Cortical myoclonus and epilepsy in a family with a new SLC20A2 mutation

Coppola, Antonietta; Hernández-Hernández, Laura; Balestrini, Simona; Krithika, S.; Moran, Nicholas; Hale, Blake; Cordivari, Carla; Sisodiya, Sanjay M.

doi:10.1007/s00415-020-09821-4

Cited by 5 publications

(3 citation statements)

References 30 publications

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“…SLC20A2 is the most common PFBC gene; heterozygous variants have been identified in more than 60% of genetically confirmed PFBC patients [ 3 ]. A missense change is the most common variant type, followed by frameshift, nonsense, and splice site variations, without obvious hotspots for pathogenic variants ( Figure 1 a) [ 3 , 6 , 7 , 17 , 18 , 21 , 23 , 37 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 ]. Functionally, both haploinsufficiency and dominant negative effects have been described; the loss of normal PiT2 function results in extracellular Pi accumulation and subsequent calcium phosphate formation [ 6 , 42 ].…”

Section: Genetics and Disease Mechanismmentioning

confidence: 99%

The Genetics of Primary Familial Brain Calcification: A Literature Review

Chen

et al. 2023

IJMS

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Primary familial brain calcification (PFBC), also known as Fahr’s disease, is a rare inherited disorder characterized by bilateral calcification in the basal ganglia according to neuroimaging. Other brain regions, such as the thalamus, cerebellum, and subcortical white matter, can also be affected. Among the diverse clinical phenotypes, the most common manifestations are movement disorders, cognitive deficits, and psychiatric disturbances. Although patients with PFBC always exhibit brain calcification, nearly one-third of cases remain clinically asymptomatic. Due to advances in the genetics of PFBC, the diagnostic criteria of PFBC may need to be modified. Hitherto, seven genes have been associated with PFBC, including four dominant inherited genes (SLC20A2, PDGFRB, PDGFB, and XPR1) and three recessive inherited genes (MYORG, JAM2, and CMPK2). Nevertheless, around 50% of patients with PFBC do not have pathogenic variants in these genes, and further PFBC-associated genes are waiting to be identified. The function of currently known genes suggests that PFBC could be caused by the dysfunction of the neurovascular unit, the dysregulation of phosphate homeostasis, or mitochondrial dysfunction. An improved understanding of the underlying pathogenic mechanisms for PFBC may facilitate the development of novel therapies.

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Section: Genetics and Disease Mechanismmentioning

confidence: 99%

The Genetics of Primary Familial Brain Calcification: A Literature Review

Chen

et al. 2023

IJMS

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“…In carriers of pathogenic variants of SLC20A2, additional features have been reported including forms of tremor (head tremor, intention tremor of the upper limbs), blepharospasm, torticollis, facial palsy, apraxia, palilalia, myoclonus (described as mostly cortical), cramps, active denervation at electromyographic (EMG) recording, polyneuropathy, syncope, as well as ischemic episodes (both transitory and stroke) [40,41,[44][45][46][47][48][49][50][51]. Seizures have been described as both grand mal generalized or focal.…”

Section: Primary Familial Brain Calcifications: Clinical Aspectsmentioning

confidence: 99%

“…Intrafamilial variability can be observed for all these genes, both in terms of age of onset as well as clinical presentation, arguing against a strong genotype-phenotype correlation [40]. However, gene variants, clinical traits, and/or age of onset or both showed consistency among family members in certain families [16,44,48,50,56,59].…”

Section: Primary Familial Brain Calcifications: Clinical Aspectsmentioning

confidence: 99%

Brain Calcifications: Genetic, Molecular, and Clinical Aspects

Monfrini

Arienti

Rinchetti

et al. 2023

IJMS

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Many conditions can present with accumulation of calcium in the brain and manifest with a variety of neurological symptoms. Brain calcifications can be primary (idiopathic or genetic) or secondary to various pathological conditions (e.g., calcium–phosphate metabolism derangement, autoimmune disorders and infections, among others). A set of causative genes associated with primary familial brain calcification (PFBC) has now been identified, and include genes such as SLC20A2, PDGFB, PDGFRB, XPR1, MYORG, and JAM2. However, many more genes are known to be linked with complex syndromes characterized by brain calcifications and additional neurologic and systemic manifestations. Of note, many of these genes encode for proteins involved in cerebrovascular and blood–brain barrier functions, which both represent key anatomical structures related to these pathological phenomena. As a growing number of genes associated with brain calcifications is identified, pathways involved in these conditions are beginning to be understood. Our comprehensive review of the genetic, molecular, and clinical aspects of brain calcifications offers a framework for clinicians and researchers in the field.

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Autosomal Dominant Hypocalcemia Type 1 (ADH1) Associated With Myoclonus and Intracerebral Calcifications

Elston

Elajnaf

Hannan

et al. 2022

Journal of the Endocrine Society

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Autosomal dominant hypocalcemia type 1 (ADH1) is a disorder of extracellular calcium homeostasis caused by germline gain-of-function mutations of the calcium-sensing receptor (CaSR). Over 35% of ADH1 patients have intracerebral calcifications predominantly affecting the basal ganglia. The clinical consequences of such calcifications remain to be fully characterized, although the majority of patients with these calcifications are considered to be asymptomatic. We report a 20-year-old female proband with a severe form of ADH1 associated with recurrent hypocalcemic and hypercalcemic episodes, persistent childhood hyperphosphatemia, and a low calcium/phosphate ratio. From the age of 18 years, she had experienced recurrent myoclonic jerks affecting the upper limbs that were not associated with epileptic seizures, extra-pyramidal features, cognitive impairment, or alterations in serum calcium concentrations. Computerised tomography (CT) scans revealed calcifications of the globus pallidus regions of the basal ganglia bilaterally, and also the frontal lobes at the grey-white matter junction, and posterior horn choroid plexuses. The patient’s myoclonus resolved following treatment with levetiracetam. CASR mutational analysis identified a reported germline gain-of-function heterozygous missense mutation, c.2363T>G; p.(Phe788Cys), which affects an evolutionarily conserved phenylalanine residue located in transmembrane domain helix 5 of the CaSR protein. Analysis of the cryo-electron microscopy CaSR structure predicted the wild-type Phe788 residue to form interactions with neighbouring phenylalanine residues, which likely maintain the CaSR in an inactive state. The p.(Phe788Cys) mutation was predicted to disrupt these interactions, thereby leading to CaSR activation. These findings reveal myoclonus as a novel finding in an ADH1 patient with intracerebral calcifications.

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Cortical myoclonus and epilepsy in a family with a new SLC20A2 mutation

Cited by 5 publications

References 30 publications

The Genetics of Primary Familial Brain Calcification: A Literature Review

The Genetics of Primary Familial Brain Calcification: A Literature Review

Brain Calcifications: Genetic, Molecular, and Clinical Aspects

Autosomal Dominant Hypocalcemia Type 1 (ADH1) Associated With Myoclonus and Intracerebral Calcifications

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