Hypophosphatasia

Hypophosphatasia is a rare inherited disorder characterized by defective bone and tooth mineralization, and deficiency of serum and bone alkaline phosphatase activity. The frequency of the disease has been estimated to be one in 100 000 for severe forms, but mild forms of hypophosphatasia may be more common. The symptoms are highly variable in their clinical expression, which ranges from stillbirth without mineralized bone to early tooth loss without bone symptoms. The transmission of severe forms is autosomal recessive, while milder forms may be transmitted as dominant or recessive autosomal traits. The diagnosis is based on serum alkaline phosphatase assay and molecular analysis of the liver/bone/kidney alkaline phosphatase gene (ALPL). Currently, there is no treatment for the disease. Over the past 10 years, great progress has been made in understanding the structure of tissue non-specific alkaline phosphatase, its function in bone mineralization, and the effect of ALPL mutations responsible for hypophosphatasia.     

Hypophosphatasia

We review here clinical, pathophysiological, diagnostic, genetic and molecular aspects of Hypophosphatasia (HPP), a rare inherited metabolic disorder. The clinical presentation is a continuum ranging from a prenatal lethal form with no skeletal mineralization to a mild form with late adult onset presenting with nonpathognomonic symptoms. The prevalence of severe forms is low, whereas less severe forms are more frequently observed. The disease is caused by loss-of-function mutations in the ALPL gene encoding the Tissue Nonspecific Alkaline Phosphatase (TNSALP), a central regulator of mineralization. Severe forms are recessively inherited, whereas moderate forms are either recessively or dominantly inherited, and the more severe the disease is, the more often it is subject to recessive inheritance. The diagnosis is based on a constantly low alkaline phosphatase (AP) activity in serum and genetic testing that identifies ALPL mutations. More than 340 mutations have been identified and are responsible for the extraordinary clinical heterogeneity. A clear but imperfect genotype-phenotype correlation has been observed, suggesting that other genetic or environmental factors modulate the phenotype. Enzyme replacement therapy is now available for HPP, and other approaches, such as gene therapy, are currently being investigated.     

Hypophosphatasia in the adult

Two sisters are presented, now aged forty-one and forty-two, whom we think represent adult survivors of hypophosphatasia, a disease hitherto only described in children. Both sisters had had “rickets” in childhood, from which they had made a spontaneous recovery. The elder is now crippled because of fractures and painful bones, the other remains symptom free. They both constantly manifest a low alkaline phosphatase level in the plasma and a large excretion of phosphoethanolamine in the urine, as in the childhood disease. Studies of the relatives who all have normal bones, show that minor degrees of both these biochemical features frequently occur among them. Metabolic studies of the elder sib have shown results consistent with a mild degree of an overdose of vitamin D. However, this condition was largely uninfluenced by the administration of small doses of vitamin D, cortisone, and a diet low in vitamin D.     

Hypophosphatasia: The Disease in Adults

Hypophosphatasia is an inherited skeletal disorder due to mutations within the ALPL gene that encodes the “tissue-nonspecific isoenzyme of alkaline phosphatase”. This disease is characterized by a low serum alkaline phosphatase. If the severe paediatric forms are quite rare (<1/100,000 births), the prevalence of moderate form is theoretically estimated at 1/6,370, suggesting some unrecognized cases. This condition is inherited in an autosomal recessive manner for a majority of cases, but some moderate adult phenotypes and odonto-hypophosphatasia are autosomal dominant. In adult, the presentation is highly variable, being either manifestations of HPP diagnosed in paediatric age or adult-onset HPP. Adult HPP typically manifests during middle age, as variable osteoarticular pain and recurrent slowly healing fractures of metatarsal bone and proximal femur. The presence of chondrocalcinosis and ectopic calcifications around joints and tendon attachments to bone are also reported. Biochemically, this disease is characterized by an excessive urinary excretion of phosphoethanolamine and elevated serum pyridoxical 5’-phosphate. Elevated serum calcium and phosphorus may be found. The molecular diagnosis is today easily performed, by ALPL gene analysis. Adult patients have to be referred in consultation with a genetics professional, to discuss the related genetic counselling issues with the potential risks to offspring, and depending on the individual case, the possibility of prenatal diagnosis. There is no curative treatment, but symptomatic treatments such as non-steroidal anti-inflammatory agents and teriparatide may improve the symptoms. Enzyme replacement therapy is currently evaluated in phase II clinical trials in children and infants and will, hopefully, be soon discussed in some adults presenting with a significant and progressive disease.     

Hypophosphatasia: From Diagnosis to Treatment

Purpose of Review

Hypophosphatasia (HPP) is a rare genetic disorder caused by mutations of the ALPL gene. ALPL encodes the tissue-non-specific isoenzyme of alkaline phosphatase (TNSALP). Consequently, bone mineralization is decreased leading to fractures, arthralgia, and extra-skeletal manifestations including tissue calcification, respiratory failure, and neurological complications. This review summarizes the most important clinical findings, diagnosis, and treatment options for HPP.

