Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification.

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% of individuals affected by PFBC have no molecular diagnosis. We report four unrelated families presenting with initial learning difficulties and seizures and later psychiatric symptoms, cerebellar ataxia, extrapyramidal signs, and extensive calcifications on brain imaging. Through a combination of homozygosity mapping and exome sequencing, we mapped this phenotype to chromosome 21q21.3 and identified bi-allelic variants in JAM2. JAM2 encodes for the junctional-adhesion-molecule-2, a key tight-junction protein in blood-brain-barrier permeability. We show that JAM2 variants lead to reduction of JAM2 mRNA expression and absence of JAM2 protein in patient's fibroblasts, consistent with a loss-of-function mechanism. We show that the human phenotype is replicated in the jam2 complete knockout mouse (jam2 KO). Furthermore, neuropathology of jam2 KO mouse showed prominent vacuolation in the cerebral cortex, thalamus, and cerebellum and particularly widespread vacuolation in the midbrain with reactive astrogliosis and neuronal density reduction. The regions of the human brain affected on neuroimaging are similar to the affected brain areas in the myorg PFBC null mouse. Along with JAM3 and OCLN, JAM2 is the third tight-junction gene in which bi-allelic variants are associated with brain calcification, suggesting that defective cell-to-cell adhesion and dysfunction of the movement of solutes through the paracellular spaces in the neurovascular unit is a key mechanism in CNS calcification.

Clinical feature of familial idiopathic basal ganglia calcification / 临床神经病学杂志

Objective To investigate the clinical features of familial idiopathic basal ganglia calcification (FIBGC).Methods Clinical data of 4 FIBGC patients from 2 families were analyzed retrospectively.Results The average age of 4 patients was(62.7 ±13.4)years old.The first symptom of 2 female patients was depression and schizophrenia, while 2 male patients displayed dementia and Parkinson's syndrome.Patients treated with vitamin D capsules,follow-up period for 3 to 6 months.All patients showed symptomatic improvement.Conclusions Clinical symptoms of FIBGC are complicated,and progressive development.The main symptom of female is mental symptoms, and male patients accompanied with dementia and dyskinesia.There is still no effective therapeutic plan for FIBGC.

Clinical research study of Familial Idiopathic Basal Ganglia Calcification from 8 family analysis / 中国神经精神疾病杂志

Objective To better understand the clinical characteristics of Familial Idiopathic Basal Ganglia Calcifi?cation (FIBGC), including at the perspective of hereditary pattern, clinical test results, onset age, clinical heterogeneity and the volume of basal ganglia calcification (VBGC). Method 8 Eight FIBGC families were collected and draw family pedigrees were draw. Analysis of was conducted on the patient's clinical test results, head CT and MRI changes, onset ag?es, relationship of clinical manifestations with VBGC. Results No significant difference was found in serum calcium, alu?minum, arsenic, cobalt, magnesium, phosphorus, iron, parathyroid hormone and calcitonin concentration between the fam?ily members of patients and healthy controls (P>0.05). Family members from 8 FIBGC families including the two with consanguineous marriage manifested autosomal dominant heredity. The severity of , symptomatic s was correlated with VBGCpatients showed the same clinical manifestations in the dyskinesia family. The psychiatric symptoms was not asso? ciated with VBGC whereas patients with dyskinesia had a large VBGC. There was a significant difference in onset age be?tween patients with psychiatric symptoms and those with dyskinesia. P.atients with dyskinesia suffer larger VBGC, and is characterized by Patients with dyskinesia had relatively later onset age (43.95 ± 2.47 y) whereas those with. psychiatric symptoms hadsymptomatic patients with early onset age (31.32±10.16y). The comparison of the onset age (43.954±2.473 vs. 31.319±10.156 y, t=4.438, P=0.001) and VBGC (1.748±0.622 vs. 0.392±0.276 cm3, t=2.518, P=0.028) with symptom?atic patients between dyskinesia and psychogenic families was significant. Conclusions Eight FIBGC families manifested autosomal dominant heredity. Patients with dyskinesia suffer have a larger VBGC and are associated with a, and is char?acterized by relatively later onset age. In contrast, patients with psychiatric symptomspsychogeny is not related withhave a the small VBGC and showedand their age of onset is young. earlier onset age.

