Hypophosphatasia as a rare cause of neonatal seizures

Severe forms of hypophosphatasia due to loss-of-function in the ALPL gene may present with diverse neurological problems including pyridoxine-responsive seizures. We present a short report of pyridoxine-responsive neonatal seizures. Due to severe osteopenia with unmeasurable levels of alkaline phosphatase, targeted genetic screening was performed and two pathogenic variants in the gene for the nonspecific alkaline phosphatase confirmed the diagnosis of hypophosphatasia. We would like to emphasize the importance of considering infantile hypophosphatasia in the differential diagnosis of pyridoxine-responsive seizures with concomitant low alkaline phosphatase level and bone pathology, especially with the new treatments becoming available in the future.     

Hipofosfatasia: manifestaciones clínicas,recomendaciones diagnósticas y opciones terapéuticas

Hypophosphatasia is a very rare bone metabolism disorder caused by a deficiency in alkaline phosphatase activity, due to mutations in the ALPL gene. Its clinical hallmark is the impairment of skeletal and teeth mineralisation, although extra-skeletal manifestations are frequent. Its phenotypic spectrum is widely variable from a subtype with exclusive odontological impairment (odontohypophosphatasia) to five subtypes with systemic involvement, classified according to the age at the onset of the first symptoms (four of them in the paediatric age range: perinatal lethal, perinatal benign, infant and childhood hypophosphatasia). Those subtypes of hypophosphatasia with an earliest onset usually involve a worse prognosis, due to the risk of developing potentially lethal complications, such as seizures or severe respiratory insufficiency, secondary to rib cage malformations.Due to the extremely low prevalence of the severe forms of hypophosphatasia, its clinical variability and overlapping phenotypic features with several more prevalent conditions, the diagnosis of hypophosphatasia in the clinical setting is challenging. However, its potential lethality and impact on the patient's quality of life, along with the recent availability of an enzyme replacement therapy, increases the relevance of the early and accurate identification of patients affected with hypophosphatasia.On the basis of published evidence and clinical experience, this article suggests an algorithm with practical recommendations for the differential diagnosis of childhood hypophosphatasia, as well as an updated review of current therapeutic options.     

Childhood hypophosphatasia: a case report due to a novel mutation]

Hypophosphatasia is characterized by defective bone mineralization associated with impaired activity of the tissue non-specific alkaline phosphatase (TNSALP) due to mutations in the TNSALP gene. We describe a child with a mutation that has not been described up to now. CASE REPORT: A 4-year-old child presented with clinical symptoms of rickets and premature loss of decideous teeth. Reduced serum alkaline phosphatase activity and radiographic features led to the diagnosis of hypophosphatasia, which was confirmed by genetic investigation. The molecular study showed two missense mutations, of which one is a novel mutation. CONCLUSION: Hypophosphatasia is suspected in a child with rickets and premature loss of decideous teeth. Such symptoms should prompt the search of a reduced serum alkaline phosphatase activity. The clinical and molecular diagnosis of the disease is important for the genetic counseling but also for a proper determination of prognosis, as it is related to the type of mutation.     

Severe hypercalcaemia and respiratory insufficiency associated with infantile hypophosphatasia caused by two novel mutations of the tissue-nonspecific alkaline phosphatase gene

We report the case of a male patient with infantile hypophosphatasia associated with severe hypercalcaemia and mild respiratory insufficiency. At the age of 2 months, severe hypercalcaemia, low levels of serum alkaline phosphatase activity, and elevated urinary excretion of calcium and phosphoethanolamine were noted. Radiological findings showed generalized osteopenia and disturbed and irregular ossification of the metaphyses. Their involvement had spontaneously improved at the age of 6 months. A genetic study revealed that the tissue-nonspecific alkaline phosphatase gene of the patient had two novel mutations, K207E and G409C, derived from the mother and father, respectively. A reconsitution experiment revealed that both mutant gene products had low but significant enzymatic activity. Conclusion The detection of tissue-nonspecific alkaline phosphatase gene mutations and expression studies to determine the enzymatic activity of mutant gene products was useful for assessing the clinical course of this patient with hypophosphatasia. Received: 26 July 1999 / Accepted: 30 November 1999     

Neonatal hypophosphatasia and seizures. A case report

Hypophosphatasia is a rare genetic disease characterized by deficiency of tissue-nonspecific alkaline phosphatase (TNSALP) activity, excessive urinary excretion of phosphoethanolamine, poor bone mineralization and skeletal anomalies. The shortage of alkaline phosphatase (ALP) alters the process of mineralization of skeleton causing a reduced transformation of phosphoethanolamine into phosphatidylethanolamine (cerebral phospholipid) with consequent high serum and urinary levels of phosphoethanolamine, a sensitive and highly specific marker for the disease. Four clinical forms have been described based on the age of onset with different courses and prognoses. An unusual case of lethal perinatal hypophosphatasia associated with seizures observed in a newborn admitted to Neonatal Intensive Care Unit of the University of Catania is described.     

