Basal Ganglia Calcification Research Articles

Neuroprotective effect of 5-aminolevulinic acid against low inorganic phosphate in neuroblastoma SH-SY5Y cells

PiT-1 (encoded by SLC20A1) and PiT-2 (encoded by SLC20A2) are type-III sodium-dependent phosphate cotransporters (NaPiTs). Recently, SLC20A2 mutations have been found in patients with idiopathic basal ganglia calcification (IBGC), and were predicted to bring about an inability to transport Pi from the extracellular environment. Here we investigated the effect of low Pi loading on the human neuroblastoma SH-SY5Y and the human glioblastoma A172 cell lines. The results show a different sensitivity to low Pi loading and differential regulation of type-III NaPiTs in these cells. We also examined whether 5-aminolevulinic acid (5-ALA) inhibited low Pi loading-induced neurotoxicity in SH-SY5Y cells. Concomitant application of 5-ALA with low Pi loading markedly attenuated low Pi-induced cell death and mitochondrial dysfunction via the induction of HO-1 by p38 MAPK. The findings provide us with novel viewpoints to understand the pathophysiology of IBGC, and give a new insight into the clinical prevention and treatment of IBGC.

Expansion of the phenotype of Kosaki overgrowth syndrome.

Skeletal overgrowth is a characteristic of several genetic disorders that are linked to specific molecular signaling cascades. Recently, we established a novel overgrowth syndrome (Kosaki overgrowth syndrome, OMIM #616592) arising from a de novo mutation in PDGFRB, that is, c.1751C>G p.(Pro584Arg). Subsequently, other investigators provided in vitro molecular evidence that this specific mutation in the juxtamembrane domain of PDGFRB causes an overgrowth phenotype and is the first gain-of-function point mutation of PDGFRB to be reported in humans. Here, we report the identification of a mutation in PDGFRB, c.1696T>C p.(Trp566Arg), in two unrelated patients with skeletal overgrowth, further confirming the existence of PDGFRB-related overgrowth syndrome arising from mutations in the juxtamembrane domain of PDGFRB. A review of all four of these patients with an overgrowth phenotype and PDGFRB mutations revealed postnatal skeletal overgrowth, premature aging, cognitive impairment, neurodegeneration, and a prominent connective tissue component to this complex phenotype. From a functional standpoint, hypermorphic mutations in PDGFRB lead to Kosaki overgrowth syndrome, infantile myofibromatosis (OMIM #228550), and Penttinen syndrome (OMIM #601812), whereas hypomorphic mutations lead to idiopathic basal ganglia calcification (OMIM #615007). In conclusion, a specific class of mutations in PDGFRB causes a clinically recognizable syndromic form of skeletal overgrowth.

Inherited Arterial Calcification Syndromes: Etiologies and Treatment Concepts.

We give an update on the etiology and potential treatment options of rare inherited monogenic disorders associated with arterial calcification and calcific cardiac valve disease. Genetic studies of rare inherited syndromes have identified key regulators of ectopic calcification. Based on the pathogenic principles causing the diseases, these can be classified into three groups: (1) disorders of an increased extracellular inorganic phosphate/inorganic pyrophosphate ratio (generalized arterial calcification of infancy, pseudoxanthoma elasticum, arterial calcification and distal joint calcification, progeria, idiopathic basal ganglia calcification, and hyperphosphatemic familial tumoral calcinosis; (2) interferonopathies (Singleton-Merten syndrome); and (3) others, including Keutel syndrome and Gaucher disease type IIIC. Although some of the identified causative mechanisms are not easy to target for treatment, it has become clear that a disturbed serum phosphate/pyrophosphate ratio is a major force triggering arterial and cardiac valve calcification. Further studies will focus on targeting the phosphate/pyrophosphate ratio to effectively prevent and treat these calcific disease phenotypes.

Teaching NeuroImages: Fahr syndrome caused by hypoparathyroidism.

A 57-year-old woman with a remote history of thyroidectomy but no prior neurologic symptoms developed seizures, fever, and coma. Limited evaluation at her local hospital in rural Haiti demonstrated serum hypocalcemia (4 mg/dL) and extensive bilateral subcortical calcification in the cerebral and cerebellar hemispheres on CT (figure). This pattern of calcification can occur in inherited conditions such as familial idiopathic basal ganglia calcification (Fahr disease) and acquired conditions (referred to as Fahr syndrome) including parathyroid dysfunction and intrauterine infection.1,2 Given our patient's severe hypocalcemia, Fahr syndrome was attributed to presumed hypoparathyroidism related to prior thyroidectomy in her case.

