiring pulmonologist awareness.
• •Radiographic ILD presents in >90 % of chronic visceral ASMD, even in asymptomatic cases.
• •Pulmonologists play a crucial role in early ASMD suspicion and timely diagnosis.
• •Unexplained ILD with hepatosplenomegaly may warrant metabolic screening for ASMD.
• •Systematic lung evaluation is essential in ASMD to detect ILD and prevent complications.

1. Introduction

Lysosomal storage diseases (LSD) are a group of inherited diseases caused by pathogenic mutations affecting genes that encode the function of the lysosomal enzymes [1]. Acid sphingomyelinase deficiency (ASMD) is an ultra-rare, progressive, and often fatal LSD. The estimated prevalence is 1 in 50,000–250,000 [2]. The PrevASMD epidemiological study established the prevalence of ASMD in Spain at 35 patients [3].

ASMD occurs due to the deficient activity of the enzyme acid sphingomyelinase (ASM). ASM is a lysosomal lipid hydrolase required to degrade the sphingolipid sphingomyelin into ceramide and phosphocholine [4]. A deficiency of this enzyme results in sphingomyelin accumulation, which is the underlying pathologic defect [1]. ASMD results primarily in the progressive accumulation of sphingomyelin within the mononuclear phagocytic system and hepatocytes, and manifests as a multi-system disease involving the spleen, liver, lung, bone marrow, and lymph nodes. In severe forms of the disease the central and peripheral nervous systems are involved [5]. Storage disorder should be suspected when combined with hepatosplenomegaly and typical biological abnormalities [6].

While the same metabolic defect is common to all ASMD patients, disease severity is determined by the presence or absence of neurological involvement, the extent of systemic disease, and the rate of disease progression, resulting in a wide spectrum of clinical manifestations [5]. Clinical features, time of onset, and disease severity can vary greatly among subtypes and even within families bearing identical genetic alterations [4]. The rarity of the disease and the scarcity of expertise contribute to misdiagnosis, delayed diagnosis, and barriers to adequate care. This may lead to inadequate or inappropriate care, even though a prompt, correct diagnosis combined with supportive management improves the quality of life of ASMD patients [4]. Early diagnosis is still limited by a lack of awareness of the disease among healthcare professionals.

Almost all patients with ASMD present asymptomatic interstitial lung disease (ILD), although some exhibit respiratory symptoms and are referred to a pulmonologist [6]. Pulmonary involvement is a key feature of the multisystem manifestation of sphingomyelin storage, and most patients (>90 %) with chronic visceral ASMD have radiographic evidence of infiltrative lung disease [7]. Interestingly, lung-only involvement, in the absence of organomegaly, has been reported in adult ASMD patients [8]. Periodic patient assessments (yearly or as dictated by symptoms) include pulmonary function testing, including assessment of lung diffusing capacity for carbon monoxide (DLco) and forced vital capacity (FVC), O₂ saturation, and exercise tolerance testing using the modified Medical Research Council scale for assessment of dyspnea and the 6-min walk test (6MWT). Although patients may have no overt respiratory symptoms, chest radiography usually shows typical ground-glass opacities with/without reticulonodular patterns of infiltration. It should be noted that there is frequently a dissociation between the extent of infiltrative lung disease assessed on imaging and the degree of lung compromise indicated by pulmonary function test parameters [5]. The lung is a target organ of ASMD, contributing to patient morbidity and mortality, highlighting the importance of diagnostic suspicion among pulmonologists treating patients with ILD.

This case series aims to emphasize the importance of taking into consideration LSDs, specifically ASMD, in patients diagnosed with ILD. ILD may be a feature of ASMD, and a well-founded diagnostic suspicion would allow for a multidisciplinary approach to ensure the proper management and follow-up of these patients.

2. Case series

2.1. Case 1

Case report of a 7-year-old girl referred to Hospital Universitario y Politécnico La Fe for evaluation of asymptomatic splenomegaly. She was the firstborn child of healthy, non-consanguineous parents with no significant medical history. The pregnancy, delivery, and perinatal period was uneventful, and the child had a birth weight of 2650 g, length of 46 cm, and a head circumference of 33 cm (25th-50th percentiles). Her growth and development were normal, with weight and height in the 50th to 75th percentile, and her academic performance was appropriate for her age.

The patient has been under monitoring since the age of 4 due to asymptomatic splenomegaly, which was diagnosed after mononucleosis syndrome. Initial blood tests revealed low platelet levels (see Table 1), and serological studies were positive for the Epstein-Barr Virus (EBV IgG, IgM ELISA ++) with activated lymphocytes in peripheral blood.

Table 1.

Blood test results EBV disease.

