Brahim Tabarki, MD
Shatha Al-Shafi, MD
Saad Al-Shahwan, MD
Zeeshan Azmat, MD
Amel Al-Hashem, MD
Nawal Al-Adwani, MD
Nabil Biary, MD
Sonia Khan, MD
Giulio Zuccoli, MD
Supplemental data at
Biotin-responsive basal ganglia disease
Clinical, radiologic, and genetic findings
Objective: To investigate the clinical, genetic, and neuroradiologic data of biotin-responsive basal
ganglia disease (BBGD) and clarify the disease spectrum.
Methods: We first investigated all patients attending our Division of Pediatric Neurology with
a genetically proven diagnosis of BBGD between 2009 and 2011. All patients underwent
a detailed medical history and clinical examination, extensive laboratory investigations including
genetic tests, and brain MRI. Finally, we conducted a systematic review of the literature.
Results: We enrolled 10 patients meeting the diagnostic criteria for BBGD, and analyzed the data
on 14 patients from 4 previous reports. The BBGD occurred predominantly in preschool/school-
aged patients in the Saudi population, but it was also observed in other ethnic groups. The typical
clinical picture consisted of recurrent subacute encephalopathy leading to coma, seizures,
and extrapyramidal manifestations. The brain MRI typically showed symmetric and bilateral
lesions in the caudate nucleus and putamen, infra- and supratentorial brain cortex, and in the
brainstem. Vasogenic edema characterized the acute crises as demonstrated by diffusion-
weighted imaging/apparent diffusion coefficient MRI. Atrophy and gliosis in the affected regions
were observed in patients with chronic disease. Early treatment with a combination of biotin and
thiamine resulted in clinical and neuroradiologic improvement. Death and neurologic sequelae
including dystonia, mental retardation, and epilepsy were observed in those who were not treated
or were treated late.
Conclusion: BBGD is an underdiagnosed pan-ethnic treatable condition. Clinicians caring for pa-
tients with unexplained encephalopathy and neuroimaging showing vasogenic edema in the bilat-
eral putamen and caudate nuclei, infra- and supratentorial cortex, and brainstem should consider
this disorder early in the hospital course because a therapeutic trial with biotin and thiamine can
be lifesaving. Neurology?2013;80:261–267
BBGD 5 biotin-responsive basal ganglia disease; hTHTR2 5 human thiamine transporter 2; WE 5 Wernicke encephalopathy.
Biotin-responsive basal ganglia disease (BBGD; OMIM #607483) was first described by Ozand
et al.1in Saudi Arabia in 1998. Patients with BBGD typically presented in childhood with
subacute episodes of encephalopathy, which were often triggered by febrile illness and charac-
terized by confusion, dysarthria, dysphagia, and external ophthalmoplegia, and patients pro-
gressed to severe dystonia, quadriparesis, and coma. These symptoms disappeared within a few
days after administration of high doses of biotin. The brain MRI showed bilateral lesions of the
caudate nuclei and putamen.1The disease is autosomal recessive and associated with mutations
in the SLC19A3 gene.2The SLC19A3 gene encodes human thiamine transporter 2
(hTHTR2),3a second thiamine transporter. Because biotin is not a substrate for hTHTR2,
the precise mechanism by which biotin is effective in improving this condition remains
From the Divisions of Pediatric Neurology (B.T., S. Al-Shafi, S. Al-Shahwan) and Genetics (A.A.-H.), Department of Pediatrics; Department of
Radiology (Z.A., N.A-A.); Department of Neurosciences (N.B., M.A.-Z., S.K.), Riyadh Military Hospital, Kingdom of Saudi Arabia; and
Department of Radiology (G.Z.), Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the
© 2012 American Academy of Neurology261
The literature on BBGD is poor (only 14
cases reported),1,5–7and there are no systematic
reviews of published cases. This report includes
the detailed clinical and neuroradiologic data of
10 genetically proven cases of BBGD, and pro-
vides a systematic review of the literature up to
April 2012. We aimed to identify the recent
advances in the diagnostic, genetic, and man-
agement tools of this enigmatic disease, and to
discuss the nosology of this disease.
