Case Report

Ischemic stroke in a patient with Fahr’s disease carrying
biallelic mutations in the MYORG gene
Yan Li, MD, Wei Fang, MD, Wenying Long, PhD, Guohua Zhao, MD.

ABSTRACT
‫) اضطراب تنكسي عصبي يتميز بتكلسات‬FD( ‫يعد مرض فهر‬
‫ من املعروف‬.‫متناظرة في العقد القاعدية الثنائية والنواة املسننة‬
‫ نستعرض‬،‫ في هذا التقرير‬.FD ‫ جينات تسبب‬6 ‫أن الطفرات في‬
‫ عا ًما بسبب بطء احلركة الذي بدأ في‬44 ‫حالة امرأة تبلغ من العمر‬
‫ اظهر التصوير املقطعي للدماغ والتصوير بالرنني‬.‫ سنوات‬3 ‫التطور منذ‬
، ‫ املهاد‬،‫املغناطيسي عن تكلس شديد في العقد القاعدية الثنائية‬
‫ وكشف تسلسل اإلكسوم‬.‫ واملادة البيضاء حتت القشرية‬،‫نوى املسنن‬
‫الكامل عن طفرتني مركبتني متغايرتني وصفناهم سابق ًا داخل جني‬
‫ أصيبت املريضه بظهور مفاجئ لشلل نصفي‬،‫ بعد عام‬.MYORG
‫ كشف التصوير بالرنني املغناطيسي عن احتشاء‬.‫في اجلانب األيسر‬
‫ فإن نتائج تقرير احلالة‬،‫ لذلك‬.‫صغير في الكبسولة الداخلية اليمنى‬
‫ واملهم االرتباط بني السكتة‬.FD ‫احلالي ضاعف النطاق السريري لـ‬
.‫ يحتاج إلى مزيد من الدراسة‬FD ‫الدماغية و‬
Fahr’s disease (FD) is a neurodegenerative disorder
characterized by symmetric calcifications in the
bilateral basal ganglia and dentate nuclei. Mutations
in six genes are known to cause FD. In the present
case, a 44-year-old woman was admitted because of
bradykinesia that had started developing 3 years ago.
Brain CT and MRI revealed severe calcification in the
bilateral basal ganglia, thalamus, dentate nuclei, and
subcortical white matter. Whole-exome sequencing
revealed two previously described compound
heterozygous mutations within the MYORG gene.
About one year later, the patient developed suddenonset left-sided hemiparesis. The MRI revealed a small
infarction in the right internal capsule. Therefore, the
present case findings expand the clinical spectrum of
FD. Importantly, the association between ischemic
stroke and FD needs to be further studied.
Neurosciences 2022; Vol. 27 (4): 270-274
doi: 10.17712/nsj.2022.4.20220047
From the Department of Neurology (Li, Zhao), The Fourth Affiliated
Hospital, Zhejiang University, School of Medicine, Department
of Neurology (Fang), Hangzhou Hospital of Traditional Chinese
Medicine, Hangzhou, Zhejiang, Central Laboratory (Long), The
Fourth Affiliated Hospital, Zhejiang University School of Medicine,
Yiwu, Zhejiang, China.
Received 24th April 2022. Accepted 2nd August 2022.

270 Neurosciences 2022; Vol. 27 (4)

Address correspondence and reprint request to: Dr. Guohua Zhao,
Department of Neurology, The Fourth Affiliated Hospital, Zhejiang
University School of Medicine, Yiwu, Zhejiang, China. E-mail:
gzhao@zju.edu.cn.
ORCID ID: https://orcid.org/0000-0001-7943-209X

F

ahr’s disease (FD), is a rare neurodegenerative
disorder which is characterized by symmetric
calcium deposits in the basal ganglia, globus pallidus,
putamen etc.1 In patients with these imaging
characteristics, FD may be diagnosed after other causes
of secondary calcification are ruled out. Clinically, FD
shows a wide spectrum of neurologic and psychiatric
symptoms including parkinsonism, tremor, dystonia,
ataxia, seizures, migraine, cognitive impairment, and
psychosis, among others.
The clinical symptoms and severity of FD are
variable even between members of the same family, and
some family members may be asymptomatic. The FD
shows an autosomal dominant or recessive pattern of
inheritance.1 Dominantly inherited forms of FD have
been well identified by former studies, while recent
studies have shown that the myogenesis-regulating
glycosidase (MYORG) gene and junctional adhesion
molecule 2 (JAM2) gene are associated with recessive
forms of FD.1-3 In the present report, we have described
a rare case of a female patient diagnosed with FD who
carried biallelic mutations in the MYORG gene and
presented with parkinsonism and acute ischemic stroke.
Case Report. Patient information. A 44-year-old
Chinese woman (II:1, Figure 1A) was admitted because
of bradykinesia in October 2018. Her symptoms began
manifesting about 3 years ago, and were accompanied

Disclosure. This work was funded by the Major Health
Science and Technology Program of Zhejiang Province,
Zhejiang, China (grant no. WKJ-ZJ-2208).

