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Ataxia and elevated CSF-Pi associated with a mutation in the SLC20A2 gene

A SLC20A2 gene mutation carrier displaying ataxia and increased levels of

cerebrospinal fluid phosphate

Primary familial brain calcifications (PFBC) are a group of rare autosomal dominant disorders

with wide phenotype variability and reduced clinical penetrance. Mutations in the SLC20A2

gene were the first cause of PFBC to be discovered (1), followed by discoveries of three other

PFBC genes: PDGFB, PDGFBR and XPR1 (2, 3).

Here we provide a comprehensive characterization of a patient harboring the heterozygous

c.1399C>T (R467X) mutation in the SLCA20A2 gene. This truncating mutation has been

previously described in a young Japanese male affected by early-onset paroxysmal

kinesigenic dyskinesia (PKD), his mother being asymptomatic despite the presence of brain

calcifications (4). Brain calcifications in PFBC were proposed to be progressive, based on the

distribution of total calcification scores (TCS) according to age (5). However, the more

widespread and severe calcifications in the youngest generation in one of the families (Family

SD-IBGC) in which the SLC20A2 mutations were discovered challenge this suggestion (1).

Progressive brain calcifications have been demonstrated only once before in genetically-

proven SLC20A2-associated PFBC (6), otherwise longitudinal clinical and radiological

assessments in SLC20A2-associated PFBC have not yet been reported. Instead, single clinical

observations like ours provide insights into the natural history of this PFBC form.

1. Methods

The ethics committee in Stockholm and the radiation protection organization at the

Karolinska University Hospital (Etikprövningsnämnden dnr 2013/924-31) approved this

research.

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The following motor scales, with score range given in parenthesis, were used in our

assessment: Scale for the Assessment and Rating of Ataxia (SARA) (0-40), Inventory of non-

ataxia Symptoms (INAS) (0-16), Tremor rating scale (TRS) (0-144), Unified Huntington’s

disease rating scale (UHDRS) (0-124) and Unified Parkinson’s disease rating scale (UPDRS)

part III (0-108). The main motor features are presented in a video recording performed in

2015 (available as supplementary material).

A brain CT scan was performed in 2012 using single energy technique at a different center,

the thickness of these CT slices was 4 mm created from thin slices (0.62 mm). A 3T MRI of

the brain and the second CT scan with thin slices (0.62 mm) were performed in March 2015 at

our center. The second CT scan was performed using a scanner from the same manufacturer

but with a different X-ray technique namely double energy technique; details of imaging

acquisition are summarized in a previous publication (7). The severity of calcification in the

first brain imaging was assessed using the total calcification score (TCS) (5). The TCS scores

range between 0-80. The rate of calcification progression was determined using both the TCS

and image coregistration. A modified version of a coregistration method previously reported

was used (7) since an automated optimal 3D match between CT sections was not possible to

obtain. Briefly, a coregistration volume match was performed (GE AW server 3.2), 4 mm

slices with 1 mm increment were created and then manually matched in the local picture

archiving and communication system (PACS) to the first CT scan. Two experienced

neuroradiologists matched the images as exactly as possible and multiple 2D ROIs were

determined. Hounsfield units (HU) were measured in these 2D ROIs and the average of these

measurements was used to calculate the differences in HU. Increases over 10 HU were

considered significant (7). Neuropsychological testing was carried out with the following

batteries: 1. Brief cognitive status: Montreal Cognitive Assessment (MoCA); 2. General

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intellectual ability (IQ): full scale IQ and Ravens progressive matrices; 3. Evaluation of verbal

episodic memory: Rey Auditory Verbal Learning Test RAVLT (RAVLT) and Buschke’s Free

and Cued Selective Reminding Test (BFCSRT); 4. Visuospatial episodic memory: Rey

Osterrieth Complex Figure Test (ROCFT); 5. Working memory: digit span of the Wechsler

Adult Intelligence Scale (WAIS-IV); 6. Spatial/visual construction: ROCFT, Copy and Block

Design/WAIS-IV; 7. Verbal concept formation: Similarities in WAIS-IV; 8. Word fluency:

Controlled Oral Word Association Test (FAS/COWAT); 9. Picture Naming: Boston Naming

Test (BNT); 10. Information processing speed: Symbol Digit Modalities Test (SDMT); 11.

