Basal Ganglia Calcification Research Articles

Autosomal Dominant Hypocalcemia Due to a GNA11 Variant: The First Case in Japan

Abstract Background: Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia and hyperphosphatemia due to hypoparathyroidism. ADH type 1 is caused by gain-of-function variants in CASR gene coding the calcium-sensing receptor. Recently, ADH type 2 caused by gain-of-function variants in GNA11 gene coding G-protein subunit α11 has been recognized. Case: A 32-year-old female patient visited our hospital because she suffered from hyperhidrosis, exertional dyspnea, and palpitations. She had a past medical history of paroxysmal kinesigenic dyskinesia confirmed by genetic analysis of PRRT2. Although her sister has unspecified epilepsy, no members of her kindred have episodes of tetany. Her height was 155.7 cm and weight was 64.1 kg. She had goiter with tremor and tachycardia and was diagnosed as Graves’ disease (fT3 >32.55 pg/mL, fT4 >7.77 ng/dL, TSH <0.005 µIU/mL, and TRAb 36.9 IU/L). Thiamazole therapy ameliorated her hyperthyroidism, while serum calcium level was low (7.5 mg/dL) and serum phosphate level was slight high (5.1 mg/dL). Hypoparathyroidism was confirmed because intact-PTH was relatively low (20 pg/mL) under the hypocalcemia. Her episode of tetany that she could not sit on her heels from childhood and her basal ganglia calcification in head CT scan suggest the long disease duration. Germline whole exome sequence detected a rare variant in GNA11 gene; c.1023C>A resulted in p.Phe341Leu. There were no relevant pathogenic variants in other candidate genes such as CASR, PTH, and GCM2. Treatment with 2 µg/day of alfacalcidol and 1200 mg/day of calcium aspartate could not normalize serum calcium level (7.0 mg/dL) and serum phosphate level (5.3 mg/dL) even after 1 year. Conclusions: The pathogenicity of the variant, p.Phe341Leu, in GNA11 gene was previously confirmed [1]. ADH type 2 is extremely rare as our literature review found only four previous reports; 17 patients in 5 families [1–4]. Phenotypes of the present case are mild and skeletal growth is normal. Meanwhile, we are having difficulty in management of her hypocalcemia, even though Graves’ disease might affect her bone metabolism. Optimal therapy for ADH type 2 needs further investigation.

Bilateral Basal Ganglia Calcification; An Unusual Initial Presentation of Pseudohypoparathyroidism

Physiological intracranial calcification occurs in about 0.3–1.5% of cases. Hypoparathyroidism and pseudohypoparathyroidism are the most common causes of pathological basal ganglia calcification.A 21-year-old female who was initially evaluated by neurology team for headache and diplopia, underwent MRI of brain which revealed Calcifications involving the bilateral basal ganglia, thalami, dentate nuclei as well as juxtacortical frontal lobes. She reported Fatigue and muscle pain, usually in her arms especially after playing sports which had been going on for many years. She had no history of fractures, seizures, psychiatric disorders, developmental delay or obvious cognitive impairments. She denied any family history of calcium disorders or autoimmune diseases. As she had been generally healthy in her whole life, she never had any lab testing done. On examination, Height 5’1”, Chvostek’s sign was positive. Fundoscopy was normal. she had no dysmorphic features or shortened 4th metacarpal. Investigations revealed serum calcium less than 5.0 mg (N 8.3 - 10.1 mg/dl), PTH 205.1 pg/ml (N 18.4 - 80.1 pg/ml), phosphate 7.1 mg (N 2.5 - 5 mg), Vitamin-D 36.2 ng/ml (N 30.0 - 100.0 pg/ml),magnesium 2.0 m (N 1.6 - 2.6 mg/dl) with normal albumin, alkaline phosphatase and renal function test. She was diagnosed with pseudohypoparathyroidism and started on calcium and active vitamin D supplement and was referred for genetic testing study. She reported significant improvement in myalgia after a few weeks of starting calcium and active vitamin D supplementations and repeat lab testing showed improved hypocalcemia and hyperphosphatemia. This case illustrates unusual presentation of PTH resistance with basal ganglia calcification as initial presentation prompting further workup. She likely has pseudohypoparathyroidism type 1b.Since adequate treatment of hypoparathyroidism may lead to marked clinical improvement, determination of serum calcium, phosphorus, and parathyroid hormone is mandatory in all individuals with calcification of the basal ganglia to rule out hypoparathyroidism.