OPEN ACCESS

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Fahr’s disease presenting stroke … Li et al

by slurred speech and urinary disturbance. These
symptoms had gradually developed over the last three
years. Her past history was unremarkable.
Clinical findings. Neurological examination
revealed hypomimia, bradykinesia, and festinating gait.
Paroxysmal forced laughter or crying was also observed.
Computed tomography (CT) and MRI imaging of her
brain revealed severe calcification in the basal ganglia,
thalamus, dentate nuclei, and subcortical white matter
(Figure 2 A, B, C). The results of routine laboratory
tests including blood sugar, HbA1c, lipid profile,
erythrocyte sedimentation rate (ESR) and D2 dimers
were unremarkable, and her serum calcium, calcitonin,
thyroid hormone, and parathyroid hormone levels were
normal. Based on these findings, other diseases that
cause secondary intracranial calcification were ruled
out.
Diagnostic assessment. Her parents were in a
consanguineous marriage. Neither her parents nor her
younger sisters had experienced the same symptoms.
We collected peripheral blood samples from the patient,
her parents, and a sibling (II:1, I:1, I:2, and II:2) with
their written informed consent. Genomic DNA was
extracted using a standard method. Whole-exome
sequencing was performed in the proband and revealed

2 previously described compound heterozygous
mutations within the MYORG gene: c.687G>T
(p.W229C) and c.348_349insCTGGCCTTCCGC
(p.116_117insLAFR).4 She had inherited the
c. 687G>T variant from her father and the
c.348_349insCTGGCCTTCCGC variant from her
mother (Figure 1 B, C, D, E). This variant was absent
in 500 controls with normal chromosomes and was
not included in the HGMD, Clinvar, ExAC, dbSNP,
1000G, and gnomAD databases. Then, the patient was
considered as FD.
Therapeutic intervention. The patient was discharged
with a prescription for oral levodopa and buspirone. At
the time this manuscript was being prepared, we found
that the clinical and genetic information of the family
had been reported in February 2019.4 The ethical
committee of the Fourth Affiliated Hospital, Zhejiang
University School of Medicine, had approved of the
study.
Follow-up and outcome. About one year after her
last hospitalization in October 2019, the patient was
admitted for sudden-onset left-sided hemiparesis that
had occurred 2 days ago. Neurological examination
revealed weakness of the left-sided extremities (Medical
Research Council grade 2 in the left arm and leg),

Figure 1 - Genetic analysis results for the patient and her family. A) The pedigree of the patient’s family with compound heterozygous MYORG mutations.
B &D) Normal control sequences. C) The c.687G>T variant. E) The c.348_349insCTGGCCTTCCGC variant. Family members I:1 and II:1
were carriers of c.687G>T, and family members I:2 and II:1 were carriers of c.348_349insCTGGCCTTCCGC.

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Fahr’s disease presenting stroke … Li et al

Figure 2 - Imaging findings from October 2018 and October 2019. Axial non-contrast CT (A & B) and MRI (C) scans of the brain taken in October
2018. Extensive symmetric calcifications can be observed in the bilateral basal ganglia, thalamus, dentate nuclei, and subcortical white matter.
MRA (D) showed that there was no stenotic segment or occlusion in the intracranial arteries. DWI (E) of the brain taken in October 2019
showing hyperintense spots in the right internal capsule. DTI (F) showing the region of interest.

with positive Babinski sign on the left side. There were
no changes in the results of the other neurological
examinations compared with the results obtained
during the previous hospitalization. Her brain CT
findings were unremarkable, with the exception of
severe calcification, and MRI showed a small infarction
in the right internal capsule (Figure 2D). Magnetic
resonance angiography (MRA) revealed that there was
no stenotic segment or occlusion in the intracranial
arteries (Figure 2E). Diffusion tensor imaging (DTI)
showed that the fractional anisotropic (FA) values of the
right internal capsule were lower than those of the left
side (0.3787±0.1466 vs. 0.4218±0.1042) (Figure 1F).
Routine laboratory tests, ambulatory blood pressure,
dynamic electrocardiogram, heart ultrasound and
CT angiography of neck were all normal. As soon as
ischemic stroke was identified, she was administered
acute therapy with 200 mg oral aspirin and 40 mg
atorvastatin per day. After her condition had stabilized,
she was transferred to the Department of Rehabilitation
to continue the rehabilitation process. About 2 years
after the stroke, the patient was still not able to ambulate

