Cerebral Calcifications Research Articles

Clinical outcomes of pediatric patients with congenital toxoplasmosis in a fourthlevel center Introduction. Congenital

Congenital toxoplasmosis is a highly prevalent parasitic disease worldwide, with a high burden of disease and neurodevelopmental involvement in pediatric patients. To describe the clinical sequelae and neurodevelopmental state of pediatric patients with congenital toxoplasmosis at the Hospital Militar Central during 2013 to 2020. We conducted an observational, descriptive, cross-sectional study with an analytical component, including pediatric patients diagnosed with congenital toxoplasmosis. Patients consulted the Hospital Militar Central from January 2013 to December 2020. The Ages and Stages Questionnaires 3 neurodevelopmental scale was applied to children under six years old. Forty-five patients with confirmed congenital toxoplasmosis were included, with a mean age of 5.9 years; 60% were male; 11.2 % were symptomatic at birth, and 33% presented chorioretinitis. During the follow-up, 73% presented ophthalmologic sequelae, 64% cerebral calcifications, 4.4% hydrocephalus, 11.2% cerebral palsy, and 13.4% focal epilepsy. In children under six years old, 58% presented neurodevelopmental compromise, and in those over six years old, 62% had cognitive deficits. In this cohort, 68% of the patients received posnatal treatment, with a statistically significant association between not receiving treatment and ophthalmological sequelae (OR = 5.2; p < 0.001). Congenital toxoplasmosis is associated with important long-term sequelae similar to those described in several Latin American series. These findings highlight the importance of early diagnosis, evaluation, treatment, and timely interdisciplinary follow-up of patients in our country to improve their prognosis.

Differentiating calcifications from cerebral microbleeds using quantitative susceptibility mapping.

To differentiate cerebral microbleeds (CMBs) and calcifications using quantitative susceptibility mapping (QSM). CMBs were visualized and located using QSM from susceptibility-weighted imaging data collected on a 3-T MR scanner. Calcifications of the pineal gland and the choroid plexus were localized first using CT. All calcifications and CMBs were assessed using QSM to evaluate their magnetic susceptibility. The distribution of the magnetic susceptibility for the CMBs was determined and the CT attenuation was correlated with the mean magnetic susceptibility for the calcifications. A total of 232 hypointense foci were selected from the QSM data: 121 were CMBs and 111 were calcifications. The mean magnetic susceptibility was -214 ± 112 ppb for the calcifications and 392 ± 204 ppb for the CMBs. The minimum value of magnetic susceptibility was 75 ppb for all the CMBs and the maximum value was -52 ppb for all the calcifications. The calcifications were clearly differentiable from the CMBs from the sign alone (p < 0.001). The magnetic susceptibility for the CMBs was 299 ± 133 ppb in the lobar subcortical white matter and 499 ± 220 ppb for deep CMBs in the basal ganglia, thalamus, and brainstem. There was a significant difference in the susceptibility between these two regions (p < 0.001). The sign of the magnetic susceptibility was sufficient to differentiate calcifications and CMBs. The concentration of calcium or iron can be determined from the susceptibility value itself. The deep CMBs had higher susceptibility on average than lobar bleeds. This study's ability to differentiate between CMBs and calcifications using QSM could enhance diagnostic accuracy, guiding more precise treatment decisions for stroke or tumor patients. The sign of magnetic susceptibility is sufficient to differentiate calcifications and CMBs. QSM can successfully differentiate calcifications from microbleeds. The concentration of calcium or iron can be determined from the susceptibility value itself.

A rare case of reversible hemidystonia in chronic hypoparathyroidism with extensive cerebral calcification

A rare case of reversible hemidystonia in chronic hypoparathyroidism with extensive cerebral calcification

Imaging Feature of Leukoencephalopathy with Calcifications and Cysts (Labrune Syndrome)

Labrune syndrome is an uncommon central nervous system disorder characterized by leukoencephalopathy, cerebral calcifications, and cysts on brain imaging. The basic pathology is microangiopathy resulting from a mutation in the SNORD118 gene. Radiological imaging is the hallmark of the disease.