Pathological basal ganglia calcification in isolated idiopathic hypoparathyroidism: a case report

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

KBG syndrome: An Australian experience.

In 2011, heterozygous mutations in the ANKRD11 gene were identified in patients with KBG syndrome. Since then, 100 cases have been described with the expansion of the clinical phenotype. Here we present 18 KBG affected individuals from 13 unrelated families, 16 with pathogenic mutations in the ANKRD11 gene. Consistent features included intellectual disability, macrodontia, and the characteristic broad forehead with hypertelorism, and a prominent nasal bridge. Common features included hand anomalies, cryptorchidism, and a large number of palate abnormalities. Distinctive findings in this series included malrotation of the abdominal viscera, bilateral inguinal herniae in two patients, basal ganglia calcification and the finding of osteopenia in three patients. Nine novel heterozygous variants were found and the genotype-phenotype correlation was explored. This report highlights the need for thorough examination and investigation of the dental and skeletal systems. The results confirm the specificity of ANKRD11 mutations in KBG and further evidence for this transcription repressor in neural, cardiac, and skeletal development. The description of further cases of KBG syndrome is needed to further delineate this condition, in particular the specific neurological and behavioral phenotype.

Teaching NeuroImages: Adult-onset leukoencephalopathy with intracranial calcifications and cysts (Labrune syndrome).

A 42-year-old woman was admitted for a complex partial seizure. At age 18 years, she had transient diplopia, which was considered a simple strabismus. Current examination revealed a left VI cranial nerve palsy and right arm hyperreflexia. Neuroimaging showed multiple intraparenchymal cystic lesions in white matter (figure), multiple calcifications in basal ganglia, and extensive bilateral leukoencephalopathy. Lack of extraneurologic involvement and genetic testing ( CTC1 gene) ruled out other disorders (mainly Coats plus syndrome). Leukoencephalopathy with intracranial calcifications and cysts is considered a diffuse microangiopathy affecting children.1 Adult-onset patients may present a heterogeneous and milder clinical picture, with slow progression.2

Pseudohypoparathyroidism with basal ganglia calcification

Rationale:Parkinsonism can be secondary to many internal diseases, in some certain conditions, it seems that the clinical manifestations of parkinsonism presenting reversible. We report a case of patient with parkinsonism secondary to pseudohypoparathyroidism, who improved markedly after the supplement of serum calcium.Patient concerns and diagnoses:A 52-year-old woman with acute parkinsonism was diagnosed as pseudohypoparathyroidism after the conducting of brain computed tomography, laboratory examinations, and gene detection. The son of the patient was also examined and was diagnosed as pseudohypoparathyroidism, who had ever complained of the history of epilepsy. The clinical manifestations of parkinsonism of the patient was reevaluated after the supplement of serum calcium according to the diagnosis.Interventions and outcomes:The brain computed tomography revealed the basal ganglia calcification of the patient, accompanying by serum hypocalcemia and hyperphosphatemia. Loss of function mutation also confirmed the diagnosis. Five days after the therapy targeting at correction of serum hypocalcemia, the patient improved greatly in dyskinesia.Lessons:This study reported a patient presenting as acute reversible parkinsonism, who was finally diagnosed as pseudohypoparathyroidism. It indicated us that secondary parkinsonism should be carefully differentiated for its dramatic treatment effect. And the family history of seizures might be an indicator for the consideration of pseudohypoparathyroidism.

Fahr’s Disease Presenting as Bipolar Affective Disorder - Case Report

We present a case of a 59-year-old woman with bipolar affective disorder and idiopathic calcium accumulation in the basal ganglia (lenticular nuclei). Her physical and neurological examinations were without clinically significant abnormalities. Neuropsychological assessment shows mild cognitive deficit. Clinical and laboratory data meet the diagnostic criteria for Fahr’s disease. Discussions were held about the relationship between calcification of basal ganglia and the occurrence of the bipolar disorder.

