- Email: [email protected]
Glucose Transporter 1 Deficiency: A Treatable Cause of Opsoclonus and Epileptic Myoclonus
Accepted Manuscript Glucose Transporter 1 Deficiency: a Treatable Cause of Opsoclonus and Epileptic Myoclonus Brian Appavu, Tara Mangum, Makram Obeid PII:
S0887-8994(15)00280-5
DOI:
10.1016/j.pediatrneurol.2015.05.019
Reference:
PNU 8681
To appear in:
Pediatric Neurology
Received Date: 25 February 2015 Revised Date:
9 May 2015
Accepted Date: 12 May 2015
Please cite this article as: Appavu B, Mangum T, Obeid M, Glucose Transporter 1 Deficiency: a Treatable Cause of Opsoclonus and Epileptic Myoclonus, Pediatric Neurology (2015), doi: 10.1016/ j.pediatrneurol.2015.05.019. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Glucose Transporter 1 Deficiency: a Treatable Cause of Opsoclonus and Epileptic Myoclonus
RI PT
Running title: Opsoclonus and Myoclonus in GLUT1DS
Brian Appavu1, Tara Mangum2, Makram Obeid3
Department of Pediatric Neurology, Barrow Neurological Institute at Phoenix Children’s Hospital. 1919 E. Thomas Road, Ambulatory Building B 3rd Floor, Phoenix AZ. Phoenix AZ 85016. Phone: (602)933-0970. Fax: (602) 933-0469. Email: [email protected]
SC
1.
M AN U
2. Department of Pediatric Neurology, Barrow Neurological Institute at Phoenix Children’s Hospital. 1919 E. Thomas Road, Ambulatory Building B 3rd Floor, Phoenix AZ. Phoenix AZ 85016. Phone: (602)933-0970. Fax: (602) 933-0469. Email: [email protected]
TE D
3. Division of Epilepsy, Department of Pediatric Neurology, Barrow Neurological Institute at Phoenix Children’s Hospital. 1919 E. Thomas Road, Ambulatory Building B 3rd Floor, Phoenix AZ. Phoenix AZ 85016. Phone: (602)933-0970. Fax: (602) 933-0469. Email: [email protected]
AC C
EP
Keywords: GLUT1, opsoclonus, myoclonus, epilepsy, developmental delays Word Count: 1,287 References: 12 1 Table
Corresponding author: Makram Obeid Mail:1919 E. Thomas Road, Ambulatory Building 3rd Floor Phoenix AZ. Phoenix AZ 85016. Email: [email protected], phone: (602) 933-0970, fax: (602) 933-0469
1
ACCEPTED MANUSCRIPT
Introduction Glucose transporter 1 deficiency syndrome (GLUT1DS) is a genetic metabolic condition
RI PT
that is associated with developmental delay, ataxia, hypotonia, and seizures [1]. The diagnosis of this condition is made either by genetic testing for a known pathologic SLC2A1 mutation or by cerebrospinal fluid (CSF) analysis. The diagnostic CSF criteria have included either a glucose level less than 40 mg/dL or a CSF to serum glucose ratio less than 0.4, along with normal or low
SC
CSF lactate values [1]. Early diagnosis is critical for patients with GLUT1DS, as early intervention with the initiation of the ketogenic diet may lead to dramatic clinical improvements.
M AN U
If left untreated, patients develop acquired microcephaly with motor and cognitive impairments. Epileptic myoclonus in infancy is associated with various pathological conditions. In the absence of an identifiable central nervous system lesion, epileptic myoclonus is usually secondary to genetic metabolic causes, with a spectrum of etiologies. These range from a benign
TE D
genetic nonlesional etiology, the so called "benign myoclonic epilepsy of infancy" (BMEI), to more severe genetic metabolic derangements in infants with developmental delays [2]. Historically classified as one of the earliest onset idiopathic generalized epilepsies, BMEI refers
EP
to a benign form of a genetic nonlesional cause of epileptic myoclonus in a developmentally normal infant. While the genetics of this condition remain unknown, the diagnosis is often made
AC C
on clinical and electrographic grounds between the ages of 4 months and 2 years. Myoclonic seizures remit in the majority of these children after 3 years of age, although a minority will develop additional seizure types [3].