Further delineation of phenotype and genotype of Kenny-Caffey syndrome type 2 (phenotype and genotype of KCS type 2).

Kenny-Caffey syndrome type 2 (KCS2) is an extremely rare inherited disorder characterized by proportionate short stature, skeletal defects, ocular and dental abnormalities, and transient hypocalcemia. It is caused by variants in FAM111A gene. Diagnosis of KCS2 can be challenging because of its similarities to other syndromes, the absence of clear hallmarks and the deficient number of genetically confirmed cases. Here, we aimed to further delineate and summarize the genotype and phenotype of KCS2, in order to get a better understanding of this rare disorder, and promote early diagnosis and intervention. We present clinical and genetic characteristics of eight newly affected individuals with KCS2 from six families, including one family with three individuals found to be a father-to-daughter transmission, adding to the limited literature. Furthermore, we performed a review of genetically confirmed KCS2 cases in PubMed, MEDLINE and CNKI databases. There were six females and two males in our cohort. All the patients presented with short stature (100.0%). Clinical manifestations included ocular defects such as hypermetropia (5/8), dental problems such as defective dentition (3/8) and dental caries (3/8), skeletal and brain anomalies such as delayed closure of anterior fontanelle (6/8), cerebral calcification (3/8), cortical thickening (3/8) and medullary stenosis (4/8) of tubular bones. Endocrinologic abnormalities included hypoparathyroidism (5/8) and hypocalcemia (3/8). One male patient had micropenis and microorchidism. All cases harboured missense variants of FAM111A, and nucleotides c.1706 arose as a mutational hotspot, with seven individuals harbouring a c.1706G>A (p.Arg569His) variant, and one child harbouring a c.1531T>C (p.Tyr511His) variant. Literature review yielded a total of 46 patients from 20 papers. Data analysis showed that short stature, hypoparathyroidism and hypocalcemia, ocular and dental defects, skeletal features including cortical thickening and medullary stenosis of tubular bones, and seizures/spasms were present in more than 70% of the reported KCS2 cases. We provide detailed characteristics of the largest KCS2 group in China and present the first genetically confirmed instance of father-to-daughter transmission of KCS2. Our study confirms that Arg569His is the hot spot variant and summarizes the typical phenotypes of KCS2, which would help early diagnosis and intervention.

Analysis of congenital Zika syndrome clinicopathologic findings reported in the 8 years since the Brazilian outbreak

Aim: A Zika virus outbreak that began in Brazil, developed into an international public health emergency that extended from February 2015 until November 2016. Zika-infected pregnant women gave birth to a cohort of infants with congenital Zika syndrome (CZS) originally defined by severe microcephaly, retinal scarring, joint deformities, and hypertonia. This study examines the nature, extent, and severity of all CZS clinicopathologic findings described to date, compiled and analyzed by system. It reviews studies monitoring disease progression and proposing classification schemes for CZS stages. The teratogenic cellular and molecular mechanisms implicated in CZS pathogenesis are also discussed. Methods: A systematic review was conducted by literature search through WorldCat.org and ProQuest Central databases to identify studies on case series from the 2015–2016 CZS outbreak. Results: Twenty-six reports were included describing radiologic, ophthalmologic, audiologic, orthopedic, and laboratory test results in CZS cases including stillborns between 2016 and 2023. CZS neuropathology included prenatal and postnatal microcephaly, cerebral calcifications, quadriparesis, epilepsy, ventriculomegaly, reduced cerebral parenchyma, malformation of cortical development, and sleep electroencephalogram disturbances. Visual deficits were due to retinal and optic nerve lesions. Conductive and sensorineural hearing deficits were stable. Hypertonia, hypotonia, and spasticity with foot, hip, knee, and shoulder deformities resulted in arthrogryposis and restricted joint mobility. There was enlargement of immune organs, increased leukocyte counts, and cytokine dysregulation. Oro-craniofacial deformities affected the midface and caused dental eruption delay. Additional studies proposed that these systemic teratogenic effects could be attributable to transplacental Zika virus infection of multiple fetal progenitor cell lineages. Conclusions: The CZS-associated impairments in brain, eye, musculoskeletal, and immunologic functions caused disabilities that varied from moderate to severe, and significantly increased age-specific mortality rates. Further research is warranted to assess progression, classify stages, elucidate the precise molecular mechanisms mediating Zika teratogenicity, develop suitable therapeutic strategies, and design supportive social policies.