A Case of Psychosis Due to Acute Hypocalcemia From Hypoparathyroidism

A 61-year-old female with past medical history of depression, hypoparathyroidism (hypoPtH), and hypothyroidism had disappeared from her home and was found wandering a few hours away with persecutory delusions, visual and auditory hallucinations. Serum calcium (Ca) was 6.3 mg/dL (range 8.6–10.2), albumin 3.7 g/dL (range 3.5–5.2) and ionized Ca 0.89 mmol/L (range 1.12–1.30). She was admitted and treated with Ca and calcitriol. Work-up for altered mental status was negative except for hypocalcemia (hypoCa) and scattered bilateral basal ganglia calcifications (BGC) with cortical and subcortical frontal lobe calcifications on CT. Psychiatry diagnosed delirium due to hypoCa. Acute psychosis resolved once Ca levels improved. Diagnosis of idiopathic hypoPtH was in 1997. Her regimen included Ca citrate 1500mg daily and 10 mcg of Forteo twice daily. She had skipped her medications for at least 2 days prior to presentation.Her medical records revealed that she was seen for severe depression, progressive gait abnormalities, slowed movements, and imbalance, in 2015. CT scan and MRI brain showed BGC. Her son gave a history of multiple admissions for psychosis, violence, delusions with agitation, and wandering at times when the patient was hypoCa, which was diagnosed as schizophrenia. Neuropsychiatric disturbances are commonly associated with hypercalcemia. Review of literature found a few case reports of psychosis and hypoPtH 1,2 BGC is common in hypoPtH. Psychotic symptoms due to BGC include auditory hallucinations, delusions of influence, paranoid states, and complex perceptual distortions.3,5 HypoCa is associated with cognitive impairment. Neurological manifestations tend to improve with Ca correction, but psychiatric symptoms do not improve substantially.4,5 Further studies are needed in hypoPtH with BGC to appropriately diagnose organic psychosis. This is important in management of the vicious cycle of psychiatric illness leading to noncompliance resulting in psychosis. Prevention of BGC will play a key role.

The “Eyes” Have It. Ophthalmological Findings of Bilateral Cataract in a Boy with Hypoparathyroidism

Background: Hypoparathyroidism is a relatively rare pediatric endocrine disorder in which parathyroid hormone (PTH) production is low or absent, resulting in low serum calcium and high phosphorus. In children, hypoparathyroidism is either congenital or acquired and is often associated with a genetic syndrome. Clinical manifestations include neuromuscular hyperexcitability, tetany, cardiac arrhythmias, and seizure. Radiographic findings include basal ganglia calcifications. In adult literature, ophthalmological findings of lenticular opacities and cataract have also been reported in hypoparathyroidism. Due to the rarity of this condition, there is a paucity of ophthalmological findings in children. We report a pediatric case with severe hypocalcemia, recurrent generalize seizures, intracranial calcifications and bilaterally cataracts secondary to hypoparathyroidism. Case: A 7-year-old boy, from a remote area in China, presented to a local hospital with one-year history of paresthesia in hands and feet. Initial lab evaluation revealed hypocalcemia with serum calcium of 1.76 mmol/L (2.03-2.68). Oral calcium supplement was started but symptoms progressively worsened. He was transferred to a tertiary hospital for further evaluation. On admission, physical exam was significant for positive Chvostek and Trousseau signs and lab evaluation showed serum calcium: 1.28 mmol/L (2.15-2.57), phosphorus: 4.2 mmol/L (0.95-1.75), magnesium: 0.97 mmol/L (0.73-1.06), PTH: 2.2 pg/mL (8.7-79), and 25(OH)Vit D: 97.1 mmol/L (36-126). Multiple symmetrical calcifications were found in the frontal lobe and basal ganglia. Ophthalmology consultation revealed bilateral cataracts with impaired vision. Trio whole exome sequencing with copy number variation testing reveled no pathogenic or likely pathogenic copy number and sequence level variants. He was diagnosed with idiopathic acquired hypoparathyroidism. The seizure disorder, intracranial calcification, and bilateral cataracts were attributed to severe and prolonged hypocalcemia secondary to hypoparathyroidism. He had a second episode of seizure after he was admitted, and seizure resolved after treated with midazolam and IV calcium gluconate. He was started on 1,25 (OH)2 vitamin D. Clinical symptoms resolved and he became biochemically eucalcemic with titrated therapy. Summary: Although lenticular changes have been observed in adults with hypoparathyroidism since the 1950’s, hypoparathyroidism and resulting cataract formations are relatively rare. Proposed mechanism of cataract formation in hypoparathyroidism is prolonged hypocalcemia resulting in membrane damage in the aqueous humor and subsequent sodium content increase in the lens. To our knowledge there are no prior pediatric reports of cataracts associated with hypoparathyroidism and signifies the importance of ophthalmologic referral and evaluation.

