What Is Acid Sphingomyelinase Deficiency (ASMD)? Symptoms, Causes, Diagnosis, Treatment, and Prevention

Acid sphingomyelinase deficiency (ASMD) sounds like something out of a sci-fi script, but it’s a very real, very rare genetic condition.
Also known as Niemann–Pick disease types A, B, and A/B, ASMD affects how the body handles certain fats (lipids), leading to a buildup that can damage organs like the liver, spleen, lungs, and sometimes the brain.
Because it’s so uncommon, many people (including some clinicians) may go most of their career without seeing a case in person.

In this guide, we’ll unpack what ASMD is, what symptoms to watch for, how it’s diagnosed, the latest on treatments (including the first disease-specific therapy), and what prevention really means in the context of a genetic disorder.
We’ll also walk through lived-experience style examples to help you understand what daily life with ASMD can look like for real families.

What Is Acid Sphingomyelinase Deficiency (ASMD)?

ASMD is a rare lysosomal storage disorder. “Lysosomal” means the issue comes from tiny recycling centers inside cells called lysosomes.
In healthy cells, an enzyme called acid sphingomyelinase (ASM) breaks down a fatty substance called sphingomyelin. In ASMD, mutations in the SMPD1 gene mean the ASM enzyme is missing or doesn’t work properly.
As a result, sphingomyelin accumulates in cells, particularly in the liver, spleen, bone marrow, lungs, and sometimes the brain, leading to progressive organ damage.

Historically, ASMD was grouped under Niemann–Pick disease types A and B. Today, clinicians often use “ASMD” as the umbrella name and then describe the specific type or severity.
The disease spectrum ranges from rapidly fatal infantile disease to milder forms compatible with adulthood.

ASMD is considered ultra-rare, with combined birth prevalence for the main types estimated roughly between 1 in 167,000 and 1 in 250,000 births.
That means most people will never meet someone with ASMDanother reason awareness and accurate information are so important.

Types of ASMD

ASMD isn’t a one-size-fits-all condition. Clinicians recognize three major forms that exist on a continuum of severity:​

Infantile Neurovisceral ASMD (Type A)

Sometimes called Niemann–Pick disease type A, this is the most severe form. Symptoms typically appear in early infancy and include:

• Rapidly enlarging liver and spleen (hepatosplenomegaly)
• Feeding difficulties and failure to thrive
• Developmental delay and loss of milestones
• Pronounced neurologic decline

Sadly, infantile type A usually leads to death in early childhood, often by age 3, due to severe neurodegeneration and multi-organ failure.

Chronic Visceral ASMD (Type B)

Niemann–Pick disease type B, or chronic visceral ASMD, is generally milder and does not involve the same degree of progressive neurologic damage seen in type A.
People with type B may live into adulthood but often face significant health issues such as:​

• Persistent enlargement of the liver and spleen
• Low platelet counts and easy bruising
• High “bad” cholesterol and triglycerides, increasing cardiovascular risk
• Chronic lung disease and shortness of breath
• Growth delay in children

Chronic Neurovisceral ASMD (Type A/B)

Type A/B falls between types A and B. It features both visceral (organ) involvement and some neurologic problems, but typically with slower progression than pure type A.
Symptoms can vary widely even within the same family, making prognosis and counseling more complex.

What Causes ASMD?

ASMD is caused by pathogenic variants (mutations) in the SMPD1 gene, which provides instructions for making the acid sphingomyelinase enzyme.
These variants can severely reduce or completely eliminate enzyme activity. The less enzyme activity a person has, the more severe the disease tends to be.

The condition is inherited in an autosomal recessive pattern. That means:

• Each parent is typically a healthy carrier with one normal and one mutated copy of SMPD1.
• For every pregnancy between two carriers, there is:
  • a 25% chance the child will have ASMD (two non-working copies),
  • a 50% chance the child will be a carrier like the parents, and
  • a 25% chance the child will inherit two working copies and be unaffected and not a carrier.

More than 100–200 different pathogenic SMPD1 variants have been identified, and some are associated with more severe infantile disease, while others track with milder chronic forms.

Symptoms of ASMD

Signs and symptoms of ASMD depend on the type, age at onset, and which organs are most affected. However, certain patterns are common across the spectrum.

Common Early Signs in Infants and Young Children

In more severe forms, symptoms can start in the first months of life and may include:​

• Protruding abdomen from enlarged liver and spleen
• Poor weight gain or failure to thrive
• Frequent respiratory infections or trouble breathing
• Feeding difficulties
• Delayed motor milestones or regression
• Low muscle tone (hypotonia)

Symptoms in Older Children, Teens, and Adults

In chronic visceral or A/B forms, individuals may present later with:​

• Enlarged spleen and liver discovered on exam or imaging
• Easy bruising, frequent nosebleeds, or heavy menstrual periods due to low platelets
• Shortness of breath, chronic dry cough, or reduced exercise tolerance
• Abdominal pain, diarrhea, or early satiety (feeling full quickly)
• Abnormal cholesterol and triglyceride levels
• Bone pain, skeletal abnormalities, or delayed growth in children

In types that involve the nervous system, there may also be challenges such as coordination problems, learning difficulties, or progressive neurologic decline.