Presentation of hypoparathyroidism in Italy: a nationwide register-based study.

We sought to assess the clinical presentation of hypoparathyroidism (HypoPT) in Italy. We performed a nationwide study retrieving data from the hospital discharge ICD-9 codes database of the Italian Health Ministry, from 2007 through 2017. The codes corresponding to diagnosis of cardiovascular disease, cancer, infection, renal failure, psychiatric disease, upper airway tract infection and pneumonia, seizures, nephrolithiasis, cognitive impairment, cerebral calcifications, skin disorders, fracture, and cataract were retrieved when associated with the diagnosis of HypoPT (252.1). We excluded codes corresponding to diagnoses of cancer of the neck region. In-hospital mortality rate was calculated. We retrieved the same data from an age- and sex-matched non-HypoPT control population. Fourteen thousand five hundred seventy-nine hospitalizations for HypoPT and controls were analyzed. Hospitalization for cardiovascular disease, cancer, infection, renal failure, seizures, nephrolithiasis, cerebral calcifications (p < 0.0001), and cognitive impairment (p < 0.05) were more common in HypoPT compared to controls. Mean age of HypoPT with cardiovascular disease, cancer, and renal failure was younger compared to controls (p < 0.0001). The OR of hospitalization for cardiovascular disease, cancer, renal failure, seizures (OR 2, 40, 48 and1.6, respectively), and nephrolithiasis (OR 1.6) were significant in HypoPT compared to non-HypoPT. The OR of hospitalization for infection and cognitive impairment were significant only in HypoPT women (OR 1.3 and 2.3, respectively). In-hospital mortality rate was lower in HypoPT vs controls (0.5% and 3.7%; p < 0.0001). Hospitalizations for cardiovascular disease, cancer, and renal failure are more prevalent and occur at a younger age in HypoPT vs non-HypoPT. Hospitalizations for seizures and nephrolithiasis are frequent in HypoPT; those for infection and cognitive impairment are more common in HypoPT women.

Chapter 7 - White matter disorders with cerebral calcification in adulthood

This chapter provides a comprehensive overview of adult-onset leukoencephalopathies with cerebral calcification (CC), emphasizing the importance of age at presentation, systemic clinical features, and neuroimaging patterns for accurate diagnosis. CC is a multifaceted phenomenon associated with various neurologic, developmental, metabolic, and genetic conditions, as well as normal aging. Here, we explore the distinction between primary familial brain calcification (PFBC) and secondary forms, including metabolic and mitochondrial causes. We discuss genetic causes, e.g., SLC20A2, XPR1, PDGFB, PDGFRB, MYORG, NAA60 and JAM2, in the context of autosomal dominant and recessive PFBC and other inherited conditions. The chapter delineates the diagnostic approach involving family history, clinical assessments, and detailed investigations of calcium-phosphate metabolism. Neuroimaging modalities, including computed tomography and magnetic resonance imaging, are crucial for assessing calcification patterns and localizations. Genetic testing, especially next-generation sequencing, plays a pivotal role in providing a final molecular diagnosis. The management of patients with CC encompasses symptomatic treatment and cause-specific approaches, requiring a multidisciplinary care approach. In conclusion, this chapter highlights the complexity of leukoencephalopathies with CC, emphasizing the need for integrated and evolving management to optimize patient care.

