Bilateral Calcification of Basal Ganglia in a Patient with Duplication of Both 11q13.1q22.1 and 4q35.2 with New Phenotypic Features

We report on a female patient who presented with severe intellectual disability and autistic behavior, dysmorphic features, orodental anomalies, and bilateral calcification of basal ganglia. Using a high-density oligonucleotide microarray, we have identified a de novo duplication of 11q13.1q22.1 involving the dosage sensitive genes FGF3 and FGF4, genes related to autosomal dominant disorders KMT5B, GAL, SPTBN2, and LRP5, susceptibility loci SCZD2, SLEH1, and SHANK2, mitochondrial genes NDUFV1, NDUFS8, and TMEM126B, and many loss of function genes, including PHOX2A, CLPB, MED17, B3GNT1, LIPT2, and CLPB. However, the duplication did not involve Ribonuclease H2, subunit C (RNASEH2C) which is considered to be located in the critical region for Aicardi-Goutières syndrome. In combination with the duplication at 11q13.1, a 1.849-Mb heterozygous duplication at 4q35.2 was also identified. Although this duplicated region does not contain causative genes related to brain calcification, the duplication at 4q35 was reported previously in a patient with basal ganglia calcification, coats' like retinopathy, and glomerulosclerosis. Our patient's presentation and genomic findings indicate that duplication of 4q35.2 could be a novel genetic cause of calcification of basal ganglia. Our report also underscores the clinical significance of rearrangements in 11q13.1q22.1 in the pathogenesis of basal ganglia calcification.

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A novel CASR mutation (p.Glu757Lys) causing autosomal dominant hypocalcaemia type 1

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-18-0107 ◽

2018 ◽

Vol 2018 ◽

Author(s):

Benjamin Kwan ◽

Bernard Champion ◽

Steven Boyages ◽

Craig F Munns ◽

Roderick Clifton-Bligh ◽

...

Keyword(s):

Basal Ganglia ◽

Autosomal Dominant ◽

Family Members ◽

Normal Serum ◽

Mirror Image ◽

List Type ◽

Basal Ganglia Calcification ◽

Proper Management ◽

Serum Pth

Summary Autosomal dominant hypocalcaemia type 1 (ADH1) is a rare familial disorder characterised by low serum calcium and low or inappropriately normal serum PTH. It is caused by activating CASR mutations, which produces a left-shift in the set point for extracellular calcium. We describe an Australian family with a novel heterozygous missense mutation in CASR causing ADH1. Mild neuromuscular symptoms (paraesthesia, carpopedal spasm) were present in most affected individuals and required treatment with calcium and calcitriol. Basal ganglia calcification was present in three out of four affected family members. This case highlights the importance of correctly identifying genetic causes of hypocalcaemia to allow for proper management and screening of family members. Learning points: ADH1 is a rare cause of hypoparathyroidism due to activating CASR mutations and is the mirror image of familial hypocalciuric hypercalcaemia. In patients with ADH1, symptoms of hypocalcaemia may be mild or absent. Basal ganglia calcification may be present in over a third of patients. CASR mutation analysis is required for diagnostic confirmation and to facilitate proper management, screening and genetic counselling of affected family members. Treatment with calcium and activated vitamin D analogues should be reserved for symptomatic individuals due to the risk of exacerbating hypercalciuria and its associated complications.

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A Novel SETBP1 Gene Disruption by a De Novo Balanced Translocation in a Patient with Speech Impairment, Intellectual, and Behavioral Disorder

Journal of Pediatric Genetics ◽

10.1055/s-0040-1715639 ◽

2020 ◽

Author(s):

Ivona Vrkić Boban ◽

Futoshi Sekiguchi ◽

Mirela Lozić ◽

Noriko Miyake ◽

Naomichi Matsumoto ◽

...