Blood test	Value	Normal range
Hemoglobin g/dL	11.4	12–14.5
Leukocytes x103/mL	6.5	3.5–10.5
Neutrophil %	48	45–50
Lymphocytes %	42	40–45
Monocytes %,	5	4–12
Platelets x 103/mL	143	150–400
GPT U/L	16	0–55
GOT U/L	35	5–34

As splenomegaly persisted during follow-up, a hematologic study was performed together with a bone marrow biopsy; histiocytes with eccentric nuclei and foamy cytoplasm, and the presence of dark blue histiocytes (stained with acid phosphatase) was reported, so the patient was referred with suspicion of LSD.

During her physical examination for LSD, several studies were ordered: growth parameter assessment (showing a weight of 23 kg [in the 50th percentile] and a height of 120 cm [25th −50th percentiles]); oxygen saturation >95 %; heart rate of 120 beats per minute.

Abdominal examination revealed distension and splenomegaly (10 cm below the costal margin), and the abdominal ultrasound- RM showed increased hepatic echogenicity suggestive of steatosis, and spleen (18 cm). The spleen size increased from 650 cc (14 multiple of the normal value [MN]) to 1030 cc (17 MN) during follow-up between 2018 April to 2023 May [9].

Cardiac ultrasound and neurological studies were unremarkable.

Pulmonary function tests (see Table 2) showed a restrictive pattern with reduced DL_CO, and subsequent high-resolution computed tomography (HRCT) of the lungs (Fig. 1) showed an interstitial pattern with thickening of inter- and intralobular septa and ground-glass opacities.

Table 2.

Abnormal pulmonary function tests.

Pulmonary function tests (January 2020)	Value	Normal Range
FVC (% predicted)	68	>80
FEV1 (% predicted)	75	>80
FEV1/FVC (%)	94	>80
DLCO (% predicted)	61	>80

Fig. 1.

HRCT. Interstitial pattern with thickening of inter- and intralobular septa, ground-glass opacities, and intralobular trapping.

Blood tests were repeated (see Table 3) and showed relevant findings supporting the primary suspicion of LSD. Cholesterol and vitamin D were out of range, and treatment was indicated for both alterations.

Table 3.

Blood test.

Blood test	Value	Normal range
Hemoglobin g/dL	13	12–14
Leucocytes103/mL	6.7x	4–12
Neutrophils %	52	45–50
Platelets x 103/μL	164	150–400
Hepatic function
GOT U/L	78	5–34
GPT U/L	111	0–55
GGT U/L	46	9–36
Cholesterol mg/dL	210	200
LDL mg/dL	141	<115
HDL mg/dL	25	40–100
Triglycerides mg/dL	217	0–149
25-(OH) vitamin D ng/mL	8.6	>20
Macrophage activity biomarkers
Chitotriosidase nmol/ml	1152	4.0–133.0
CCL18/PARC ng/ml	558	12–165
ASM activity in peripheral leukocytes (nmol/mg prot h)	0.056
Liso sphingosine mmol/L/h	13.6	0.45–1.44

To confirm the diagnosis of LSD, genetic tests were conducted, revealing the presence of the following mutations in the molecular genetic analysis of SMPD1 gene: pathogenic variant p.Arg230Cys + p.Arg610del. Both parents are carriers. ASMD was thus diagnosed.

The comprehensive evaluation of a pediatric patient with splenomegaly led to a diagnosis of LSD ASMD, in which respiratory pathology was evidenced by complementary studies but did not impair the patient's clinical status.

2.2. Case 2

Case report of a 59-year-old man, non-smoker, working as a carpenter who presented with hepatosplenomegaly and polycythemia and was under evaluation in the Internal Medicine department of Hospital Universitario 12 de Octubre. He was subsequently referred to the Pulmonology Department to investigate the presence of ILD after an HRCT of the lungs performed in April 2018 (Fig. 2) revealed ground-glass opacities with intermixed intralobular lines and interlobular septal thickening at the lung bases.

Fig. 2.

HRCT. Ground-glass opacities with intermixed intralobular lines and interlobular septal thickening at the lung bases.

On physical examination, the patient exhibited crackles in the lower lobes of both lungs without cough, expectoration, or dyspnea. Subsequent pulmonary function tests were normal (see Table 4).

Table 4.

Patient's normal pulmonary function tests.

Pulmonary function tests	August 2018	July 2023	Normal Range
FVC (% predicted)	123	121	80–120
FEV1 (% predicted)	115	109	80–120
FEV1/FVC (%)	74	69	80–120
DLCO (% predicted)	81	74	80–120

Abdominal examination revealed hepatosplenomegaly with no associated abdominal pain. Abdominal ultrasonography indicated normal liver size and splenomegaly (17 cm); portal hypertension was ruled out. Cardiac ultrasound was performed during imaging studies, and revealed no signs of cardiac dysfunction or pulmonary hypertension.

