Neurological and Neurosurgical Aspects of Hypophosphatasia

Hypophosphatasia is a rare hereditary progressive disease caused by a mutation in ALPL gene and characterized by low activity of alkaline phosphatase. Due to the disruption of the bone mineralization process, ricket-like deformations of the skeleton occur in the clinic picture more frequently but other systemic manifestations can be also observed as respiratory insufficiency, urinary tract damage, and neurological disorders. Seizures, delayed physical and psychomotor development, attention deficit disorder, muscle weakness, fatigue, intracranial hypertension associated with the development of craniosynostosis are revealed in these patients. The severity of the disease depends on age: the highest mortality is reported in younger patients, in perinatal and infantile forms of hypophosphatasia. Diagnosis is based on the identification of specific clinical manifestations: retardation of growth and development, skeletal deformities, pain in muscles and joints, premature tooth loss. In laboratory tests, a steady decrease in alkaline phosphatase level is detected taking into account age and sex specification. If possible, alkaline phosphatase substrates are measured: levels of pyridoxal-5-phosphate in the blood and phosphoethanolamine in urine are higher at low enzyme activity. Radiographs of long bones typically reveal characteristic ‘tongues’ of lucency projecting from growth plates into metaphyses, hypomineralization, osteopenia, various kinds of deformation. All patients with suspected hypophosphatasia should be consulted by a clinical geneticist and evaluated to identify possible mutation in the ALPL gene.

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Hypophosphatasia: A Unique Disorder of Bone Mineralization

International Journal of Molecular Sciences ◽

10.3390/ijms22094303 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4303

Author(s):

Juan Miguel Villa-Suárez ◽

Cristina García-Fontana ◽

Francisco Andújar-Vera ◽

Sheila González-Salvatierra ◽

Tomás de Haro-Muñoz ◽

...

Keyword(s):

Alkaline Phosphatase ◽

Genetic Disease ◽

Therapeutic Strategy ◽

Pediatric Patients ◽

Bone Mineralization ◽

Clinical Manifestations ◽

Allelic Heterogeneity ◽

Specific Enzyme ◽

Inorganic Pyrophosphate ◽

Enzyme Replacement

Hypophosphatasia (HPP) is a rare genetic disease characterized by a decrease in the activity of tissue non-specific alkaline phosphatase (TNSALP). TNSALP is encoded by the ALPL gene, which is abundantly expressed in the skeleton, liver, kidney, and developing teeth. HPP exhibits high clinical variability largely due to the high allelic heterogeneity of the ALPL gene. HPP is characterized by multisystemic complications, although the most common clinical manifestations are those that occur in the skeleton, muscles, and teeth. These complications are mainly due to the accumulation of inorganic pyrophosphate (PPi) and pyridoxal-5′-phosphate (PLP). It has been observed that the prevalence of mild forms of the disease is more than 40 times the prevalence of severe forms. Patients with HPP present at least one mutation in the ALPL gene. However, it is known that there are other causes that lead to decreased alkaline phosphatase (ALP) levels without mutations in the ALPL gene. Although the phenotype can be correlated with the genotype in HPP, the prediction of the phenotype from the genotype cannot be made with complete certainty. The availability of a specific enzyme replacement therapy for HPP undoubtedly represents an advance in therapeutic strategy, especially in severe forms of the disease in pediatric patients.

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Hypophosphatasia in children. Three faces of one disease

Russian Journal of Woman and Child Health ◽

10.32364/2618-8430-2020-3-2-136-141 ◽

2020 ◽

Vol 3 (2) ◽

pp. 136-141

Author(s):

S.A. Boykov ◽

◽

I.Yu. Chernyak ◽

N.S. Shatokhina ◽

E.Yu. Gurkina ◽

...