Familial Idiopathic Basal Ganglia Calcification: A Father-Son Dyad Demonstrate Heterogeneity of Presentation and Disease Progression.

Familial idiopathic basal ganglia calcification (FIBGC) is a rare, heritable disease characterized by calcium deposition in the basal ganglia and other brain regions. Clinical presentations are diverse, featuring an array of neurologic, psychiatric, and/or cognitive symptoms. This dyad report presents neurogenetic, neuroimaging, neurological, and serial neuropsychological data from a father (S1) and son (S2) with FIBGC. The SLC20A2 genetic mutation c.1828-1831delTCCC was identified for each patient, both of whom evidenced similar patterns of brain calcification mainly in the basal ganglia and cerebellum on neuroimaging. S1's onset was in his late 60s with primary motor abnormalities followed by cognitive decline; S2's younger onset (late 30s) was characterized by predominant psychiatric symptoms and mild cognitive changes. Our unique, detailed longitudinal study revealed that both subjects demonstrated largely stable performance across most neuropsychological domains assessed. The subjects' differences in presentation demonstrate the variable expressivity in FIBGC even with the same pathogenic variant within a single family. Distinct phenotypes may be associated with age of onset even in persons with the same mutation, consistent with past research. Disease progression may feature an initial period of notable change from baseline followed by relative stability, as seen both on imaging and neuropsychological evaluation.

A RARE CASE OF SECONDARY FAHR'S SYNDROME AS A SEQUELAE OF POST THYROIDECTOMY HYPOPARATHYROIDISM REPORTED TO A TERTIARY CARE HOSPITAL.

OBJECTIVES: To emphasize the presentation, etiopathogenesis and various diagnostic findings in a case of secondary Fahr's syndrome. METHODOLOGY: A 35 year old female who had undergone total thyroidectomy 9 yrs ago due to papillary carcinoma of thyroid, presented with seizures and weakness in both lower limbs, secondary to hypoparathyroidism. Non contrast computed tomography of brain showed bilateral calcification in basal ganglia, centrum semiovale and cerebellar hemisphere. RESULT: The patient was diagnosed with Fahr's syndrome as a sequelae of post thyroidectomy hypoparathyroidsm. CONCLUSION: We recommend the follow up of blood calcium, phosphorus , PTH levels every 3 months during 1st year after Thyroidectomy and every 6 months subsequently, for the long term follow up of post -thyroidectomy patients along with routine CT scanning.