Blood tests performed in May 2018 revealed isolated polycythemia (Hb 17,1 g/dl), with previous hemoglobin determinations showing levels of 18 g/dL.

To identify the different ILDs that could be considered, flexible bronchoscopy with transbronchial lung biopsy was conducted, confirming the presence of foamy, blue-stained macrophages in the alveolar spaces. A subsequent BMA biopsy also revealed foamy, blue-stained macrophages, some containing ceroid material and others stained with periodic acid-schiff (PAS).

With a diagnostic suspicion of ASMD, SMPD1 genetic tests were requested, revealing the presence of the following mutation: p.Arg610del + p.Arg610del. The patient was ultimately diagnosed with ASMD, and his plasma Lyso-SM levels were 200.2 ng/ml.

No changes in follow-up HRCTs have been observed since July 2023. At the time of writing of this manuscript, the patient has continued to show normal respiratory function tests and remained asymptomatic. Monitoring continued with further respiratory function tests performed every 4 months and annual lung HRCT scans.

During the evaluation of an adult patient with hepatosplenomegaly and polycythemia, HRCT revealed pathologic findings consistent with ILD, albeit with no accompanying clinical symptoms. Final diagnosis: ASMD.

2.3. Case 3

Case report of a 33-year-old woman with ASMD diagnosed during a family screening prompted several months earlier by a prior diagnosis in her brother. The patient reported no respiratory or gastrointestinal symptoms, but did mention a history of hepatosplenomegaly during childhood, without a formal diagnosis.

Because of her family history, she underwent enzymatic and genetic studies to evaluate the diagnosis of ASMD. Assessment of acid sphingomyelinase reported 51 pmol/spot∗20h (reference values: 200–3500) and mutation assays (SMPD1 gene) showed the following: p.Tyr469Ser/p.Arg610del.

Based on these results, the patient was diagnosed with ASMD type B, visceral, chronic. During physical examination, splenomegaly and hepatomegaly were palpable and confirmed by ultrasound (hepatomegaly 20 cm and splenomegaly 21 cm).

Although no dyspnea or respiratory symptoms were described and X-rays did not reveal pulmonary infiltrates, the ASMD diagnosis prompted the patient to be referred to the Pulmonology Department (ILD area) for a complete evaluation. Pulmonary function tests showed abnormalities (see Table 5). HCRT (Fig. 3) showed discreet thickening of the interlobular septa and multiple intralobular micronodules, predominantly in the lower lobes.

Table 5.

Abnormal patient's pulmonary function tests.

Pulmonary function tests	Value	Normal Range
FVC (% predicted)	84	>80
FEV1 (% predicted)	72	>80
FEV1/FVC (%)	85	>80
DLCO (% predicted)	57	>80

Fig. 3.

HRCT. Discreet thickening of the interlobular septa and multiple intralobular micronodules.

Blood tests revealed isolated moderate thrombocytopenia (121.000/μl) with no other abnormalities in either hemogram or biochemistry.

An adult patient with a known diagnosis of ASMD was referred for ILD evaluation due to an underlying condition with no respiratory symptoms. However, abnormalities in functional parameters and HRCT findings were detected.

2.4. Case 4

Case report of a 4-year-old boy born in Cataluña and referred to the hospital for evaluation of abdominal distension and delayed psychomotor development (he walked for the first time when he was 18 months). The patient had no significant family medical history.

During the initial consultation, a physical examination showed hepatomegaly and splenomegaly, which were subsequently confirmed on abdominal ultrasound (May 2015). Blood tests revealed elevated transaminase levels (ALT 391 IU/L, AST 362 IU/L). Respiratory evaluation was normal.

A hepatic biopsy revealed the presence of histiocytes with microvacuolated cytoplasm, commonly referred to as "foamy histiocytes," which were positive for CD68 and formed aggregates in portal spaces and sinusoids. Hepatocytes showed homogeneous nuclei, some binucleated, and the cytoplasm had a micro vacuolated appearance. Hepatocytes stained positive on Periodic Acid-Schiff (PAS but negative on PAS with diastase digestion. No evidence of ferric pigment was observed. Techniques for lipid detection in frozen material (Oil Red O, Sudan Black) revealed mild deposition of lipid material.

Histopathological changes suggested LSD, so further studies were ordered to confirm the diagnosis. Electronic microscopy showed massive proliferation of macrophages with multiple clear vacuoles containing dense inclusions. On the basis of these findings, the patient was diagnosed with LSD characterized by accumulation of simple and complex lipids.

SMPD1 genetic tests were requested, and showed the presence of the following heterozygous mutation: p.Arg418Ter + p.Arg610del. ASM enzymatic assays reported 2 nmol/17h/mg (normal range 8.5–26). The ASMD diagnosis was confirmed, and complementary studies were ordered.