Recent Findings

Asfotase alfa is a recombinant human alkaline phosphatase, used as treatment for the underlying cause of HPP. Asfotase alfa enhances the survival in life-threatening HPP and improves bone mineralization, muscle strength, and pulmonary function. However, discontinuation of asfotase alfa leads to reappearance of bone hypomineralization.

Summary

Due to its varied manifestations, HPP often mimics rheumatological and other bone diseases, thereby delaying its diagnosis. Asfotase alfa, a recombinant alkaline phosphatase, is available for the long-term enzyme replacement therapy in patients with pediatric-onset HPP to treat the bone manifestations of the disease.

     

Clinical Aspects of Hypophosphatasia: An Update

Hypophosphatasia (HPP) is a heterogeneous rare inborn error of bone and mineral metabolism caused by mutations in the ALPL gene encoding the isoenzyme, tissue-nonspecific alkaline phosphatase (TNAP). These mutations result in a decreased level of TNAP activity and increased levels of its substrates, including inorganic pyrophosphate, pyridoxal-5′-phosphate and phosphoethanolamine. Clinical presentations are highly variable, ranging from stillbirth and absence of mineralization in severe disease to mild dental problems or osteopenia in adulthood. Further clinical symptoms include defective bone mineralization with bone deformities, recurrent fractures, chronic non-bacterial osteomyelitis, craniosynostosis, neonatal seizures, nephrocalcinosis, muscular hypotonia, failure to thrive and dental abnormalities with premature exfoliation of teeth and caries. Prognosis is very poor in severe perinatal forms with most patients dying from pulmonary complications of their skeletal disease but patients with mild phenotypes (adult form or Odonto-HPP) usually do not have a limitation in their life expectancy. Although TNAP is a ubiquitous enzyme, mostly known for its crucial role during mineralization of bone and teeth, its exact biological role in different human organs is still unclear, and the pathophysiology of symptoms due to TNAP deficiency in HPP are not understood in detail. Since inflammation and tissue destruction of the musculoskeletal system may occur in HPP, TNAP may also play an important role in controlling inflammatory processes. Recent investigations provide evidence that TNAP is also essentially involved in the development of the central nervous system and might contribute to multiple functions of the human brain. HPP can be diagnosed on clinical, biochemical and radiological criteria, and genetic testing confirms the diagnosis and is useful for genetic counseling. Since clinical symptoms are highly variable, patients should be followed up by a multidisciplinary team having experience in HPP treatment. Up to now, no curative treatment of HPP is available. Therefore, symptomatic treatment in particular with regard to pain, seizures and other metabolic phenomena is most important. However, recently, enzyme replacement therapy with a bone-targeted recombinant human TNAP molecule has been reported to improve bone mineralization, respiratory function and physical activity in severely affected infants with HPP, and further clinical trials are ongoing. Hopefully, this and other new therapeutic strategies may improve the prognosis and quality of life of patients with HPP and may contribute to our understanding of bone metabolism in general.     

Hypophosphatasia in Taiwan: report of two cases

Hypophosphatasia is a rare inherited metabolic disease characterized by rickets with reduced plasma and tissue alkaline phosphatase activity. It may be present in infancy, childhood, or adulthood. Various clinical manifestations reflect different forms of alkaline phosphatase gene expression. In this report, we present two cases of hypophosphatasia, one of the infantile and the other of the adult form. The infantile case presented with failure to thrive, hypotonia, and radiologic rickets at 4 months old. The adult case had repeated fractures and marked loss of bone density demonstrated by radiographs. Both cases showed extremely low levels of alkaline phosphatase. To the best of our knowledge, they are the first reported patients with hypophosphatasia from the Taiwanese population.     

Hypophosphatasia associated with calcium pyrophosphate dihydrate deposits in cartilage

A 51-year-old woman with hypophosphatasia had diffuse bone pain and widespread calcification in articular cartilage. Attacks of monarthritis had occurred for 27 years. Analysis of cartilage from the pubic symphysis revealed calcium pyrophosphate crystals.     

Genetics of osteoporosis

Osteoporosis is a common multifactorial disorder of reduced bone mass. The disorder in its most common form is generalized, affecting the elderly, both sexes, and all racial groups. Multiple environmental factors are involved in the pathogenesis. Genes also play a major role as reflected by heritability of many components of bone strength. Quantitative phenotypes in bone strength in the normal population do not conform to a monogenetic mode of inheritance. The common form of osteoporosis is generally considered to be a polygenic disorder arising from the interaction of common polymorphic alleles at quantitative trait loci, with multiple environmental factors. Finding the susceptibility genes underlying osteoporosis requires identifying specific alleles that coinherit with key heritable phenotypes in bone strength. Because of the close correspondence among mammalian genomes, identification of the genes underlying bone strength in mammals such as the mouse is likely to be of major assistance in human studies. Identification of susceptibility genes for osteoporosis is one of several important approaches toward the long-term goal of understanding the molecular biology of the normal variation in bone strength and how it may be modified to prevent osteoporosis. As with all genetic studies in humans, these scientific advances will need to be made in an environment of legal and ethical safeguards that are acceptable to the general public.