POS-094 A CASE OF HYPOPARATHYROIDISM: WHEN A NEPHROLOGIST TURNS INTO AN ENDOCRINOLOGIST

Hypoparathyroidism is a rare endocrine disorder infrequently seen in everyday practice. It may be primary due to a genetic cause or secondary which is by far the most common form and due to a variety of etiologies for instance during radiation, auto-immune diseases or acquired after neck surgery with the latter being the most common cause accounting for 75 % of cases. Herein we report the case of a patient who presented to our department as a potential kidney donor to her husband. The pre-transplant workup has shown features of hypoparathyroidism that were subsequently confirmed. The patient is a 36-year-old female with no past medical history of auto-immune disease and no history of neck surgery. She denies any over the counter consumption of dietary or supplemental intake of calcium or vitamin D. She also denied any family history of hypoparathyroidism or consanguinity thus ruling out a genetic cause and no history of autoimmune disease or other endocrine disorders. She had dry scaly skin, thin hair, and fragile nails. No mucocutaneous candidiasis. No scars of previous trauma or surgery in the neck. No malar rash. A carpal spasm was observed during the inflation of the blood pressure cuff on the arm classically know as The Trousseau sign. An ophthalmology exam has shown a cataract at an early onset. An electrocardiogram has shown a slightly prolonged QT interval. A laboratory exam was performed. Her creatinine was normal at 62 uoml/l. She had hypocalcemia of 1.35 mmol/l, a phosphatemia of 1.7 mmol/l, a normal magnesium level of 0.8mmol/l, a PTH level of 12 pg/ml, vitamin D was 18.1 ng/ml. Additional workup was performed seeking other endocrine disorders that may be associated. For instance, her thyroid-stimulating hormone was normal at 2.98 UI/ml with a normal level of free thyroxin at 13.3 ng/ml. Her cortisol level was slightly low at 84 ug/l compared to the laboratory inferior normal limit of 100 but she did not exhibit any signs of adrenal insufficiency. Ultrasonography did not show any kidney stones or abnormalities. A cerebral scan was also performed looking for basal ganglia calcifications and luckily came back normal. An immunologic assessment was performed including antinuclear antibodies, anti-thyroid peroxidase antibodies, anti-thyroglobulin antibodies and came back negative The patient was treated with IV supplementation of calcium in the acute phase in order to alleviate the cardiovascular signs seen in the electrocardiogram. She was then supplemented with oral calcium and vitamin D. Her calcium levels were at 1.9 mmol/l. Her symptoms improved at discharge. Hypoparathyroidism is a rare endocrine disorder. A thorough work-up should be done to look for a cause. It may be due to a variety of etiologies but so far neck surgery represents 75 % of cases.

Histology and computed tomography of incidental calcifications in the human basal ganglia

Incidental basal ganglia calcifications are a common finding on computed tomography (CT). We investigated the histological characteristics of these calcifications and their association with CT findings, using post-mortem basal ganglia tissue from 22 patients. Eight patients had basal ganglia calcifications on histology, and six patients had calcifications on CT, varying from mild to severe. Four patients had calcifications identified by both histology and CT, and two patients had calcifications detected by CT but not by histology, possibly because of insufficient tissue available. Calcifications were found mainly in the tunica media of arterioles located in the globus pallidus, which suggests that incidental CT calcifications are vascular in nature. However, tunica media calcifications, and thereby incidental basal ganglia calcifications, are probably not related to atherosclerosis.