Reported below are two infants diagnosed with GLUT1DS that presented with epileptic myoclonus, one with an electroclinical phenotype mimicking BMEI, and the other also with
2
ACCEPTED MANUSCRIPT
opsoclonus, a novel mutation, and a significant response to high dose oral prednisolone. After a diagnosis of GLUT1DS was made, both infants were placed on the ketogenic diet with beneficial
RI PT
yet variable treatment responses.
Case 1
A 16-month-old girl presented at 8 months of age with very frequent daily paroxysms
SC
consisting of bilateral arm abduction and neck flexion. These events occurred up to 12 times per
M AN U
hour and proved to be epileptic myoclonus on video-EEG monitoring. Magnetic resonance imaging (MRI) of the brain was normal. Her development as well as her neurological exam were normal with a head circumference of 44 cm (62%), compared with 35 cm (83%) at birth. She was subsequently diagnosed with BMEI, and initially treated with levetiracetam with complete resolution of myoclonus within few days. Further genetic testing however, revealed a previously
TE D
described [4] pathogenic frameshift mutation in the SLC2A1 gene (del. c.505-507). She was therefore diagnosed with GLUT1DS at 12 months of age, and the ketogenic diet was subsequently initiated. She remains normocephalic with a head circumference of 45.4 (37%) and
AC C
EP
developmentally on track.
Case 2
A 15 month old girl initially presented with opsoclonus at 1.5 months of age and
subsequently developed epileptic myoclonus at 4 months of age. She was normocephalic with mild appendicular and axial hypotonia on examination. A brain MRI was normal, and an EEG revealed multifocal spikes superimposed upon an otherwise normal background. Her opsoclonus was confirmed to be non-epileptic by video-EEG. After a failed 2 month trial of levetiracetam, 3
ACCEPTED MANUSCRIPT
she did respond to prednisolone within 4 days of its initiation with an initial dose of 40 mg daily. After weaning steroids at 7 months, she experienced a recurrence of opsoclonus and seizures which persisted despite adding topiramate to her antiepileptic treatment regimen. A workup for
RI PT
neuroblastoma included a normal abdominal ultrasound. A lumbar puncture was performed and revealed a CSF glucose level of 37 mg/dL and a concurrent plasma glucose level of 84 mg/dL. Subsequent genetic testing revealed a heterozygous missense gene mutation in the SLC2A1 gene
SC
(c460G>A; p.Gly164Arg). While this is a previously unreported causative mutation of GLUT1DS, it was deemed pathologic in the context of her laboratory data [1]. She was started
M AN U
on the ketogenic diet at the age of 8 months and achieved resolution of seizures and opsoclonus. Whereas her developmental milestone acquisition was slow and plateaued when seizures worsened, she had an acceleration of milestone acquisition once her seizures were controlled. She remains normocephalic with a head circumference of 47 cm (83%) (35.4 cm / 83% at birth),
TE D
has a pincer grasp, says ‘mama’, responds to her name, and is currently able to maintain balance
Discussion
EP
if placed in the sitting position.
Here, we present two patients with GLUT1DS that presented with epileptic myoclonus.
AC C
The diagnosis was made based on a known pathologic mutation in the first child, and a low CSF glucose and a corresponding unreported SLC2A1 gene mutation in the second child. Both of our patients responded to the ketogenic diet with remission of presenting symptomatology, though one of them remains with developmental delays.
4
ACCEPTED MANUSCRIPT
These infants experienced epileptic myoclonus in the setting of normal structural imaging. The presentation of the first patient was electroclinically compatible with BMEI, though genetic testing revealed GLUT1DS. The initial diagnosis of BMEI was based on epileptic
RI PT
myoclonus superimposed on a normal electrographic interictal background, a normal development, and a typical age for BMEI onset. Gaspard et al. reported an infant with GLUT1DS who initially also presented with an electroclinical picture consistent with BMEI [5].
