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Hypophosphatasia

Disease Details

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Description: Hypophosphatasia is a rare hereditary disorder characterized by the abnormal development of bones and teeth due to defective mineralization caused by mutations in the ALPL gene.
Type: Hypophosphatasia is a rare metabolic bone disease. It can be inherited in both an autosomal recessive and an autosomal dominant manner, depending on the specific genetic mutations and the severity of the disease.
Signs And Symptoms: **Signs and Symptoms of Hypophosphatasia:**

1. **Infantile and Childhood Forms:**
- Premature loss of primary (baby) teeth
- Poor bone formation, leading to rickets or soft bones
- Short stature and bowed limbs
- Muscle weakness
- Chronic pain

2. **Adult Forms:**
- Stress fractures, especially in the feet and thighs
- Chronic joint pain and stiffness
- Premature tooth loss

3. **Perinatal (Severe) Form:**
- Respiratory complications due to underdeveloped chest
- Hypercalcemia (high calcium levels in the blood)
- Severe skeletal abnormalities at birth

4. **Odontohypophosphatasia:**
- Premature loss of teeth without significant bone symptoms

**Neurological Symptoms:**
- In severe cases, intracranial pressure can increase due to underdeveloped skull bones.

Hypophosphatasia symptoms can vary in severity, and they generally correspond to the age when the disease first manifests.
Prognosis: Hypophosphatasia (HPP) is a rare genetic disorder affecting bone and teeth development due to defective mineralization caused by mutations in the ALPL gene. The prognosis of hypophosphatasia can vary widely depending on the type and severity of the disease. Severe forms, particularly perinatal and infantile hypophosphatasia, often have a poor prognosis and may be life-threatening, with complications such as respiratory issues and profound skeletal abnormalities. Milder forms that present in childhood or adulthood tend to have a better prognosis, with patients typically experiencing issues like premature loss of teeth, fractures, and sometimes muscle weakness, but generally having a normal lifespan. Early diagnosis and management, including supportive care and potential enzyme replacement therapy, can significantly improve outcomes for individuals with hypophosphatasia.
Onset: Hypophosphatasia can have various onset patterns, classified as perinatal, infantile, childhood, and adult forms, each presenting at different stages of life. The perinatal form is the most severe and can be detected in utero. The infantile form typically manifests within the first six months of life. The childhood form usually appears before age 18, often around the time children start walking. The adult form generally becomes evident in middle age but can also appear earlier. There is also an odonto-hypophosphatasia form, which primarily affects dental health and can occur at any age.
Prevalence: The prevalence of hypophosphatasia is estimated to range from 1 in 100,000 to 1 in 300,000 live births for the severe forms. For milder forms, it may be as common as 1 in 6,370 individuals.
Epidemiology: Hypophosphatasia is a rare inherited metabolic disorder characterized by defective bone mineralization and deficiency in alkaline phosphatase (ALP) activity. Its epidemiology includes:

- Occurrence: Hypophosphatasia is very rare, with an estimated prevalence of 1 in 100,000 live births for severe forms and 1 in 6,370 for milder forms.
- Demographics: It affects individuals of all racial and ethnic backgrounds, though some populations may have higher carrier frequencies.
- Inheritance: The disorder is usually inherited in an autosomal recessive manner, but autosomal dominant forms also exist.

Further information such as detailed statistics or studies on specific populations could provide more nuanced insights.
Intractability: Hypophosphatasia is currently considered intractable, meaning there is no cure for it. However, management focuses on alleviating symptoms and improving quality of life. Recent advancements have introduced enzyme replacement therapy, such as asfotase alfa, which has shown to improve outcomes in some patients, especially those with perinatal and infantile forms of the disease. Despite these advancements, treatment efficacy varies, and long-term management is often required.
Disease Severity: Hypophosphatasia can vary significantly in severity. It ranges from severe forms that present in utero or early infancy and can be life-threatening to milder forms that may only manifest in adulthood with symptoms such as early loss of teeth, bone pain, or fractures. The severity largely depends on the specific genetic mutations involved and their impact on the function of the enzyme alkaline phosphatase.
Healthcare Professionals: Disease Ontology ID - DOID:14213
Pathophysiology: Hypophosphatasia is a rare, inherited metabolic bone disorder characterized by defective mineralization of bones and teeth and deficiency of alkaline phosphatase (ALP) activity. The pathophysiology involves mutations in the ALPL gene, which encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). This enzyme is crucial for the breakdown of certain substrates, including inorganic pyrophosphate (PPi). Elevated levels of PPi inhibit hydroxyapatite crystal formation, leading to impaired bone mineralization, skeletal abnormalities, and dental issues. The severity of the disease can range from fatal perinatal forms to mild adult forms, depending on the specific genetic mutation and its impact on enzyme activity.
Carrier Status: Hypophosphatasia is inherited in an autosomal recessive or autosomal dominant manner. Carrier status typically refers to individuals who have one mutated copy of the gene associated with the recessive form of the disease. These carriers usually do not show symptoms but can pass the mutation to their offspring. In cases of autosomal dominant hypophosphatasia, carriers can exhibit a range of symptoms, which might include mild to severe forms of the disease. Genetic testing is required for accurate determination of carrier status.
Mechanism: Hypophosphatasia is a rare, inherited metabolic disorder characterized by defective bone and teeth mineralization due to deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP).