Executive function: Trail Making Test, B (TMT); 12. Motor speed: Finger-tapping test (FT),

dominant and non-dominant hand. Based on established reference values (8,9) z-scores were

assigned with a value ≤ -1.5 SD indicating a significant deficit. The cognitive features are

summarized in table e-3. Biochemical analyses included the work-up for secondary brain

calcifications (10) and lumbar punctures on two occasions, at ages 50 and 53. The following

biomarkers of neurodegeneration were analyzed both times: tau, phospho-tau (CSF P-tau), β-

amyloid and neurofilament (CSF-NfL). Phosphate levels in the CSF (CSF-Pi) and CSF-

oxysterols were analyzed in samples from the second lumbar puncture and compared with

samples from twelve age-matched female controls and one patient from the F13 family (III:2,

a 29 year old male) harboring the L9R mutation in the PDGFB gene (7). Those results are

summarized in tables 1 and e-4.

2. Clinical synopsis

The patient is a 54 year-old female affected by dementia, progressive ataxia,

psychiatric/behavioral symptoms and widespread brain calcifications. Details of her clinical

onset are provided in the main draft. Her past medical history consists of type 1 diabetes

mellitus (T1DM) with onset at age 8, obesity (current BMI = 27), mild obstructive sleep

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apnea (OSA) and sensory polyneuropathy. For OSA a splint was recommended but rarely

used. Surgery was performed for goiter during childhood; however no hormonal substitution

was required. In May 2016 the subject had bilateral cataracts removed. Her glycemic control

has been very poor for many years as reflected by markedly elevated glycated hemoglobin

(HbA1C) levels and despite the use of an insulin pump. Over time, the patient developed

several complications related to diabetes: polyneuropathy, retinopathy, episodes of

ketoacidosis and increasing impairment of glomerular filtration leading to a nephrotic

syndrome. The latter was diagnosed in March 2016. Her father has an undetermined form of

tremor but was not available for evaluation or genetic testing. Gait difficulties and impaired

balance were noticed after an episode of diabetes ketoacidosis at age 50. While hospitalized,

widespread and symmetric brain calcifications were found on a CT scan. Onset of insidious

cognitive difficulties and a personality change was noticed at age 42. The patient started to

put things in unusual places, became irritable and restless. Less often she described

persecutory delusions, for instance she could become convinced that burglars were breaking

into her home. Later, her movements became slow, she was prone to falls and her fine motor

skills became also impaired. During the entire course of disease, the patient has been devoid

of insight and declined repeated offers for help with the administration of prescribed drugs via

home health. Treatment with venlafaxine first and citalopram later were attempted. Both

drugs dampened her irritability to some degree; due to her unfavorable metabolic profile we

refrained from treatment with neuroleptics. The reported delusions were somehow responsive

to reassurance. Since age 53 the patient has been urine incontinent. Her bone density was

measured with dual-energy X-ray absorptiometry (DEXA) in August 2015, her T-score in the

hip and in the column were -1.8 and -0.9 respectively, which is compatible with osteopenia.

For this indication and based on an account of possible benefit of bisphosphonates on PFBC

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(11), treatment with clodronic acid was started two months later. Her SARA score was

unchanged during an evaluation in February 2016. Six months later the patient developed an

acute and marked left hemiparesis due to an infarction of the contraleral internal capsule.

Rehabilitation was attempted but did not lead to any functional improvement. The patient

requires support for mobilization. Worsened kidney function with edema and severe fatigue

were major factors limiting the patient’s rehabilitation. For these reasons, treatment with

clodronic acid was interrupted at this point.

3. Results

3.1 Phenotype and genetic analysis: The main features are consistent with axial ataxia, mild

dysmetria, supranuclear palsy (SNP) and mild posturing of the feet (see video). Upon physical

exam at age 51 a broad-based gait and slightly stooped posture were evident. The patient

could not perform tandem gait but recovered unaided in the retropulsion test. Dystonia in the

feet was noticed. She used a crutch but could walk without it. There was a mild upper limb

dysmetria and the alternating hand movements were irregular. General areflexia was evident

but the Romberg’s test was normal. There were no signs of resting tremor, rigidity,

bradykinesia or micrographia during several evaluations. The finger taps were of reduced

amplitude and the alternating hand movements were irregular. Her eye movements were also

abnormal and characterized by the presence of saccadic pursuit, hypometric and blink

mediated saccades. The latter feature was more pronounced in vertical eye movements with

an inability to look downward and limited upward range. SARA score at first evaluation (age

51) was 5.5 and two years later 7.5, the corresponding INAS scores were 4 respectively 5.

TRS in 2013 and 2016 was 15 and 19, UHDRS 19 and 26 while UPDRS part III remained 15

respectively 16.

