Inorganic phosphorus (Pi) in CSF is a biomarker for SLC20A2-associated idiopathic basal ganglia calcification (IBGC1).

INTRODUCTION: Idiopathic basal ganglia calcification (IBGC), also called Fahr's disease or recently primary familial brain calcification (PFBC), is characterized by abnormal deposits of minerals including calcium mainly and phosphate in the brain. Mutations in SLC20A2 (IBGC1 (merged with former IBGC2 and IBGC3)), which encodes PiT-2, a phosphate transporter, is the major cause of IBGC. Recently, Slc20a2-KO mice have been showed to have elevated levels of inorganic phosphorus (Pi) in cerebrospinal fluid (CSF); however, CSF Pi levels in patients with IBGC have not been fully examined. METHODS: We investigated the cases of 29 patients with IBGC including six patients with SLC20A2 mutation and three patients with PDGFB mutation, and 13 controls. The levels of sodium (Na), potassium (K), chloride (Cl), calcium (Ca), and Pi in sera and CSF were determined by potentiometry and colorimetry. Moreover, clinical manifestations were investigated in the IBGC patients with high Pi levels in CSF. RESULTS: The study revealed that the average level of Pi in the CSF of the total group of patients with IBGC is significantly higher than that of the control group, and the levels of Pi in CSF of the IBGC patients with SLC20A2 mutations are significantly higher than those of the IBGC patients with PDGFB mutations, the other IBGC patients and controls. CONCLUSION: Results of this study suggest that the levels of CSF Pi will be a good biomarker for IBGC1.

SLC20A2 Deficiency in Mice Leads to Elevated Phosphate Levels in Cerbrospinal Fluid and Glymphatic Pathway-Associated Arteriolar Calcification, and Recapitulates Human Idiopathic Basal Ganglia Calcification.

Idiopathic basal ganglia calcification is a brain calcification disorder that has been genetically linked to autosomal dominant mutations in the sodium-dependent phosphate co-transporter, SLC20A2. The mechanisms whereby deficiency of Slc20a2 leads to basal ganglion calcification are unknown. In the mouse brain, we found that Slc20a2 was expressed in tissues that produce and/or regulate cerebrospinal fluid, including choroid plexus, ependyma and arteriolar smooth muscle cells. Haploinsufficient Slc20a2 +/- mice developed age-dependent basal ganglia calcification that formed in glymphatic pathway-associated arterioles. Slc20a2 deficiency uncovered phosphate homeostasis dysregulation characterized by abnormally high cerebrospinal fluid phosphate levels and hydrocephalus, in addition to basal ganglia calcification. Slc20a2 siRNA knockdown in smooth muscle cells revealed increased susceptibility to high phosphate-induced calcification. These data suggested that loss of Slc20a2 led to dysregulated phosphate homeostasis and enhanced susceptibility of arteriolar smooth muscle cells to elevated phosphate-induced calcification. Together, dysregulated cerebrospinal fluid phosphate and enhanced smooth muscle cell susceptibility may predispose to glymphatic pathway-associated arteriolar calcification.

Slc20a2 is critical for maintaining a physiologic inorganic phosphate level in cerebrospinal fluid.

Mutations in the SLC20A2-gene encoding the inorganic phosphate (Pi) transporter PiT2 can explain approximately 40% of the familial cases of the rare neurodegenerative disorder primary familial brain calcification (Fahr's disease). The disease characteristic, cerebrovascular-associated calcifications, is also present in Slc20a2-knockout (KO) mice. Little is known about the specific role(s) of PiT2 in the brain. Recent in vitro studies, however, suggest a role in regulation of the [Pi] in cerebrospinal fluid (CSF). We here show that Slc20a2-KO mice indeed have a high CSF [Pi] in agreement with a role of PiT2 in Pi export from the CSF. The implications in relation to disease mechanism are discussed.