Seroprevalence of Toxoplasma gondii among Aborted Women Admitted to Erbil Maternity Teaching Hospital

Background: Toxoplasma gondii is an obligate intracellular parasite responsible for causing congenital toxoplasmosis. Congenital infection during the first and second trimesters of pregnancy may result in spontaneous abortion, mental retardation, and cerebral calcifications, while the severity of fetal damage is decreased during the third trimester.&#x0D; &#x0D; Objectives: This study aimed to determine the seroprevalence of toxoplasmosis and its association with clinical-obstetric determinants and sociodemographic factors in aborted women.&#x0D; &#x0D; Materials and Methods: The present study was a Hospital-based Cross-sectional Study comprised 100 women who admitted to Erbil Maternity Hospital with a spontaneous abortion. A questionnaire was filled by the researchers after verbal consent, and 5 ml of venous blood was collected from each participant, centrifuged at 3500 rpm, and stored in 2 Eppendorf tubes, and tested by ELISA and Electrochemiluminescence Immunoassay by Cobas e 411 for Toxoplasma IgG and IgM according to Manufacturer’s instructions.&#x0D; &#x0D; Results: The highest seroprevalence for toxoplasmosis was observed in illiterate females aged 26-35 and living in Erbil City's urban areas. A statistically significant association was recorded regarding seropositivity to Toxoplasma IgG and having a history of abnormal babies (P=0.023), Toxoplasma IgG seropositivity and a history of having toxoplasmosis (P=0.016), and seropositivity to Toxoplasma IgM and parity of the females (P=0.037).&#x0D; &#x0D; Conclusions: Screening for toxoplasmosis during pregnancy is crucial for all women for the prevention of disease progression. Although there are various screening methods for the detection of toxoplasmosis, not all the methods are applicable and financially suitable for the patients.

Fahr’s syndrome revealed by convulsive seizures

Fahr's syndrome is a fairly rare antomo-clinic entity, it is defined by the existence of bilateral and symmetrical cerebral calcifications, especially of the central grey nuclei and is often associated with dysparathyroidism. We report the case of a young 29-year-old patient who presented with seizures and headaches. A CT scan of the brain showed calcifications of the central grey nuclei, the periventricular and subcortical white matter as well as the dentate cerebellar nuclei. The biological assessment showed hypoparathyroidism and hypocalcaemia. Substitutive medical treatment based on calcium and vitamin D allowed a clear rapid clinical improvement.

MRI reveals cerebral iron, calcification and spinal cord atrophy in M83 mouse model of Parkinson’s disease

AbstractBackgroundRodent models of Parkinson’s disease have been crucial tools for understanding the pathogenic mechanisms of alpha‐synuclein‐associated alterations. Here, we employed multiparametric high‐field magnetic resonance imaging (MRI) to examine the molecular alterations and neurodegeneration in the brain and spinal cord of transgenic M83 (A53T) murine model of Parkinson’s disease.MethodTen nontransgenic littermates and twelve M83 mice at 10‐11 months of age were assessed. Gradient echo MR for susceptibility‐weighted imaging (SWI) and T1 MR scans were acquired ex vivo at 9.4 T in the brain and spinal cord of mice. Histology and immunofluorescence staining for alpha‐synuclein inclusions (phospho‐S129), NeuN, GFAP and Iba‐1 for gliosis were used to investigate the nature of the imaging observations.ResultFrom T1 MR, a reduced area of white matter in the thoracic spinal cord (T1) and a reduced area of gray matter in the cervical (C6‐C8) and thoracic (T1) spinal cord were observed in the M83 mice compared to nontransgenic mice. In addition, lower left‐right length measurements in the cervical (C8) spinal cord were observed in M83 mice than in nontransgenic mice. SW images revealed regional hypointensities in the hippocampus, cortex, striatum, midbrain and thalamus of M83 mice, which in corresponding phase images indicated both diamagnetic (calcification) and paramagnetic (iron) lesions in the brains of M83 mice. Immunofluorescence staining demonstrated an increased Iba‐1 level in the brains of M83 mice, indicating microgliosis.ConclusionWe found cerebral iron, calcification, microgliosis and spinal cord atrophy in M83 mice.