Cognitive consequences of COVID-19 in older adults with cognitive impairment

IntroductionCoronavirus disease 2019 (COVID-19) is due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with significant morbidity and mortality that is well documented. This includes significant central nervous system (CNS) involvement that ranges from acute delirium to meningoencephalitis. While acute symptoms and manifestations have been noted, long-term neuropsychiatric and cognitive outcomes remain unclear in convalescent COVID-19 patients. Characterizing the convalescence is particularly important since 80% recover, yet the relationship between exacerbated cognitive dysfunction and COVID-19 remains unclear. We describe 3 adults above age 65 who reported worsening cognitive symptoms in the convalescent stage of COVID-19.MethodsThree adults above the age of 65 who noted worsening cognitive difficulties after SARS-CoV-2 infection and COVID-19 were evaluated in the Memory Clinic of the Duke Neurological Disorders Clinic. Electronic medical records were retrospectively reviewed. Exam included a comprehensive neurological evaluation, formal neuropsychological evaluation, and neuroimaging. Prior history was collected for comparison with their current clinical evaluation profile data.ResultsPatient 1 is a 69 year old diabetic, hypertensive male with a history of depression and a first-order relative and a maternal aunt with late-onset Alzheimer's disease dementia who presented for evaluation of memory loss first noted about one year prior but had significantly worsened in the five months since his recovery from COVID-19. He had documented antibodies to SARS-CoV-2. The patient reported forgetting when he had eaten and now evinces navigation issues even when driving on familiar roads. Head CT without contrast obtained before COVID-19 infection showed mild bilateral hippocampal atrophy. He scored 4/8 on the AD8 Dementia Screening and 20/30 on the Montreal Cognitive Assessment (MoCA). PHQ9 was 10, GAD7 was 0, and NPI was 1. Formal neuropsychological evaluation data were collected. A diagnosis of late-onset Alzheimer's disease without behavioral disturbance was made during his clinic visit. Donezepil was started. Other comorbidities included vitamin B12 deficiency, atrial fibrillation, congestive heart failure, chronic obstructive pulmonary disease, obstructive sleep apnea, and morbid obesity.Patient 2 is a 68 year old male with a history of anxiety, depression, and attention deficit disorder who presented for evaluation of poor memory, inability to “visually map,” and daily “senior moments” as well as a prolonged period of confusion while driving four months after recovering from COVID-19. He had documented antibodies to SARS-CoV-2. He had transient memory problems two years ago that improved after changing his bupropion dosage. He also takes fluoxetine. He now regularly misplaces objects and often stops a task midway through, thinking that he completed it. His GDS score was 5. Head CT was unremarkable. MRI of the brain demonstrated mild hippocampal and biparietal lobe atrophy as well as mild cerebral white matter disease. He scored 7/8 on the AD8 Dementia Screening and 27/30 on the MoCA. A diagnosis of dementia with behavioral disturbance was made. PHQ9 was 9, GAD7 was 6, and NPI was 7. B12 was normal. There is no family history of cognitive impairment.Patient 3 is a 76-year-old female with a history of bipolar 1, diabetes, hypothyroidism, hyperlipidemia who presented for evaluation of memory loss that started 6 months ago but worsened since she had recovered from COVID-19 diagnosed about 8 weeks earlier. After testing positive, she was hospitalized for 3 weeks due to acute encephalopathy attributed to lithium toxicity. She was also taking trazodone. Her GDS score was 7. She scored 8/8 on the AD8 Dementia Screening. MoCA could not be completed. PHQ9 was 3, GAD7 was 9, and NPI was 19. Formal neuropsychological evaluation data were collected. Head CT without contrast three weeks after COVID-19 diagnosis showed calcification in the right basal ganglia, a mild hypodense signal periventricularly, and gray-white differentiation. Brain MRI without contrast showed subtle hippocampal and perisylvian atrophy on T1, mild to moderate parietal lobe atrophy bilaterally, and mild to moderate periventricular leukoaraiosis/white matter hyperintensities on FLAIR sequence. A diagnosis of dementia without behavioral disturbance was made. There is a family history of bipolar disorder in siblings and cognitive impairment in her father but no specific diagnosis of dementia.ConclusionsThis case series describes the exacerbation of pre-existing psychiatric and cognitive conditions after COVID-19 recovery in 3 older adults with formal neuropsychological evaluation data. Longitudinal investigation of convalescent patients is warranted to better clinically characterize and provide insight into the long-term effects of COVID-19. This will allow further investigation into the pathophysiology regarding the long-term consequences of SARS-CoV-2 infection.FundingNot Applicable.

Human induced pluripotent stem cells generated from a patient with idiopathic basal ganglia calcification

Idiopathic basal ganglia calcification (IBGC) is a rare neurodegenerative disease, characterized by abnormal calcium deposits in basal ganglia of the brain. The affected individuals exhibit movement disorders, and progressive deterioration of cognitive and psychiatric ability. The genetic cause of the disease is mutation in one of several different genes, SLC20A2, PDGFB, PDGFRB, XPR1 or MYORG, which inheritably or sporadically occurs. Here we generated an induced pluripotent stem cell (iPSC) line from an IBGC patient, which is likely be a powerful tool for revealing the pathomechanisms and exploring potential therapeutic candidates of IBGC.

Canadian national hypoparathyroidism registry: an overview of hypoparathyroidism in Canada.

To evaluate the epidemiology, presentation and management of hypoparathyroidism in Canada. Hypoparathyroidism is associated with significant morbidity and poor quality of life. We present baseline results from the Canadian National Hypoparathyroidism Registry, a prospective observational study evaluating hypoparathyroidism in Canada. Our study enrolled 130 patients with hypoparathyroidism. Patients were followed every 6 months with clinical and lab assessments. We present baseline data in this manuscript. Seventy percent (91/130) of patients had postsurgical hypoparathyroidism, 30% (39/130) of patients had nonsurgical hypoparathyroidism due to autoimmune, genetic or idiopathic causes, and a molecular diagnosis was confirmed in 11 of these 39 patients. Pseudohypoparathyroidism was confirmed in 4/39 patients, DiGeorge syndrome in 2/39 patients, Barakat syndrome with a mutation in the GATA3 gene in 1/39, and activating mutations of the CASR gene in 3/39 patients with nonsurgical hypoparathyroidism. Renal complications with nephrocalcinosis or nephrolithiasis were present in 27% (14/52) of patients with postsurgical disease and 17% (4/24) of patients with nonsurgical hypoparathyroidism. Basal ganglia calcification was noted on imaging in 15% (n = 5/34) of patients with postsurgical hypoparathyroidism and 37% (n = 7/19) of patients with nonsurgical hypoparathyroidism. Hypercalciuria was more commonly seen in those with renal complications of nephrocalcinosis, nephrolithiasis or CKD, and hyperphosphatemia was more commonly seen in those with basal ganglia calcification. Hospitalization occurred in 28% of those with postsurgical hypoparathyroidism and 46% of those with nonsurgical hypoparathyroidism. Hypoparathyroidism is associated with significant morbidity. Effective strategies to reduce the short-and long-term complications of hypoparathyroidism need to be developed and evaluated.