METHODS We retrospectively studied patients attending the
Pediatric Neurology Division, Riyadh Military Hospital in Riyadh,
Kingdom of Saudi Arabia between 2009 and 2011 with a firm diag-
nosis of BBGD based on genetic analysis. The patients underwent a
detailed family history and neurologic examination, as well as blood
tests, CSF analysis, and neuroradiologic investigations. The neurora-
diologic investigations included a brain MRI in all patients. Brain
MRIs were reviewed independently by 2 certified neuroradiologists
(Z.A., G.Z.) with adjudication. The MRI examinations were
performed at a field strength of 1.5 T (Signa; GE Healthcare,
Milwaukee, WI). Imaging sequences of the brain included T1-
and T2-weighted sequences in multiple planes. Contrast-enhanced
T1-weighted images were obtained in 1 patient. Diffusion-weighted
imaging and apparent diffusion coefficient map images were also
evaluated. MRI findings were represented by symmetric or asym-
metric hyperintensities on T2-weighted and fluid-attenuated inver-
sion recovery images within the cortex, basal ganglia, and brainstem,
andsymmetric orasymmetric hypointensityonT1-weightedimages
within the cortex, basal ganglia, and brainstem. Increased diffusion-
weighted imaging signal and increased apparent diffusion coefficient
value were considered consistent with vasogenic edema. Single-voxel
magnetic resonance spectroscopy data obtained during the acute
phase of the disease in 4 patients were also analyzed. Molecular
genetic analysis of the SLC19A3 gene was performed in the Center
investigations included blood for lactate, pyruvate, ammonia, bio-
tinidase, creatine phosphokinase, tandem mass spectrometry, cop-
per,ceruloplasmin,biotinlevel,and thiamine level;urinefororganic
acids; and CSF for cell counts, protein level, glucose level, lactate,
and pyruvate. A PubMed/Ovid search was performed up to April
2012 using the keywords “biotin-responsive basal ganglia disease,”
“biotin deficiency,” and “SLC19A3 mutations.” We analyzed the
data for demographic and clinical features, genetic and neuroradio-
logic findings, and treatment efficacy.
Standard protocol approvals, registrations, and patient con-
sents were obtained. The local hospital ethical review committee
approved this study.
RESULTS Personal series. Ten patients were identi-
fied (5 females and 5 males), and the demographic,
clinical, genetic, and neuroradiologic findings are
shown in tables 1 and 2. All patients were Saudi.
The age of presentation ranged from 3 to 12 years,
with a mean age of 7 years. Eighty percent had pos-
itive consanguinity. We identified a trigger factor
(febrile illness or mild trauma) in half of the patients.
Nine patients (90%) had an acute-subacute onset
consisting of ataxia, seizures, and encephalopathy.
Rapid deterioration of these symptoms motivated
their transfer to the intensive care unit. All patients ex-
hibited parkinsonian signs (dystonia, cogwheel rigidity)
and pyramidal tract signs (quadriparesis, hyperreflexia).
Cerebellar signs, supranuclear facial nerve palsy, or exter-
nal ophthalmoplegia was present in 5 patients. One
patient (patient 9) had a slowly progressive course with
dystonia involving the face and 4 limbs, and mild psy-
chomotordelay.Nine patients received a combination of
biotin (2–3 mg/kg/d) and thiamine (100–300 mg/d).
One patient (10%) died with severe encephalopathy,
rhabdomyolysis, and cardiac arrest. He did not receive
any treatment, as he was diagnosed retrospectively after
the diagnosisofhis sister.Twopatients(20%) had severe
neurologic sequelae: generalized dystonia and quadriple-
gia. Both these patients had frequent attacks of decom-
pensation and were treated late. Seven patients (70%)
had a good outcome with no or minimal sequelae,
daily life or school activities. These 7 patients were diag-
nosed and treated earlier. All patients underwent MRI.