Functional respiratory tests are shown in Table 6. Chest HRCT (May 2016) showed thickening of interlobular septa and symmetric, bilateral centrilobular micronodules, predominantly affecting the upper and lower lobes, with less involvement of the lingula and middle lobe. The latest HRCT scan has shown predominantly ground-glass opacities (see Fig. 4).

Table 6.

Pulmonary function tests.

Pulmonary function tests	2015	2016	2017	2018	2021	2022	2024	Normal Range
FVC (% predicted)	81	87	87	101	94	95	90	>80
FEV1 (% predicted)	86	90	91	103	95	93	87	>80
FEV1/FVC (%)	98	94	96	92	91	88	87	>80
DLCO (% predicted)	Not performed due to age				97	100	108	>80

Fig. 4.

HRCT (2016–2022).

Abdominal ultrasound found an enlarged liver with normal echogenicity and echotexture. The spleen maintained its position and echogenicity and had increased in size (length 10.2 cm). Cardiac evaluation was normal.

Follow-up HCRT and abdominal ultrasound findings were as follows: Chest HRCT (Nov 2022) showed persistent thickening of interlobular septa and symmetric, bilateral centrilobular micronodules, and appearance of extensive areas of ground-glass opacity, predominantly in both lung bases. Abdominal ultrasound (Dec 2022) showed homogeneous hepatomegaly, slightly hyperechoic, with no focal lesions and homogeneous splenomegaly (133 mm).

The pediatric patient investigated for abdominal distension with no accompanying abnormalities and suspected LSD, received a diagnosis of ASMD. Currently under observation, the patient shows stable abnormalities on HRCT that do not affect functional parameters or respiratory function.

2.5. Case 5

Case report of a 46-year-old women with a previous diagnosis of ASMD who had been under surveillance since childhood. She was admitted when she was nearly 3 years old to study hepatosplenomegaly with bilateral infiltrates on chest imaging; by then, she underwent a bone marrow biopsy and aspiration from which ASMD was diagnosed.

She was the child of healthy, non-consanguineous parents with no significant medical history. The mother's pregnancy was normal, delivery was vacuum-assisted, and the perinatal period was uneventful. She had a birth weight of 3450 g, and her growth and development were normal. She was breastfed for 3.5 months and received vaccinations according to the recommended schedule. She did not have any allergies.

In 2004, at the age of 26, genetic testing following DGGE/SEQUENCING methodology was performed at Hospital Clinic de Barcelona, revealing NIEMANN PICK B (MIM 607616), autosomal recessive inheritance, mutation p.Arg610del + p.Thr486Ala (with no neurological involvement).

The diagnostic biomarkers and enzymatic activity together with the genetic analyses are shown in Table 7. The patient exhibited decreased enzyme activity of 0.6 μmol/liter/hour (normal value > 1.2).

Table 7.

Diagnostic biomarkers and enzymatic activity 2004.

Enzymatic activity		Normal range
Beta-hexosaminidase	17977′00 nmoles per hour per mg protein	16929′00
Sphingomyelinase	15′10 nmoles per hour per mg protein	244′00
Biomarkers		Normal range
Chitotriosidase	∗ 1200.3 μmol/h/L	5.8–44,1
Liso sphingosine	∗ 186.0 ng/mL	0.3–2.3

At the time of writing of this manuscript, the patient presents dyslipidemia, no hypertension, and describes herself as a heavy smoker (with more than 40 pack-years), with no cardiac issues. She has 3 to 4 bowel movements a day, diarrhea, and insomnia.

The patient's most recent physical examination revealed normal skin and mucous membrane coloration, a heart rate of 80 bpm, and blood pressure of 142/78 mmHg.

(she had been diagnosed with hypertension and is on medication). During the abdominal exam, the spleen border was palpable in the lower limbs, with no edema. The neurological evaluation showed weak patellar reflexes.

During the pulmonary examination, the patient was eupneic with a basal SaO2 of 98 %, and bilateral basal crackles were noted. Pulmonary function tests showed abnormalities, as shown in Table 8.

Table 8.

Abnormal pulmonary function tests.

Pulmonary function tests	2018	2021	2022	2023	Normal Range
FVC (% predicted)	112	110	97	108	>80
FEV1 (% predicted)	67	75	57	77	>80
FEV1/FVC (%)	51	55	47	58	>70
DLCO (% predicted)	72		80	69	>80

A chest CT scan performed in April 2023 (Fig. 5) showed a mediastinum of normal size and morphology, with no hilar or mediastinal adenopathy. Widespread (90 %) interstitial involvement previously described as ground glass opacity with fine reticulation persisted, forming a reticular pattern in the lung bases. There were no significant changes compared to the previous CT scan. A small, calcified nodule was present in the left lung. No pleural effusion was observed. Altogether, the scan showed stable interstitial involvement.

Fig. 5.

HRCT (2023).