Autoimmune Polyendocrine Syndrome Type 1: A Rare Case Report And Review Of The Literature

ABSTRACT Objective: The objective of this article is to present a case report of autoimmune polyendocrine syndrome type 1 (APS-1) diagnosed at a tertiary level hospital. Methods: This report summarizes the clinical presentations, laboratory values, treatments, and follow-up of a patient with APS-1. The diagnosis of APS-1 was based on clinical features and laboratory criteria. Results: The study patient with APS-1 was a 9-year-old girl that presented with recurrent seizure as a consequence of hypocalcemia due to primary hypoparathyroidism; an important component of this syndrome. A computerized tomography scan showed diffuse calcification of both basal ganglia and subcortical structures of the brain. Biochemical study showed features of primary hypothyroidism (free thyroxine = 0.31 ng/dL, free triiodothyronine = 1.0 pg/mL, thyroid-stimulating hormone >150 μIU/mL), primary hypoparathyroidism (serum calcium = 6.2 mg/dL, serum magnesium = 1.8 mg/dL, serum inorganic phosphate = 7.9 mg/dL, serum parathyroid hor...

Cockayne syndrome with intracranial calcification, hypomyelination, and cerebral atrophy.

A 5-year-old boy with global developmental delay was admitted with ataxia of 2-month duration. On examination, he had microcephaly and dysmorphic facies with large ears and sunken eyes. CT head revealed bilateral basal ganglia calcification [Figure 1]. Magnetic resonance imaging brain showed atrophy of cerebrum and hypoplasia of cerebellum, with bilateral symmetrical T2 and T2-fluid-attenuated inversion recovery hyperintensities in periventricular white matter suggestive of hypomyelination [Figure 2]. A diagnosis of Cockayne syndrome (CS) was made based on clinico-radiological features.

Fahr’s syndrome and idiopathic hypoparathyroidism: A case report

Introduction. Fahr?s syndrome is a rare, slowly progressive, neurodegenerative disorder, characterised by extensive, bilateral, and symmetrical basal ganglia calcification. It is associated with neuropsychiatric manifestations and gradually progressive cognitive impairment. Fahr's syndrome is the secondary form of brain calcification that is caused by various metabolic, infectious, or degenerative diseases. Case report. We presented a middle-aged male with Fahr's syndrome due to primary idiopathic hypoparathyroidism. Clinical diagnosis was based on signs and symptoms of hypocalcemia, progressive neuropsychiatric illnesses, laboratory evidence of hypoparathyroidism, and radiological signs of calcifications in the basal ganglia. The patient improved after only a few days of intravenous rehydration and calcium substitution, followed by oral supplemental calcitriol. Conclusion. Timely recognition of idiopathic and iatrogenic hypoparathyroidism allows appropriate treatment that can prevent the development and clinical manifestations of Fahr?s syndrome and potentially slow its progression.

Clinical analysis of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes in children

Objective To investigate the clinical, imaging, pathological and molecular biological features of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes(MELAS) in children. Methods The clinical, imaging, pathological and molecular biological features of 12 children with MELAS diagnosed through muscle biopsy or gene sequencing in the Fifth Affiliated Hospital of Zhengzhou University from January 2011 to December 2015 were retrospectively analyzed. Results (1) Clinical features: the main manifestations included headache and vomiting in 11 cases, epileptic seizures in 9 cases, short stature in 8 cases, hairy in 7 cases, intolerance fatigue in 7 cases, cognitive decline in 7 cases, visual disturbance in 6 cases, hearing disturbance in 6 cases, and 5 cases had positive family history.In addition, 7 cases had the serum lactic acid level increase in a rest for 10 min after exercise.(2) Imaging features: 4 cases showed bilateral basal ganglia calcification symmetry in 8 patients who underwent head CT scan.The most frequently involved parts of the lesion were occipital in 10 cases, temporal in 9 cases and parietal lobe in 7 cases in stroke-like episodes.The lesions were lamellar necrosis.The abnormal areas by MRI showed low signal intensity on T1 weighted imaging, high signal intensity on T2 weighted imaging and fluid attenuated inversion recovery, high or equal signal intensity on diffusion weighted imaging, high or low signal intensity on apparent diffusion coefficient; the lactate peak significantly increased on magnetic resonance spectroscopy.The distribution was not in accordance with the control region of the cerebral vessels.Dynamic observation revealed that the lesions were reversible and migratory.(3) Myopathological features: muscle biopsy was performed in all children, and ragged-red fibers were found in 10 cases by improved Gomori staining, strongly succinate dehydrogenase-reactive were found in 9 cases, and the lipid droplets slightly increased in 8 cases by oil red O staining.Besides, the crystalline inclusion bodies in mitochondria were arranged in a parking lot pattern in 9 cases by electromicroscope.(4) Molecular biological characteristics: the mitochondrial gene mutations were analyzed in peripheral blood of 9 children and their parents, including 8 cases with A3243G mutation and 1 case with G13513A mutation.Five mothers had the same A3243G mutation site in 8 cases. Conclusions Children with MELAS have complex and varied clinical manifestations and certain characteristic of neuroimaging.Moreover, muscle pathology and gene sequencing have important diagnostic value.Fully understanding the clinical, muscle pathology, imaging and molecular biological characteristics of children with MELAS can be helpful to the early diagnosis and treatment, also reduce misdiagnosis. Key words: Mitochondrial encephalomyopathy; Lactic acidosis; Stroke-like episodes; Clinical manifestation

