When TSNALP enzymatic activity is low, inorganic pyrophosphate (PPi) accumulates outside of cells in the extracellular matrix of bones and teeth, and inhibits formation of hydroxyapatite mineral, the main hardening component of bone, causing rickets in infants and children and osteomalacia (soft bones) and odontomalacia (soft teeth) in children and adults. PLP is the principal form of vitamin B6 and must be dephosphorylated by TNSALP before it can cross the cell membrane. Vitamin B6 deficiency in the brain impairs synthesis of neurotransmitters, which can cause seizures. In some cases, a build-up of calcium pyrophosphate dihydrate (CPPD) crystals in the joint can cause pseudogout. Genetics
Perinatal and infantile hypophosphatasia are inherited as autosomal recessive traits with homozygosity or compound heterozygosity for two defective TNSALP alleles. The mode of inheritance for childhood, adult, and odonto forms of hypophosphatasia can be either autosomal dominant or recessive. Autosomal transmission accounts for the fact that the disease affects males and females with equal frequency. Genetic counseling is complicated by the disease’s variable inheritance pattern, and by incomplete penetration of the trait.Hypophosphatasia is a rare disease that has been reported worldwide and appears to affect individuals of all ethnicities. The prevalence of severe hypophosphatasia is estimated to be 1:100,000 in a population of largely Anglo-Saxon origin. The frequency of mild hypophosphatasia is more challenging to assess because the symptoms may escape notice or be misdiagnosed.
Evidence against cytotoxic edema includes the high levels of hypoxemia (low bloodstream oxygen) needed to cause it.It is not known why some are more vulnerable to HACE than others. One theory is that variations in brain size play a role, but the increase in brain volume from edema does not likely cause cranial vault impingement. The presence of large sulci indicate the condition may be influenced by the brain tightly fitting. Elevated intracranial pressure is generally accepted to be a late effect of HACE. High central venous pressure may also occur late in the conditions progression.One study demonstrated that normal autorelation of cerebral blood flow does not cause HACE. What role the sympathetic nervous system plays in determining who gets HACE is unclear, but it may have an effect.Another theory about the cause of HACE is that hypoxia may induce nitrous oxide synthase. Vasodilation is caused by the release of nitric oxide and adenosine. This in turn can increase vascular permeability and causes edema. This may combine with low levels of cytokines to cause HACE. Diagnosis
Generally, high-altitude pulmonary edema (HAPE) or AMS precede HACE. In patients with AMS, the onset of HACE is usually indicated by vomiting, headache that does not respond to non-steroidal anti-inflammatory drugs, hallucinations, and stupor. In some situations, however, AMS progresses to HACE without these symptoms. HACE must be distinguished from conditions with similar symptoms, including stroke, intoxication, psychosis, diabetic symptoms, meningitis, or ingestion of toxic substances.