Benign prenatal hypophosphatasia: a treatable disease not to be missed

Prenatal bowing of the long bones is often associated with severe bone dysplasias. We report a child who presented marked bowing of the long bones at birth but showed a relatively benign postnatal course with spontaneous improvement of bowing. The fetal imaging showed normal skeletal mineralization and normal chest and abdominal circumferences despite the limb bowing and shortening. Decreased serum alkaline phosphatase activity and elevated urine phosphoethanolamine was biochemically evident, and compound heterozygous mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene were identified, which confirmed the diagnosis of a benign form of prenatal hypophosphatasia. Benign prenatal hypophosphatasia should be considered in the differential diagnosis of congenital bowing of the long bones.     

Wachstumsstillstand als einziges klinisches Zeichen eines erhöhten Hirndrucks bei einer Patientin mit Hypophosphatasie vom infantilen Typ

Background. Hypophosphatasia is a rare inherited disorder characterised by defective bone mineralisation and deficiency of the tissue-nonspecific alkaline phosphatase (TNSALP) activity. The disease is classified into four subtypes according to the time of its first presentation. The severity of the disease depends on the remaining activity of the liver/bone/kidney alkaline phosphatase which explains the clinical variety of the disease. Case report. We report on a patient suffering from the infantile type of hypophosphatasia. Mutation analysis revealed an already known point mutation for the maternal and a so far not described mutation of the TNSALP gene for the paternal allele. The girl showed a good development during her first two years of life despite the poor prognosis for this condition. A chronically raised intracranial pressure solely lead to a growth stop in her second year of life. In an infant with hypophosphatasia a raised intracranial pressure due to craniosynostosis must be excluded during follow-up examinations on a regular basis despite missing clinical symptoms.     

Infantile loss of teeth: odontohypophosphatasia or childhood hypophosphatasia

Hypophosphatasia is a hereditary disorder characterized by a deficiency of serum and bone alkaline phosphatase (ALP) activity and defective skeletal mineralization. It is caused by a loss of function mutations in the tissue nonspecific ALP gene (TNSALP) encoding the tissue nonspecific alkaline phosphatase. A 4-year-and-8-month-old girl presented with premature exfoliation of the anterior incisors and canines. Very low ALP level (27 IU/ml) suggested the diagnosis of hypophosphatasia, which was supported by an elevated urine phosphoethanolamine/Cr of 84 μmol/mmol (reference range, <25 μmol/mmol) and serum pyridoxal-5′-phosphate of 393 μg/L (reference range, 3.6–18 μg/L). The phenotype of the patient was subsequently classified as mild childhood hypophosphatasia. TNSALP gene sequencing revealed the homozygous c.382 G > A (p.V128M) mutation. This mutation was previously observed in a series of patients with severe hypophosphatasia, pointing out the possible role of other genetic or environmental factors in the modulation of the hypophosphatasia phenotype.     

Infantile hypophosphatasia: normalization of circulating bone alkaline phosphatase activity followed by skeletal remineralization. Evidence for an intact structural gene for tissue nonspecific alkaline phosphatase

After a 3-month course of weekly intravenous infusions of pooled normal plasma in an attempt at enzyme replacement therapy, we observed gradual and prolonged normalization of circulating alkaline phosphatase (AP) activity in a boy with infantile hypophosphatasia. During this 4-month period, when hypophosphatasemia had been corrected, electrophoretic and heat denaturation studies suggested that the AP in serum was skeletal in origin. Serial radiographic and histologic studies of bone demonstrated skeletal remineralization and the appearance of AP activity in osteoblasts and chondrocytes after the infusions. Considerable clinical improvement coincided with the skeletal remineralization. Our observations indicate that in one patient with infantile hypophosphatasia the structural gene for the tissue-nonspecific (bone/liver/kidney) AP isoenzyme was intact and could be expressed with marked physiologic effect. Infantile hypophosphatasia may result from absence or inactivation of a circulating factor(s) that regulates the expression of the gene for tissue nonspecific AP.     