**Mechanism:**
The disorder is caused by mutations in the ALPL gene, which encodes the TNSALP enzyme. This enzyme is crucial for hydrolyzing phosphate compounds, which play a vital role in bone mineralization. Defective TNSALP activity leads to the accumulation of substrates such as inorganic pyrophosphate (PPi), a natural inhibitor of mineralization, impeding the formation of hydroxyapatite crystals crucial for bone strength and integrity.

**Molecular Mechanisms:**
1. **Gene Mutations:** More than 300 mutations in the ALPL gene have been identified, leading to varying degrees of enzyme deficiency. These mutations can be missense, nonsense, frame-shift, or splicing variations, ultimately reducing or nullifying enzyme function.

2. **Accumulation of Substrates:** Due to the defective TNSALP enzyme, substrates like PPi, pyridoxal-5'-phosphate (PLP), and phosphoethanolamine (PEA) accumulate in tissues. PPi directly inhibits the formation of hydroxyapatite crystals, leading to poor bone calcification.

3. **Vitamin B6 Metabolism:** The accumulation of PLP, the active form of vitamin B6, interferes with neurotransmitter metabolism, contributing to seizures observed in severe cases.

These molecular dysfunctions collectively impair bone development and maintenance, resulting in the clinical manifestations of hypophosphatasia, which range from mild dental anomalies to severe, life-threatening skeletal deformities and weaknesses.
Treatment: As of October 2015, asfotase alfa (Strensiq) has been approved by the FDA for the treatment of hypophosphatasia.
Some evidence exists to support the use of teriparatide in adult-HPP.Current management consists of palliating symptoms, maintaining calcium balance and applying physical, occupational, dental and orthopedic interventions, as necessary.
Hypercalcemia in infants may require restriction of dietary calcium or administration of calciuretics. This should be done carefully so as not to increase the skeletal demineralization that results from the disease itself. Vitamin D sterols and mineral supplements, traditionally used for rickets or osteomalacia, should not be used unless there is a deficiency, as blood levels of calcium ions (Ca2+), inorganic phosphate (Pi) and vitamin D metabolites usually are not reduced.
Craniosynostosis, the premature closure of skull sutures, may cause intracranial hypertension and may require neurosurgical intervention to avoid brain damage in infants.
Bony deformities and fractures are complicated by the lack of mineralization and impaired skeletal growth in these patients. Fractures and corrective osteotomies (bone cutting) can heal, but healing may be delayed and require prolonged casting or stabilization with orthopedic hardware. A load-sharing intramedullary nail or rod is the best surgical treatment for complete fractures, symptomatic pseudofractures, and progressive asymptomatic pseudofractures in adult hypophosphatasia patients.
Dental problems: Children particularly benefit from skilled dental care, as early tooth loss can cause malnutrition and inhibit speech development. Dentures may ultimately be needed. Dentists should carefully monitor patients' dental hygiene and use prophylactic programs to avoid deteriorating health and periodontal disease.
Physical Impairments and pain: Rickets and bone weakness associated with hypophosphatasia can restrict or eliminate ambulation, impair functional endurance, and diminish ability to perform activities of daily living. Nonsteroidal anti-inflammatory drugs may improve pain-associated physical impairment and can help improve walking distance]
Bisphosphonate (a pyrophosphate synthetic analog) in one infant had no discernible effect on the skeleton, and the infant's disease progressed until death at 14 months of age.
Bone marrow cell transplantation in two severely affected infants produced radiographic and clinical improvement, although the mechanism of efficacy is not fully understood and significant morbidity persisted.
Enzyme replacement therapy with normal, or ALP-rich serum from patients with Paget's bone disease, was not beneficial.
Phase 2 clinical trials of bone targeted enzyme-replacement therapy for the treatment of hypophosphatasia in infants and juveniles have been completed, and a phase 2 study in adults is ongoing.
Pyridoxine, or Vitamin B6 may be used as adjunctive therapy in some cases, which may be referred to as Pyridoxine responsive seizures.
Compassionate Use Treatment: For hypophosphatasia, compassionate use and experimental treatments have focused primarily on enzyme replacement therapy with asfotase alfa (Strensiq). This treatment aims to address the underlying enzyme deficiency in hypophosphatasia. Though asfotase alfa is now approved in many regions for specific forms of the disease, it can be accessed through compassionate use or expanded access programs for patients who do not meet standard eligibility requirements.