THU234 An Adolescent Patient With Asymptomatic Hypocalcemia And Extensive Cerebral Calcification Due To Pseudohypoparathyroidism Type 1B: A Care Report

Abstract Disclosure: R. Alemzadeh: None. J.D. Ross: None. D. Guillen-Mendoza: None. Background: Pseudohypoparathyroidism (PHP) is a heterogeneous group of disorders due to renal resistance to parathyroid hormone (PTH) resulting in biochemical hypoparathyroidism but with skeletal sensitivity to PTH. Case Presentation: A 15-year-old African American male was incidentally found to have biochemical evidence of severe hypocalcemia during routine evaluation of his bilateral slipped capital-femoral epiphyses. The patient was at age-appropriate stage of puberty with normal height and without any features of hereditary osteodystrophy. However, he had history of mild developmental delay requiring school accommodations. On physical exam, there was some mild dyscoordination with finger and toe-tapping and a Myerson’s sign, negative tetany signs. The biochemical screening revealed markedly low serum calcium (4.9 mg/dL) with elevated phosphorus (7.8 mg/dL) and PTH (1314 pg/mL) levels. His hypocalcemia was accentuated by the presence of severe 25 hydroxy-vitamin D deficiency (7.5 ng/mL) with mild hypomagnesemia (1.4 mg/dL). He had normal renal and thyroid function tests with normal growth factors. There were minimal plasma cyclic AMP responses to a single dose of intravenous teriparatide (Ellsworth-Howard test) consistent with diagnosis of pseudohypoparathyroidism. The skeletal survey showed bowing and under-tubulation of the radius, ulna, tibia, and fibula as well as slipped capital femoral epiphysis bilaterally. His brain CT scan showed symmetrical severe dense calcifications in the basal ganglia, bilateral frontal, parietal and temporal subcortical white matter, pons and right dentate nucleus. Genetic testing did not reveal any GNAS mutations. The patient was initially treated with parenteral calcium followed by high-dose oral calcium supplements and calcitriol. His coexisting hypovitaminosis D and hypomagnesemia were corrected with oral high-dose cholecalciferol and magnesium sulfate, respectively. Conclusions: An incidental finding of severe asymptomatic hypocalcemia and elevated PTH without hereditary osteodystrophy phenotype raised the clinical suspicion of pseudohypoparathyroidism type 1B. This was associated with cerebral calcifications with increasing risk of worsening learning disabilities and minimal neurological findings. Presentation: Thursday, June 15, 2023

Carbonic anhydrase II deficiency syndrome with amelogenesis imperfecta linked to a homozygous CA2 deletion.

We performed a study to present a phenotypic and genotypic characterization of a patient clinically diagnosed with carbonic anhydrase II (CAII) deficiency syndrome. Medical records were reviewed, and oral examination was performed. Sanger sequencing was undertaken for molecular diagnosis. The patient presented with osteopetrosis, renal tubular acidosis, cerebral calcification, blindness, deafness, and development delay. The oral manifestations included anterior open bite, posterior crossbite, tooth eruption impairment, and hypoplastic amelogenesis imperfecta (AI). Molecular analysis revealed a CA2 homozygous deletion (c.753delG, p.Asn252Thrfs*14) and confirmed the clinical diagnosis. This study suggests that AI can be another feature of CAII deficiency syndrome. For the first time, a CA2 disease-causing variant is reported to be associated with syndromic AI.

Fahr's syndrome with hypoparathyroidism, thrombocytopenia, and seizure: a rare case report.