Keyword(s):

Alkaline Phosphatase ◽

Clinical Symptoms ◽

Bone Mineralization ◽

Case Reports ◽

Molecular Genetic ◽

Case Series ◽

Alp Activity ◽

Systemic Manifestations ◽

Molecular Genetic Test ◽

Reduced Mobility

Hypophosphatasia (HPP) is a rare multisystem inherited metabolic disorder caused by mutations in ALPL gene that encodes tissue nonspecific alkaline phosphatase responsible for bone mineralization. HPP is characterized by impaired bone mineralization, skeletal abnormalities, and systemic manifestations which result in significant morbidity and mortality. Clinical presentations of HPP vary greatly. Early (perinatal and infantile) HPP is characterized by the most severe symptoms, i.e., respiratory and neurological disorders are of crucial importance being the leading causes of death. Progressive skeletal impairment, rickets-like deformities, reduced mobility, and severe disability are typical of childhood-onset HPP. The biochemical hallmark of HPP is low alkaline phosphatase (ALP) activity. HPP diagnosis is verified by clinical symptoms in combination with persistently low ALP activity (adjusted for age and sex). Molecular genetic test to identify ALPL gene mutation is performed as needed. Three case reports addresses authors’ experience with the diagnosis and treatment for HPP.Keywords: hypophosphatasia, case series, alkaline phosphatase, impaired bone mineralization, asfotase alfa.For citation: Boykov S.A., Chernyak I.Yu., Shatokhina N.S. et al. Hypophosphatasia in children. Three faces of one disease. Russian Journal of Woman and Child Health. 2020;3(2):136–141. DOI: 10.32364/2618-8430-2020-3-2-136-141.

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THERAPEUTIC PLASMAPHERESIS IN A COMPLEX TREATMENT OF PATIENTS WITH CHRONIC HEPATITIS

Wiadomości Lekarskie ◽

10.36740/wlek202007126 ◽

2020 ◽

Vol 73 (7) ◽

pp. 1454-1458

Author(s):

Vladislav V. Lyubchak ◽

Viktoriia M. Plaksa ◽

Ihor M. Pelo ◽

Michael P. Kovalishyn ◽

Viktor P. Lyubchak ◽

...

Keyword(s):

Alkaline Phosphatase ◽

Chronic Hepatitis ◽

Conservative Treatment ◽

Alkaline Phosphatase Level ◽

Clinical Manifestations ◽

Complex Treatment ◽

Clinical Hospital ◽

Regional Center ◽

Chronic Toxic Hepatitis ◽

Methods Of Treatment

The aim: To determine the pathogenetic expediency, efficiency and the place of therapeutic plasmapheresis in a complex treatment of patients with chronic hepatitis. Materials and methods: It was carried out the analysis of case histories of 77 patients. In the course of treatment, the patients were diagnosed with chronic toxic hepatitis (K.71). Diagnosis was exposed in accordance with the official documentation introduced by the Gastroenterological department of Sumy Regional Clinical Hospital CH”SRCH”, Sumy Regional Infectious Diseases Clinical Hospital named after Krasovytsky ZY and Sumy Regional Center of Blood Service. Results: It was found that total protein indicator is the normal range and albumin after plasmapheresis and during conservative treatment. Markers of cytolysis and cholestasis are have great value may. The most significant changes were observed in rates indicating lesion of the hepatic parenchyma, including ALT, AsAT and alkaline phosphatase. In conservative treatment, the percentage of the alkaline phosphatase level improved by 31%, after the course of plasmapheresis – by 58%. The obtained figures of cholestasis indexes indicate the effectiveness of both methods of treatment, but treatment with plasmapheresis has a more expressed effect on the decrease of alkaline phosphatase level. The level of bilirubin improve on 38,8% after plasmapheresis and 65% in the comparison group. Conclusion: Inclusion in the complex therapy of chronic hepatitis plasmapheresis reduces the severity of cytolysis and cholestasis, increases remission and significantly improves clinical manifestations.

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SUBACUTE THYROIDITIS WITH ELEVATED SERUM ALKALINE PHOSPHATASE LEVEL

Acta Endocrinologica ◽

10.1530/acta.0.xxxiv0256 ◽

1960 ◽

Vol XXXIV (II) ◽

pp. 256-260

Author(s):

Jörgen Herman Vogt

Keyword(s):

Alkaline Phosphatase ◽

Alkaline Phosphatase Level ◽

Serum Alkaline Phosphatase ◽

Thyroid Tissue ◽

Elevated Serum ◽

Subacute Thyroiditis ◽

Serum Alkaline Phosphatase Level ◽

Transient Rise

ABSTRACT A case of subacute thyroiditis is recorded, in which a transient rise in serum alkaline phosphatase values leads to the hypothesis of a transient parathyroid hyper-activity induced by the inflammation of the thyroid tissue in which the parathyroid may be embedded.