SC
While myoclonus has been described in GLUT1DS, the accompanying electroclinical picture in this disease, is one of developmental delays and interictal EEG abnormalities, unlike BMEI
M AN U
which has an electroclinical hallmark of good treatment response and both normal development and normal interictal EEG background [6,7]. Because of these distinct electroclinical presentations, metabolic testing is not typically performed in patients with a presentation of BMEI. Early diagnosis and treatment of GLUT1DS is necessary, as it may prevent neurological
TE D
deterioration. In the report by Gaspard et al., the ketogenic diet was not started until the age of 4 years, by which time the patient had developed multiple seizure types and acquired microcephaly. Our patient, in contrast, was initiated on the ketogenic diet at 12 months of age,
AC C
her age.
EP
has maintained seizure freedom, and is now appropriately reaching developmental milestones for
Our second patient had a novel mutation in GLUT1DS and also had a unique finding of
opsoclonus. Abnormal eye movements have been previously reported in this disease but only vaguely described as movement disorders [8], yet rarely specified as dyspraxia or opsoclonus [8,9]. Moreover, epileptic oscillatory eye movements mimicking opsoclonus have also been described in GLUT1DS [10], of which the spectrum of clinical phenotypes has been expanding
5
ACCEPTED MANUSCRIPT
(Table 1). Our patient also had significant improvements in seizure control and developmental outcomes when temporarily placed on steroid therapy. The beneficial effect of steroids in GLUT1DS has been previously reported in an 8 year old girl with intractable epilepsy who
RI PT
received oral dexamethasone and might be related to steroid-induced increased expression of the GLUT1 receptor [11]. The beneficial response may also be related to steroid-induced hyperglycemia, since it is known that postprandial states coincide with electrographic
SC
improvements [12]. Our patient, with initiation of the ketogenic diet, showed a robust improvement in seizure control as well as an acceleration of developmental milestone
M AN U
acquisition.
To summarize, the patients presented here, along with the previous cases [6], reveal that not only can GLUT1DS be at the origin of infantile epileptic myoclonus, but that the condition
TE D
also has a protean presentation that includes opsoclonus, and at times, can mimic BMEI. Testing for GLUT1DS should be considered in infants who present with BMEI, as there is a strong need to initiate the ketogenic diet in a timely manner in order to maximize the possibility of milestone
EP
acquisition and seizure freedom. We also propose, alongside previous reports [11], that suspicion for GLUT1DS should be raised in infants with intractable epilepsy and an elusive pathology who
AC C
respond to steroids.
Acknowledgements
We are grateful to Michelle Wotowiec, MA for critical reading of the manuscript.
6
ACCEPTED MANUSCRIPT
Table 1. The expanding spectrum of clinical manifestations of glucose transporter 1 deficiency syndrome [1,6,8,9].
Movement disorders Dystonia Dysarthria Ataxia Ocular dyspraxia Opsoclonus Choreoathetosis
Paroxysmal nonepileptic events Alternating hemiplegia of childhood (AHC)
AC C
EP
TE D
M AN U
Paroxysmal exertion-induced dyskinesia type 2 (DYT18) Autonomic paroxysms Myoclonus
SC
Generalized seizures: Tonic, clonic, myoclonic, atonic, spasms, absence Partial seizures Irregular eye movements
RI PT
Seizures
7
ACCEPTED MANUSCRIPT
References
RI PT
1. Pong AW, De Vivo DC. Glucose Transporter Type I Deficiency Syndrome and Epilepsy. In: Pearl PL, editor. Inherited Metabolic Epilpesies New York: Demos Medical; 2013.
2. Pearl PL, Bennett HD, Khademian Z. Seizures and metabolic disease. Current neurology and
SC
neuroscience reports 2005; 5: 127-133.
