Infantile hypophosphatasia combined with vitamin B6-responsive seizures and reticular formation lesions on magnetic resonance imaging: A case report

Fukazawa, Mitsuharu; Tezuka, Junichiro; Sasazuki, Momoko; Masumoto, Natsuko; Baba, Hironori; Doi, Takehiko; Tsutsumi, Yasushi; Mizuno, Yuji; Mihara, Futoshi; Nakayama, Hideki

doi:10.1016/j.braindev.2017.07.015

Cited by 9 publications

(5 citation statements)

References 12 publications

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“…A patient was found to have MRI alterations in the dorsolateral medulla oblongata at the age of 39 days and in the further course of disease a volume loss in the white matter and basal ganglia and a cystic degeneration of the white matter [19]. In contrast to these severe changes, reversible bilateral lesions in the dorsal brain stem including the medulla oblongata have been described [20]. MRI in our patient was unremarkable at day 4, but showed a severe atrophy and signal hyperintensities periventricular and in the hippocampi at age 4.5 months.…”

Section: Discussionmentioning

confidence: 99%

“…It has therefore been discussed if additional vitamin B6 supplementation may have a deleterious effect by increasing extracellular PLP concentrations to a toxic level [30] [23]. HPP-associated encephalopathy has been observed irrespective of vitamin B6 supplementation [4, 19] and at least 1 patient with higher residual ALP activity responded to increased doses of vitamin B6 treatment [20]. Still, excessive concentrations of PLP in the extracellular space cannot be excluded as a contributing factor in HPP-associated encephalopathy.…”

Section: Discussionmentioning

confidence: 99%

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Lethal Encephalopathy in an Infant with Hypophosphatasia despite Enzyme Replacement Therapy

Raimann¹,

Haberler²,

Patsch³

et al. 2021

Horm Res Paediatr

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Hypophosphatasia (HPP) is an inborn error of metabolism caused by loss‑of‑function mutations in the biomineralization associated alkaline phosphatase (ALPL) gene, encoding tissue-nonspecific alkaline phosphatase (TNSALP). Symptoms include skeletal hypomineralization and extra-skeletal manifestations such as pyridoxine (B6) responsive seizures due to impaired cerebral B6 passage. Since the introduction of enzyme-replacement therapy (ERT) skeletal manifestations and B6-responsive seizures were reported to improve significantly. Nevertheless, there is increasing evidence of B6-independent neurological manifestation of HPP including HPP-associated encephalopathy. Here, we present for the first time the brain alterations of an infant with neonatal HPP who died of neurological complications at the age of 5 months despite early initiation of ERT. CSF analysis showed normal concentrations of biogenic amines reflecting sufficient intracellular B6 availability. Post mortem histopathology revealed severe, localized affection of the cerebral cortex including cortical lesions in layers 2 and 3 in direct proximity to TNSALP-expressing neurons and hippocampal sclerosis. Our findings confirm that TNSALP deficiency may lead to a severe encephalopathy. We hypothesize that HPP-associated encephalopathy resistant to currently available ERT may develop in addition and probably independently of typical B6-responsive seizures in some patients. Prospective, controlled studies with close neurological follow-up including brain imaging are needed to identify patients at risk for severe neurological symptoms despite ERT.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Lethal Encephalopathy in an Infant with Hypophosphatasia despite Enzyme Replacement Therapy

Raimann¹,

Haberler²,

Patsch³

et al. 2021

Horm Res Paediatr

View full text Add to dashboard Cite

show abstract

“…Brain-localized TNAP has been suggested to aid in proliferation and migration of the developing nervous system 35,36 , promote axonal growth 37 , and regulate the formation and maturation of synapse 31,38 . Additional studies suggest that changes in brain TNAP expression may contribute to Alzheimer’s disease (AD) 39 and epilepsy 40,41 . TNAP has varied levels of expression in the brain 16,31 , and the amount of total TNAP protein and catalytically active enzyme activity are not equal 42 .…”

