Novel likely pathogenic SLC20A variant in primary familial brain calcification
- 1 Department of Neurology, University of Minnesota Medical School Twin Cities, Minneapolis, Minnesota, USA
- 2 Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA
- Correspondence to Rishi Sharma; sharm415@umn.edu
Abstract
A woman in her 30s was referred to our neurology outpatient clinic following an incidental finding of significant bilateral and symmetric basal ganglia, thalamic, cerebellar and subcortical white matter calcification on brain CT and MRI. A diagnosis of asymptomatic primary familial brain calcification (PFBC) was made. Targeted genetic testing revealed a likely pathogenic variant in the SLC20A2 gene, the most common gene in which pathogenic variants have been implicated in PFBC. These findings prompted genetic testing and brain CT of our patient’s asymptomatic 64-year-old father. These tests revealed the same variant in SLC20A2 and similar brain calcification on CT in the patient’s father.
Background
Primary familial brain calcification (PFBC, also variably referred to in the past as Fahr disease, idiopathic basal ganglia calcification, bilateral striopallidodentate calcinosis) is a rare genetic disorder characterised by bilateral calcifications primarily involving the basal ganglia, thalamus, cerebellum and subcortical white matter.1 2 Considerable clinical and genetic heterogeneity exists. Patients typically present with onset between the third and fifth decade of life with psychiatric disturbance, cognitive impairment, movement disorders or cerebellar dysfunction. A third of patients may remain asymptomatic.
A heterozygous pathogenic variant in SLC20A2, PDGF-B, PDGFRB or XPR1 results in an autosomal dominant inheritance,3–6 while biallelic pathogenic variants in MYORG are responsible for autosomal recessive PFBC.7 Sporadic cases are well recognised. PFBC-causing variants have complete penetrance for the neuroradiological phenotype but incomplete penetrance for the clinical phenotype. Both the clinical and radiological penetrance is age related. Why some patients remain asymptomatic is unknown. Over 100 pathogenic changes in these five PFBC genes are known to cause PFBC in approximately half of all PFBC cases.3 In this report we describe a novel variant in SLC20A2 that was present in two individuals of a family afflicted by the disease. This variant was reported as being likely pathogenic variant.8–10
Case presentation
A woman in her 30s was evaluated for recurrent transient unilateral mydriasis with photophobia. Her history was remarkable for hyperhidrosis treated with glycopyrronium towelettes and propantheline bromide tablets. Her neurological examination was otherwise unremarkable. The mydriasis resolved on discontinuation of the anticholinergic medications. Her work up included a head CT that showed bilateral, symmetric calcification involving the basal ganglia, thalami, cerebellum and subcortical white matter (figure 1A).
(A) Patient’s head CT showing basal ganglia calcification. (B) Patient’s brain MRI showing T1-hyperintensity in the areas corresponding to the calcification on the head CT. (C) Patient’s father’s head CT showing basal ganglia and cerebellar white matter calcification.
Investigations
Brain MRI revealed non-enhancing T1 hyperintensity and corresponding gradient echo sequence darkening affecting the same areas (figure 1B). Investigations looking into other causes of basal ganglia calcification were unremarkable (parathyroid/calcium studies, heavy metal screen and serology for cytomegalovirus, HIV and syphilis). Genetic testing for PFBC directed at the five known genes revealed heterozygosity in the SLC20A2 gene at position c.1781C>T (which is predicted to result in the amino acid substitution p.Thr594IIe). Of note, a different missense alteration at the adjacent amino acid (p.Thr595Met) has been documented as pathogenic for PFBC.3 This variant identified in our patient was reported by the laboratory as being ‘likely pathogenic’. (Targeted testing via SLC20A2 gene sequencing was done using a combination of next generation sequencing and Sanger sequencing technologies to cover the full coding region of the gene plus approximately 10 bases of non-coding DNA flanking each exon.)
This prompted the recommendation for a head CT and genetic testing in our patient’s father. His head CT showed basal ganglia and cerebellar calcifications (figure 1C), and genetic testing revealed the same variant as the one seen in our patient in SLC20A2. Her father was not clinically examined for this indication, so subtle neurological deficits could not be ruled-out, but family members available reported no subjective concerns that would suggest he was symptomatic (figure 2). The patient was referred to a geneticist for further discussion of the implications of an autosomal dominant disorder for someone in the reproductive age group as well as to help her understand implications for other family members.
Pedigree showing an autosomal dominant inheritance pattern for the afflicted members over two generations. Our patient was the afflicted woman depicted in the second generation of the pedigree, II-2. Note that her, her father (I-2), was afflicted and asymptomatic. The patient and her father both had genetic testing, and both individuals were noted to have significant calcification via CT. Note: the unaffected family members were not examined.