3. Dravet C, Bureau M. Benign myoclonic epilepsy in infancy. Advances in Neurology 2005; 95:
M AN U
127-137.
4. Leen WG, Klepper J, Verbeek MM, et al. Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder. Brain : a journal of neurology 2010; 133: 655-670.
5. Gaspard N, Suls A, Vilain C, De Jonghe P, Van Bogaert P. "Benign" myoclonic epilepsy of
TE D
infancy as the initial presentation of glucose transporter-1 deficiency. Epileptic disorders : international epilepsy journal with videotape 2011; 13: 300-303.
EP
6. Pong AW, Geary BR, Engelstad KM, Natarajan A, Yang H, De Vivo DC. Glucose transporter type I deficiency syndrome: epilepsy phenotypes and outcomes. Epilepsia 2012; 53: 1503-1510.
AC C
7. Leary LD, Wang D, Nordli DR, Jr, Engelstad K, De Vivo DC. Seizure characterization and electroencephalographic features in Glut-1 deficiency syndrome. Epilepsia 2003; 44: 701-707. 8. Pons R, Collins A, Rotstein M, Engelstad K, De Vivo DC. The spectrum of movement disorders in Glut-1 deficiency. Movement disorders : official journal of the Movement Disorder Society 2010; 25: 275-281. 9. Chenouard A, Vuillaumier-Barrot S, Seta N, Kuster A. A Cause of Permanent Ketosis: GLUT-1 Deficiency. JIMD reports 2015; 18: 79-83. 8
ACCEPTED MANUSCRIPT
10. De Vivo DC, Trifiletti RR, Jacobson RI, Ronen GM, Behmand RA, Harik SI. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, siezures, and developmental delay. N Engl J Med 1991; 325(10): 703-9.
treatment in intractable
childhood
RI PT
11. Vieker S, Schmitt J, Langler A, Schmidt W, Klepper J. Unusual sensitivity to steroid epilepsy suggests GLUT1
Neuropediatrics 2012; 43: 275-278.
deficiency syndrome.
SC
12. von Moers A, Brockmann K, Wang D, et al. EEG features of glut-1 deficiency syndrome.
AC C
EP
TE D
M AN U
Epilepsia 2002; 43: 941-945.
9
S0887-8994(15)00280-5
DOI:
10.1016/j.pediatrneurol.2015.05.019
Reference:
PNU 8681
To appear in:
Pediatric Neurology
Received Date: 25 February 2015 Revised Date:
9 May 2015
Accepted Date: 12 May 2015
Please cite this article as: Appavu B, Mangum T, Obeid M, Glucose Transporter 1 Deficiency: a Treatable Cause of Opsoclonus and Epileptic Myoclonus, Pediatric Neurology (2015), doi: 10.1016/ j.pediatrneurol.2015.05.019. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Glucose Transporter 1 Deficiency: a Treatable Cause of Opsoclonus and Epileptic Myoclonus
RI PT
Running title: Opsoclonus and Myoclonus in GLUT1DS
Brian Appavu1, Tara Mangum2, Makram Obeid3
Department of Pediatric Neurology, Barrow Neurological Institute at Phoenix Children’s Hospital. 1919 E. Thomas Road, Ambulatory Building B 3rd Floor, Phoenix AZ. Phoenix AZ 85016. Phone: (602)933-0970. Fax: (602) 933-0469. Email: [email protected]
SC
1.