During the acute crisis, brain MRI revealed bilateral and
symmetric involvement of the putamen and caudate
nuclei in all patients (figures 1 and 2). Seven patients
(70%) showed symmetric involvement of the medial
dorsal nucleus of the thalamus. Five patients (50%)
showed involvement of the brainstem nuclei. Eight
patients (80%) showed extensive involvement of the
cortex. Seven patients (70%) showed alterations in
the cerebellar cortex and vermis. One patient (10%)
showed involvement of the periventricular regions of
the third ventricle. None of our patients disclosed sub-
cortical white matter involvement. Vasogenic edema
was identified in the affected brain regions during
the acute phase of the disease. None of the patients
copy was obtained in 4 patients disclosing decreased
e-1 on the Neurology®Web site at www.neurology.
org). Follow-up MRI showed evolving brain lesions
consistent with remote injury (figure 3, table e-1). Lab-
oratory investigations including blood, urine, and CSF
tests were negative in all patients. Sequencing of
c.1264A.G (p.Thr422Ala) in all 10 patients, and their
parents were heterozygous for the mutation.
Review of the literature. We collated 14 cases that were
reported in 4 publications. The demographic, clini-
cal, genetic, and neuroradiologic findings are shown
in table e-2. Of these 14 patients, 9 were female
and 5 male. The mean age at presentation was 5.5
years (range 1–12 years). Seven patients were Saudi,
2 Portuguese, 2 Yemeni, 1 Indian, 1 Lebanese, and
1 Syrian. Eight patients presented with acute/suba-
cute encephalopathy. The remaining patients pre-
sented with extrapyramidal manifestations. Seizures
262 Neurology 80January 15, 2013
were observed in 10 patients. Brain MRI showed
lesions in the caudate and putamen nuclei in all pa-
tients. Other involvement was reported in only 2
patients. At follow-up evaluation, 4 patients were
found to be neurologically normal and 10 showed
neurologic sequelae including mild mental retarda-
tion and/or dystonia.
DISCUSSION From this study of 10 patients with
genetically proven BBGD, followed by a systematic
review of the literature (table e-2), we obtained a
detailed picture of the clinical presentation, genetics,
and treatment of BBGD.
Although this disease is a pan-ethnic condition, it is
school- and school-aged children.1,5–7The typical clinical
episodes of encephalopathy, often triggered by febrile ill-
ness or mild trauma and characterized by confusion, seiz-
ures, dystonia, external ophthalmoplegia, and dysphagia,
Table 1 Clinical and genetic findings in patients with BBGD
at onset, y OriginConsanguinityNeurologic presentation SeizuresTreatment Outcome
Biotin 1 thiamine Mild dystonia,
Biotin 1 thiamineNormal c.1264ArG
Biotin 1 thiamineNormal c.1264ArG
ataxia, dystonia, dysphagia
Biotin 1 thiamine Mild ataxia, dystonia,
Biotin 1 thiamineNormal c.1264ArG
ataxia, dystonia, dysarthria
Biotin 1 thiamineMild ataxia and
Biotin 1thiamine Normal c.1264ArG
ataxia, dystonia, dysarthria
No treatmentDied c.1264ArG
Severe dystonia of the
face and limbs
Biotin 1 thiamineDystoniac.1264ArG
Biotin 1 thiamine
(started 1 mo after the
onset of encephalopathy
Abbreviation: BBGD 5 biotin-responsive basal ganglia disease; 2 5 absent (negative), 1 5 present (positive).
aPatients 1 and 2 are siblings, as are 6 and 7, and 8 and 9.
Table 2MRI findings during the acute crisis (before treatment)
CH, VP, CDMYesYesYesYes YesYesYes
NoNoP, C DMYesYesYesYesYesYesNA
CH, VP, CDMYesYesYesYesYesYesYes
CH, DNP, C DM, PR
YesYes YesYesYes YesYes
Abbreviations: C 5 caudate nucleus; CH 5 cerebellar hemispheres; CN3 5 oculomotor nerve nucleus; DLF 5 dorsal longitudinal fasciculus; DM 5 dorso-
medial nucleus of the thalamus; DN 5 dentate nucleus; NA 5 not available; P 5 putamen; PGM 5 periaqueductal gray matter; PR 3rd V 5 periaqueductal
regions of the 3rd ventricle; R 5 raphe; RN 5 red nucleus; R-SCN 5 raphe, superior central nucleus; SN 5 substantia nigra; V 5 vermis.
bPatient 6 underwent contrast administration with no enhancement identified. Please note that none of the patients disclosed restricted diffusion.
