Introduction

Acid sphingomyelinase deficiency (ASMD), also known as Niemann–Pick disease types A and B, is a rare lysosomal storage disorder caused by mutations in the SMPD1 gene. This resulted in reduced or absent activity of acid sphingomyelinase (ASM), which leads to the accumulation of sphingomyelin within lysosomes, particularly in cells of the liver, spleen, lungs, and central nervous system (CNS).¹ 

ASMD spans a clinical spectrum that includes

• The rapidly progressive neurovisceral form (Type A)
• The intermediate form (Type A/B)
• The chronic visceral form (Type B)

Each subtype carries varying degrees of systemic and neurological involvement, with growth and developmental impairments as core features.

Growth impairment across the ASMD spectrum

Growth impairment is a hallmark of ASMD, though it presents differently across the phenotypic spectrum. In infantile neurovisceral ASMD (Type A)

• Type A (infant neurovisceral): Failure to thrive becomes evident within the first few months of life, often due to poor feeding, gastrointestinal dysfunction, chronic illness, and metabolic stress. Affected infants typically display hepatosplenomegaly, hypotonia, and developmental stagnation, which together impair nutritional intake and growth.² These patients rarely live beyond 2–3 years of age, with most succumbing to complications of progressive neurodegeneration and multi-organ failure³
• Type B (chronic visceral):  Growth failure tends to be more gradual. Children may be born at a normal weight but show declining growth velocity over time. A multicenter natural history study showed that mean height and weight-for-age z-scores were significantly below average, with skeletal maturation lagging by 2 to 3 years.⁴ Puberty may be delayed, and final adult height often remains below the population average, particularly in patients with persistent organomegaly or pulmonary dysfunction⁵

Type A/B (Chronic neurovisceral): Growth delays are moderate in early childhood, with the potential for partial catch-up in adolescence. However, growth can be impaired by systemic symptoms such as interstitial lung disease, splenomegaly, and dyslipidemia. Endocrine assessments have revealed reduced levels of insulin-like growth factor 1 (IGF-1), suggesting that chronic inflammation and malnutrition further suppress growth signaling.⁶

Developmental delays and neurological manifestations

Neurological and developmental impairments in ASMD vary considerably by subtype. 

• Type A: Neurologic symptoms usually present by 6 months of age and include hypotonia, decreased motor activity, and loss of developmental milestones. Infants may initially achieve early milestones but rapidly regress due to relentless neurodegeneration. By the end of the first year, motor and cognitive functions decline, and affected children eventually become nonverbal and immobile before succumbing to disease³
• Type A/B (chronic neurovisceral): Developmental outcomes are more variable. Some patients demonstrate normal cognitive development early in life but may later experience learning difficulties, attention deficits, or mild intellectual disability. In a retrospective cohort of 100 children, 40%  had evidence of developmental delay or neurologic involvement, including ataxia, tremors, and peripheral neuropathy.⁷ These manifestations typically progress slowly, underscoring the importance of regular neurodevelopmental monitoring

Type B (chronic visceral) Cognitive function is usually retained. Nevertheless, subtle developmental issues have been reported, including delayed speech or fine motor skills, particularly in those with significant systemic involvement. These findings, while less severe than in neurovisceral forms, may still impact quality of life and academic performance.⁸

Pathophysiological mechanisms of growth and developmental delays

Several interconnected mechanisms contribute to the growth and developmental abnormalities seen in ASMD:

• Organomegaly: Marked enlargement of the liver and spleen can cause mechanical compression of the stomach and intestines, leading to early satiety, reduced food intake, and chronic undernutrition^2,4
• Chronic inflammation: Ongoing systemic inflammation, as reflected by elevated cytokines and altered lipid profiles, may disrupt the hypothalamic-pituitary axis and interfere with the secretion of growth hormone and IGF-1⁶
• Pulmonary dysfunction: Interstitial lung disease, common in ASMD, compromises oxygen exchange, reduces physical activity, and further limits energy availability and growth⁹
• Neurodegeneration: In types A and A/B, accumulation of sphingomyelin in CNS cells leads to demyelination, gliosis, and apoptosis of neurons. This directly impairs cognitive and motor development, leading to loss of previously acquired skills.^3,7
• Metabolic stress: Increased metabolic demands due to systemic disease, coupled with decreased caloric intake, result in a cachexia-like state, further stunting growth and development⁵

Long-term outcomes and prognosis

In Type A ASMD, the prognosis is poor, with most affected infants dying in early childhood. No current treatments reverse CNS damage, and supportive care remains the primary approach. In chronic forms, survival into adulthood is common, but morbidity is significant. Many patients require long-term support for respiratory complications, hepatic involvement, and growth failure.^4,5

A longitudinal study followed patients with chronic ASMD for more than a decade and found persistent growth deficits despite medical support. Even in those with relatively stable disease, most failed to reach expected adult height or weight percentiles, and some experienced progressive neurologic impairment.⁴ This underscores the importance of early diagnosis, nutritional support, and close monitoring of growth parameters in all ASMD patients.

Enzyme replacement therapy and future outlook

In 2022, olipudase alfa, a recombinant human acid sphingomyelinase, received regulatory approval as the first disease-specific treatment for non-CNS manifestations of ASMD. Clinical trials have demonstrated improvements in organ size, pulmonary function, lipid profiles, and linear growth, particularly in pediatric patients.¹⁰

In one study, children treated with olipudase alfa showed accelerated catch-up growth and normalisation of IGF-1 levels after 12 months of therapy. Skeletal maturation also improved, suggesting a direct benefit of enzyme replacement on endocrine and metabolic pathways.¹⁰ However, because olipudase alfa does not cross the blood-brain barrier, it does not impact neurological symptoms in Type A or A/B patients. Research into CNS-targeted therapies, including gene therapy and substrate reduction therapy, remains ongoing.

Conclusion

Growth failure and developmental delays are central clinical features of ASMD, resulting from a complex interplay of metabolic, neurologic, and systemic factors. While the severity of these impairments varies by subtype, even patients with milder forms often experience chronic undernutrition, delayed skeletal maturation, and learning difficulties. 

The advent of enzyme replacement therapy offers new hope for improving growth outcomes in non-neuronopathic ASMD. However, continued research is needed to address the neurological aspects of the disease. A multidisciplinary care model encompassing paediatricians, neurologists, endocrinologists, dietitians, and therapists is essential for improving quality of life and long-term prognosis.