M AN U
2. Department of Pediatric Neurology, Barrow Neurological Institute at Phoenix Children’s Hospital. 1919 E. Thomas Road, Ambulatory Building B 3rd Floor, Phoenix AZ. Phoenix AZ 85016. Phone: (602)933-0970. Fax: (602) 933-0469. Email: [email protected]
TE D
3. Division of Epilepsy, Department of Pediatric Neurology, Barrow Neurological Institute at Phoenix Children’s Hospital. 1919 E. Thomas Road, Ambulatory Building B 3rd Floor, Phoenix AZ. Phoenix AZ 85016. Phone: (602)933-0970. Fax: (602) 933-0469. Email: [email protected]
AC C
EP
Keywords: GLUT1, opsoclonus, myoclonus, epilepsy, developmental delays Word Count: 1,287 References: 12 1 Table
Corresponding author: Makram Obeid Mail:1919 E. Thomas Road, Ambulatory Building 3rd Floor Phoenix AZ. Phoenix AZ 85016. Email: [email protected], phone: (602) 933-0970, fax: (602) 933-0469
1
ACCEPTED MANUSCRIPT
Introduction Glucose transporter 1 deficiency syndrome (GLUT1DS) is a genetic metabolic condition
RI PT
that is associated with developmental delay, ataxia, hypotonia, and seizures [1]. The diagnosis of this condition is made either by genetic testing for a known pathologic SLC2A1 mutation or by cerebrospinal fluid (CSF) analysis. The diagnostic CSF criteria have included either a glucose level less than 40 mg/dL or a CSF to serum glucose ratio less than 0.4, along with normal or low
SC
CSF lactate values [1]. Early diagnosis is critical for patients with GLUT1DS, as early intervention with the initiation of the ketogenic diet may lead to dramatic clinical improvements.
M AN U
If left untreated, patients develop acquired microcephaly with motor and cognitive impairments. Epileptic myoclonus in infancy is associated with various pathological conditions. In the absence of an identifiable central nervous system lesion, epileptic myoclonus is usually secondary to genetic metabolic causes, with a spectrum of etiologies. These range from a benign
TE D
genetic nonlesional etiology, the so called "benign myoclonic epilepsy of infancy" (BMEI), to more severe genetic metabolic derangements in infants with developmental delays [2]. Historically classified as one of the earliest onset idiopathic generalized epilepsies, BMEI refers
EP
to a benign form of a genetic nonlesional cause of epileptic myoclonus in a developmentally normal infant. While the genetics of this condition remain unknown, the diagnosis is often made
AC C
on clinical and electrographic grounds between the ages of 4 months and 2 years. Myoclonic seizures remit in the majority of these children after 3 years of age, although a minority will develop additional seizure types [3].
Reported below are two infants diagnosed with GLUT1DS that presented with epileptic myoclonus, one with an electroclinical phenotype mimicking BMEI, and the other also with
2
ACCEPTED MANUSCRIPT
opsoclonus, a novel mutation, and a significant response to high dose oral prednisolone. After a diagnosis of GLUT1DS was made, both infants were placed on the ketogenic diet with beneficial
RI PT
yet variable treatment responses.
Case 1
A 16-month-old girl presented at 8 months of age with very frequent daily paroxysms
SC
consisting of bilateral arm abduction and neck flexion. These events occurred up to 12 times per
M AN U
hour and proved to be epileptic myoclonus on video-EEG monitoring. Magnetic resonance imaging (MRI) of the brain was normal. Her development as well as her neurological exam were normal with a head circumference of 44 cm (62%), compared with 35 cm (83%) at birth. She was subsequently diagnosed with BMEI, and initially treated with levetiracetam with complete resolution of myoclonus within few days. Further genetic testing however, revealed a previously
TE D
described [4] pathogenic frameshift mutation in the SLC2A1 gene (del. c.505-507). She was therefore diagnosed with GLUT1DS at 12 months of age, and the ketogenic diet was subsequently initiated. She remains normocephalic with a head circumference of 45.4 (37%) and
AC C
EP
developmentally on track.
