How to manage areflexia (absence of reflexes) in patients with Hypophosphatasia (HPP)?

Management of Areflexia in Hypophosphatasia (HPP)

Areflexia in HPP is a manifestation of the underlying neuropathy and muscle weakness caused by deficient tissue-nonspecific alkaline phosphatase (TNSALP), and should be managed primarily with enzyme replacement therapy (asfotase alfa) in symptomatic patients, particularly in pediatric-onset disease, as this addresses the root pathophysiology rather than just the symptom. 1, 2

Understanding Areflexia in HPP Context

Areflexia (absence of reflexes) occurs in HPP as part of the broader neuromuscular manifestations of the disease, which include:

• Muscle weakness and hypotonia that can present across all age groups 1, 3
• Myalgias and chronic pain affecting quality of life 1, 4
• Neurologic complications particularly in infantile and childhood forms, including seizures from pyridoxine-responsive epilepsy 3, 4
• Respiratory compromise in severe cases due to chest wall deformity and muscle weakness 3, 2

The areflexia stems from the accumulation of TNSALP substrates (particularly inorganic pyrophosphate and phosphorylated osteopontin) that impair not only bone mineralization but also affect neuromuscular function 4, 5.

Primary Treatment Approach

Enzyme Replacement Therapy (Asfotase Alfa)

For pediatric-onset HPP with significant symptoms including neuromuscular manifestations, asfotase alfa is the definitive treatment that addresses the underlying enzyme deficiency 2:

• Dosing: Subcutaneous administration as bone-targeted recombinant TNSALP replacement 2
• Efficacy on neuromuscular function: Clinical trials demonstrated improvements in muscle strength (with normalization documented), gross motor function, fine motor function, and ability to perform activities of daily living 2
• Timeline: Improvements typically begin within 24 weeks, with sustained benefits beyond 3 years of treatment 2
• Survival benefit: In life-threatening perinatal and infantile HPP, asfotase alfa improved overall survival, which is critical given mortality rates of 50-100% in untreated severe forms 3, 2

Supportive Management

While enzyme replacement is primary, supportive measures remain important 1, 4:

• Physical therapy: To maintain muscle strength and function, prevent contractures, and optimize motor development 1
• Monitoring for complications: Regular neurologic assessment for progression of weakness or development of new deficits 1
• Pain management: Address myalgias and chronic pain that often accompany the muscle weakness 1, 4
• Respiratory support: May be necessary in severe cases with chest wall involvement and respiratory muscle weakness 3, 2

Critical Contraindications to Avoid

Never use bisphosphonates, denosumab, or other potent antiresorptive agents in HPP patients - these are absolutely contraindicated as they further impair bone mineralization by increasing pyrophosphate levels, potentially worsening the underlying pathophysiology 4.

Vitamin D supplementation should be used cautiously and is generally not indicated unless there is documented deficiency, as HPP patients may already have elevated serum calcium and phosphate due to impaired skeletal mineralization 3, 4.

Diagnostic Confirmation Before Treatment

Before initiating therapy for areflexia presumed due to HPP, confirm the diagnosis 5:

• Biochemical hallmark: Persistently low serum alkaline phosphatase (ALP) for age 1, 5
• Elevated substrates: Increased pyridoxal 5'-phosphate and phosphoethanolamine 5
• Genetic confirmation: ALPL gene sequencing for definitive diagnosis 4, 5
• Radiological findings: Evidence of impaired bone mineralization, rickets, or osteomalacia 1, 5

Multidisciplinary Team Approach

Management requires coordination among multiple specialists 5:

• Metabolic bone disease specialist or endocrinologist for overall disease management
• Neurologist for assessment and monitoring of neuromuscular complications
• Physical medicine and rehabilitation for functional optimization
• Respiratory specialist if pulmonary complications present
• Geneticist for family counseling and inheritance patterns

Prognosis and Monitoring

The natural history of untreated HPP includes significant morbidity with disability and poor quality of life in surviving patients 3. Regular monitoring of neuromuscular function is essential to assess treatment response and adjust supportive care 1. Areflexia may improve with successful enzyme replacement therapy as muscle strength normalizes, though the timeline varies by disease severity and age at treatment initiation 2.