Understanding Historical Infant Mortality: Why Enzyme Replacement Has Changed Outcomes

Severe infantile hypophosphatasia (HPP) is a rare genetic disorder characterized by deficient activity of tissue-nonspecific alkaline phosphatase (TNSALP). In its most serious forms—perinatal and infantile—this enzyme deficit disrupts bone mineralization and leads to life-threatening complications. Before the advent of enzyme replacement therapy (ERT), infants with severe HPP faced extremely high mortality. Today, thanks to ERT, outcomes have dramatically improved.

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What Is Severe Infantile Hypophosphatasia?

• Genetic cause: Mutations in ALPL gene → reduced TNSALP activity
• Key consequences
  • Poor bone mineralization → rickets-like deformities
  • Respiratory failure due to chest wall instability
  • Seizures from low blood levels of vitamin B6
• Clinical forms
  • Perinatal (lethal): Signs before or at birth; often fatal without intervention
  • Infantile: Onset within first six months; high risk of severe complications

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Historical Mortality Without ERT

Before 2012, when asfotase alfa (a recombinant human TNSALP) became available, no approved therapy existed to replace the missing enzyme. Outcomes in published cohorts showed:

• Perinatal HPP
  • Nearly 100% mortality within days to weeks of birth
  • Death typically from respiratory failure
• Infantile HPP
  • Reported mortality rates ranged from 50% to 80% within the first year
  • Survivors often faced severe skeletal deformities and long-term respiratory support

Key factors contributing to high mortality:

• Underdeveloped lungs and weak chest wall
• Inability to mineralize bone sufficiently for structural integrity
• Seizures that could be difficult to control

(Sources: Orphanet Journal of Rare Diseases, British Journal of Haematology)

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Enzyme Replacement Therapy: Asfotase Alfa

In 2012, asfotase alfa gained approval for treating HPP. This bioengineered enzyme targets mineralizing tissues to restore alkaline phosphatase activity.

Mechanism of Action

• Targeted delivery: Bone-targeting peptide domain directs the enzyme to bone surfaces
• Restored function: Hydrolyzes substrates (e.g., pyrophosphate) that inhibit mineralization
• Improved mineral deposition: Promotes normal bone and tooth development

Dosing & Administration

• Subcutaneous injections: Often administered 3–6 times per week
• Weight-based dosing: Adjusted as the child grows
• Long-term commitment: Lifelong therapy may be needed

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How ERT Has Transformed Outcomes

Since ERT became available, multiple registries and clinical studies have documented survival and quality-of-life gains:

• Survival improvement
  • Infantile HPP survival at 1 year has risen to over 95% in treated cohorts
  • Perinatal cases once deemed “lethal” now show meaningful survival
• Respiratory benefits
  • Reduced need for mechanical ventilation
  • Improved chest wall stability and lung function
• Skeletal development
  • Normalization of bone mineral density within months
  • Decrease in rickets-like deformities
• Neurodevelopmental gains
  • Fewer seizures due to correction of vitamin B6 deficiency
  • Better overall growth and motor milestones

(Source: Global HPP Registry; New England Journal of Medicine)

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Ongoing Challenges & Monitoring

While ERT has revolutionized care, families and clinicians must remain vigilant:

• Injection-site reactions: Common but usually mild
• Antibody formation: Rarely, patients develop neutralizing antibodies over time
• Bone overgrowth: Very infrequent reports of ectopic calcifications
• Regular assessments
  • Physical exams and growth tracking
  • Radiographs to monitor bone healing
  • Blood tests for alkaline phosphatase activity and substrate levels
• Multidisciplinary care
  • Pediatric endocrinology, pulmonology, orthopedics, dentistry, and genetics
  • Social and psychological support for families

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What This Means for Families

Understanding the shift from historically high mortality to strikingly improved survival can guide decision-making:

• Early diagnosis matters
  • Genetic testing and serum alkaline phosphatase levels
  • Radiographic evidence of poor bone mineralization
• Timely initiation of ERT
  • The earlier treatment begins, the better the outcomes
• Supportive therapies
  • Physical and occupational therapy
  • Nutritional support and vitamin B6 supplementation
• Long-term outlook
  • Many children treated in infancy lead active, fulfilling lives
  • Ongoing research aims to refine dosing and minimize side effects

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Taking the Next Step

If you suspect your child may have hypophosphatasia or another bone-mineralization disorder, consider a free, online symptom check, using the doctor approved Ubie Symptom Checker to help you gather information and prepare for your medical appointment.

Important: This overview is educational. Always speak to a doctor or qualified healthcare professional about symptoms that could be serious or life-threatening. They can guide genetic testing, confirm a diagnosis, and discuss if enzyme replacement therapy is right for your child.