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Briefly, the following domains were found to be significantly impaired during the first

cognitive evaluation at age 51: verbal function, working memory, processing speed, visual

memory, verbal fluency, visuospatial construction and executive functions. The latter domain

was particularly affected. Deficits in attention, psychomotor slowness, a tendency to

confabulations and lack of insight were also evident during the test. The patient was

reassessed two years later. A brief cognitive screening with MoCA yielded 21 points at that

point. At that time, her verbal abilities were in the average range and her visual memory

improved, indicating variability of the cognitive testing. However, other domains (a

subdomain of perceptual function, processing speed and verbal memory) worsened.

Furthermore, the BFCRST detected major deficits in verbal memory.

At the time of first evaluation in 2013 levels of parathyroid hormone (PTH), P-phosphate (Pi)

and albumin corrected calcium (Ca) were normal (Table e-4). After ruling out other secondary

causes of brain calcification (10) we evaluated the patient for the possibility of a

mitochondrial disease. However a muscle biopsy, biochemistry assessment of respiratory

chain enzymes and sequencing of mitochondrial DNA yielded normal results. Thus

Mitochondrial Encephalomyopathy; Lactic Acidosis; Stroke (MELAS) was ruled out.

Sequencing identified the R467X mutation in exon 8 of the SLC20A2 gene (reference

sequence NM_006749.4), MLPA analysis of this gene was normal (Centogene AG,

Germany). The patient has the E3/E4 Apo E genotype.

3.2 Neuroimaging: Symmetric, confluent and dense calcifications conferred a maximum TCS

subscore in the cerebellum, lentiform and caudate nuclei during the first assessment in 2012

(Figure 1 and table e-1). Pronounced were also the calcifications in thalamus and some

cortical areas (frontal and occipital sulci). Faint calcifications were found in the midbrain.

Even though CT is the optimal imaging modality to visualize brain calcifications it does not

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provide close details of complex structures like the thalamus, midbrain or pons. MRI imaging

demonstrated that the faint midbrain calcifications extended into the substantia nigra (SN) and

to a lesser degree into the red nucleus (Figure e-1). In addition, we found white matter

abnormalities (WMA) outside the calcified areas (Figure e-2). We did not find calcifications

in the pons or medulla. The TCS of 55 was unchanged during the course of three years. We

identified increased of calcification in the right cerebellar hemisphere by visual assessment

that did not yield a change in TCS. However using the coregistration method described above

we found increases in HU in the cerebellum (both cerebellar hemispheres and vermis) and to a

lesser degree in the thalamus (Table e-2 and figure e-3). This increase is compatible with a

progression of calcifications. With the used MRI resolution it was not possible to determine

which of the thalamic nuclei were calcified other than the pulvinar nucleus and the medial

part of the thalamus.

3.3 Biochemistry: CSF-phosphate (CSF-Pi) levels are normally ~0.4 mM (12). In May 2015,

the patient’s CSF-Pi was 0.58 mM as compared to 0.41 + 0.03 mM (mean + SEM, range 0.38

- 0.45) in seven age-matched female controls (mean age 53, SD 2.83). The age range in the

control group was 50-57 years. One patient from the F13 family (III:2) harboring the L9R

mutation in the PDGFB gene (7) had a CSF-Pi level of 0.45 mM. Levels of P-Pi at this point

and two years later were normal. CSF-NfL levels were markedly elevated while oxysterol and

protein levels in the CSF were normal (Table e-4).

HbA1C levels have been markedly elevated ranging from 65-106 (ref. 31-46 mmol/mol)

during the last 3 years. During the last ten years albuminuria was evident and a nephrotic

syndrome was diagnosed in March 2016. Besides hypoalbuminemia (28 g/L, ref. 36-45 g/L)

mildly increasing levels of PTH were evident since October 2015 (Table e-4). However,

calcium and phosphate levels have remained normal.

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4. Discussion:

Mutations in the SLC20A2 gene, the most common cause of PFBC, are associated with

complex phenotypes that include a combination of movement disorders, cognitive deficits

and/or psychiatric symptoms. Migraine has also been described in some SLC20A2 gene

mutation carriers but is far less common than in other PFBC forms (13). Akinesia is the most

common movement disorder seen in SLC20A2-associated PFBC (5) while ataxia is an unusual

feature (13). The patient we present here is also affected by progressive ataxia, dementia,

psychiatric/behavioral symptoms and widespread progressive brain calcifications. The

progression rate of the motor symptoms in this case (12 years approximately) is in contrast

with the faster rate of cognitive decline leading to dementia. These calcifications do not

always have clinical manifestations or correlates, only 60% of the mutation carriers display

symptoms (13, 14). Ataxia, for instance, is more common in patients with calcifications in BG

calcifications than in the cerebellum (13). The apparent reduced clinical penetrance in PFBC

has to be contrasted with the full radiological penetrance of SLC20A2 mutations. It is still

unknown at what point these calcifications will appear, the earliest documented onset was in a

4 year-old child (15).