Why ASMD Is Often Missed

Many of these symptomsbig spleen, abnormal lipids, shortness of breathare not unique to ASMD. They overlap with more common conditions like fatty liver disease, asthma, or other blood disorders.
Because ASMD is so rare, it can take years before someone connects the dots. In some studies, patients reported long diagnostic journeys, seeing multiple specialists before getting a genetic answer.

How Is ASMD Diagnosed?

Diagnosing ASMD involves a combination of clinical suspicion, lab testing, and genetic confirmation. Current consensus guidelines recommend several key steps:​

1. Clinical Evaluation

A specialist (often a metabolic geneticist, hematologist, or hepatologist) reviews:

• Physical findings such as enlarged liver/spleen and growth patterns
• Respiratory issues and imaging showing interstitial lung disease
• Blood counts and lipid profile
• Family history of early childhood deaths or similar symptoms

2. Enzyme Activity Testing

The next step is measuring acid sphingomyelinase activity in blood (often in dried blood spots, leukocytes, or cultured fibroblasts).
Markedly reduced ASM activity strongly supports ASMD.

3. Genetic Testing

Genetic testing of the SMPD1 gene confirms the diagnosis by identifying two disease-causing variants.
This step is also essential for family counseling, carrier testing, and prenatal or preimplantation testing if desired.

4. Organ Function and Disease Burden Assessment

Once ASMD is diagnosed, clinicians usually assess how far the disease has progressed using:

• Ultrasound, CT, or MRI of liver and spleen
• Pulmonary function tests and high-resolution CT scans of the lungs
• Cardiac evaluation and lipid profiling
• Growth charts and bone assessments in children

These baseline measurements are critical for monitoring progression and response to therapy over time.

Treatment Options for ASMD

For a long time, ASMD management focused solely on supportive caretreating symptoms and complications without addressing the underlying enzyme deficiency.
That landscape changed with the approval of the first disease-specific therapy, olipudase alfa (Xenpozyme).

Supportive and Symptom-Directed Care

Even in the era of enzyme replacement therapy, supportive care remains essential and can include:​

• Monitoring and managing low platelets and bleeding risk
• Treating interstitial lung disease and preventing infections (vaccines, prompt antibiotics when needed)
• Managing dyslipidemia and cardiovascular risk factors
• Nutritional support to optimize growth and energy intake
• Physical and occupational therapy, especially for children
• Psychological support for patients and caregivers

Enzyme Replacement Therapy: Olipudase Alfa (Xenpozyme)

In August 2022, the U.S. Food and Drug Administration (FDA) approved olipudase alfa-rpcp (Xenpozyme), a recombinant form of acid sphingomyelinase, for the treatment of non–central nervous system manifestations of ASMD in adult and pediatric patients.
It is currently the only approved disease-specific treatment for ASMD.

Olipudase alfa works by replacing the missing or deficient enzyme, allowing cells to break down sphingomyelin and reducing its buildup in organs such as the liver, spleen, and lungs. Clinical studies have shown:​

• Significant reductions in spleen and liver volumes
• Improved lung function (for example, better diffusing capacity)
• Improvements in some quality-of-life measures

Importantly, olipudase alfa is not expected to cross the blood–brain barrier in meaningful amounts, so it does not treat severe neurologic involvement seen in classic infantile type A disease.
Because of this, the greatest benefit is expected in patients with chronic visceral or A/B forms without advanced neurologic decline.

Like any biologic therapy, olipudase alfa is given by intravenous infusion on a regular schedule (often every two weeks), and patients need careful monitoring for infusion-related reactions, liver function changes, and other potential side effects.

Can ASMD Be Prevented?

You can’t “prevent” ASMD in the sense of changing someone’s genes after conception. However, several strategies can help families understand and potentially reduce the risk of having a child affected by ASMD:​

• Carrier testing: If there is a known family history of ASMD, relatives can be tested to see whether they carry SMPD1 mutations. This helps with reproductive planning.
• Prenatal diagnosis: For couples who are carriers, testing during pregnancy (via chorionic villus sampling or amniocentesis) can determine whether the fetus has ASMD.
• Preimplantation genetic testing: For some families using in vitro fertilization (IVF), embryos can be tested for ASMD-causing variants before implantation.
• Early detection: While routine universal newborn screening for ASMD is not yet widespread, some pilot studies and high-risk screening programs are exploring its feasibility, particularly in populations with higher incidence.

Genetic counseling is strongly recommended for families with ASMD. A genetic counselor can explain inheritance patterns, testing options, and the emotional and ethical aspects of reproductive choices.