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independently (Medical Research Council grade 3 in
the left arm and 4 in the left leg) (Figure 3).
Discussion. Only a few case reports have described
acute ischemic stroke or transient ischemic attack-like
episodes in FD,5-9 so this makes the findings in this case
valuable in terms of prediction and management of
stroke in patients with FD in the future.
Brain CT is a sensitive, economical, and rapid tool
for detecting excessive intracranial calcification. The
MRI using susceptibility-weighted imaging (SWI) is
useful for detecting calcifications in FD patients, and
some scholars have found that SWI can reveal calcium
deposition in areas that cannot be observed by CT.5 In
the present case, CT and MRI were adequate, as they
revealed calcification patterns that are typical of FD.
In addition, based on the other routine laboratory
parameters, other causes of secondary calcification
could be eliminated.
Former studies have identified only autosomal
dominant FD, including those associated with
mutations in the SLC20A2, PDGFRB, PDGFB, and
XPR1 genes.1-3 In 2018, Yao et al1 reported the first

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Fahr’s disease presenting stroke … Li et al

Figure 3 - The timeline table of the case in this study.

gene responsible for a recessive FD—the MYORG gene.
Recently, Cen et al2 identified biallelic mutations of the
JAM2 gene in individuals with primary familial brain
calcification. The present patient had 2 compound
heterozygous mutations within the MYORG gene that
have been described before.4 Therefore, the patient
had a recessive form of FD. The typical parkinsonism
and brain CT and MRI findings in this case were
characteristic of FD, and genetic testing confirmed the
diagnosis.
The association between ischemic stroke and FD
has not been clearly determined. Former studies have
shown that calcification is seen in the walls of capillary
vessels, arterioles, and the perivascular space of FD
patients, so this might represent a potential causative
mechanism.10 For example, Nishimoto et al5 described
a case of FD associated with cerebral micro-infarcts and
found impaired cerebrovascular reactivity on SPECT
with acetazolamide challenge in their patient.5 Based

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on these findings, they speculated that the decrease in
vascular diastolic capacity associated with calcification
might be one of the mechanisms. Further, Zhang
et al9 reported a case of a 56-year-old man with an
SLC20A2 mutation (c.C344T) who had melena for 6
days and somnolence for 3 days. Blood examination
showed anemia, indicated by a hemoglobin level of
73 g/L. Cranial MRI revealed bilateral acute ischemic
stroke, and hypoperfusion was assumed. Grangeon
et al. reported a case with compound heterozygous
mutations (c.C1427A and c.T1967C) of the MYORG
gene associated with a stroke-like episode but no MRI
changes.6 In contrast, another patient with homozygous
MYORG gene mutations (c.G191A) had both stroke
and MRI changes.6 Malaquias et al7 reported three FD
patients with MYORG gene mutations who presented
with episodes of acute hemiparesis without any evident
MRI changes.Based on the location and diameter of the
infarct lesion in DWI and the normal MRA findings

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Fahr’s disease presenting stroke … Li et al

in the present case, we classified the infarct as a smallartery occlusion. However, we did not identify any risk
factors of arteriosclerosis. In addition, based on the
SWI findings and normal results of immunological
tests, the possibility of cerebral amyloid angiopathy
and immunologically related small vessel disease was
excluded. Therefore, we postulated that the small-artery
occlusion in our patient was caused by extensive calcium
and mineral deposition in affected vessels because of
FD. However, further investigation is needed to confirm
this hypothesis. Currently, it is not clear whether stroke
caused by FD requires different therapeutic approaches
from stroke caused by atherosclerosis, and this requires
further investigation in the future.
Interestingly, ischemic stroke did not cause severe
symptoms or poor recovery in the present patient.
This mismatch between the ischemic stroke lesion and
clinical severity was confusing, so DTI was performed.
The FA values of both sides of the internal capsule were
lower than those in normal individuals. Based on this
finding, it is possible that the corticospinal tract may
have been damaged by calcium deposits that had not
been detected at the first examination conducted before
the episode of stroke. Further follow-up is needed to
confirm this hypothesis.
In conclusion, based on the findings, it is possible
that extensive calcium deposits in affected vessels
might lead to small-artery occlusion, and subsequently,
ischemic stroke. Further study is required to elucidate
the relationship between FD and ischemic stroke, as
well as the treatment approach for these patients.
Acknowledgement. We are thankful to the patient
for providing her consent for the publication of this case report.

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We appreciate the technical support from Mrs. Ying Liu and the
clarity and correctness of Figure 2 from Dr. Sheng Hu. We would
like to thank ELIXIGEN Company for English language editing.

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