The etiology and clinical features of basal ganglia calcification

The prevalence of basal ganglia calcification is increasing, and it is a rare neurodegenerative disease.Its pathological changes are mainly bilateral basal ganglia calcification plaques.Most patients with pyramidal symptoms as the starting symptoms, but also manifested cerebellar dysfunction, language disorder, dementia, epilepsy and neurological symptoms, some patients can be asymptomatic.At present, there is no specific method to treat or delay the progress of the disease, and the majority of the drug effect is not good or poor tolerability.This article reviews the etiology, pathogenesis, pathological changes, imaging features, clinical features and treatment methods. Key words: Basal ganglia cerebrovascular disease; Idiopathic; Syndrome

Fahr’s syndrome: a rare case report

Fahr’s syndrome is a rare neurodegenerative disorder characterized by bilateral basal ganglia calcification. The exact incidence of Fahr’s syndrome is still unknown but estimated to be <1/1,000,000. On routine non-contrast-CT scan examination, 0.3-1.2% cases of intracranial calcification can be incidentally detected. It is caused by several medical conditions, with hypothyroidism as the most common one. Patient may come with neurologic or psychiatric symptoms. CT scan is the main supportive examination; it is used to determine the location and extension of calcification. Therapy is directed to the underlying etiology and usually symptomatic. A female, 46 years old, came with stiffness on both hands. This symptom appeared multiple times during past decade but with mild intensity. CT scan revealed calcification in both cerebral hemisphere and cerebellum. Blood test showed low calcium concentration. Patient was diagnosed with Fahr’s syndrome and given anticonvulsant and calcium supplementation. She was getting better during hospitalization and then discharged 4 days later with oral home medication.

A Middle Aged Man Presented with Recurrent Hypokalaemia and Basal Ganglia Calcification

Abstract not availableJ MEDICINE January 2016; 17 (1) : 57-58

Clinical Reasoning: A complicated case of MELAS

A 48-year-old right-hand-dominant woman presented to the emergency department with sudden onset of visual loss of her left visual field. She had a complicated medical history—end-stage renal disease requiring renal transplant 6 years prior to presentation secondary to biopsy-proven focal segmental glomerulosclerosis (FSGS), coronary artery disease, left atrial enlargement due to pulmonic stenosis, progressive sensorineural hearing loss 10 years prior and subsequent placement of a right cochlear implant, hypertension, and type 2 diabetes mellitus for the last year. At presentation, the patient's medications included cotrimoxazole prophylaxis, mycophenolate mofetil, tacrolimus, insulin, and folic acid. On examination, she was of short stature and had a low-grade fever and a left homonymous hemianopsia (L-HH). Within the next 3 weeks, she subsequently developed further visual disturbance to the point of being cortically blind in addition to new left upper extremity paresthesias. Initial CT head scan showed a subacute right occipital infarct and bilateral basal ganglia calcification. Subsequent CT imaging done 3 weeks later demonstrated interval development of new left temporoparietal and left occipital infarcts (figure, A). CT angiogram showed intracranial stenoses affecting basilar artery, both posterior cerebral arteries, and to a lesser degree bilateral anterior cerebral arteries and middle cerebral arteries, suggestive of possible atherosclerosis, but were not believed to be hemodynamically significant (figure, B). Due to her cochlear implant, significant streak artifact affected the interpretation of her CT scans and precluded her from obtaining an MRI.

Living with idiopathic basal ganglia calcification 3: a qualitative study describing the lives and illness of people diagnosed with a rare neurological disease.