Neurology 80 January 15, 2013263
eventually leading to coma and even death.1,5–7Less fre-
quently, patients with BBGD present with a chronic or
slowly progressive condition characterized by dystonia,
seizure disorders, and psychomotor delay. Seizures are
mainlysimplepartialseizuresorgeneralized and areeasily
controlled with 1 antiepileptic drug. Early administration
of biotin and thiamine results in partial or complete
improvement within days. Treatment given later in the
disorder or the lack of treatment may result in death or
neurologic sequelae including dystonia, quadriparesis,
epilepsy, or mild mental retardation.
Ozand et al.1demonstrated that the MRI pattern of
patients with BBGD is bilateral necrosis in the central
partof the caudate heads and partor all of the putamen;
our study confirms this, and adds important additional
with acute-subacute encephalopathy. During the acute
crisis, other neuroimaging features, including vasogenic
edema and infra- and supratentorial cortex and brain-
stem involvement, are present and potentially reversible
if treated in a timely manner. However, in not-treated
or late-treated chronic patients, gliosis and atrophy are
present, particularly in the caudate and putamen nuclei.
Our patient population with BBGD shares multi-
ple neuroradiologic findings observed in Wernicke
encephalopathy (WE),8–10such as involvement of the
medial dorsal nucleus in the thalami (same butterfly
appearance), periventricular regions of the third ventri-
cle, brainstem, central gray matter, basal ganglia, and
cerebellum. However, based on the study at hand, the
main MRI difference between BBGD and WE is that
inBBGD mamillary bodiesare sparedand thatBBGD
leads to a more extensive infra- and supratentorial cor-
tical involvement compared with that observed in
peaks and decreased N-acetylaspartate in injured areas,
accounting for an early brain injury and neuronal loss;
these findings are nonspecific.
BBGD maps to chromosome 2q36.3, and is due
to mutations in SLC19A3.2Several mutations have
been described in the SLC19A3 in patients with
BBGD, including the following mutations in decreas-
ing order of frequency: c.1264A.G (p.Thr422Ala),
c.68 G.T (p.G23V), c.74dupT, c.980-38dupA,
and c.980-14 A.G.2,7The SLC19A3 gene is one of
the SLC19 (solute carrier family 19) gene family
(comprising SLC19A1, SLC19A2, and SLC19A3) that
is responsible for the uptake of water-soluble vitamins
into cells.2,11The SLC19A3 was cloned based on its
homology with SLC19A1 and SLC19A2, and encodes
hTHTR2, a second thiamine transporter.11,12Three
apparently unrelated disease phenotypes are associated
Figure 1 Patient 8
Axial fluid-attenuated inversion recovery image shows bilateral basal ganglia (arrows, A) and cortical involvement (asterisks, A).
for vasogenic edema in the same regions as demonstrated by increased diffusion on apparent diffusion coefficient (ADC) map
(C). Cortical involvement observed on DWI (B) represents shine-through artifact as demonstrated by lack of signal alteration in
the cortex on ADC map (B). Coronal T2-weighted images demonstrate bilateral basal ganglia (arrowheads, D) and thalamus and
red nucleus involvement (arrowheads and arrows, E) and cerebellar (arrows, F) and vermian (arrowhead, F) edema.
264 Neurology 80 January 15, 2013
with mutations of SLC19A3. In 2005, it was demon-
strated that homozygous mutations in SLC19A3 are the
cause of BBGD.2Recently, compound heterozygous
mutations (E320Q, K44E) in SLC19A3 have been
associated with Wernicke-like encephalopathy, charac-
ophthalmoplegia in the second decade of life. Thiamine
treatment effectively alleviated symptoms.13The third
phenotype includes epileptic spasms in early infancy,
severe psychomotor retardation, and characteristic brain
MRI findings of progressive brain atrophy and bilateral
thalami and basal ganglia lesions, and is caused by a
homozygous mutation (c.958G.C [p.E320Q]) in
Early diagnosis of BBGD is crucial because expedi-
tious treatment may reverse all its manifestations.1,5–7
Treatment with a combination of biotin and thiamine
results in improvement of the clinical symptoms and
Figure 2Patient 10
Asymmetric cerebellar edema is noted on fluid-attenuated inversion recovery image (arrows, A). Involvement of the dorsal
longitudinal fasciculus (arrows, B) and of the raphe superior central nucleus (arrowhead, B) is demonstrated. Periaqueductal
signal intensity alteration resembling Wernicke encephalopathy is noted (arrows, C). Mild involvement of the substantia
nigra is present (arrows, D). Bilateral involvement of the red nucleus is present in (E) (arrows). Basal ganglia (arrowheads,
F) and periventricular region of the third ventricle (arrows, E) involvement is also identified. Diffuse bilateral cortical involve-
ment is noted (asterisks, A–F).