A 32-year-old male was brought with a repeated history of twitching of hands, tingling sensation, and uncontrolled seizure despite medications. Computed tomography findings showed bilateral basal ganglia, cerebellar dentate nuclei, and subcortical cerebral white matter calcifications. Laboratory studies revealed reduced levels of calcium, parathyroid hormone, and thrombocyte count. Based on these investigations Fahr's syndrome probably due to hypoparathyroidism with thrombocytopenia was diagnosed. The patient was initially treated with intravenous calcium gluconate and platelet transfusion followed by oral calcium supplementation. Fahr's syndrome due to hypoparathyroidism should be suspected in any patient with neurological symptoms and hypocalcemia. Seizures in the patient of Fahr's syndrome with thrombocytopenia could be very detrimental due to the risk of intracranial hemorrhage. Hence, treatment should be started as early as possible.

Fahr’s Syndrome Secondary to Hypoparathyroidism Presenting with Paralysis and Recurrent Seizures: A Case Report

Aim: To describe a rare case of Fahr’s syndrome (FS) associated with chronic post-surgical hypoparathyroidism and hypocalcemia.&#x0D; Case Presentation: A 63-year-old female with a previous history of total thyroidectomy and hemiplegia presented to our hospital with altered mentation and recurrent generalized tonic-clonic seizures. Laboratory evaluation revealed hypoparathyroidism, hypocalcemia, and hypokalemia. Head computed tomography (CT) scan was consistent with FS, demonstrating extensive, bilateral, and symmetrical calcified deposits in the brain, predominantly in basal ganglia, corona radiata, and cerebellar hemispheres. The association with post-surgical hypoparathyroidism and relevant biochemical indices determined the suspected etiology of the pathologic process of ectopic calcification.&#x0D; Discussion: FS is a rare, neurodegenerative disorder characterized by abnormal bilateral ectopic calcified deposits in the basal ganglia and other brain structures. FS presents with a wide variety of neurological and psychiatric manifestations. The diagnosis is confirmed by neuroimaging studies such as a head CT scan or magnetic resonance imaging, which displays the calcification of BG and other structures in a bilateral and symmetrical pattern. Biochemical analysis may adjunctively identify the underlying risk factor of the disease.&#x0D; Conclusion: Our case represents a long-term severe consequence of untreated post-surgical hypoparathyroidism, which has consequently led to irreversible secondary FS. Maintenance of eucalcemic and euphosphatemic states is essential to prevent the progression of ectopic cerebral calcification.

Fahr disease presenting with multiple cerebral calcifications

Fahr disease, also known as idiopathic basal ganglion calcification, is a rare and genetically heterogeneous neurological disorder. Herein, we report a rare case of Fahr disease presenting with multiple cerebral calcifications. A 63-year-old woman presented with dizziness to a local clinic. Brain computed tomography performed on admission revealed multiple high-intensity lesions in both basal ganglia, both cerebellar hemispheres, and the left frontal lobe. In contrast, brain magnetic resonance imaging (MRI) showed no prominent lesions on T2- and T1-weighted images, and there was no contrast enhancement after gadolinium injection. However, multiple dark signals were detected on gradient echo MRI. The location and radiological appearance of the lesion resembled those of a physiological intracranial calcification, except for asymmetric calcification in both cerebellar hemispheres and the left frontal subcortical white matter. The patient was diagnosed with basal ganglion calcification with multiple cerebral cavernous malformations or, less likely, brain tumors. Through a careful radiological and clinical review, the calcifications were diagnosed as Fahr disease. Follow-up was planned. It is important to consider the presence of multiple intracranial calcifications in the basal ganglia, cerebellum, or deep subcortical white matter as a warning sign for Fahr disease.