An abdominal ultrasound showed the liver to be of normal size and echogenicity, with a smooth surface and homogeneous echostructure with no lesions. A permeable portal vein of normal diameter with hepatopedal flow was confirmed on color Doppler. No abnormalities were observed in the suprahepatic veins. Splenomegaly (18 cm) was observed, and the right adrenal gland measured 25 × 18 mm, with homogeneous hypoechogenicity.

The patient's latest results are shown below (Table 9).

Table 9.

Blood test results, hepatic function, and biomarkers values.

Blood test	November 2023	Normal range
Hemoglobin g/dL	15.8	12–16
Leucocytes∗10^3/μL	3.90	4.50–11.00
Neutrophils ∗10^3/μL	2.36	1.80–8.00
Platelets x 10^3/μL	140	135–450
Hepatic function
GOT U/L	62	5–47
GPT U/L	45	5–47
GGT U/L	13	5–40
Cholesterol mg/dL	178	110–200
LDL mg/dL	122	<115 mg/dL
HDL mg/dL	22	50–90 mg/dL
Triglycerides mg/dL	170	0–150 mg/dL
25-(OH) vitamin D ng/mL		>20
Macrophage activity biomarkers
Chitotriosidase μmol/h/L	2451.0	5.8–44.1
CCL18/PARC
ASM activity in peripheral leukocytes
Liso sphingosine μmol/h/L	124.5	0.3–2.3

An adult patient with a known diagnosis of ASMD under multidisciplinary follow-up shows radiological and pulmonary abnormalities but no clinical manifestations despite being a habitual smoker.

2.6. Cases 6 and 7

The same mutations in the same gene in both siblings highlight the variability of the clinical expression of ASMD and its respiratory involvement.

2.6.1. Case 6

The first sibling involves a female patient, born from healthy non-consanguineous parents, with a history of prematurity. She was delivered at 33 + 3 weeks gestational age due to premature rupture of membranes, with a birth weight of 2135 g and an Apgar score of 9/9. She presented immediate neonatal respiratory distress requiring CPAP for 3 hours after birth. She remained hospitalized in the Neonatology Unit for 18 days due to prematurity, infectious risk with antibiotic coverage, and multifactorial non-isoimmune jaundice.

At the age of 2, she developed symptoms of nasal respiratory insufficiency and adenoid hypertrophy, leading to adenoidectomy at 5 years of age (July 2014). She presented persistent postoperative bleeding, and due to difficulty with extubation was transferred to the Pediatric Intensive Care Unit (PICU) where she presented cardiac and respiratory arrest after accidental extubation. She remained on invasive mechanical ventilation for 5 days, followed by scheduled extubation and favorable recovery. During this hospital stay, coagulation abnormalities, mild thrombocytopenia, hepatosplenomegaly, and an interstitial pattern on chest X-ray were observed, which were attributed to acute respiratory distress syndrome in the PICU. Following discharge and clinical suspicion of a storage disorder, she was admitted for further evaluation.

Genetic analysis revealed a compound heterozygous genotype of the SMPD1 gene with mutations p.Trp32Ter and p.Phe368Serfs∗17. The parents are carriers with normal biomarker levels. The second mutation, detected in the father, had not previously been described in the literature in relation to ASMD. As a result, a diagnosis of ASMD type B was confirmed. See Table 10 for more information on macrophage activity biomarkers.

Table 10.

Macrophage activity biomarkers.

Macrophage activity biomarkers		Normal Range
ASM activity (nmol/mg prot/h)	29 %	0.013–0.081
Chitotriosidase (mol/ml/h)	607	4–133
CCL18/PARC (ng/mL)	1039	12–165
7-CC (ng/mL)	400.8	3.5–52

On examination, the patient showed moderate hepatosplenomegaly (spleen 14 cm) with laboratory values showing mild thrombocytopenia, prolonged activated partial thromboplastin time (aPTT), mild, stable hepatic dysfunction, and dyslipidemia with atherogenic risk.

In terms of lung function, she remained asymptomatic at diagnosis with saturation within the normal range despite findings on HCRT performed at the age of 5 (October 2014), which revealed diffuse bilateral interlobular septal thickening extending widely across both lung fields (Fig. 6).

Fig. 6.

HRCT (2014).

In 2016, she was referred to Hospital Universitario La Paz, Madrid for multidisciplinary follow-up. Since then, the patient had been under the care of the Pediatric Pulmonology Unit, and her lung function has remained stable. She has presented recurrent respiratory infections, primarily during early childhood and in the winter season, which have occasionally been treated with antibiotics, oral corticosteroids, aerosol therapy with mucolytics, respiratory physiotherapy, bronchodilators, and inhaled corticosteroids, with no complications or need for hospitalization. Spirometry showed values within the normal range until the age of 10, after which successive controls revealed a non-obstructive pattern compatible with moderate restrictive impairment. See Table 11 for more detailed information.