Figure 3Patient 1 follow-up MRI
Chronic changes consistent with atrophy and gliosis are identified in the basal ganglia (arrows, A–C) and cerebral cortex
(arrowheads, A–C) on axial fluid-attenuated inversion recovery images.
Neurology 80 January 15, 2013265
death. Patients require counseling regarding lifelong
treatment. The mechanism of action of biotin remains
unclear. The absence of serum biotin and thiamine defi-
ciency and the efficacy of high doses of biotin in the
of the mutated receptor by increasing its expression.15–17
The optimal dose of biotin in this disease, however,
remains unknown. Ozand et al.1reported high doses
of biotin: 5 to 10 mg/kg/d. Our study and others used
lower doses (2–3 mg/kg/d) in addition to thiamine
(100–300 mg/d) with the same efficacy. Interestingly,
a fewpatients did notimprove withhigh dosesofbiotin7
reinforcing the hypothesis that impaired thiamine trans-
port has a critical role in BBGD, and that biotin and
thiamine may act synergistically. We suggest using
a combination of high doses of biotin and thiamine dur-
ing the acute crisis of the disease and lower doses for
BBGD is a novel entity, first reported by Ozand
et al.1In the original study, patients responded only
to high doses of biotin and not to thiamine. Of note,
thiamine only was used for 1 patient for 3 months’
duration without improvement. However, our recent
understanding of the disease has advanced regarding
the following issues: 1) the SLC19A3 gene mutation
inhibits thiamine transport via hTHTR2; 2) biotin is
not a substrate for hTHTR2; 3) patients in acute
crisis share several neuroradiologic features of WE;
4) several patients improve only after adding thiamine
to biotin, reinforcing the hypothesis that both biotin
and thiamine are important lifesaving drugs in this
disease. Based on these available data, it is inaccurate
to append only the word “biotin” to BBGD. We
therefore recommend that the medical community
open the dialog to consider formally discontinuing
this nosology (“BBGD”) and to adopt the use of
the term “biotin-thiamine responsive basal ganglia
disease associated with SLC19A3 gene mutations.”
treatable condition. Clinicians caring for patients with
unexplained encephalopathy and neuroimaging showing
vasogenic edema in the bilateral putamen and caudate
nuclei, infra- and supratentorial cortex, and brainstem
should consider this disorder early in the hospital course
because a therapeutic trial with biotin and thiamine can
be lifesaving. The prognosis of the disease largely de-
pends onthe time fromdiagnosistobiotinand thiamine
Dr. Tabarki, Dr. Al-Shafi, and Dr. Al-Shahwan conceptualized the study;
have access to all the data; take responsibility for the data; participated in
the design of the study; collected, analyzed, and interpreted the data; and
participated in drafting the manuscript. Dr. Azmat and Dr. Zuccoli inter-
preted the MRI data and revised the manuscript for intellectual content.
Dr. Al-Hashem, Dr. Al-Adwani, Dr. Biary, Dr. Al-Zawahmah, and
Dr. Khan revised the manuscript for intellectual content.
The authors thank Maj. Gen. Dr. Saeed Bin Mohamed Al-Asmary, Director
of the Armed Forces Medical Services Department, for his kind support over
many years. The authors also thank Betty Weir and Susan Douglas for their
help with the English editing of the manuscript.
No targeted funding reported.
The authors report no disclosures relevant to the manuscript. Go to
Neurology.org for full disclosures.
Received May 9, 2012. Accepted in final form August 27, 2012.
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Neurology 80January 15, 2013267
DOI 10.1212/WNL.0b013e31827deb4c Download full-text
2013;80;261-267 Published Online before print December 26, 2012
Brahim Tabarki, Shatha Al-Shafi, Saad Al-Shahwan, et al.
Biotin-responsive basal ganglia disease revisited: Clinical, radiologic, and genetic
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