PurposeIdiopathic basal ganglia calcification (IBGC) is a rare, intractable disease with unknown etiology. IBGC3 is a familial genetic disease defined by genetic mutations in the major causative gene (SLC20A2). People with IBGC3 experience distress from the uncommon nature of their illness and uncertainty about treatment and prognoses. The present study aimed to describe the lives and illness of people with IBGC3.MethodsParticipants were recruited from patients aged 20 years or older enrolled in a genetic study, who were diagnosed with IBGC3 and wanted to share their experiences. In-depth semi-structured interviews were conducted with six participants. Interviews were conducted between December 2012 and February 2014, and were recorded and transcribed verbatim. Qualitative data analysis was performed to identify categories and subcategories. Efforts were made to ensure the credibility, transferability, dependability, conformability, and validity of the data.ResultsSix thematic categories, 17 subcategories, and 143 codes emerged. The six categories were: (1) Frustration and anxiety with progression of symptoms without a diagnosis; (2) Confusion about diagnosis with an unfamiliar disease; (3) Emotional distress caused by a genetic disease; (4) Passive attitude toward life, being extra careful; (5) Taking charge of life, becoming active and engaged; and (6) Requests for healthcare.ConclusionsThe qualitative data analysis indicated a need for genetic counseling, access to disease information, establishment of peer and family support systems, mental health services, and improvement in early intervention and treatment for the disease.

Primary familial brain calcification in the 'IBGC2' kindred: All linkage roads lead to SLC20A2.

Linkage analyses of families with primary familial brain calcification (formerly idiopathic basal ganglia calcification [IBGC]) identified 3 candidate loci (IBGC1-3). Recently, SLC20A2 mutations were found in the IBGC1 and IBGC3 families, merging these 2 loci. We here elucidate the genetic cause of primary familial brain calcification in the 'IBGC2' kindred. We sequenced known primary familial brain calcification genes and quantified SLC20A2 and PDGFB. Moreover, CT scans of affected and unaffected family members were evaluated by 2 blinded neuroradiologists for distribution of brain calcification. A heterozygous multiexonic SLC20A2 deletion was detected in several affected family members. A reevaluation of neuroimaging data revealed a subset of mutation-negative individuals with only mild and/or unilateral calcification. The identified SLC20A2 mutation resolves the genetic cause of primary familial brain calcification in the 'IBGC2' kindred, collapsing 'IBGC2' into IBGC1. We suggest an algorithm for predicting the chances of finding genetic mutations that has to be validated in further studies. Our study enhances criteria for the evaluation of neuroimaging data, contributing further to the much needed harmonization of diagnostic and research data collection in primary familial brain calcification. © 2016 International Parkinson and Movement Disorder Society.

Cockayne syndrome: a diffusion tensor imaging and volumetric study

Cockayne syndrome (CS) is a rare disorder characterized by severe brain atrophy, white matter (WM) hypomyelination and basal ganglia calcifications. This study aimed to quantify atrophy and WM abnormalities using diffusion tensor imaging (DTI) and volumetric analysis, to evaluate possible differences between CS subtypes and to determine whether DTI findings may correspond to a hypomyelinating disorder. 14 patients with CS and 14 controls underwent brain MRI including DTI and a volumetric three-dimensional T1 weighted sequence. DTI analysis was made through regions of interest within the whole brain to obtain fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values and in the left centrum semiovale to obtain DTI eigenvalues. The Student's t-test was used to compare patients and controls, and CS subtypes. Given the small number of patients with CS, they were pooled into two groups: moderate (CS1/CS3) and severe (CS2/cerebro-oculo-facio-skeletal syndrome). Total brain volume in CS was reduced by 57%, predominantly in the infratentorial area (68%) (p < 0.001). Total brain volume reduction was greater in the severe group, but there was no difference in the degree of infratentorial atrophy in the two groups (p = 0.7). Mean FA values were lower, whereas ADC was higher in most of the WM in patients with CS (p < 0.05). ADC in the splenium of the corpus callosum and the posterior limb of the internal capsule and FA in the cerebral peduncles were significantly different between the two groups (p < 0.05). Mean ADC values corresponded to a hypomyelinating disorder. All DTI eigenvalues were higher in patients with CS, mainly for transverse diffusivity (+51%) (p < 0.001). DTI and volumetric analysis provide quantitative information for the characterization of CS and may be particularly useful for evaluating therapeutic intervention. Advances in knowledge: DTI combined with volumetric analysis provides additional information useful for not only the characterization of CS and distinction of clinical subtypes but also monitoring of therapeutic interventions.