Performance of an artificial intelligence tool with real-time clinical workflow integration - Detection of intracranial hemorrhage and pulmonary embolism.

Performance of an artificial intelligence tool with real-time clinical workflow integration - Detection of intracranial hemorrhage and pulmonary embolism.

Osteogenic Mechanisms of Basal Ganglia Calcification and its ex vivo Model in the Hypoparathyroid Milieu.

Basal-ganglia calcification (BGC) is common (70%) in patients with chronic hypoparathyroidism. Interestingly, cortical gray matter is spared from calcification. The mechanism of BGC, role of hyperphosphatemia, and modulation of osteogenic molecules by parathyroid hormone (PTH) in its pathogenesis is not clear. We assessed the expression of a large repertoire of molecules with proosteogenic or antiosteogenic effects, including neuroprogenitor cells in caudate, dentate, and cortical gray matter from normal autopsy tissues. The effect of high phosphate and PTH was assessed in an ex vivo model of BGC using striatum tissue culture of the Sprague-Dawley rat. The messenger RNA and protein expression of 39 molecules involved in multiple osteogenic pathways were assessed in 25 autopsy tissues using reverse-transcriptase polymerase chain reaction, Western blot, and immunofluorescence. The striatal culture was maintained in a hypoparathyroid milieu for 24 days with and without (a) high phosphate (10-mm β-glycerophosphate) and (b) PTH(1-34) (50 ng/mL Dulbecco's modified Eagle's medium-F12 media) for their effect on striatal calcification and osteogenic molecules. Procalcification molecules (osteonectin, β-catenin, klotho, FZD4, NT5E, LRP5, WNT3A, collagen-1α, and SOX2-positive neuroprogenitor stem cells) had significantly higher expression in the caudate than gray matter. Caudate nuclei also had higher expression of antiosteogenic molecules (osteopontin, carbonic anhydrase-II [CA-II], MGP, sclerostin, ISG15, ENPP1, and USP18). In an ex vivo model, striatum culture showed an increased propensity for calcified nodules with mineral deposition similar to that of bone tissue on Fourier-transformed infrared spectroscopy, alizarin, and von Kossa stain. Mineralization in striatal culture was enhanced by high phosphate and decreased by exogenous PTH through increased expression of CA-II. This study provides a conceptual advance on the molecular mechanisms of BGC and the possibility of PTH therapy to prevent this complication in a hypoparathyroid milieu.

Idiopathic basal ganglia calcification (Fahr’s disease) in a 9-year-old Nigerian child

Fahr’s disease is a rare neurodegenerative disorder characterized by deposition of calcium on the walls of blood vessels of the Basal ganglia and Dentate nuclei of the Cerebellum. Patient can present with diverse array of symptoms including but not limited to seizure, extrapyramidal symptoms and mental retardation. We report a case of a 9-year-old female child with history of recurrent seizure. Brain CT showed symmetrical calcification in the basal ganglia.

