Epidemiologically, Acid Sphingomyelinase Deficiency (ASMD) is estimated to have a prevalence of 1:250,000. The key cause of mortality in ASMD type B patients remains the failure of the respiratory system and liver.¹ With no disease-modifying treatments currently available, it is therefore integral to closely understand pulmonary involvement in ASMD. Research directed towards the treatment and management of ASMD will also be reviewed in this article. 

Pathophysiology

ASMD types A and B are characterised by the lysosomal accumulation of sphingomyelin caused by a genetic sphingomyelinase deficiency. Ubiquitously located in cellular and organellar membranes, sphingomyelin is a type of lipid that plays an integral role in maintaining membrane structure as well as cell signalling pathways. Macrophages ingest and degrade unwanted cells with the use of enzyme-containing lysosomes. Encoded by the sphingomyelin phosphodiesterase 1 gene (SMPD1 gene), the enzyme sphingomyelinase is responsible for the breakdown of sphingomyelin.² Individuals with ASMD type A and B present a mutation in their SMPD1 gene, leading to a deficiency in sphingomyelinase, which inherently hinders the degradation of sphingomyelin, allowing it to accumulate in affected cells. 

When this occurs in the macrophages of lung tissue, ‘foamy cells’ form. These can aggregate and impair the alveoli, interstitium and bronchioles, leading to the impairment of gas exchange and alveolar proteinosis, where proteinaceous material fills the alveoli and further impairs gas exchange. This leads to the development of restrictive lung diseases such as pulmonary fibrosis and reduced lung compliance, involving the infiltration of foamy macrophages, causing scarring in the lung tissue, hence, reduced lung compliance.³ These factors inhibit the regular function of the lungs and promote progressive lung damage and complications. Pulmonary vascular resistance can increase, causing pulmonary hypotension, where the architecture of the lungs alters, often due to fibrosis and a lower lung volume. This heightens the pressure in the pulmonary arteries and complicates interactions between the cardiac and respiratory systems.⁴ This impairment of gas exchange can lead to chronic hypoxemia and respiratory muscle fatigue, inducing the progression of respiratory failure. 

Clinical manifestations

• Cough: A non-productive and ongoing cough can often occur in patients
• Dyspnea: This involves shortness of breath and a feeling of tightness in the chest. Relaxation techniques, breathing exercises or medication such as bronchodilators would be prescribed to relax airways
• Hypoxemia: This refers to impairment of gas exchange, causing low levels of oxygen in the blood. Supplemental oxygen through an oxygen delivery device would be used
• Respiratory Failure: In more severe cases, progressive pulmonary complications can induce respiratory failure, causing low oxygen or high carbon dioxide in the blood. In response to this, mechanical ventilation or long-term oxygen therapy would be required

Diagnostic techniques and procedures

Pulmonary function tests are implemented. Spirometry is a tool used to examine the volume of air inhaled and exhaled by the patient, highlighting whether the lungs are functioning normally. In ASMD patients facing pulmonary complications, a restrictive pattern would be exhibited with an airflow that is relatively preserved.⁵ Moreover, the diffusing capacity of the lung for carbon monoxide (DLCO) is a test that assesses how able the lungs are to transfer gas inspired from the air to the bloodstream. ASMD patients would show low diffusion capacity as a result of impaired gas exchange. Imagery and Histopathological techniques are integral for a more accurate diagnosis. A chest X-ray enables interstitial infiltrates or reticulonodular patterns to be detected, indicating interstitial lung disease. Alternatively, a high-resolution CT (HRCT) proves to be a more sensitive approach, showing ground-glass opacities (dense areas in the lungs), honeycombing (cystic airspaces in the lungs) and septal thickening in the lungs, particularly in advanced stages.⁶ Lung biopsies are invasive but can show the presence of foamy macrophages containing sphingomyelin, alveolar proteinosis and interstitial fibrosis. 

Management

The efficacy of Enzyme Replacement Therapy (ERT) in managing the systemic and pulmonary manifestations of ASMD is continually being researched. By targeting the root cause of ASMD, ERT provides a recombinant form of the sphingomyelinase enzyme, which reduces sphingomyelin accumulation and a reduction in the formation of foamy macrophages that induce lung damage.⁷ Initiating ERT earlier allows for better management of the pulmonary complications, slowing the progression of lung disease, pulmonary hypertension and various other pulmonary-related issues. Another management technique would be a symptomatic treatment involving the use of supplemental oxygen, steroids and bronchodilators to combat clinical manifestations such as dyspnea and hypoxemia (SULTAN W). Lung transplantation is considered as a last resort. 

Prognosis

Depending on the severity of lung disease, whether the patient has ASMD type A or type B, and the effectiveness of treatments, the prognosis varies. Pulmonary issues in type A patients are uncommon due to their rapid progression and severity of neurological decline. Type A is more common in infants and proves to rapidly progress leading to most children not surviving beyond the age of 3, although not the primary cause of death, pulmonary complications contribute in some cases. Pulmonary involvement is highly common in patients with intermediate forms and type B shows to have a more chronic course, predominantly eliciting either a gradual decline in lung function over years or decades or a more rapid progression, which often occurs if lung pulmonary hypertension or lung fibrosis develops.⁸ Pulmonary complications majorly contribute to the progression of morbidity and mortality in ASMD type B patients. Early diagnosis and treatment are key aspects that can improve outcomes.

Summary

• Acid Sphingomyelinase Deficiency (ASMD) is estimated to have a prevalence of 1:250,000.
• Pulmonary issues are more common in ASMD type B patients
• ASMD types A and B are characterised by the accumulation of sphingomyelin 
• Sphingomyelin is a type of lipid located in the plasma membrane
• The enzyme sphingomyelinase is encoded by the sphingomyelin phosphodiesterase 1 gene (SMPD1 gene)
• Individuals with ASMD type A and B, present a mutation in their SMPD1 gene, leading to a deficiency in sphingomyelinase
• Sphingomyelinase is an enzyme responsible for the degradation of sphingomyelin, and a deficiency in this enzyme leads to an accumulation of sphingomyelin
• The respiratory clinical manifestations of ASMD patients are often coughing, dyspnea, hypoxemia and respiratory failure
• Common detection methods are spirometry, DLCO, chest X-rays, HRCT and lung biopsies
• ERT, supplemental oxygen, steroids and bronchodilators are useful in managing the respiratory issues faced by ASMD patients
• Depending on the severity of lung disease, whether the patient has ASMD type A or type B, and the effectiveness of treatments, the prognosis varies