Mielopatia torácica por calcificação do ligamento amarelo cursando com hiperproteinorraquia e resposta à corticoterapia: relato de caso / Thoracic myelopathy due to calcification of the ligamentum flavum with hyperproteinorachia and responsive to steroid therapy: case report

Calcificação e ossificação do ligamento amarelo ou do ligamento longitudinal posterior são causas de mielopatia compressiva, mais frequentes nos níveis torácicos inferiores e bastante raras em populações ocidentais. A descompressão cirúrgica é a única terapia proposta, mas a doença costuma ser progressiva e sua recorrência após a cirurgia não é incomum. Mediadores inflamatórios podem ter algum papel na progressão da mielopatia compressiva, mas não se tem notícia de qualquer proposta de abordagem terapêutica envolvendo agentes anti-inflamatórios. Neste contexto, relatamos um caso de mielopatia compressiva por calcificação do ligamento amarelo em que se observou hiperproteinorraquia e resposta à corticoterapia. Tais informações são inéditas e podem fornecer novas ideias para a compreensão da doença.

Calcification and ossification of the ligamentum flavum or of the posterior longitudinal ligament are causes of compressive myelopathy, more frequent in the lower thoracic levels, and extremely rare in Western populations. Surgical decompression is the only therapy, but the disease is usually progressive, and its recurrence after surgery is common. Inflammatory mediators might play a role in the progression of compressive myelopathy, but, to our knowledge, the therapeutic approach involving anti-inflammatory agents has never been tried before. We report a case of compressive myelopathy due to calcification of the ligamentum flavum, in which hyperproteinorachia and response to steroid therapy have been observed. Those data have not been published before and might provide new ideas for the disease understanding.

Thoracic myelopathy due to calcification of the ligamentum flavum with hyperproteinorachia and responsive to steroid therapy: case report.

Calcification and ossification of the ligamentum flavum or of the posterior longitudinal ligament are causes of compressive myelopathy, more frequent in the lower thoracic levels, and extremely rare in Western populations. Surgical decompression is the only therapy, but the disease is usually progressive, and its recurrence after surgery is common. Inflammatory mediators might play a role in the progression of compressive myelopathy, but, to our knowledge, the therapeutic approach involving anti-inflammatory agents has never been tried before. We report a case of compressive myelopathy due to calcification of the ligamentum flavum, in which hyperproteinorachia and response to steroid therapy have been observed. Those data have not been published before and might provide new ideas for the disease understanding.

Quantification of Fas protein in CSF of patients with neurocysticercosis.

UNLABELLED: Neurocysticercosis is a parasitic disease that affects the central nervous system. The objective of this study was to investigate the correlation between neuronal death evaluated by the quantification of Fas apoptotic factor and the different evolutive forms of neurocysticercosis accompanied or not by epileptic seizures. METHODS: Cerebrospinal fluid samples from 36 patients with a diagnosis of neurocysticercosis divided into the following groups: active cystic form (n=15), 9 patients with and 6 without seizures, and calcified form (=21), 9 with and 12 without seizures. Fourteen patients comprised the control group. Fas protein concentrations were determined by ELISA. RESULTS: Only the group of patients with calcified cysts without seizures presented cerebrospinal fluid levels of Fas similar to those of the control group. Higher levels were observed for the other groups. CONCLUSIONS: The present finding suggests high cerebrospinal fluid levels of soluble Fas protein, except for patients with calcified cysts without seizures. Significant differences were observed for the group with calcified cysts and seizures, suggesting greater neuronal damage in these patients. Replacement of the term inactive cyst with reactive inactive cyst is suggested.

Quantification of Fas protein in CSF of patients with neurocysticercosis / Quantificação da proteína Fas no LCR de pacientes com neurocisticercose

Neurocysticercosis is a parasitic disease that affects the central nervous system. The objective of this study was to investigate the correlation between neuronal death evaluated by the quantification of Fas apoptotic factor and the different evolutive forms of neurocysticercosis accompanied or not by epileptic seizures. METHODS: Cerebrospinal fluid samples from 36 patients with a diagnosis of neurocysticercosis divided into the following groups: active cystic form (n=15), 9 patients with and 6 without seizures, and calcified form (=21), 9 with and 12 without seizures. Fourteen patients comprised the control group. Fas protein concentrations were determined by ELISA. RESULTS: Only the group of patients with calcified cysts without seizures presented cerebrospinal fluid levels of Fas similar to those of the control group. Higher levels were observed for the other groups. CONCLUSIONS: The present finding suggests high cerebrospinal fluid levels of soluble Fas protein, except for patients with calcified cysts without seizures. Significant differences were observed for the group with calcified cysts and seizures, suggesting greater neuronal damage in these patients. Replacement of the term inactive cyst with reactive inactive cyst is suggested.