Section: Discussionmentioning

confidence: 99%

Systemic inhibition of tissue-nonspecific alkaline phosphatase alters the brain-immune axis in experimental sepsis

Brichacek

Benkovic

Chakraborty

et al. 2019

Sci Rep

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Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitous enzyme present in many cells and tissues, including the central nervous system. Yet its functions at the brain-immune axis remain unclear. The goal of this study was to use a novel small molecular inhibitor of TNAP, SBI-425, to interrogate the function of TNAP in neuroimmune disorders. Following intraperitoneal (IP) administration of SBI-425, mass spectrometry analysis revealed that the SBI-425 does not cross the blood-brain barrier (BBB) in healthy mice. To elucidate the role of TNAP at the brain-immune axis, mice were subjected to experimental sepsis and received either vehicle or SBI-425 (25 mg/kg, IP) daily for 7 days. While SBI-425 administration did not affect clinical severity outcomes, we found that SBI-425 administration suppressed CD4 + Foxp3+ CD25− and CD8 + Foxp3+ CD25− splenocyte T-cell populations compared to controls. Further evaluation of SBI-425’s effects in the brain revealed that TNAP activity was suppressed in the brain parenchyma of SBI-425-treated mice compared to controls. When primary brain endothelial cells were treated with a proinflammatory stimulus the addition of SBI-425 treatment potentiated the loss of barrier function in BBB endothelial cells. To further demonstrate a protective role for TNAP at endothelial barriers within this axis, transgenic mice with a conditional overexpression of TNAP were subjected to experimental sepsis and found to have increased survival and decreased clinical severity scores compared to controls. Taken together, these results demonstrate a novel role for TNAP activity in shaping the dynamic interactions within the brain-immune axis.

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“…Delayed myelination and spinal abnormalities are seen in Alpl-deficient mice. MRI investigations of HPP infants shows hypodensity of white matter, multicystic encephalopathy, dilated ventricles, and parenchymal lesions [ 149 , 150 ]. Dephosphorylation and interaction with ECM proteins including collagen and laminin is also contributed by TNAP in brain development [ 151 ].…”

Section: Tnapmentioning

confidence: 99%

The Physiological and Pathological Role of Tissue Nonspecific Alkaline Phosphatase beyond Mineralization

2021

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Tissue-nonspecific alkaline phosphatase (TNAP) is a key enzyme responsible for skeletal tissue mineralization. It is involved in the dephosphorylation of various physiological substrates, and has vital physiological functions, including extra-skeletal functions, such as neuronal development, detoxification of lipopolysaccharide (LPS), an anti-inflammatory role, bile pH regulation, and the maintenance of the blood brain barrier (BBB). TNAP is also implicated in ectopic pathological calcification of soft tissues, especially the vasculature. Although it is the crucial enzyme in mineralization of skeletal and dental tissues, it is a logical clinical target to attenuate vascular calcification. Various tools and studies have been developed to inhibit its activity to arrest soft tissue mineralization. However, we should not neglect its other physiological functions prior to therapies targeting TNAP. Therefore, a better understanding into the mechanisms mediated by TNAP is needed for minimizing off targeted effects and aid in the betterment of various pathological scenarios. In this review, we have discussed the mechanism of mineralization and functions of TNAP beyond its primary role of hard tissue mineralization.

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Infantile hypophosphatasia combined with vitamin B6-responsive seizures and reticular formation lesions on magnetic resonance imaging: A case report

Cited by 9 publications

References 12 publications

Lethal Encephalopathy in an Infant with Hypophosphatasia despite Enzyme Replacement Therapy

Lethal Encephalopathy in an Infant with Hypophosphatasia despite Enzyme Replacement Therapy

Systemic inhibition of tissue-nonspecific alkaline phosphatase alters the brain-immune axis in experimental sepsis

The Physiological and Pathological Role of Tissue Nonspecific Alkaline Phosphatase beyond Mineralization

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