Coregistration but not TCS detected again progression of brain calcifications in the presented

case. These results illustrate again the ceiling effect of the TCS (7). Radiological progression

has been described only once in a Japanese male affected by parkinsonism and dementia with

the c.1909A>C (S637R) mutation in the SLC20A2 gene. For this radiological progression

documented in the course of 10 years the TCS was not provided (6). The extent and severity

of calcification in the case we described is remarkable even though it is known that patients

with SLC20A2 mutations display calcifications in more brain regions and have higher TCS

than patients with mutations in the PDGFB, PDGFRB or XPR1 genes (5). A TCS of 55 is

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among the highest ever reported in SLC20A2-associated PFBC, G. Nicolas et al reported a

TCS ranging from 20 to 58 in a group of nine patients with SLC20A2 mutations. (5).

Confluent calcifications in the cerebellum extending into the vermis and widespread cortical

calcifications have been described associated with SLC20A2 gene mutations. For instance, 3

patients in the family where the SLC20A2 locus was discovered had widespread cortical

calcifications that included the occipital lobes as in the presented case (1, 15). Calcifications

in the SN have not been described in SLC20A2-associated PFBC though. O.C. Cockerel

described calcifications of the SN in patient with akinesia and rigidity (16), however the

etiology of these calcifications has not been reported. The patient we describe does not

display obvious signs of parkinsonism despite widespread calcifications in the BG and SN.

Hypotonia due to cerebellar ataxia may not be the only compensating mechanism preventing

parkinsonism at least in other hereditary ataxias. L. Schöls et al found for instance that

degeneration of the STN in SCA2 and SCA3 patients seemed to prevent parkinsonism despite

severe concomitant degeneration of the SN (17).

So far 54 mutations in the SLC20A2 gene have been described, most of them located in exon

8 (18–22). The patient we have described here is to our understanding the first PFBC case

associated with a mutation in the SLC20A2 gene ever reported in Sweden. The R467X

mutation has been described in a Japanese male whose phenotype consisted of PKD, his brain

CT scan displayed calcifications in the globus pallidus, thalamus, subcortical white matter and

dentate nuclei (4). His mother was asymptomatic despite the presence of a less degree of brain

calcifications. It is evident by visual assessment that the calcifications of the Japanese male

are much milder than in our patient, however TCS for the Japanese families were not

provided in the article (4). An alternative explanation to the apparent discrepancy between the

radiological features and absence of obvious clinical signs is probably the limited depth of

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assessments and lack of longitudinal studies in PFBC. It is probable that subclinical cognitive

and/or mild motor deficits as well as psychiatric features are overseen in routine visits.

Whether the penetrance of the R467X mutation is also reduced among relatives of our patient

was not possible to evaluate.

The rate of early-onset cognitive decline leading to subcortical dementia in this case was fast

and reasonably explained by other contributing factors such as poor glycemic control and

WMA. The cognitive profile in this case is otherwise similar to what has been described in

patients with brain calcifications (24). As previously described, the pattern of calcifications in

SLC20A2 mutations is more widespread than in other forms of PFBC (13, 23) but it is not

specific. The short treatment period with clodronic acid precludes any conclusion about its

effect.

Similar to PDGFB-associated PFBC we also found elevated NfL levels in the CSF (7). These

findings add support to the notion that diseases in the PFBC group are neurodegenerative

conditions. It is reasonable to assume that the widespread calcifications described here impair

brain connectivity in a similar way amyloid accumulation affects different brain hubs (25). A

plethora of mechanisms have been proposed to be involved in the process of cognitive decline

in T1D patients (26–28). In addition, WMAs also evident in this case, contribute to cognitive

deficits particularly in those whose T1DM started in childhood (29, 30). OSA as well

increases the risk of cognitive decline (31). However, the early onset of dementia, disease

severity and severity of the widespread brain calcifications argue for the R467X mutation as

the main cause of her cognitive decline. There is pathological evidence of calcifications in the

tunica media of CNS small arteries, arterioles and capillaries but not veins in a patient with

the c.1909A>C mutation in SLC20A2 (6). In our case, BBB permeability was intact as

reflected by normal levels of oxysterols. Thus, neither this study nor the SLC20A knockout

10


mouse supports the notion of increased BBB permeability in this form of PFBC (32, 33). Poor

glycemic control in this case led to a nephrotic syndrome with secondary mild

hyperparathyroidism. It is likely that secondary hyperparathyroidism will contribute to the

process of brain calcifications. We emphasize, however, that at the moment of the first

evaluation PTH, calcium and phosphate levels were normal. Whether poor glycemic control

contributes, for instance by microvascular complications, to accelerate the rate of brain

calcifications is unknown.

