Hypophosphatasia: from birth to adulthood

Abstract

Hypophosphatasia (HPP) is an inherited disease caused by a low activity of tissue-nonspecific alkaline phosphatase, a hydrolase that removes phosphate groups from many molecules. Decreased alkaline phosphatase activity leads to the accumulation of three main metabolites, i.e., pyridoxal 5´-phosphate (PLP), inorganic pyrophosphate (PPi), and phosphoethanolamine. Impairment in PLP dephosphorylation induces seizures, while PPi accumulation inhibits bone mineralization. Clinically, HPP has a wide spectrum of presentations, ranging from neonatal death to an apparent lack of symptoms. This disease is classified into six subtypes according to the age at onset of first signs or symptoms. The clinical manifestations of the disease include rickets-like bone changes, bone demineralization, fragility fractures, reduced muscular strength, chest deformity, pulmonary hypoplasia, nephrolithiasis, nephrocalcinosis, and chondrocalcinosis. Treatment of HPP consists of enzyme replacement therapy. Before this therapy was approved, treatment was palliative and associated with high morbidity and mortality. Asfotase alfa has changed the prognosis of the disease by reducing bone deformity and improving bone mineralization, lung function, and muscle weakness, among other benefits. In adults, teriparatide and anti-sclerostin antibody have been used off-label in selected cases, demonstrating benefit in accelerating fracture healing and in concomitant treatment of osteoporosis. This review summarizes the main aspects of HPP and identifies the particularities of the disease in adult patients.

Keywords: Hypophosphatasia; TNSALP mutation; alkaline phosphatase; asfotase alfa.

Figure 1. (A) Pathophysiology of bone demineralization in hypophosphatasia. (B) Pathophysiology of seizure in hypophosphatasia.: A. Mineralization begins with the formation of hydroxyapatite crystals from calcium and phosphate (Pi). Inorganic pyrophosphate (PPi) inhibits the formation of hydroxyapatite crystals. Thus, it must be hydrolyzed by alkaline phosphatase (TNSALP) for mineralization to occur. With the reduced TNSALP activity in hypophosphatasia, PPi is not hydrolyzed, and bone mineralization is decreased.: B. In the most severe cases of hypophosphatasia, pyridoxal 5'-phosphate (PLP) is not dephosphorylated effectively, and pyridoxal (PL) becomes unable to cross the blood-brain barrier and participate in the formation of gamma-aminobutyric acid (GABA). This leads to vitamin B6-dependent seizure.

Figure 2. Male patient with a benign prenatal form of hypophosphatasia. He had presented manifestations before birth but was only diagnosed with the disease at the age of 1 year and 8 months. He was started on asfotase alfa at the age of 2 years and 10 months. (A) Age 1 year and 2 months: upper limb radiograph showing diffuse bone hypomineralization, cupping, fraying, and widening metaphyses, thin cortical bone, and diaphyseal shortening. (B) Metaphyseal radiolucent “tongues” (arrows). (C) “Beaten copper” sign. (D) Age 5 years, after 2 years of treatment, showing improved bone mineralization and formation, cupping, fraying and widening metaphyses, and radiolucent “tongues.” The long bone became better defined, and the lytic and sclerotic metaphyseal areas resolved.: Adapted from: Arch Endocrinol Metab. 2021;64(5):623-9.

Figure 3. Male patient with hypophosphatasia since childhood, which was mistreated as rickets. The diagnosis of hypophosphatasia was established at the age of 49 years. The patient had short stature, skull deformity, and pseudofractures (arrows) in the left foot (A), right femur (B), and right tibia (C), which compromised his gait and significantly impaired his quality of life and ability to work. After starting treatment with asfotase alfa, the patient's clinical manifestations improved.