Neurocisticercose é uma doença parasitária que afeta o sistema nervoso central. O objetivo deste estudo foi investigar a correlação entre morte neuronal por meio da quantificação do fator apoptótico Fas e a presença de neurocisticercose nas suas diferentes fases evolutivas, acompanhadas ou não de crises epilépticas. MÉTODOS: Foram analisadas amostras de líquido cefalorraquidiano em 36 pacientes com diagnóstico de neurocisticercose, determinando-se as concentrações da proteína Fas pelo método ELISA. Foram considerados os seguintes grupos: forma cística ativa n=15 (9 com crises, 6 sem crises), forma calcificada n=21 (9 com crises, 12 sem crises) e 14 pacientes (grupo controle). RESULTADOS: Apenas o grupo com calcificações sem crises apresentou níveis de Fas semelhantes ao controle. Maiores níveis foram observados nos outros grupos. CONCLUSÕES: As formas ativa e calcificada apresentam níveis elevados da proteína Fas, exceto para as formas calcificadas sem crises. No grupo de calcificações com crise, observamos diferenças mais expressivas, sugerindo maior dano neuronal. Sugerimos a substituição da denominação "cisto inativo" por "cisto inativo reagente".

Calcificaciones intracraneales extensas y crisis epilépticas debido a hipoparatiroidismo idiopático / Extensive intracranial calcifications and seizures due to idiopathic hypoparathyroidism

Introducción: El hipoparatiroidismo presenta diversas manifestaciones neurológicas dentro de las cuales las crisis epilépticas y las calcificaciones intracraneales son algunas de las principales. En el presente reporte se describe a tres pacientes con hipoparatiroidismo que presentaron crisis epilépticas y calcificaciones intracraneales extensas. Casos clínicos: Tres pacientes fueron admitidos en el Departamento de Epilepsia del Instituto Nacional de Ciencias Neurológicas por presentar crisis epilépticas tónico-clónico generalizadas. Ellos no tenían diagnóstico previo de hipoparatiroidismo, el cual fue sospechado a partir del hallazgo por tomografía computarizada de cráneo de calcificaciones extensas bilaterales simétricas en núcleos basales, sustancia blanca y cerebelo, y exámenes bioquímicos que mostraron bajos niveles de calcio sérico. En los tres casos presentados los niveles bajos de parathormona y la ausencia de causas secundarias de destrucción o remoción del tejido paratiroideo confirmaron el diagnóstico de hipoparatiroidismo idiopático. Los pacientes fueron tratados con carbonato de calcio, vitamina D y fármacos antiepilépticos. En los controles posteriores se evidenció que dos de los tres casos persistieron con hipocalcemia y sólo uno de ellos reportó una completa remisión de los síntomas neurológicos. Conclusiones: En pacientes con crisis epilépticas y calcificaciones intracraneales extensas se debe considerar el diagnóstico de hipoparatiroidismo.

Introduction: Hypoparathyroidism presents several neurological manifestations including seizures and intracranial calcifications. We describe three patients with idiopathic hypoparathyroidism who presented seizures and extensive intracranialcalcifications. Cases reports: Three patients were admitted to the Department ofEpilepsy ofthe National Institute of Neurological Sciences for presenting generalized tonic-clonic seizures. They had no previous diagnosis of hypoparathyroidism but it was suspected from CT scans finding of extensive bilateral symmetrical calcifications in basal nuclei, white matter and cerebellum and biochemical tests, which showed low levels of serum calcium. In all cases, low levels of parathyroid hormone and the absence ofsecondary causes of destruction or removal of the parathyroid tissue confirmed the diagnosis of idiopathic hypoparathyroidism. The cases were treated with calcium carbonate, vitamin D and antiepileptic drugs. In subsequent evaluations, two ofthe three cases with hypocalcaemia persisted and only one of them reported Ir complete remission of neurologic symptoms. Conclusions: Inpatients with seizures and extensive intracranial calcifications should consider the diagnosis of hypoparathyroidism.