Fahr’s syndrome due to hypoparathyroidism revisited: A case of parkinsonism and a review of all published cases

IntroductionFahr’s syndrome due to hypoparathyroidism refers to bilateral basal ganglia (BG) calcifications and manifests with movement disorders, seizures, cognitive and behavioral symptoms. Case presentationWe report a case of a 74-year-old woman, who presented with parkinsonism due to post-surgical hypoparathyroidism and normal DaT scan, despite extensive calcifications of the BG, periventricular white matter, and cerebellum. MethodsA comprehensive literature review of all reported cases of Fahr’s syndrome due to hypoparathyroidism was conducted in the electronic databases PubMed and Web of science. Moreover, demographic and clinical characteristics of the patients overall were calculated and associated with radiological findings. ResultsWe reviewed a total of 223 cases with Fahr’s syndrome due to hypoparathyroidism (124 female, 99 male). Mean age on presentation was 44.6 ± 17.7 years. Thirty nine percent of patients had idiopathic hypoparathyroidism, 35.4 % acquired and 25.6 % pseudohypoparathyroidism. Almost half of the patients had tetany, seizures or a movement disorder and approximately 40 % neuropsychiatric symptoms. The patients with a movement disorder had a 2.23 likelihood of having neuropsychiatric symptoms as well (OR 2.23, 95 % CI 1.29–3.87). Moreover, there was a statistically significant association between the phenotype severity (i.e. the presence of more than one symptom) and the extent of brain calcifications (χ2 = 32.383, p = 0.009). ConclusionFahr’s syndrome is a rare disorder, which nonetheless manifests with several neurological symptoms. A head CT should be considered for patients with hypoparathyroidism and neurological symptoms. More studies using DaT scan are needed to elucidate the effects of calcifications on the dopaminergic function of the BG.

Systemic inflammation and chronic kidney disease in a patient due to the RNASEH2B defect

IntroductionAicardi-Goutières (AGS) is a rare immune dysregulated disease due to mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, or IFIH1. Clinical features include basal ganglia calcifications, white matter abnormalities, and cerebral atrophy. Severe systemic inflammation and chronic kidney disease (CKD) are extremely rare in AGS. Herein, we report a patient presenting with systemic inflammation and CKD to broaden the clinical phenotype spectrum of the RNASEH2B defect.MethodsAll testing and molecular genetic analysis were performed after obtaining the informed consent of the parents. Demographic, clinical, and laboratory findings were abstracted from outpatient and inpatient encounters. Cerebral magnetic resonance imaging (MRI), computed tomography (CT) scans, and renal biopsy histopathology reports were reviewed and summarized. Whole exome sequencing (WES) was performed on peripheral blood cells. After exposure to cGAMP in vitro for 24 h, mRNA expression of 12 IFN-stimulated cytokine genes in PBMCs was assessed. Serum cytokine levels were detected by Milliplex.ResultsA 11-year-old girl presented with recurrent aseptic fever, arthritis, chilblains, failure to thrive, mild hearing loss, and neurological manifestations. Laboratory and immunologic findings demonstrated lymphopenia, low complement levels, positive autoantibodies, elevated levels of acute-phase reactants and inflammatory cytokines. Cerebral imaging showed cerebral atrophy, white matter abnormalities, and intracranial calcification. Renal biopsy showed glomerular sclerosis in 3 of 14 glomeruli, infiltration of lymphocytes and other mononuclear cells. WES revealed a homozygous and heterozygous mutations in RNASEH2B. Over-expression of IFN-stimulated cytokine genes was observed, including IFI44, IFI27, IFIT1, IFIT2, IFIT3, ISG15, OAS1, and SIGLEC1.ConclusionsTo date, only two cases with AGS have been reported to have renal disease. Here, we describe a patient with both homozygous and heterozygous variants in RNASEH2B, presenting with neurological manifestations, persistently systemic autoinflammation, and CKD. CKD has never been reported in patients with AGS due to the RNASEH2B defect.Trial registrationNot applicable; this was a retrospective study.

MAP3K6 Mutations in a Neurovascular Disease Causing Stroke, Cognitive Impairment, and Tremor.