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Clinico-Haematological Alterations in Goats Affected with Ruminal Acidosis

THE INDIAN JOURNAL OF VETERINARY SCIENCES AND BIOTECHNOLOGY ◽

10.21887/ijvsbt.v13i02.10042 ◽

2017 ◽

Vol 13 (02) ◽

Author(s):

P. R. Chavelikar ◽

G. C. Mandali ◽

D. M. Patel

Keyword(s):

Clinical Signs ◽

Clinical Manifestations ◽

Nasal Discharge ◽

Mean Values ◽

Ruminal Acidosis ◽

Reduced Body ◽

Muscle Twitching ◽

Haematological Profile ◽

The Mean ◽

Severity Of The Disease

Ruminal acidosis is one of the most important clinical emergencies in sheep and goats resulting into high mortality rate. In the present study, eight healthy farm goats and 24 goats presented to the TVCC of the college with clinical signs of ruminal acidosis like anorexia, tympany, increased pulse and respiratory rate, reduced body temperature, doughy rumen, enteritis, oliguria, grinding of teeth, purulent nasal discharge, muscle twitching, arched back, dehydration and recumbency with rumen liquor pH below 6 were examined for haematological alterations using autohaematoanalyzer. Among various haematological parameters evaluated from acidotic goats, the mean values of Hb (12.21±0.17 vs. 10.86±0.15 g/dl), TEC (14.28±0.16 vs. 12.04±0.36 ×106/ μl), TLC (13.43±0.11 vs. 11.11±0.27 ×103/μl), PCV (36.91±0.53 vs. 29.88±0.55%), neutrophils (64.54±0.93 vs. 28.13±0.92%), MCV (23.38±0.37 vs. 19.38±1.34 fl) and MCH (7.03±0.08 vs. 6.31±0.25 pg) were found significantly increased, while the mean values of lymphocytes (28.00±0.82 vs. 65.38±0.80%) and MCHC (24.55 ±0.26 vs. 34.88±0.97 g/dl) were decreased significantly from the base values of healthy goats. It was concluded that ruminal acidosis induced due to accidental heavy ingestion of readily fermentable carbohydrate rich grains and food waste significantly altered the haematological profile concurrent with clinical manifestations in goats, and hence can be used to assess the severity of the disease.

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Respiratory tract damage with bocavirus infection in children

CHILDREN INFECTIONS ◽

10.22627/2072-8107-2020-19-2-14-18 ◽

2020 ◽

Vol 19 (2) ◽

pp. 14-18

Author(s):

E. V. Sharipova ◽

I. V. Babachenko ◽

M. A. Shcherbatyh

Keyword(s):

Respiratory Tract ◽

Lower Respiratory Tract ◽

Clinical Manifestations ◽

Respiratory Viruses ◽

Community Acquired Pneumonia ◽

Human Bocavirus ◽

Long Time ◽

Clinically Significant ◽

Tract Infections ◽

Tract Damage

Long time the main pathogens associated with the development of community-acquired pneumonia were bacteria. However, in recent years in the Russian Federation, like all over the world, the view of the damage of lower respiratory tract changed, including a unique approach to community-acquired pneumonia as a bacterial infection, and respiratory viruses have become seen as a direct cause of lower respiratory tract damage, or as part of a viral-bacterial co-infection. These studies became possible since the widespread introduction of PCR techniques in the clinical setting, identification of respiratory viruses has increased and new microorganisms such, one as human bocavirus have been discovered. Objective: to study the features of respiratory tract damage in acute bocavirus infection in children of different ages. Materials and methods: A retrospective analysis of 97 medical hospital documentation of children with acute bocavirus infection, detected confirmed by PCR in nasopharyngeal aspirate. Results: In this work, it was shown that human bocavirus spread throughout the year with an increase in the incidence of clinically significant forms in the autumnwinter period, including during the period of an increase in the incidence of influenza. HBoV infection requiring hospitals is most significant in the first three years of life. In 74.2% of hospitalized children, bocavirus infection occurs with lower respiratory tract infections in the form of bronchitis — 77.8%, pneumonia — 28.9% and rarely bronchiolitis and is complicated by the development of respiratory failure in 28.9% of cases. Changes in the blood test are non-specific, and the level of C-reactive protein in children with various clinical manifestations of HBoV infection generally does not exceed 50 mg / l. An x-ray of the chest organs does not objectively reflect the existing volume and nature of the inflammatory process in the lungs.