Recessive mutations in the gene encoding the tight junction protein occludin cause band-like calcification with simplified gyration and polymicrogyria.

Band-like calcification with simplified gyration and polymicrogyria (BLC-PMG) is a rare autosomal-recessive neurological disorder showing highly characteristic clinical and neuroradiological features. Affected individuals demonstrate early-onset seizures, severe microcephaly, and developmental arrest with bilateral, symmetrical polymicrogyria (PMG) and a band of gray matter calcification on brain imaging; as such, the disorder can be considered as a "pseudo-TORCH" syndrome. By using autozygosity mapping and copy number analysis we identified intragenic deletions and mutations in OCLN in nine patients from six families with BLC-PMG. The OCLN gene encodes occludin, an integral component of tight junctions. Neuropathological analysis of an affected individual showed similarity to the mouse model of occludin deficiency with calcification predominantly associated with blood vessels. Both intracranial calcification and PMG are heterogeneous in etiology. Neuropathological and clinical studies of PMG have suggested that in utero ischemic or vascular insults may contribute to this common cortical abnormality. Tight junctions are functional in cerebral blood vessels early in fetal development and continue to play a vital role in maintenance of the blood-brain barrier during postnatal life. We provide evidence that the tight junction protein occludin (encoded by the OCLN gene) is involved in the pathogenesis of malformations of cortical development.

Beta2-microglobulin concentrations in cerebrospinal fluid correlate with neuroimaging findings in newborns with symptomatic congenital cytomegalovirus infection.

OVERVIEW: In newborns with symptomatic congenital cytomegalovirus (CMV) infection, neuroimaging is the best available predictor of neurodevelopmental outcome. Cerebrospinal fluid (CSF) findings in congenital CMV infection have seldom been described. Neonates with central nervous system infections present high CSF Beta(2)-microglobulin (beta(2)-m) levels. OBJECTIVES: The objectives of this study were: (1) to determine whether CSF beta(2)-m is increased in newborns with symptomatic congenital CMV infection, and (2) to examine its correlation with neuroimaging findings. MATERIALS AND METHODS: Fourteen newborns with symptomatic congenital CMV infection admitted to La Paz Hospital from 1990 through 2004 underwent determination of CSF beta(2)-m. Ninety-three newborns, constituting the comparison group, underwent CSF beta(2)-m determination as part of a sepsis or meningo/encephalitis work-up, and at discharge had sterile cultures and normal neurological status. Neuroimaging findings were scored according to a semiquantitative system: (0) no abnormalities; (1) single punctate periventricular (PV) calcification and/or hyperechogenic areas in the thalamus and basal ganglia; (2) multiple discrete PV calcifications and/or ventriculomegaly; and (3) extensive PV calcifications and/or brain atrophy. DISCUSSION AND CONCLUSION: CSF beta(2)-m was increased in newborns with CMV infection (median 6.21 mg/L) compared with controls (1.68 mg/L) (P<.001). beta(2)-m showed a correlation with neuroimaging scores (r (s)=0.753, P=.002). beta(2)-m was higher in patients who scored 2-3 (12.83 mg/L) than in patients who scored 0-1 (5.52 mg/L) (P=.028). CSF beta(2)-m is increased in newborns with symptomatic congenital CMV infection and correlates with neuroimaging abnormalities. beta(2)-m appears to be an indicator of the severity of brain involvement in congenital CMV infection.

Elevated cerebrospinal fluid lactate levels and the pathomechanism of calcification in Fahr's disease.