Table 11.

Pulmonary function tests (2016–2023).

	2016		2017		2018		2019		2020		2021		2022		2023		Normal Range Z-Score
	Value	Z-Score	Value	Z-Score	Value	Z-Score	Value	Z-Score	Value	Z-Score	Value	Z-Score	Value	Z-Score	Value	Z-Score
FEV1 (% predicted)	86	−1,16	87	−1,07	83	−1,42	78	−1,81	75	−2,07	72	−2,38	69	−2,55	66	−2,9	≥1645
FVC (% predicted)	82	−1,42	83	−1,39	80	−1,7	73	−2,37	71	−2,54	75	−2,18	67	−2,83	69	−2,63	≥1645
FEV1/FVC (%)	104	0,66	104	0,79	103	0,56	107	1,39	106	1,09	96	−0,66	93	0,5	93	0,52	≥1645
DLCO (% predicted)															75	−3,44	>1645

Despite altered pulmonary function tests, she presented no resting or exercise desaturation, with good tolerance to physical activity with no limitations and no respiratory symptoms. Gasometry was normal, indicating no signs of respiratory failure. Overnight pulse oximetry-capnography (EtCO2) recordings did not reveal hypoxemia or hypercapnia during sleep. The 6MWT has been consistently normal with no desaturation or dyspnea on exertion.

The patient presented with hepatomegaly with severe hepatic fibrosis (Fibroscan: F4), accompanied by mild-to-moderate elevation of serum transaminases (AST and ALT) and no other signs of hepatic dysfunction. AST and ALT have remained stable with vitamin K therapy. Additionally, she exhibited hypersplenism with maximal splenomegaly of 24 cm (+11.7 SD) and mild thrombocytopenia.

At the age of 10, she was diagnosed with thrombopathy due to decreased PAC-1 binding with borderline levels of FXII and FXIII. Metabolically, she was diagnosed with hypercholesterolemia with dyslipidemia and hypertriglyceridemia, which had shown improvement with dietary therapy. She also presented with multifactorial short stature (−2.4 SD), delayed bone age, and decreased bone mineral density, for which she received supplementation with vitamin D and a multivitamin. Cardiac evaluations revealed newly diagnosed moderate to severe aortic insufficiency, for which she has started treatment with enalapril.

2.6.2. Case 7

This case is the younger brother of the patient described above. He has no significant perinatal history, and was admitted at 8 months for acute bronchiolitis due to RSV, with subsequent episodes of bronchospasms triggered by respiratory infections treated with bronchodilators. As the boy also presented a particular phenotype, with abdominal distension and moderate hepatosplenomegaly, he was also studied and diagnosed with ASMD type B at age 2 years and 11 months. See Table 12 for more information on biomarkers.

Table 12.

Macrophage activity biomarkers.

Macrophage activity biomarkers		Normal Range
ASM activity (nmol/mg prot/h)	26 %	0.073–0.003 nmol/mg prot/h
Chitotriosidase (mol/ml/h)	727 ng/mL	12–165
CCL18/PARC (ng/mL)	298 mol/ml/h	4–133
7-CC (ng/mL)	432.5 ng/mL	3.5–52

He had the same mutations in the SMPD1 gene: p.Trp32Ter and p.Phe368Serfs∗17. Blood tests revealed mild thrombocytopenia, stable hepatic dysfunction, and dyslipidemia. Chest X-ray showed a clear diffuse bilateral reticular nodular pattern, but no respiratory symptoms, and baseline oxygen saturation (SaO2) was 95 %. He was referred with his sister to the Hospital Universitario La Paz for multidisciplinary follow-up.

Since starting follow-up by the Pediatric Pulmonology Unit at 4 years of age (July 2016), his respiratory evolution had been more challenging than his sister. An initial nocturnal pulse oximetry recording in August 2016 showed hypoxemia with 16 % of the recording demonstrated O₂ saturation below 90 %, so he started oxygen therapy during sleep with 1–2 L per minute (lpm) with no signs of hypoventilation. He was admitted in October 2016 for respiratory worsening with distress and blood oxygen saturation of 83 % in the context of respiratory coinfection by Rhinovirus, Bocavirus, and Enterovirus. After discharge, the patient's baseline respiratory condition worsened, and he required 24-h oxygen therapy, despite intensification of treatment.

HCRT in October 2016 showed bilateral and diffuse lung involvement with significant inter and intralobular septal thickening and diffuse ground-glass pattern (Fig. 7).

Fig. 7.

HRCT (2016).