The SLC20A2 gene encodes type III sodium-dependent phosphate transporter 2 (PiT-2) that is

expressed ubiquitously. High levels of expression are found in the vascular smooth muscle,

bone, parathyroid glands, kidney, gut (34, 35) and placental pericytes (36). It is also highly

expressed in the brain (neurons, endothelial cells and astrocytes), particularly in the calcified

areas of patients with SLC20A2 mutations (35). Some insights into the pathogenesis of disease

have started to emerge by studies based on a SLC20A2 knockout mouse (33, 37, 38) and

neuropathology of genetically-proven SLC20A2-associated PFBC (6, 39). The SLC20A2

knockout mice display age-dependent calcifications mainly in the thalamus and to some

degree in the BG and cortex but not in the cerebellum (33, 37). These findings suggest

haploinsufficiency but the exact mechanism/s of disease are still unknown (1, 37). Two

groups have recently and independently of each other found elevated CSF-Pi in heterozygous

and homozygous SLC20A2 knockout mice (33, 37). We also found significantly elevated

levels CSF-Pi (41% higher) in the patient with the R467X mutation in the SLC20A2 gene but

neither in one patient with the L9R mutation in the PDGFB gene nor in twelve age-matched

controls. This is, to the best of our knowledge, the first time such abnormality is described in

humans.

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In a large Canadian dystonia kindred with a deletion in chromosome 8 that included both the

SLC20A2 and THAP1 genes vessel calcification was described in the brain (39) in addition to

brain parenchyma calcifications. T. Kimura et al confirmed these findings in a detailed piece

of work demonstrating calcifications in the tunica media of CNS small arteries, arterioles and

capillaries (6). In addition T. Kimura et al found gliosis, weak reactivity of PiT2 in astrocytes

of calcified brain areas and low PiT2 levels in homogenates of frontal cortex, putamen and

cerebellum (6). An unexpected PiT2 expression was found in the Purkinje cell layer and in the

SN (6). Some authors suggest that the calcification process starts in the brain vessels (38, 40,

41). Some findings seem to support his notion, for instance hyperphospatemia due to chronic

kidney failure usually leads to calcification of peripheral vessels (38). N. Jensen et al

suggested a similar mechanism in the CNS when CSF-Pi levels are elevated (38). Previously,

P.M. Guerreriro et al provided evidence supporting the role of PiT2 for active removal of

phosphate from the CSF in the spiny dog shark (42). Different to the knockout model we did

not find any signs of hydrocephalus or calcification in the lens or optic nerve. The SLC20A2

knockout model displays also cataracts and microphtalmia (33), the latter has not been

described in humans so far. Our patient was treated for cataracts which is otherwise a

common condition in the general population particularly among patients with diabetes (43).

Up to 23% of SLC20A2 knockout mice displays tremor during pregnancy, placental

abnormalities that include calcifications and abnormal vascular structure (36). In addition, the

knockout mice have subviable pups and die prematurely likely due to hydrocephalus (33).

Intriguingly, lamininα1 positive cells were found in the placenta of SLC20A2 knockout mice

and also in placenta of women with preeclampsia (33). It is still unknown whether the

SLC20A2 knockout mouse displays behavioral and/or memory deficits.

12


Our results suggest elevated CSF-Pi levels may help to differentiate SLC20A2-associated

PFBC from at least cases with the L9R mutation in the PDGFB gene. However, the potential

use of CSF-Pi analysis as a disease biomarker of SLC20A2-associated PFBC requires further

evaluation in PFBC cohorts.

The differential diagnosis of SLC20A2 mutations includes other forms of PFBC mainly (7).

and the much rarer spinocerebellar ataxia type 20 (SCA20) (44). Brain calcifications also

occur in other genetic disorders like mitochondrial conditions (MELAS patients mainly) (45),

the severe autosomal recessive pediatric conditions (Aicardi-Goutières syndrome, cerebral

folate deficiency and band-like calcification with simplified gyration and polymicrogyria),

and as acquired disease (7).

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€¦ · Web viewgene. This truncating mutation has been previously described in a young Japanese male affected by early-onset paroxysmal kinesigenic dyskinesia (PKD), his mother