Acute psychosis as initial presentation for Neurofibromatosis Type 2 (P11-9.006)

<h3>Objective:</h3> To describe the clinical course of a pediatric patient presenting with acute auditory hallucinations with workup revealing a new diagnosis of NF2. <h3>Background:</h3> NF2 is an autosomal dominant neurocutaneous disorder characterized by vestibular schwannomas, meningiomas, neurofibromas, gliomas, cerebral calcifications, cataracts, and cognitive impairment. Acute onset psychosis is an uncommon sequela of NF2, and if present, is usually attributed to the known prior history of NF2. However, here we present a case of acute psychosis that precipitated the <i>initial</i> diagnosis of NF2. <h3>Design/Methods:</h3> NA <h3>Results:</h3> A 13-year-old Hispanic male with no known intracranial tumors or other neurocutaneous stigmata presented with acute-onset psychosis, agitation, delusions, and painless monocular vision loss. Upon further review, he was reported to have a remote history of morning headaches, right upper extremity weakness and paresthesias thought to be due to a trampoline accident, and multiple dermal lesions that were diagnosed as pilonidal cysts despite biopsy and sectioning. He presented with complaints of hearing a constant “airplane sound,” poor sleep, agitation, persecutory delusions and paranoia, pressured speech, and discontinuity of thought. On exam, he was agitated and not oriented to situation, responding rapidly to questions with the incorrect answer, hyperkinetic, and generally distressed and labile. MRI brain with and without contrast demonstrated bilateral enhancing vestibular schwannomas, a meningioma, and nerve sheath tumor, all radiographically diagnostic for NF2. Though he was initially treated empirically for encephalitis with steroids, he improved rapidly upon initiation of antipsychotics; all other workup for the psychosis was unremarkable and a pathogenic variant of NF2 was confirmed. <h3>Conclusions:</h3> It is important to look for stigmata of NF2 in patients with psychosis as bilateral vestibular schwannomas can cause auditory hallucinations secondary to continuous tinnitus. Early identification of NF2 will lead to targeted therapeutic/surgical intervention that may relieve cranial nerve compression and thus reduce the odds of developing psychosis. <b>Disclosure:</b> Dr. Domingue has nothing to disclose. Dr. Sandweiss has nothing to disclose. Dr. Salazar has nothing to disclose. Dr. Gill has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Elite Medical Experts. The institution of Dr. Gill has received research support from NIH-NINDS.

Carbonic anhydrase II deficiency.

Carbonic anhydrase II deficiency (OMIM # 259730), initially called "osteopetrosis with renal tubular acidosis and cerebral calcification syndrome", reveals an important role for the enzyme carbonic anhydrase II (CA II) in osteoclast and renal tubule function. Discovered in 1972 and subsequently given various names, CA II deficiency now describes >100 affected individuals encountered predominantly from the Middle East and Mediterranean region. In 1983, CA II deficiency emerged as the first osteopetrosis (OPT) understood metabolically, and in 1991 the first understood molecularly. CA II deficiency is the paradigm OPT featuring failure of osteoclasts to resorb bone due to inability to acidify their pericellular milieu. The disorder presents late in infancy or early in childhood with fracturing, developmental delay, weakness, short stature, and/or cranial nerve compression and palsy. Mental retardation is common. The skeletal findings may improve by adult life, and CA II deficiency can be associated with a normal life-span. Therefore, it has been considered an "intermediate" type of OPT. In CA II deficiency, OPT is uniquely accompanied by renal tubular acidosis (RTA) of proximal, distal, or combined type featuring hyperchloremic metabolic acidosis, rarely with hypokalemia and paralysis. Cerebral calcification uniquely appears in early childhood. The etiology is bi-allelic loss-of-function mutations of CA2 that encodes CA II. Prenatal diagnosis requires mutational analysis of CA2. Although this enzymopathy reveals how CA II is important for the skeleton and kidney tubule, the pathogenesis of the mental subnormality and cerebral calcification is less well understood. Several mouse models of CA II deficiency have shown growth hormone deficiency, yet currently there is no standard pharmacologic therapy for patients. Treatment of the systemic acidosis is often begun when growth is complete. Although CA II deficiency is an "osteoclast-rich" OPT, and therefore transplantation of healthy osteoclasts can improve the skeletal disease, the RTA and central nervous system difficulties persist.