Over the following 2 years, chronic hypoxemic respiratory failure continued with exacerbations due to recurrent respiratory infections, resting dyspnea, and increased oxygen requirements up to 3 lpm, all of which affected his quality of life and led to frequent school absenteeism. To improve his respiratory condition, when he was 6 years and 8 months (December 2018) it was decided to start nocturnal non-invasive mechanical ventilation (NIV), even though there were no signs of hypoventilation. Additionally, adenotonsillar hypertrophy with snoring and bilateral serous otitis media was noted, so adenotonsillectomy was performed in May 2019. After starting NIV, he reported progressive improvement, with less dyspnea and daytime oxygen requirements, and better tolerance to exercise. He had previously desaturated during the 6MWT, but has since increased his distance from 300 m to 322 m. This improvement also permitted occasional oxygen disconnects at rest, with no desaturation or increased dyspnea.

Since performing spirometry, he has shown a mixed pattern (see Table 13).

Table 13.

Pulmonary function tests (2018–2023).

	2018		2020		2021		2022		2023		Normal Range Z-Score
	Value	Z-Score	Value	Z-Score	Value	Z-Score	Value	Z-Score	Value	Z-Score
FEV1 (% predicted)	56	−3,44	74	−2,18	72	−2,43	62	−3,37	60	−3,49	≥1645
FVC (% predicted)	58	−3,31	73	−2,22	72	−2,44	69	−2,67	71	−2,57	≥1645
FEV1/FVC (%)	87	−0,67	91	0,04	89	0,09	78	−1,51	75	−1,93	≥1645
DLCO (% predicted)									46	−6,4	>1645

He has not yet been able to perform reproducible plethysmography for accurate measurement of lung volumes, but estimated TLC by DLCO technique reveals severe impairment.

He had less hepatic fibrosis (F1) than his sister but greater hypersplenism: platelets 74,000/μL, maximum spleen size of 23 cm (+14.6SD). He was also diagnosed with thrombopathy due to decreased PAC-1 binding, with FXII and FXIII levels at the upper limit of normal. A metabolic profile showed hypercholesterolemia (TC 203 mg/dl) with dyslipidemia (HDLc 22 mg/dl, LDLc 170 mg/dl) and hypertriglyceridemia, which improved with dietary treatment. He show greater impairment in height compared to his sister (−3.1SD) with delayed bone age and decreased bone mineral density (z-score −3.1), and is receiving vitamin D supplementation and multivitamins. Recent cardiac evaluations showed moderate aortic insufficiency and dilation of the ascending aorta, for which treatment with enalapril was started.

Patients with identical genotypes have clearly differentiated phenotypes, as shown in case 6 and 7. Expression, especially regarding respiratory involvement, varies greatly between these cases. Despite having similar radiological involvement, the clinical and functional respiratory expression differs significantly.

3. Discussion

ASMD is a rare disease, primarily because the scarcity of clinical expertise contributes to misdiagnosis, delayed diagnosis, and barriers to adequate patient care. As with all rare diseases the main problem is lack of timely suspicion due to the low prevalence of the disease and the heterogeneity of clinical presentations. Accurate diagnostic suspicion of rare diseases increases the likelihood of diagnosing them and improving the patient's quality of life [4].

Frequent inter-consultations between physicians involved in the care of patients with ASMD is important to correctly manage the multisystem impact of the disease and ensure that all are aware of the routine assessments required. Patients with a confirmed diagnosis of ASMD are typically treated by metabolic disease specialists; however these patients are often seen first by primary care providers and other specialists who observe symptoms compatible with the disease (e.g., pediatricians, cardiologists, pulmonologists, hepatologists, and hematologists). In the chronic forms of ASMD, the liver is prominently affected, so hepatologists or gastroenterologists are often the first specialists to see pediatric patients with both chronic visceral and chronic neurovisceral ASMD. Some adults with chronic visceral ASMD may not receive a diagnosis until they present with respiratory disease in late adulthood, and they will be treated by a pulmonologist [5].

As highlighted in case 2, adult pulmonologists treating patients with ILD play a key role in ASMD because they can recognize the early signs of the disease. Awareness of this comorbidity enables timely diagnosis and intervention, which can significantly improve the patient's quality of life and prognosis [8]. Pulmonary involvement may occur at any time, although it is rarely the first manifestation. It generally appears at a relatively advanced phase of the disease in adulthood, and is preceded by signs and symptoms related to the involvement of other organs before slowly and progressively evolving to severe respiratory failure, pulmonary hypertension, or infectious complications [10]. Pulmonary involvement in ASMD is currently receiving increased attention due to more precise clinical investigations, better identification of diffuse parenchymal lung disease on HRCT, and the implementation of a standardized management protocol.

Therefore, a key feature of the multisystem manifestation of sphingomyelin storage in patients with ASMD is pulmonary involvement. Most patients (>90 %) with chronic visceral ASMD show radiographic evidence of infiltrative lung disease, as we describe in the foregoing adult cases.