Living With ASMD: Practical Tips for Patients and Families

Living with a rare disease can feel like having a browser open with 50 tabsmedical visits, test results, insurance paperwork, emotional stressrunning in the background at all times. A few strategies can make the journey more manageable:

• Build a multidisciplinary team: This may include a metabolic specialist, pulmonologist, hepatologist, cardiologist, nutritionist, and mental health professional.
• Track your data: Keep a simple log of symptoms, energy levels, infections, infusions, and lab results. It will help you and your doctors see trends over time.
• Stay on top of vaccines: Respiratory infections can hit harder when lungs and spleen are affected, so immunizations and prompt treatment of infections matter.
• Protect the spleen: If the spleen is enlarged, avoid contact sports or activities that might cause abdominal trauma, and follow emergency instructions if there’s sudden severe abdominal pain.
• Connect with others: Patient support organizations for Niemann–Pick disease and ASMD can provide community, advocacy, and practical tips that you won’t find in textbooks.

Experience-Style Examples: What ASMD Can Look Like in Real Life

Every person with ASMD is unique, but certain patterns emerge when you read case reports, talk to families, and look at long-term follow-up studies. The scenarios below are composite examples inspired by published descriptions and clinical experience, not real named patients.

1. The Toddler With the “Big Belly”

Imagine a 14-month-old whose parents notice that her tummy seems unusually large. She’s small for her age, bruises easily, and gets tired faster than other toddlers at daycare. A pediatrician orders an ultrasound and finds that her liver and spleen are both enlarged.
Initial work-ups look for common causesviral hepatitis, blood disorders, fatty liver diseasebut everything comes back inconclusive.

Eventually, a hematologist notices the combination of big spleen, low platelets, and abnormal lipids and wonders about a lysosomal storage disorder. Enzyme testing reveals low acid sphingomyelinase, and genetic testing confirms ASMD.
Her parents go from vague worry to a named diagnosisterrifying, but also strangely relievingbecause now they know what they’re facing and what monitoring and treatment options exist.

2. The Teen Who Always Comes in Last at Sports

A 16-year-old boy has always been “the slow one” in PE. He’s not unfit, but he’s breathless climbing stairs and has a nagging dry cough. He also has a slightly enlarged spleen discovered after a minor sports injury.
His lipid panel shows high LDL cholesterol and triglycerides despite a fairly normal diet, and he has low platelets on repeated blood tests.

For years, his symptoms are brushed off as “just how he is,” but as his fatigue and shortness of breath worsen, a pulmonologist orders advanced lung imaging and suspects interstitial lung disease.
Combined with the spleen findings and abnormal lipids, this prompts testing for ASMD. When he’s finally diagnosed with chronic visceral ASMD, he’s a candidate for olipudase alfa therapy, whichover timemay reduce his spleen size, improve his lung function, and help him keep up better with daily activities.

3. The Adult Who Never Knew

A 40-year-old woman goes in for a routine checkup and gets the classic “your cholesterol is high, let’s talk” conversation. On exam, her doctor notices the tip of her spleen on abdominal palpation, which is unusual.
A follow-up ultrasound confirms that both her liver and spleen are enlarged. She remembers being told she had “big organs” during a pregnancy ultrasound years ago, but no one ever pursued it.

A savvy internist, remembering a rare-disease lecture, orders specific enzyme testing for acid sphingomyelinase. When ASMD is confirmed, the patient suddenly has an explanation for her lifelong easy bruising and slightly reduced stamina.
She’s referred to a metabolic specialist, starts seeing a cardiologist for proactive heart risk management, and discusses whether enzyme replacement therapy makes sense for her stage of disease.

4. The Family Perspective

From the family’s point of view, ASMD isn’t just a list of lab values and organ volumesit’s missed days of school, planning around infusion days, worry about the next cold or flu, and lots of “What if?” conversations about the future.
Parents learn to juggle specialist appointments with everyday life, siblings learn to be extra gentle in play to protect a brother’s enlarged spleen, and grandparents become experts in rare-disease acronyms.

Families often describe an emotional roller coaster: grief at the diagnosis, hope when new treatments like olipudase alfa become available, frustration with insurance or access issues, and pride when their child hits milestones others doubted they’d reach.
Mental health carecounseling, support groups, or just a trusted therapistcan be just as critical as pulmonary function tests and MRIs.

5. Building a Future With ASMD

With earlier recognition, better supportive care, and access to disease-specific treatment for eligible patients, many people with chronic forms of ASMD can realistically plan for college, careers, relationships, and family life.
The journey may come with extra medical fine print, but it is increasingly a story of adaptation rather than resignation.

For families considering future pregnancies, reproductive optionscarrier testing, prenatal diagnosis, and preimplantation genetic testingbring their own blend of comfort and complexity.
Genetic counselors help navigate those choices so parents can make decisions that align with their values, culture, and goals.

Key Takeaways

Acid sphingomyelinase deficiency is a complex, ultra-rare genetic disease that affects multiple organs and can range from rapidly fatal infantile disease to chronic forms compatible with adulthood.
It’s caused by mutations in the SMPD1 gene, inherited in an autosomal recessive pattern, and diagnosed through enzyme and genetic testing.

The approval of olipudase alfa has transformed care for many patients with non-CNS ASMD, offering the first therapy that targets the underlying enzyme deficiency. But supportive care, vigilant monitoring, and strong psychosocial support remain the backbone of living well with ASMD.

If ASMD is suspected, early referral to a metabolic or genetic specialist, timely testing, and connection with patient organizations can make a real differencenot just in lab numbers, but in everyday quality of life.

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