Keyword(s):

Intellectual Disability ◽

Autosomal Dominant ◽

De Novo ◽

Chromosomal Abnormalities ◽

Chromosome Translocation ◽

Behavioral Disorder ◽

Behavioral Difficulties ◽

Speech Impairment ◽

Balanced Translocation ◽

Severe Intellectual Disability

AbstractBalanced chromosomal abnormalities (BCAs) can disrupt gene function resulting in disease. To date, BCA disrupting the SET binding protein 1 (SETBP1) gene has not been reported. On the other hand, de novo heterozygous variants in the highly conserved 11-bp region in SETBP1 can result in the Schinzel–Giedion syndrome. This condition is characterized by severe intellectual disability, a characteristic face, and multiple-system anomalies. Further other types of mutations involving SETBP1 are associated with a different phenotype, mental retardation, autosomal dominant 29 (MRD29), which has mild dysmorphic features, developmental delay, and behavioral disorders. Here we report a male patient who has moderate intellectual disability, mild behavioral difficulties, and severe expressive speech impairment resulting from a de novo balanced chromosome translocation, t(12;18)(q22;q12.3). By whole genome sequencing, we determined the breakpoints at the nucleotide level. The 18q12.3 breakpoint was located between exons 2 and 3 of SETBP1. Phenotypic features of our patient are compatible with those with MRD29. This is the first reported BCA disrupting SETBP1.

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Idiopathic Basal Ganglia Calcification Presented with Impulse Control Disorder

Case Reports in Endocrinology ◽

10.1155/2015/287586 ◽

2015 ◽

Vol 2015 ◽

pp. 1-4

Author(s):

Cem Sahin ◽

Mustafa Levent ◽

Gulhan Akbaba ◽

Bilge Kara ◽

Emine Nese Yeniceri ◽

...

Keyword(s):

Basal Ganglia ◽

Impulse Control ◽

Cerebellar Nuclei ◽

Impulse Control Disorder ◽

Metabolic Disturbances ◽

Basal Ganglia Calcification ◽

Brain Calcification ◽

Idiopathic Basal Ganglia Calcification ◽

Anatomic Localization ◽

Current Report

Primary familial brain calcification (PFBC), also referred to as Idiopathic Basal Ganglia Calcification (IBGC) or “Fahr’s disease,” is a clinical condition characterized by symmetric and bilateral calcification of globus pallidus and also basal ganglions, cerebellar nuclei, and other deep cortical structures. It could be accompanied by parathyroid disorder and other metabolic disturbances. The clinical features are dysfunction of the calcified anatomic localization. IBGC most commonly presents with mental damage, convulsion, parkinson-like clinical picture, and neuropsychiatric behavior disorders; however, presentation with impulse control disorder is not a frequent presentation. In the current report, a 43-year-old male patient who has been admitted to psychiatry policlinic with the complaints of aggressive behavior episodes and who has been diagnosed with impulse control disorder and IBGC was evaluated in the light of the literature.

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A de novo nonsense PDGFB mutation causing idiopathic basal ganglia calcification with laryngeal dystonia

European Journal of Human Genetics ◽

10.1038/ejhg.2014.9 ◽

2014 ◽

Vol 22 (10) ◽

pp. 1236-1238 ◽

Cited By ~ 32

Author(s):

Gaël Nicolas ◽

Agnès Jacquin ◽

Christel Thauvin-Robinet ◽

Anne Rovelet-Lecrux ◽

Olivier Rouaud ◽

...

Keyword(s):

Basal Ganglia ◽

De Novo ◽

Basal Ganglia Calcification ◽

Laryngeal Dystonia ◽

Idiopathic Basal Ganglia Calcification

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A de novo STUB1 variant associated with an early adult-onset multisystemic ataxia phenotype

Journal of Neurology ◽

10.1007/s00415-021-10524-7 ◽

2021 ◽

Author(s):

David Mengel ◽

Andreas Traschütz ◽

Selina Reich ◽

Alejandra Leyva-Gutiérrez ◽

Friedemann Bender ◽

...

Keyword(s):