Due to clinical features, time of onset, and disease severity, there can be significant variability among subtypes of ASMD, even within families with identical genetic alterations, as shown in cases 6 and 7.

The pathophysiology of pulmonary disease involves the accumulation of lipid-laden macrophages in the alveolar septa, bronchial walls, and pleura, leading to progressive restriction of lung volumes and impaired gas exchange, as reported in the majority of respiratory functional test results (cases 2,3, 5, 6 and 7). Interestingly, lung-only involvement, in the absence of organomegaly, has been reported in adult ASMD patients. Although patients may have no overt respiratory symptoms, chest radiography showed typical reticulonodular infiltration patterns in all the cases we have described. It should be noted that there is often a dissociation between the extent of infiltrative lung disease assessed on imaging and the degree of lung compromise indicated by pulmonary function test parameters, as mentioned in all the cases described [5]. This kind of lung involvement emphasizes the need for each ASMD patient to be evaluated by a pulmonologist from the time of diagnosis. This is particularly important in pediatric patients in whom ILD could eventually develop. Close monitoring and early detection of ILD is crucial, as it significantly contributes to the morbidity and mortality associated with this disease as respiratory failure and liver disease are the two most common causes of death [11].

Considering the possibility of a rare disease enables timely, accurate, and appropriate diagnosis, and allows the correct treatment to be started. The diagnostic suspicion of pulmonologists treating patients with ILD is crucial in ASMD, especially in patients who reach adulthood without a prior diagnosis. Similarly, pediatric patients with a recent diagnosis of ASMD should be evaluated and followed up by a pulmonologist, as the manifestations of pulmonary involvement can vary.

CRediT authorship contribution statement

Jordi Costa i Colomer: Writing – review & editing, Investigation, Formal analysis, Data curation, Conceptualization. Marta García Moyano: Writing – review & editing, Investigation, Formal analysis, Data curation, Conceptualization. Luis Maiz: Writing – review & editing, Investigation, Formal analysis, Data curation, Conceptualization. Santiago Perez-Tarazona: Writing – review & editing, Investigation, Formal analysis, Data curation, Conceptualization. Marta Ruiz de Valbuena: Writing – review & editing, Investigation, Formal analysis, Data curation, Conceptualization. Leticia Ceberio: Writing – review & editing, Investigation, Formal analysis, Data curation, Conceptualization. Patricia Correcher: Writing – review & editing, Investigation, Formal analysis, Data curation, Conceptualization. Natalia Juliá-Palacios: Writing – review & editing, Investigation, Formal analysis, Data curation, Conceptualization. Montse Morales: Writing – review & editing, Investigation, Formal analysis, Data curation, Conceptualization. Gema Pérez-Yagüe: Writing – review & editing, Investigation, Formal analysis, Data curation, Conceptualization. Jesús Villarrubia: Writing – review & editing, Investigation, Formal analysis, Data curation, Conceptualization. Raquel Pérez Rojo: Writing – review & editing, Investigation, Formal analysis, Data curation, Conceptualization.

Funding

Throughout the creation of this document the authors have received logistical support from MS-C., which was hired by Sanofi España. All authors have maintained editorial independence and independence of opinion and none of them have received direct funding from the industry for the development of this manuscript.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors report writing assistance was provided by Sanofi. Jordi Costa i Colomer reports a relationship with Sanofi that includes: consulting or advisory and speaking and lecture fees. Marta García Moyano reports a relationship with AstraZeneca, Boehringer Ingelheim, Chiesi, and Sanofi that includes: consulting or advisory and speaking and lecture fees. Santiago Pérez-Tarazona reports a relationship with Sanofi that includes: consulting or advisory fees. Leticia Ceberio reports a relationship with Sanofi and Takeda that includes: consulting or advisory and speaking and lecture fees. Patricia Correcher reports a relationship with Sanofi that includes: consulting or advisory and speaking and lecture fees. Natalia Juliá-Palacios declares a relationship with PTC therapeutics and Sanofi, Instituto de Salud Carlos III (ISCIII) and Fondo Europeo de Desarrollo Regional (FEDER) that includes: speaking and lecture fees, and funding or grants. Montse Morales declares a relationship with Sanofi, Takeda, Amicus, Nutricia, and Vitaflo that includes: speaking and lecture fees. Jesús Villarrubia declares a relationship with Sanofi and Takeda that includes: consulting or advisory fees, and funding or grants. Raquel Pérez Rojo (corresponding author) declares a relationship with Sanofi, Boehringer Ingelheim, Sandoz, Zambon, and Menarini that includes: board membership and consulting or advisory and speaking and lecture fees. Raquel Pérez Rojo (corresponding author) declares a relationship with Sociedad Española de Neumología y Cirugía Torácica (SEPAR) that includes: unpaid coordination of the Interstitial Lung Disease Group.If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.