新生儿磷酸酶过少症

低磷酸酯酶症是一种少见的先天性代谢疾病。该文对其发病机制、分型及临床表现、鉴别诊断、治疗和预后进行了综述,并介绍了在该院诊断明确的1例新生儿型的罕见病例,患儿为出生30 min女婴,产前B超提示胎儿双顶径与四肢长骨不成比例,生后即有明显的颅骨软化、呼吸困难和紫绀等表现,血碱性磷酸酶（ALP）显著低下,X线表现及尸检结果均提示骨骼矿化极度低下,4 d后因呼吸衰竭死亡。     

低磷酸酶血症治疗新进展

低磷酸酶血症(HPP)是由编码组织非特异性碱性磷酸酶(TNSALP)的基因变异导致功能缺失引起的。HPP的症状、体征和并发症非常多变,包括骨骼低矿化、钙和磷酸盐代谢障碍、反复发生的骨折、疼痛、活动受限、牙齿过早脱落、生长发育迟缓和癫痫等。针对HPP有不同的治疗尝试,Asfotase alfa是一种骨靶向重组TNSALP...     

Vitamin D metabolism in hypophosphatasia

A 4-month-old boy with the infantile form of hypophosphatasia was followed for 9 months with measurements of serum calcium, phosphate, alkaline phosphatase and various vitamin D metabolites, together with urinary excretion of cyclic AMP. During the initial hypercalcemic stage the serum concentration of 25-hydroxyvitamin D was normal. Urinary cyclic AMP was low and the serum concentration of the dihydroxymetabolites of vitamin D were appropriate to the high serum calcium with low 1,25-(OH)2D and relatively high 24,25(OH)2D and 25,26(OH)2D levels. Due to restrictions of the vitamin D intake and lack of exposure to sun he developed vitamin D-deficiency rickets at 9 months of age with very low serum concentration of 25-hydroxyvitamin D and markedly increased urinary excretion of cyclic AMP. Following vitamin D treatment the serum level of 1,25(OH)2D showed a brisk rise to a considerably elevated value. Initially the serum concentration of alkaline phosphatase was well below the normal range, rose markedly during the stage of active rickets and returned to the characteristic low levels of hypophosphatasia with healing of the rickets.     

Hypophosphatasia with phenylketonuria

Hypophosphatasia and phenylketonuria have been encountered in a 9-month-old male infant as two independent inborn errors of metabolism. The pathognomonic triad of bony demineralization, subnormal alkaline phosphatase levels and increased excretion of phosphoethanolamine established the diagnosis of hypophosphatasia. The pattern of urinary metabolites and the results of phenylalanine tolerance testing confirmed the diagnosis of PKU. Serum alkaline phosphatase activity in this patient showed no variation with serum phenylalanine levels.Supported in part by The National Institutes of Health (Grant Nos. HD-01594 and RR-86) and the Maternal and Child Health Service, Health Services and Mental Health Administration (Grant No. MCHS-911) U.S. Department of Health, Education and Welfare, Washington, D.C.     

VITAMIN D METABOLISM IN HYPOPHOSPHATASIA

ABSTRACT. A 4-month-old boy with the infantile form of hypophosphatasia was followed for 9 months with measurements of serum calcium, phosphate, alkaline phosphatase and various vitamin D metabolites, together with urinary excretion of cyclic AMP. During the initial hypercalcemic stage the serum concentration of 25-hydroxyvitamin D was normal. Urinary cyclic AMP was low and the serum concentration of the dihydroxymetabolites of vitamin D were appropriate to the high serum calcium with low 1,25(OH)₂D and relatively high 24, 25(OH)₂ and 25, 26(OH)₂D levels. Due to restrictions of the vitamin D intake and lack of exposure to sun he developed vitamin D deficiency rickets at 9 months of age with very low serum concentration of 25-hydroxyvitamin D and markedly increased urinary excretion of cyclic AMP. Following vitamin D treatment the serum level of 1,25(OH)₂D showed a brisk rise to a considerably elevated value. Initially the serum concentration of alkaline phosphatase was well below the normal range, rase markedly during the stage of active rickets and returned to the characteristic low levels of hypophosphatasia with healing of the rickets.     