Early Onset ◽

Autosomal Recessive ◽

Autosomal Dominant ◽

De Novo ◽

Family Members ◽

Start Codon ◽

Mrna Levels ◽

Adult Onset ◽

Loss Of Function ◽

Autosomal Dominant Disorder

Abstract Background Biallelic STUB1 variants are a well-established cause of autosomal-recessive early-onset multisystemic ataxia (SCAR16). Evidence for STUB1 variants causing autosomal-dominant ataxia (SCA48) so far largely relies on segregation data in larger families. Presenting the first de novo occurrence of a heterozygous STUB1 variant, we here present additional qualitative evidence for STUB1-disease as an autosomal-dominant disorder. Methods Whole exome sequencing on an index patient with sporadic early-onset ataxia, followed by Sanger sequencing in all family members, was used to identify causative variants as well as to rule out alternative genetic hits and intronic STUB1 variants. STUB1 mRNA and protein levels in PBMCs in all family members were analysed using qRT-PCR and Western Blot. Results A previously unreported start-lost loss-of-function variant c.3G>A in the start codon of STUB1 was identified in the index case, occurring de novo and without evidence for a second (potentially missed) variant (e.g., intronic or copy number) in STUB1. The patient showed an early adult-onset multisystemic ataxia complicated by spastic gait disorder, distal myoclonus and cognitive dysfunction, thus closely mirroring the systems affected in autosomal-recessive STUB1-associated disease. In line with the predicted start-lost effect of the variant, functional investigations demonstrated markedly reduced STUB1 protein expression in PBMCs, whereas mRNA levels were intact. Conclusion De novo occurrence of the loss-of-function STUB1 variant in our case with multisystemic ataxia provides a qualitatively additional line of evidence for STUB1-disease as an autosomal-dominant disorder, in which the same neurological systems are affected as in its autosomal-recessive counterpart. Moreover, this finding adds support for loss-of-function as a mechanism underlying autosomal-dominant STUB1-disease, thus mirroring its autosomal-recessive counterpart also in terms of the underlying mutational mechanism.

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A novel de novo hemizygous ARHGEF9 mutation associated with severe intellectual disability and epilepsy: a case report

Journal of International Medical Research ◽

10.1177/03000605211058372 ◽

2021 ◽

Vol 49 (11) ◽

pp. 030006052110583

Author(s):

Tong Qiu ◽

Qian Dai ◽

Qiu Wang

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Developmental Delay ◽

De Novo ◽

Clinical Symptoms ◽

Genetic Diagnosis ◽

Epileptic Seizures ◽

Autism Spectrum ◽

Loss Of Function ◽

Severe Intellectual Disability

ARHGEF9 encodes collybistin, a brain-specific guanosine diphosphate-guanosine-5′-triphosphate exchange factor that plays an important role in clustering of gephyrin and γ-aminobutyric acid type A receptors in the postsynaptic membrane. Overwhelming evidence suggests that defects in this protein can cause X-linked intellectual disability, which comprises a series of clinical phenotypes, including autism spectrum disorder, behavior disorder, intellectual disability, and febrile seizures. Here, we report a boy with clinical symptoms of severe intellectual disability, epilepsy, and developmental delay and regression. Trio exome sequencing ( trio-clinical exome sequencing) identified a novel hemizygous deletion, c.656_c.669delACTTCTTTGAGGCC (p. His219Leu fs*9), in exon 5 of ARHGEF9. This variant was not reported in either the Genome Aggregation Database or our database of 309 patients with neurodevelopmental disorders. Oxcarbazepine and levetiracetam reduced the frequency of the patient’s epileptic seizures to a certain extent, but psychomotor developmental delay and developmental regression became more obvious with age. This case study seeks to report a de novo loss-of-function mutation of ARHGEF9, aiming to emphasize the genetic diagnosis of X-linked intellectual disability and further improve knowledge of the ethnic distribution of ARHGEF9 mutations.

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Loss of Function of Slc20a2 Associated with Familial Idiopathic Basal Ganglia Calcification in Humans Causes Brain Calcifications in Mice

Journal of Molecular Neuroscience ◽

10.1007/s12031-013-0085-6 ◽

2013 ◽

Vol 51 (3) ◽

pp. 994-999 ◽

Cited By ~ 64

Author(s):

Nina Jensen ◽

Henrik Daa Schrøder ◽

Eva Kildall Hejbøl ◽

Ernst-Martin Füchtbauer ◽

João Ricardo Mendes de Oliveira ◽

...

Keyword(s):

Basal Ganglia ◽

Loss Of Function ◽

Basal Ganglia Calcification ◽

Idiopathic Basal Ganglia Calcification

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Partial reduced Pi transport function of PiT-2 might not be sufficient to induce brain calcification of idiopathic basal ganglia calcification

Scientific Reports ◽

10.1038/s41598-019-53401-0 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Kazuya Nishii ◽

Ritsuko Shimogawa ◽

Hisaka Kurita ◽

Masatoshi Inden ◽

Michio Kobayashi ◽

...