In this study, we report the case of a 68-year-old man complaining of involuntary movement of his left shoulder and lower jaw plus dyspnea. On cranial computed tomography and magnetic resonance imaging, marked and symmetrical calcification at the basal ganglia and dentate nuclei was documented. An elevated cerebrospinal fluid (CSF) lactate level was confirmed by spinal tap examination and magnetic resonance spectroscopy. The raised CSF lactate level, clinical characteristics such as diabetes, bilateral hearing loss and symmetrical cerebral calcification strongly suggested some kinds of mitochondrial disease. However, gene analysis of peripheral blood leukocytes revealed no typical or known mutations. Under the diagnosis of Fahr's disease, we treated him with haloperidol, which completely abolished his symptoms. In Ellsworth-Howard test, he showed markedly decreased phosphaturic response to parathyroid hormone with same pattern as type 2 pseudohypoparathyroidism. This abnormal response in our patient, probably due to respiratory alkalosis reflecting chronic hyperventilation, might in part explain similar mechanism of ectopic calcification underlying these two diseases.

Aicardi-Goutières syndrome.

Aicardi-Goutieres syndrome is a familial progressive early onset encephalopathy with basal ganglia calcifications, chronic CSF lymphocytosis and high level of interferon-alpha in CSF. Cutaneous necrotic lesions and the neuropathological aspect of microangiopathy and microinfarctions suggest a vascular process in relation to elevated interferon-alpha. A genetic defect in the regulation of its synthesis may be the causal factor of the disorder.

Aicardi-Goutieres syndrome in siblings.

Two siblings with familial encephalopathy, calcification of the basal ganglia, and cerebrospinal fluid lymphocytosis, constituting the triad of Aicardi-Goutieres syndrome, are reported. This syndrome resembles congenital intrauterine infections, which must be meticulously excluded. Aicardi-Goutieres syndrome is extremely rare and is being reported from the Arab world for the first time to our knowledge.

Cerebrospinal fluid viral load is related to cortical atrophy and not to intracerebral calcifications in children with symptomatic HIV disease.

The relationships between viral load in plasma and cerebrospinal fluid (CSF) and computed tomography (CT) brain scan abnormalities were studied in 39 children between 0.5 and 13 years of age with symptomatic HIV-1 disease. Quantitative RNA PCR was used to determine HIV-1 RNA levels and a semiquantitative analog rating technique was used to evaluate non-contrast CT brain scans. CSF HIV-1 RNA copy number correlated significantly with CT brain scan ratings for severity of cortical atrophy (r = 0.36; P < 0.05) but not with ratings of intracerebral calcifications (r = -12; NS). The difference between these two correlations was significant (P < 0.05). Plasma HIV-1 RNA copy number did not correlate significantly with any CT brain scan ratings or with CSF viral load (r = 0.05; NS). Severity of cortical atrophy appeared to reflect the level of viral load in the CSF, supporting the notion that active HIV-1 replication in the CNS is at least in part responsible for such brain abnormalities in children. The lack of correlation of intracerebral calcifications with other CT brain scan abnormalities as well as with CSF viral load suggests that this lesion is relatively independent and may reflect a different neuropathologic process.

Aicardi-Goutières syndrome: an update and results of interferon-alpha studies.

Twenty-seven patients with familial encephalopathy with calcification of the basal ganglia and chronic cerebrospinal fluid (CSF) lymphocytosis (Aicardi-Goutières syndrome) are reviewed. In 19 children, the onset was within the first 4 months of life. Most patients had normal head circumference at birth, but 21 developed microcephaly between 3 and 12 months. Neuroimaging showed severe and progressive brain atrophy in all patients. The extent and intensity of the calcification was variable even in the same sibship. CSF lymphocytosis persisted beyond 12 months of age in 7 children. High levels of interferon-alpha were found in serum and CSF in 14 patients. The higher CSF levels suggest intrathecal synthesis. Tubuloreticular inclusions related to the presence of interferon were found in 4 additional children. The 19 patients still alive (6 older than 10 years) are profoundly disabled. However, the syndrome may present with individual variations in severity, rapidity of evolution, and imaging features. Neuropathological examination in 2 patients failed to detect significant inflammatory lesions and showed only foci of necrosis and wide-spread demyelination. This study supports an autosomal recessive inheritance for this syndrome. The high level of interferon-alpha is not explained but may play a role in the pathogenesis of the disorder.