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P1237TISSUE-NONSPECIFIC ALKALINE PHOSPHATASE, A CULPRIT DURING ARTERIAL MEDIA CALCIFICATION BUT INDISPENSABLE DURING PHYSIOLOGICAL BONE FORMATION/-MINERALIZATION IN RATS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p1237 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Britt Opdebeeck ◽

José Millan Luis ◽

Anthony Pinkerton ◽

Anja Verhulst ◽

Patrick D'Haese ◽

...

Keyword(s):

Alkaline Phosphatase ◽

Bone Formation ◽

Vascular Calcification ◽

Rat Model ◽

Bone Mineralization ◽

Calcium Content ◽

Marker Genes ◽

Peripheral Arteries ◽

Calcium Phosphorus ◽

Chondrogenic Marker

Abstract Background and Aims Vascular media calcification is frequently seen in elderly and patients with chronic kidney disease (CKD), diabetes and osteoporosis. Pyrophosphate is a well-known calcification inhibitor that binds to nascent hydroxyapatite crystals and prevents further incorporation of inorganic phosphate into these crystals. However, the enzyme tissue-nonspecific alkaline phosphatase (TNAP), which is highly expressed in calcified arteries, degrades extracellular pyrophosphate into phosphate ions, by which pyrophosphate loses its ability to block vascular calcification. Here, we aimed to evaluate whether a TNAP inhibitor is able to prevent the development of arterial calcification in a rat model of warfarin-induced vascular calcification. Method To induce vascular calcification, rats received a diet containing 0.30% warfarin and 0.15% vitamin K1 throughout the entire study and were subjected to the following daily treatments: (i) vehicle (n=10) or (ii) 10 mg/kg/day TNAP-inhibitor (n=10) administered via an intraperitoneal catheter from start of the study until sacrifice at week 7. Calcium, phosphorus and parathyroid hormone (PTH) levels were determined in serum samples as these are important determinants of vascular calcification. As TNAP is also expressed in the liver, serum alanine aminotransferase (ALT) and aspartate (AST) levels were analyzed. At sacrifice, vascular calcification was evaluated by measurement of the total calcium content in the arteries and quantification of the area % calcification on Von Kossa stained sections of the aorta. The mRNA expression of osteo/chondrogenic marker genes (runx2, TNAP, SOX9, collagen 1 and collagen 2) was analyzed in the aorta by qPCR to verify whether vascular smooth muscle cells underwent reprogramming towards bone-like cells. Bone histomorphometry was performed on the left tibia to measure static and dynamic bone parameters as TNAP also regulates physiological bone mineralization. Results No differences in serum calcium, phosphorus and PTH levels was observed between both study groups. Warfarin exposure resulted in distinct calcification in the aorta and peripheral arteries. Daily dosing with the TNAP inhibitor (10 mg/kg/day) for 7 weeks significantly reduced vascular calcification as indicated by a significant decrease in calcium content in the aorta (vehicle 3.84±0.64 mg calcium/g wet tissue vs TNAP inhibitor 0.70±0.23 mg calcium/g wet tissue) and peripheral arteries and a distinct reduction in area % calcification on Von Kossa stained aortic sections as compared to vehicle condition. The inhibitory effects of SBI-425 on vascular calcification were without altering serum liver markers ALT and AST levels. Furthermore, TNAP-inhibitor SBI-425 did not modulate the mRNA expression of osteo/chondrogenic marker genes runx2, TNAP, SOX9, collagen 1 and 2. Dosing with SBI-425 resulted in decreased bone formation rate and mineral apposition rate, and increased osteoid maturation time and this without significant changes in osteoclast- and eroded perimeter. Conclusion Dosing with TNAP inhibitor SBI-425 significantly reduced the calcification in the aorta and peripheral arteries of a rat model of warfarin-induced vascular calcification and this without affecting liver function. However, suppression of TNAP activity should be limited in order to maintain adequate physiological bone mineralization.

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