Keyword(s):

Basal Ganglia ◽

Reference Level ◽

Transport Function ◽

Transport Activity ◽

Wild Type ◽

Causative Gene ◽

Basal Ganglia Calcification ◽

Pi Transport ◽

Brain Calcification ◽

Idiopathic Basal Ganglia Calcification

AbstractIdiopathic basal ganglia calcification (IBGC) is a rare intractable disease characterized by abnormal mineral deposits, including mostly calcium in the basal ganglia, thalamus, and cerebellum. SLC20A2 is encoding the phosphate transporter PiT-2 and was identified in 2012 as the causative gene of familial IBGC. In this study, we investigated functionally two novel SLC20A2 variants (c.680C > T, c.1487G > A) and two SLC20A2 variants (c.82G > A, c.358G > C) previously reported from patients with IBGC. We evaluated the function of variant PiT-2 using stable cell lines. While inorganic phosphate (Pi) transport activity was abolished in the cells with c.82G > A, c.358G > C, and c.1487G > A variants, activity was maintained at 27.8% of the reference level in cells with the c.680C > T variant. Surprisingly, the c.680C > T variant had been discovered by chance in healthy members of an IBGC family, suggesting that partial preservation of Pi transport activity may avoid the onset of IBGC. In addition, we confirmed that PiT-2 variants could be translocated into the cell membrane to the same extent as PiT-2 wild type. In conclusion, we investigated the PiT-2 dysfunction of four SLC20A2 variants and suggested that a partial reduced Pi transport function of PiT-2 might not be sufficient to induce brain calcification of IBGC.

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Neuroimaging Findings in Patients with EBF3 Mutations: Report of Two Cases

Molecular Syndromology ◽

10.1159/000513583 ◽

2021 ◽

pp. 1-8

Author(s):

Mar Jiménez de la Peña ◽

Ana Jiménez de Domingo ◽

Pilar Tirado ◽

Beatriz Calleja-Pérez ◽

Luis A. Alcaraz ◽

...

Keyword(s):

Transcription Factor ◽

Intellectual Disability ◽

Neurodevelopmental Disorders ◽

Autosomal Dominant ◽

De Novo ◽

Diffusion Tensor ◽

Loss Of Function ◽

Normal Range ◽

Early B Cell Factor ◽

And Diffusion

Early B cell factor 3 (EBF3) is a transcription factor involved in brain development. Heterozygous, loss-of-function mutations in EBF3 have been reported in an autosomal dominant neurodevelopmental syndrome characterized by hypotonia, ataxia, and developmental delay (sometimes described as “HADD”s). We report 2 unrelated cases with novel de novo EBF3 mutations: c.455G>T (p.Arg152Leu) and c.962dup (p.Tyr321*) to expand the genotype/phenotype correlations of this disorder; clinical, neuropsychological, and MRI studies were used to define the phenotype. IQ was in the normal range and diffusion tensor imaging revealed asymmetric alterations of the longitudinal fasciculus in both cases. Our results demonstrate that EBF3 mutations can underlie neurodevelopmental disorders without intellectual disability. Long tract abnormalities have not been previously recognized and suggest that they may be an unrecognized and characteristic feature in this syndrome.

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Primary familial brain calcification: a clinical case

Fundamental and Clinical Medicine ◽

10.23946/2500-0764-2019-4-3-128-132 ◽

2019 ◽

Vol 4 (3) ◽

pp. 128-132

Author(s):

Yu. A. Malyshenko ◽

I. V. Soroko ◽

D. V. Kober ◽

R. S. Bogachev ◽

A. E. Mityukov

Keyword(s):

Computed Tomography ◽

Basal Ganglia ◽

Multislice Computed Tomography ◽

Endocrine Disorders ◽

Efficient Treatment ◽

Basal Ganglia Calcification ◽

Primary Familial Brain Calcification ◽

Brain Calcification ◽

Proper Diagnosis ◽

The Brain

Primary familial brain calcification (familial idiopathic basal ganglia calcification, Fahr’s disease) is a rare neurodegenerative syndrome characterised by a symmetrical bilateral calcification in the basal ganglia, dentate nucleus, cerebral cortex, and other regions of the brain. The widespread use of multislice computed tomography and magnetic resonance imaging increased the number of diagnosed cases, yet neither causes nor efficient treatment of this disease are known to date. Due to variable symptoms, primary familial brain calcification can resemble multiple neurological, mental, and endocrine disorders. Here we describe a case of a 38-year-old woman where timely multislice computed tomography led to the proper diagnosis and successful treatment.

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