Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026827 (hypotonia)
 5,860 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypophosphatasia is a rare inherited disorder of bone and mineral metabolism caused by a number of loss-of-function mutations in the ALPL gene. It is characterized by defective bone and tooth mineralisation associated with low serum and bone alkaline phosphatase activity. The clinical presentation of this disease is extremely variable. For this reason, the diagnosis can be difficult and is often missed out or delayed. Hypophosphatasia is classified into subtypes based on the age of onset and clinical features. The clinical severity is associated with the age at diagnosis and the lack of tissue-nonspecific alkaline phosphatase activity; the severe forms of hypophosphatasia are primarily perinatal and infantile forms. Severe forms may present with many neurological problems such as seizures, hypotonia, irritability. Herein, we report the case of an infantile hypophosphatasia patient who presented with pyridoxine-responsive seizures and a novel homozygous mutation in the ALPL gene was detected. There is a limited number of hypophosphatasia patients with pyridoxine-responsive seizures in the literature, so early diagnosis of infantile hypophosphatasia in the clinically compatible patients allows more effective postnatal care/management and genetic counseling for further pregnancies.
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PMID:Pyridoxine-Responsive Seizures in Infantile Hypophosphatasia and a Novel Homozygous Mutation in ALPL Gene. 2708 62

Hypophosphatasia is a rare hereditary disorder characterized by defective bone and tooth mineralization and deficiency of tissue non-specific alkaline phosphatase activity. The prognosis for the infantile form is poor, with approximately 50% of patients dying within the first year of life from respiratory failure. We describe the clinical and biochemical findings as well as the molecular analysis of a Korean boy with infantile hypophosphatasia and present a literature review. A 1-month-old boy visited the clinic because of poor feeding, frequent vomiting, hypotonia, and failure to thrive from birth. Laboratory tests revealed high total calcium, low phosphorous, low alkaline phosphatase, low parathyroid hormone, and normal 25-hydroxyvitamin D. Intravenous hydration with normal saline was started, and dietary calcium intake was restricted. Skeletal X-rays showed a markedly increased distance of the anterior fontanelle, impaired mineralization, and rachitic changes in the metaphyses. By Sanger sequencing of the ALPL gene, we identified two heterozygous variants, including a missense (c.334G>A; p.Gly112Ser) and a nonsense (c.1039C>T; p.Gln347*) variant. The c.334G>A (p.Gly112Ser) variant had previously been reported in a patient with lethal type hypophosphatasia, while the nonsense c.1039C>T (p.Gln347*) variant was novel. In the current case, the accurate diagnosis and prompt intervention-including dietary calcium intake restriction, tracheostomy to prevent progression to respiratory failure, and fundoplication with gastrostomy to ensure the administration of adequate calories-seemed to play an important role for avoiding preventable morbidity and premature mortality.
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PMID:First Korean Case of Infantile Hypophosphatasia with Novel Mutation in ALPL and Literature Review. 2731 57

The pathophysiology of the neuromuscular manifestations of hypophosphatasia (HPP) remains unknown. Pyridoxine-sensitive seizures characterize severe forms of infantile HPP. Young children and infants affected with severe forms of HPP, but also adults often present with myopathy characterized by hypotonia or muscle weakness. Chronic pain, of unclear mechanism is also often present. Tissue-non-specific alkaline phosphatase (Alkaline Phosphatase-Liver/Bone/Kidney [ALPL]) is expressed in brain neuronal cell and in muscle cells during development and adulthood. The knockout of the ALPL impacts neuronal functions in animal models. This may occur through metabolic anomalies involving gamma-aminobutyric acid (GABA) and other neurotransmitters via the metabolism of pyridoxal phosphate (vitamin B6) and phosphoethanolamine. In this context, a greater understanding of the neuromuscular pathophysiology of HPP is critical to assess the potential impact of new therapies.
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PMID:Neuromuscular features of hypophosphatasia. 2940 39

Hypophosphatasia (HPP) is a rare disease resulting from alterations of the ALPL gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). Perinatal HPP is mainly characterized by bone hypomineralization and severe respiratory insufficiency. We describe a full-term boy diagnosed with perinatal HPP after birth, showing dramatic improvement after treatment with Asfotase Alfa, an enzyme-replacement therapy (ERT) prescribed in HPP cases. He initially presented with respiratory insufficiency due to bone hypomineralization, and severe pulmonary hypoplasia that required tracheostomy and invasive ventilation for 8 months. He was taken off ventilation at 41 weeks of age. He also presented complications including hypercalcemia, craniosynostosis, nephrocalcinosis, hypotonia, and a severe feeding disorder. He is still alive at 30 months of age, and his respiratory status and tonus is steadily improving. This case reflects the progression of HPP patients with specific therapy added to symptomatic management. Some aspects of the disease are now well known, such as nephrocalcinosis and craniosynostosis, related to the natural course of the disease, which persisted despite the ERT. The long-term prognosis and outcome for this newborn child remain unknown.
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PMID:Enzyme-replacement therapy in perinatal hypophosphatasia: Case report and review of the literature. 3024 91

Hypophosphatasia (HPP) is a rare disease caused by mutations in the ALPL gene encoding tissue-non-specific isoenzyme of alkaline phosphatase (TNSALP). Duplications of the ALPL gene account for fewer than 1% of the mutations causing HPP. It has been shown that asfotase alfa enzyme replacement treatment (ERT) mineralizes the skeleton and improves respiratory function and survival in severe forms of HPP. Our patient was a newborn infant evaluated for respiratory failure and generalized hypotonia after birth. Diagnosis of HPP was based on low-serum ALP activity, high concentrations of substrates of the TNSALP and radiologic findings. On day 21 after birth, ERT using asfotase alfa (2 mg/kg three times per week, subcutaneous injection) was started. His respiratory support was gradually reduced and skeletal mineralization improved during treatment. We were able to discharge the patient when he was seven months old. No mutation was detected in the ALPL gene by all exon sequencing, and additional analysis was done by quantitative polymerase chain reaction (qPCR). As a result, a novel homozygote duplication encompassing exons 2 to 6 was detected. Early diagnosis and rapid intervention with ERT is life-saving in the severe form of HPP. qPCR can detect duplications if a mutation cannot be detected by sequence analysis in these patients.
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PMID:A Case of the Perinatal Form Hypophosphatasia Caused by a Novel Large Duplication of the ALPL Gene and Report of One Year Follow-up with Enzyme Replacement Therapy 3046 49