Case 2
A 15 month old girl initially presented with opsoclonus at 1.5 months of age and
subsequently developed epileptic myoclonus at 4 months of age. She was normocephalic with mild appendicular and axial hypotonia on examination. A brain MRI was normal, and an EEG revealed multifocal spikes superimposed upon an otherwise normal background. Her opsoclonus was confirmed to be non-epileptic by video-EEG. After a failed 2 month trial of levetiracetam, 3
ACCEPTED MANUSCRIPT
she did respond to prednisolone within 4 days of its initiation with an initial dose of 40 mg daily. After weaning steroids at 7 months, she experienced a recurrence of opsoclonus and seizures which persisted despite adding topiramate to her antiepileptic treatment regimen. A workup for
RI PT
neuroblastoma included a normal abdominal ultrasound. A lumbar puncture was performed and revealed a CSF glucose level of 37 mg/dL and a concurrent plasma glucose level of 84 mg/dL. Subsequent genetic testing revealed a heterozygous missense gene mutation in the SLC2A1 gene
SC
(c460G>A; p.Gly164Arg). While this is a previously unreported causative mutation of GLUT1DS, it was deemed pathologic in the context of her laboratory data [1]. She was started
M AN U
on the ketogenic diet at the age of 8 months and achieved resolution of seizures and opsoclonus. Whereas her developmental milestone acquisition was slow and plateaued when seizures worsened, she had an acceleration of milestone acquisition once her seizures were controlled. She remains normocephalic with a head circumference of 47 cm (83%) (35.4 cm / 83% at birth),
TE D
has a pincer grasp, says ‘mama’, responds to her name, and is currently able to maintain balance
Discussion
EP
if placed in the sitting position.
Here, we present two patients with GLUT1DS that presented with epileptic myoclonus.
AC C
The diagnosis was made based on a known pathologic mutation in the first child, and a low CSF glucose and a corresponding unreported SLC2A1 gene mutation in the second child. Both of our patients responded to the ketogenic diet with remission of presenting symptomatology, though one of them remains with developmental delays.
4
ACCEPTED MANUSCRIPT
These infants experienced epileptic myoclonus in the setting of normal structural imaging. The presentation of the first patient was electroclinically compatible with BMEI, though genetic testing revealed GLUT1DS. The initial diagnosis of BMEI was based on epileptic
RI PT
myoclonus superimposed on a normal electrographic interictal background, a normal development, and a typical age for BMEI onset. Gaspard et al. reported an infant with GLUT1DS who initially also presented with an electroclinical picture consistent with BMEI [5].
SC
While myoclonus has been described in GLUT1DS, the accompanying electroclinical picture in this disease, is one of developmental delays and interictal EEG abnormalities, unlike BMEI
M AN U
which has an electroclinical hallmark of good treatment response and both normal development and normal interictal EEG background [6,7]. Because of these distinct electroclinical presentations, metabolic testing is not typically performed in patients with a presentation of BMEI. Early diagnosis and treatment of GLUT1DS is necessary, as it may prevent neurological
TE D
deterioration. In the report by Gaspard et al., the ketogenic diet was not started until the age of 4 years, by which time the patient had developed multiple seizure types and acquired microcephaly. Our patient, in contrast, was initiated on the ketogenic diet at 12 months of age,
AC C
her age.
EP
has maintained seizure freedom, and is now appropriately reaching developmental milestones for
Our second patient had a novel mutation in GLUT1DS and also had a unique finding of
opsoclonus. Abnormal eye movements have been previously reported in this disease but only vaguely described as movement disorders [8], yet rarely specified as dyspraxia or opsoclonus [8,9]. Moreover, epileptic oscillatory eye movements mimicking opsoclonus have also been described in GLUT1DS [10], of which the spectrum of clinical phenotypes has been expanding
5
ACCEPTED MANUSCRIPT
(Table 1). Our patient also had significant improvements in seizure control and developmental outcomes when temporarily placed on steroid therapy. The beneficial effect of steroids in GLUT1DS has been previously reported in an 8 year old girl with intractable epilepsy who
RI PT
received oral dexamethasone and might be related to steroid-induced increased expression of the GLUT1 receptor [11]. The beneficial response may also be related to steroid-induced hyperglycemia, since it is known that postprandial states coincide with electrographic
SC
improvements [12]. Our patient, with initiation of the ketogenic diet, showed a robust improvement in seizure control as well as an acceleration of developmental milestone
M AN U
acquisition.