Enfermedad de Fahr, una entidad patológica rara, revisión de la literatura a propósito de dos casos / Fahr Disease, A Rare Pathologic Entity, Literature Review in Relation of Two Cases

La enfermedad de Fahr es una entidad neurodegenerativa autosómica dominante poco frecuente, con incidencia en personas entre la cuarta y la quinta década de la vida, caracterizada por calcificaciones simétricas prominentes detectadas por tomografía computarizada en tálamo, cápsula interna, sustancia blanca, cerebelo y ganglios basales con o sin compromiso del núcleo dentado, sin que se relacione con alteraciones del metabolismo del calcio. Estos cambios pueden llevar a trastornos neuropsiquiátricos y síntomas piramidales, extrapiramidales y cerebelosos. En este artículo se exponen las manifestaciones clínicas, los hallazgos imaginológicos y la serología utilizada para llegar al diagnóstico de esta enfermedad con base en dos casos clínicos de la Clínica Universitaria Colombia en la ciudad de Bogotá.

Fahr's disease is an autosomal dominant neurodegenerative disease. It is infrequent, and it has an incidence between the fourth and fifth decade of life. It is characterized by prominent symmetrical calcifications detected in CT studies located on thalamus, internal capsule, white matter, cerebellum and basal ganglia with or without involvement of the dentate nucleus, without being related to calcium metabolism disorders. These changes may lead to neuropsychiatric disorders and pyramidal, extrapyramidal and cerebellar symptoms. In this article we expose the clinical manifestations, imaging findings and serology test used for the diagnosis of the disease based on two clinical cases in the Clínica Universitaria Colombia in Bogotá.

Mutation Analysis of SLC20A2 and SPP2 as Candidate Genes for Familial Idiopathic Basal Ganglia Calcification.

BACKGROUND: Familial Idiopathic Basal Ganglia Calcification (IBGC) is a rare neurodegenerative disorder which is usually transmitted as an autosomal dominant trait. IBGC is genetically heterogeneous and SLC20A2, on chromosome 8p21.1-8q11.23, is the first gene found in IBGC-affected patients with varied ancestry. On the other hand, several candidate genes for IBGC on chromosome 2q37, including the SPP2 gene, may play a role in inhibiting calcification. METHODS: Totally, 22 members of a three generational Iranian family affected by IBGC, with an autosomal dominant pattern of inheritance were included in this study. DNA was extracted from the whole blood using standard salting out method. To find a mutation responsible for IBGC, we sequenced the coding region of SLC20A2 as well as promoter and coding region of SPP2 in the index subject of IBGC-affected family. RESULTS: Pathogenic mutation was found neither in SLC20A2 nor in SPP2. CONCLUSION: Our results strengthen genetic heterogeneity of this condition. Additional mutation studies are necessary to find a gene or genes responsible for IBGC in this affected family.

Novel SLC20A2 mutations identified in southern Chinese patients with idiopathic basal ganglia calcification.

Idiopathic basal ganglia calcification (IBGC) is a rare neuropsychiatric disorder characterized by bilateral and symmetric cerebral calcifications. Recently, SLC20A2 was identified as a causative gene for familial IBGC, and three mutations were reported in a northern Chinese population. Here, we aimed to explore the mutation spectrum of SLC20A2 in a southern Chinese population. Sanger sequencing was employed to screen mutations within SLC20A2 in two IBGC families and 14 sporadic IBGC cases from a southern Han Chinese population. Four novel mutations (c.82G>A p.D28N, c.185T>C p.L62P, c.1470_1478delGCAGGTCCT p.Q491_L493del and c.935-1G>A) were identified in two families and two sporadic cases, respectively; none were detected in 200 unrelated controls. No mutation was found in the remaining 12 patients. Different mutations may result in varied phenotypes, including brain calcification and clinical manifestations. Our study supports the hypothesis that SLC20A2 is a causative gene of IBGC and expands the mutation spectrum of SLC20A2, which facilitates the understanding of the genotype-phenotype correlation of IBGC.

Familial Idiopathic Basal Ganglia Calcification

Familial idiopathic basal ganglia calcification(FIBGC) is an inheritable neurological condition characterized by calcium deposits in the basal ganglia and extra-basal ganglia areas. The condition manifests as parkinsonism and other variable neuropsychiatric symptoms. FIBGC is a rare condition, and its pathophysiology has not yet been fully elucidated. Here we report the results of a clinical study of two related patients diagnosed with FIBGC.