Differential diagnosis
PFBC should in particular be considered when young individuals present with parkinsonian or less commonly cerebellar manifestations. While neurological manifestations of PFBC have been well characterised, it is important to remember that patients may present with only psychiatric manifestation.11 12 The characteristic calcification is a clue to PFBC as a possible diagnosis. It is important to remember that for detection of brain calcification, CT scan is a better imaging modality than MRI.
Differential diagnostic considerations for basal ganglia calcification include a broad range of disorders including metabolic disorders (in particular disorders of calcium homeostasis and mitochondrial disease), prior head injury, certain brain tumours that have a propensity to calcify like oligodendrogliomas and a myriad of infectious diseases (parasitic infections like neurocysticercosis, tuberculosis and infections included under the TORCH complex: toxoplasmosis, others—syphilis and hepatitis B, rubella, cytomegalovirus herpes simplex).13
As is illustrated by this report, asymptomatic cases are not uncommon. Neuroimaging findings often antedate neuropsychiatric manifestations. Rarely the condition may present as late-onset levodopa responsive parkinsonism.14 The variable clinical presentations and incomplete penetrance contribute to the condition being underdiagnosed.
Discussion
In this report we describe a likely pathogenic variant in SLC20A2 in two patients with PFBC from a family. The individuals had radiographic involvement indicative of PFBC, but no attributable clinical manifestations. A limitation of this report is that the patient’s father was not examined. The identified familial sequence variant was adjacent to a different missense alteration at an adjacent amino acid that has been documented as being pathogenic for PFBC.3 The laboratory noted that this variant has never been reported before in individuals with PFBG, nor has it been reported before in a general population sample of healthy adult.
Variants in PFBC are most common in SLC20A2; its gene product is PiT2, an inorganic phosphate transporter that is involved in phosphate transport into the cell. Pathogenic missense changes in SLC20A2 are responsible for accumulation of extracellular inorganic phosphate and subsequently of calcium phosphate.15 Resulting calcification in the capillary, arteriole and small vein walls of the brain likely results in reactive gliosis and/or neuronal degeneration.
Each of the five genes implicated in PFBC are expressed in the cells comprising the neurovascular unit (NVU).16 The NVU, comprises vascular cells, glial cells and neurons and is the minimal functional unit of the brain. The role of NVU dysfunction in other neurodegeneration diseases is an area of intense current research.
Typically, the clinical manifestation cannot be predicted by the specific variant and considerable intrafamilial clinical and radiological variability exists. That said, parkinsonism is the most common clinical manifestation seen in SLC20A2 variant carriers, while speech disturbance is a common feature of MYORG variants.2
The American College of Medical Genetics and Association of Molecular Pathology standards and guidelines for the interpretation of sequence variants is an invaluable resource that recommends the use of standard terminology—‘pathogenic’, ‘likely pathogenic’, ‘uncertain significance’, ‘likely benign’ and ‘benign’—to describe variants identified in genes that cause Mendelian disorders.8 Classifying variants into these categories is a complex process that uses population data, computational data, functional data and in particular segregation data.8 9 The increasing use of high-throughput next-generation sequencing has expanded the catalogue of available genetic and epigenetic assays for genetic disorders. It is therefore imperative that due scientific rigour be exercised in the classification of a variant. A recent survey indicated fairly widespread adoption of these guidelines in just 3 years.10
In clinical practice, as in our case, multigene panel that includes all the implicated genes is often preferred over serial single-gene testing based on the relative frequency of pathogenic variants in each of the PFBC-associated genes. More comprehensive genomic testing, including exome sequencing and genomic testing may identify as yet unidentified genes that result in the disorder. Additional variants in the genes implicated in PFBC, and additional genes will no doubt add to the genetic heterogeneity of PFBC in the future. Further knowledge about these variants may provide additional insights into the underlying pathophysiology which may pave the way for rational therapeutics.
Learning points
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Primary familial brain calcification (PFBC, also referred to as Fahr disease) is a genetic disorder characterised by bilateral calcifications primarily involving the basal ganglia, thalamus, cerebellum and subcortical white matter.
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PFBC is associated with considerable clinical and genetic heterogeneity. Asymptomatic presentations and sporadic cases are well recognised. PFBC-causing variants have complete penetrance for the neuroradiological phenotype but incomplete penetrance for the clinical phenotype.
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The most common gene in which mutations have been identified in PFBC is SLC20A2. Pathogenic missense changes in SLC20A2 are likely responsible for derangement of phosphate and calcium homeostasis and subsequent vascular calcification and reactive gliosis.
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It is not known why some patients with PFBC have clinical manifestations, while others, despite comparable degree of calcification, remain asymptomatic. Understanding the functional significance of pathogenic and likely pathogenic variants may provide further insights into this.
Ethics statements
Patient consent for publication
Footnotes
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Twitter @brainsnthingz
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Contributors Both authors conceived the ideas presented. DS acquired and analysed the data. RS drafted the manuscript. Both authors revised and approved the manuscript.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
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