To summarize, the patients presented here, along with the previous cases [6], reveal that not only can GLUT1DS be at the origin of infantile epileptic myoclonus, but that the condition
TE D
also has a protean presentation that includes opsoclonus, and at times, can mimic BMEI. Testing for GLUT1DS should be considered in infants who present with BMEI, as there is a strong need to initiate the ketogenic diet in a timely manner in order to maximize the possibility of milestone
EP
acquisition and seizure freedom. We also propose, alongside previous reports [11], that suspicion for GLUT1DS should be raised in infants with intractable epilepsy and an elusive pathology who
AC C
respond to steroids.
Acknowledgements
We are grateful to Michelle Wotowiec, MA for critical reading of the manuscript.
6
ACCEPTED MANUSCRIPT
Table 1. The expanding spectrum of clinical manifestations of glucose transporter 1 deficiency syndrome [1,6,8,9].
Movement disorders Dystonia Dysarthria Ataxia Ocular dyspraxia Opsoclonus Choreoathetosis
Paroxysmal nonepileptic events Alternating hemiplegia of childhood (AHC)
AC C
EP
TE D
M AN U
Paroxysmal exertion-induced dyskinesia type 2 (DYT18) Autonomic paroxysms Myoclonus
SC
Generalized seizures: Tonic, clonic, myoclonic, atonic, spasms, absence Partial seizures Irregular eye movements
RI PT
Seizures
7
ACCEPTED MANUSCRIPT
References
RI PT
1. Pong AW, De Vivo DC. Glucose Transporter Type I Deficiency Syndrome and Epilepsy. In: Pearl PL, editor. Inherited Metabolic Epilpesies New York: Demos Medical; 2013.
2. Pearl PL, Bennett HD, Khademian Z. Seizures and metabolic disease. Current neurology and
SC
neuroscience reports 2005; 5: 127-133.
3. Dravet C, Bureau M. Benign myoclonic epilepsy in infancy. Advances in Neurology 2005; 95:
M AN U
127-137.
4. Leen WG, Klepper J, Verbeek MM, et al. Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder. Brain : a journal of neurology 2010; 133: 655-670.
5. Gaspard N, Suls A, Vilain C, De Jonghe P, Van Bogaert P. "Benign" myoclonic epilepsy of
TE D
infancy as the initial presentation of glucose transporter-1 deficiency. Epileptic disorders : international epilepsy journal with videotape 2011; 13: 300-303.
EP
6. Pong AW, Geary BR, Engelstad KM, Natarajan A, Yang H, De Vivo DC. Glucose transporter type I deficiency syndrome: epilepsy phenotypes and outcomes. Epilepsia 2012; 53: 1503-1510.
AC C
7. Leary LD, Wang D, Nordli DR, Jr, Engelstad K, De Vivo DC. Seizure characterization and electroencephalographic features in Glut-1 deficiency syndrome. Epilepsia 2003; 44: 701-707. 8. Pons R, Collins A, Rotstein M, Engelstad K, De Vivo DC. The spectrum of movement disorders in Glut-1 deficiency. Movement disorders : official journal of the Movement Disorder Society 2010; 25: 275-281. 9. Chenouard A, Vuillaumier-Barrot S, Seta N, Kuster A. A Cause of Permanent Ketosis: GLUT-1 Deficiency. JIMD reports 2015; 18: 79-83. 8
ACCEPTED MANUSCRIPT
10. De Vivo DC, Trifiletti RR, Jacobson RI, Ronen GM, Behmand RA, Harik SI. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, siezures, and developmental delay. N Engl J Med 1991; 325(10): 703-9.
treatment in intractable
childhood
RI PT
11. Vieker S, Schmitt J, Langler A, Schmidt W, Klepper J. Unusual sensitivity to steroid epilepsy suggests GLUT1
Neuropediatrics 2012; 43: 275-278.
deficiency syndrome.
SC
12. von Moers A, Brockmann K, Wang D, et al. EEG features of glut-1 deficiency syndrome.
AC C
EP
TE D
M AN U
Epilepsia 2002; 43: 941-945.
9