ObjectiveTo describe a possible novel genetic mechanism for cerebral small vessel disease (cSVD) and stroke.MethodsWe studied a Swedish kindred with ischemic stroke and intracerebral hemorrhage, tremor, dysautonomia, and mild cognitive decline. Members were examined clinically, radiologically, and by histopathology. Genetic workup included whole-exome sequencing (WES) and whole-genome sequencing (WGS) and intrafamilial cosegregation analyses.ResultsFifteen family members were examined clinically. Twelve affected individuals had white matter hyperintensities and 1 or more of (1) stroke episodes, (2) clinically silent lacunar ischemic lesions, and (3) cognitive dysfunction. All affected individuals had tremor and/or atactic gait disturbance. Mild symmetric basal ganglia calcifications were seen in 3 affected members. Postmortem examination of 1 affected member showed pathologic alterations in both small and large arteries the brain. Skin biopsies of 3 affected members showed extracellular amorphous deposits within the subepidermal zone, which may represent degenerated arterioles. WES or WGS did not reveal any potentially disease-causing variants in known genes for cSVDs or idiopathic basal ganglia calcification, but identified 1 heterozygous variant, NM_004672.4 MAP3K6 c.322G>A p.(Asp108Asn), that cosegregated with the disease in this large family. MAP3K6 has known functions in angiogenesis and affects vascular endothelial growth factor expression, which may be implicated in cerebrovascular disease.ConclusionsOur data strongly suggest the MAP3K6 variant to be causative for this novel disease phenotype, but the absence of functional data and the present lack of additional families with this disease and MAP3K6 mutations still limit the formal evidence for the variant's pathogenicity.

Basal ganglia calcifications is not inconsequential in pediatric cases

Introduction. Basal ganglia calcification (BGC) in pediatric population is rare and is considered as a pathological finding. Various causes may be responsible for BGC including hypoparathyroidism, various infectious, toxicities or hereditary disorders. Aim. We aimed to present a 8 year old boy presented with generalized seizure and bilateral small amount of globus pallidum calcifications on neuroimaging studies leading to the diagnosis of idiopathic hypoparathyroidism, which is a treatable cause of seizure. Description of the case. A 8-year-old boy presented to our emergency department with generalized seizure for the first time in his life. There was no history of previous head trauma and his family history was unremarkable. Neurological examination revealed no pathological findings. Radiological imaging studies revealed only bilateral small amount of globus pallidus calcifications. He was referred to the pediatric endocrinology department for further evaluation of the hypocalcemic convulsion, where laboratory investigations revealed idiopathic hypoparathyroidism as the cause of hypocalcemic convulsion with exclusion of the other causes. Conclusion. Even a small amount of BGC in pediatric patients may be the sign of primary hypoparathyroidism and should be evaluated with serum electrolyte levels for early diagnosis and for the prevention of multisystemic complications of hypoparathyroidism.

An accidental finding of FAHR’s syndrome during computed tomography of skull – A case report

Calcification of basal ganglia is known as FAHR’s syndrome or FAHR’s disease. It’s a rare phenomenon which generally affects the young to middle aged adults. A 39-year-old female was sent to the radiology department of Sree Balaji Medical College, Chennai for computed tomography (CT) as she had a fall and injured her forehead. An axial plain CT scan without contrast was advised and performed. The CT study revealed mild frontal peri cranial swelling and calcification of dentate nucleus, basal ganglia, central semiovale and frontoparietal subcortical white matter was observed. On examination, however patient did not present with any other movement disorders.

The relationship with age and gender of intracranial physiological calcifications: A study from Corum, Turkey

Aim: The aim of this regional study was to determine the frequency of physiological intracranial calcifications in all age groups in the province of Corum, to determine the relationship with age and gender, and through comparison with literature to present the basic data related to physiological intracranial calcifications.Materials and Methods: The study included 1011 patients aged 0-93 years that presented at the Emergency Department of Hitit University Medical Faculty Hospital because of head trauma and were applied with Brain Computed Tomography (BCT). A retrospective examination was made of the calcifications on BCT. The calcifications recorded on the CT scans were classified as choroid plexus, pineal gland, habenular commissure, dural, basal ganglia, and others. The patients were examined in 10 age groups of decades starting from zero. In this cross-sectional, retrospective, observational study, the relationship was examined statistically between age and gender of the patients and physiological intercranial calcifications. In addition, the prevalence values of physiological intercranial calcifications in the province of Corum were determined.Results: There was determined to be a statistically significant increase associated with increasing age in the frequency of pineal gland (p<0.001), choroid plexus (p<0.001) habenular commissure (p<0.001), dural (p<0.001), others (p=0.032) and basal ganglia calcifications (p=0.004). The rates of choroid plexus, pineal gland, and habenular commissure calcifications seen in males were determined to be statistically significantly higher in males than in females (p=0.044, p=0.033, p=0.032, respectively).Conclusion: This study determined the regional prevalence of physiological intracranial calcifications in the province of Corum and revealed the relationship between these calcifications with age and gender.