Other experimental approaches include:

1. **Gene Therapy:** This approach targets the root cause by attempting to correct the genetic defect responsible for the enzyme deficiency.

2. **Small Molecule Chaperones:** These are being explored to stabilize the defective enzyme, enhancing its functionality.

3. **Bone-targeting Enzyme Replacement:** Improving delivery methods to direct the enzyme precisely to affected bone tissue.

Off-label treatments are less common, given the specificity of the enzyme deficiency in hypophosphatasia, but may include supportive measures such as phosphate supplements and nonsteroidal anti-inflammatory drugs (NSAIDs) for symptom management.

Always consult with a healthcare provider for the most current and personalized medical advice.
Lifestyle Recommendations: For individuals with hypophosphatasia, lifestyle recommendations include:

1. **Regular Monitoring**: Frequent check-ins with healthcare providers to monitor bone health and overall progression.
2. **Physical Activity**: Low-impact exercises to strengthen muscles and improve mobility while minimizing stress on bones.
3. **Balanced Diet**: Consumption of foods rich in calcium and vitamin D to support bone health.
4. **Avoiding Risk Factors**: Steering clear of activities that increase the risk of fractures or bone injuries.
5. **Bone Health**: Using protective gear in situations where injuries are possible and maintaining a safe, fall-proof environment.
6. **Pain Management**: Work with healthcare providers to address chronic pain, possibly through medication, physical therapy, or alternative pain relief methods.

Implementing these lifestyle adjustments can help manage symptoms and improve quality of life for those with hypophosphatasia.
Medication: Hypophosphatasia can be treated with enzyme replacement therapy, namely asfotase alfa (Strensiq). This medication is designed to replace deficient alkaline phosphatase, thereby addressing the underlying enzymatic defect and improving symptoms and outcomes in affected individuals.
Repurposable Drugs: For hypophosphatasia (HPP), there are no widely recognized repurposable drugs currently approved specifically for the treatment of this condition. Hypophosphatasia is a rare, inherited metabolic disorder characterized by defective bone mineralization due to mutations in the ALPL gene, which encodes the enzyme tissue nonspecific alkaline phosphatase (TNSALP).

However, enzyme replacement therapy with asfotase alfa (Strensiq) is the primary approved treatment specifically targeting the root cause of hypophosphatasia. While research is ongoing, no other repurposable drugs have shown significant efficacy in treating HPP to date.
Metabolites: Hypophosphatasia is characterized by a deficiency of the enzyme alkaline phosphatase (ALP). Key metabolites involved in the disease include:

1. **Inorganic Pyrophosphate (PPi)**: Elevated levels due to deficient ALP, leading to impaired bone mineralization.
2. **Pyridoxal 5'-phosphate (PLP)**: Increased levels in plasma since ALP is involved in its dephosphorylation.
3. **Phosphoethanolamine (PEA)**: Elevated in urine and blood due to disrupted metabolism.

These metabolite abnormalities reflect the biochemical basis of hypophosphatasia and its impact on bone and other tissues.
Nutraceuticals: For hypophosphatasia, there is no established nutraceutical treatment. Hypophosphatasia is a rare genetic disorder affecting bone and tooth development due to defective bone mineralization. It is caused by mutations in the ALPL gene leading to deficient activity of the enzyme alkaline phosphatase. Management generally involves addressing symptoms and may include medications such as enzyme replacement therapy with asfotase alfa. If considering any supplements, it's essential to consult a healthcare professional for personalized advice.
Peptides: Hypophosphatasia is characterized by defective mineralization of bones and teeth due to mutations in the ALPL gene, causing decreased activity of the enzyme alkaline phosphatase. Peptides related to hypophosphatasia often involve substrates or inhibitors of alkaline phosphatase or analogs aiming to enhance its function. As for "nan," this term is unclear in the context of hypophosphatasia. If you meant "nanotechnology," it refers to using nanoscale materials to potentially deliver therapies or enhance enzyme function, which is an emerging area of research.