新复合杂合突变致婴儿型低磷酸酯酶症1例及其家系分析

该文对1例婴儿型低磷酸酯酶症(HPP)患儿及其家系进行临床特点分析及碱性磷酸酯酶基因(ALPL)检测。先证者,男,5个月,多发骨骼畸形:胸骨凹陷、双侧桡骨弯曲畸形、双膝外翻畸形,伴喂养困难、体重下降、发育迟滞、反复肺炎并呼衰,血碱性磷酸酶显著降低。患儿父母、姐姐、叔父、姨母(其他家系成员未能配合)中除父母及姨母的碱性磷酸酶略低,姨母可见脊柱侧弯畸形,余均无临床表型及实验室异常。患者ALPL基因检测到来源于母亲的c.228delG突变及来源于父亲的c.407GA复合杂合突变,其姨母携带c.228delG突变。c.407GA突变为已报道的HPP致病突变,c.228delG为新的致病性突变。低磷酸酯酶症是由ALPL基因突变所致,ALPL基因检测是有效的诊断方法。该研究拓展了ALPL基因突变谱,为HPP的基因诊断提供了理论依据。     

A Case of Vitamin D Deficiency without Elevation of Serum Alkaline Phosphatase in a Carrier of Hypophosphatasia

Elevated serum alkaline phosphatase (ALP) is a screening marker for the diagnosis of vitamin D deficiency, which may fail to be diagnosed if serum ALP is not elevated. Here, we describe a case of vitamin D deficiency without elevation of serum ALP. A 1-year-old Japanese girl was referred to our hospital for the evaluation of genu varum. Her serum intact PTH level was elevated, while her serum ALP level was normal. Furthermore, her serum 25-hydroxyvitamin D level was reduced, and her urine phosphoethanolamine (PEA) level was mildly elevated. ALPL gene analysis revealed she was a heterozygous carrier of hypophosphatasia (c.1559delT). Serum intact PTH and urine PEA evaluations were helpful for diagnosing vitamin D deficiency and hypophosphatasia carrier status, respectively. Therefore, the possibility of vitamin D deficiency without elevation of serum ALP should be considered.     

Common mutations F310L and T1559del in the tissue-nonspecific alkaline phosphatase gene are related to distinct phenotypes in Japanese patients with hypophosphatasia

A total of 22 Japanese patients with hypophosphatasia were included in a study analysing the relationship between mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene and the severity of the phenotype in Japanese patients with hypophosphatasia. The enzymatic activity of some of the identified mutant TNSALP proteins was also examined using corresponding expression vectors. Eighteen mutations, including 6 novel ones, were identified in the patients. Among them, the common mutations were F310L and T1559del. Of note, five patients with F310L mutation in one of the alleles exhibited a relatively mild phenotype without respiratory complications despite its perinatal onset. In contrast, the T1559del mutation is associated with perinatal lethal and infantile forms when not found in patients with the F310L mutation. The genotype-phenotype relationship was, to some extent, consistent with the enzymatic activity of the mutant ALP proteins; mutations K207E and G409C found in a surviving case of infantile hypophosphatasia, as well as F310L, retained some residual activities, whereas T1559del caused a complete loss of activity. Conclusion:In Japanese patients, the common mutations F310L and T1559del are associated with the relatively mild and lethal forms of hypophosphatasia, respectively. Our results may enhance the importance of genotyping patients with hypophosphatasia to predict their prognosis.     

Clinical Characteristics of Perinatal Lethal Hypophosphatasia: A Report of 6 Cases

Hypophosphatasia is a rare inherited disorder caused by deficient tissue-nonspecific alkaline phosphatase activity. It is classified into 6 subtypes, and the perinatal lethal form of hypophosphatasia is the most severe. Patients with this form suffer from various symptoms, including respiratory failure, premature craniosynostosis, rachitic changes in the metaphyses, convulsions and hypercalcemia. This report presents 6 cases of the perinatal lethal form of hypophosphatasia. All of the patients showed shortening of the long bones in utero in ultrasonographic examinations. Two of the six patients died at birth because they could not establish spontaneous breathing. Three of the remaining four patients also died before 1 yr of age. The major cause of death was respiratory failure due to hypoplastic lung. All of the patients, except for the two who died at birth, experienced convulsions in their clinical courses. Vitamin B6 therapy effectively reduced the frequency and severity of convulsions. However, it could not always make the patients convulsion free. Three patients underwent a genetic analysis. The 1559delT mutation, which abolishes Alkaline Phosphatase (ALP) activity, was a hot spot. A homozygous 1559delT mutation was observed in two patients. However, they differed in severity of symptoms. Although a good genotype-phenotype correlation has been reported in hypophosphatasia, the genotype alone does not always predict the life span of the patients. These cases therefore suggested the importance of genetic counseling.