Toxoplasma gondii infections in pediatric neurosurgery.

Toxoplasma gondii is a parasite that is estimated to infect one-third of the world's population. It is acquired by ingesting contaminated water and food specially undercooked meat, contact with domestic or wild feline feces, and during pregnancy by transplacental transmission.Immunocompetent hosts are usually asymptomatic, and infection will be self-limited, while those patients whose immune system is debilitated by HIV infection, immunosuppressive therapy, long-term steroid treatment, and fetuses infected during gestation will show evidence of systemic activity which is more severe in the central nervous system and eyes due to insufficient immune response caused by their respective blood barriers. Congenital toxoplasmosis has an estimated incidence of 8% in mothers who were seronegative at the beginning of their pregnancy. Infection in the first trimester may result in spontaneous abortion or stillbirth; however, it is estimated that the highest risk for vertical transmission is during the second and third trimesters when blood flow and placenta thickness favor parasitic transmission.Congenital toxoplasmosis can be detected with periodic surveillance in endemic areas, and with appropriate treatment, the risk of vertical transmission can be reduced, and the severity of the disease can be reversed in infected fetuses.While most infected newborns will show no evidence of the disease, those who suffer active intrauterine complications will present with cerebral calcifications in 8-12% of cases, hydrocephalus in 4-30%, and chorioretinitis in 12-15%. Also, seizure disorders, spasticity, and varying degrees of neurocognitive deficits can be found in 12%.Four distinct patterns of hydrocephalus have been described: aqueductal stenosis with lateral and third ventricle dilatation, periforaminal calcifications leading to foramen of Monro stenosis with associated asymmetrical ventricle dilatation, a mix of aqueductal and foramen of Monro stenosis, and overt hydrocephalus without clear evidence of obstruction with predominant dilatation of occipital horns (colpocephaly).While all patients diagnosed with congenital toxoplasmosis should undergo pharmacological treatment, those presenting with hydrocephalus have traditionally been managed with CSF shunting; however, there are reports of at least 50% success when selected cases are treated with endoscopic third ventriculostomy. Successful hydrocephalus management with appropriate treatment leads to better intellectual outcomes.

Intracranial calcification in Fam20c-deficient mice recapitulates human Raine syndrome

FAM20C (family with sequence similarity 20-member C) is a protein kinase that phosphorylates secretory proteins, including the proteins that are essential to the formation and mineralization of calcified tissues. FAM20C loss-of-function mutations cause Raine syndrome in humans, characterized by generalized osteosclerosis, distinctive craniofacial dysmorphism, along with extensive intracranial calcification. Our previous studies revealed that inactivation of Fam20c in mice led to hypophosphatemic rickets. In this study, we examined the expression of Fam20c in the mouse brain and investigated brain calcification in Fam20c-deficient mice. Reverse transcription polymerase chain reaction (RT-PCR), Western-blotting and in situ hybridization analyses demonstrated the broad expression of Fam20c in the mouse brain tissue. X-ray and histological analyses showed that the global deletion of Fam20c (mediated by Sox2-cre) resulted in brain calcification in mice after postnatal 3 months and that the calcifications were bilaterally distributed within the brain. There was mild perifocal microgliosis as well as astrogliosis around calcospherites. The calcifications were first observed in the thalamus, and later in the forebrain and hindbrain. Furthermore, brain-specific deletion (mediated by Nestin-cre) of Fam20c in mice also led to cerebral calcification at an older age (postnatal 6 months), but no obvious skeletal or dental defects. Our results suggest that the local loss of FAM20C function in the brain may directly account for intracranial calcification. We propose that FAM20C plays an essential role in maintaining normal brain homeostasis and preventing ectopic brain calcification.