- Email: [email protected]
Periventricular Nodular Heterotopia and Dystonia Due to an ARFGEF2 Mutation
Accepted Manuscript Dyskinetic cerebral palsy- like due to ARFGEF-2 mutation Eduardo Jesús Bardón-Cancho , Lucía Muñoz-Jiménez , María Vázquez-López , Yolanda Ruíz-Martín , Marina García-Morín , Estíbaliz Barredo-Valderrama PII:
S0887-8994(14)00284-7
DOI:
10.1016/j.pediatrneurol.2014.05.008
Reference:
PNU 8362
To appear in:
Pediatric Neurology
Received Date: 26 March 2014 Revised Date:
11 May 2014
Accepted Date: 12 May 2014
Please cite this article as: Bardón-Cancho EJ, Muñoz-Jiménez L, Vázquez-López M, Ruíz-Martín Y, García-Morín M, Barredo-Valderrama E, Dyskinetic cerebral palsy- like due to ARFGEF-2 mutation, Pediatric Neurology (2014), doi: 10.1016/j.pediatrneurol.2014.05.008. 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
Title: Dyskinetic cerebral palsy- like due to ARFGEF-2 mutation Short title: Cerebral palsy and ARFGEF2 mutation
Authors:
RI PT
- Bardón-Cancho, Eduardo Jesúsa - Muñoz-Jiménez, Lucíaa - Vázquez-López, Maríaa,b - Ruíz-Martín, Yolandac
SC
- García-Morín, Marinaa
a
M AN U
- Barredo-Valderrama, Estíbaliza,b
Department of Pediatrics, Hospital General Universitario Gregorio Marañón, Madrid,
Spain. b
Section of Neuropediatrics, Hospital General Universitario Gregorio Marañón,
Madrid, Spain.
Section of Pediatric Radiology, Hospital General Universitario Gregorio Marañón,
Madrid, Spain.
Corresponding author: María Vázquez López
TE D
c
EP
Section of Neuropediatrics. Department of Pediatrics. Hospital Materno-Infantil Gregorio Marañón.
AC C
C/ Doctor Castelo nº 47, 28009, Madrid, Spain. email: [email protected]
Word Count: 1968 words
ACCEPTED MANUSCRIPT ABSTRACT
BACKGROUND: Heterotopias are a neuronal migration disorder caused by extrinsic factors or by genetic mutations. When the location is periventricular the most frequent genetic cause is the mutation in the filamin A2 gene, which an X-linked inheritance.
RI PT
New genes for periventricular nodular heterotopia (PNH) with an autosomal inheritance pattern have been recently discovered.
PATIENTS: We introduce the cases of two siblings. The girl, who was prenatally
SC
diagnosed ventriculomegaly, had delayed development. At six months she had no head control and variable muscle tone, alternating low axial tone with jerking movements. She became microcephalic. Her MRI at 12 months showed enlarged lateral ventricles;
M AN U
periventricular nodular heterotopia, thin corpus callosum, a T2-hyperintensity of the putamen and the thalamus and a lost of volume of lenticular nucleus. At 18 months, she developed sporadic myoclonic seizures that were well controlled with valproic acid. Her younger brother also developed progressive microcephaly and psychomotor delay by 6 months. He associated axial hypotonia with important dystonic-athetoid
TE D
component. MRI performed at 15 months showed asymmetric ventriculomegaly plus diffuse nodules lining the temporal horns, a thin corpus callosum and hyperintensity signal in putamens. He had no seizures.
EP
RESULTS: Because of the association of microcephaly, development delay with important dystonic movements, the imaging results and the probable autosomal recessive inheritance, genetic analisis was requested, detecting a homozygous nonsense
AC C
mutation in ARFGEF2 gene, at the DNA level c.388C>T in exon 4.
CONCLUSIONS: The presence of dyskinetic movements in patients with acquired microcephaly could be the manifestations of PNH due to ARFGEF2 mutation.
Key words: cerebral palsy, dyskinesia, periventricular, heterotopia, ARFGEF2 mutation, psychomotor delay, extrapiramidal, putamen.
ACCEPTED MANUSCRIPT
Dyskinetic cerebral palsy- like due to ARFGEF-2 mutation Heterotopias are a neuronal migration disorder characterized by the placement of a subset of neurons in an abnormal location. They are classified into three groups, depending on the location of the aberrant neurons: periventricular nodular heterotopia (PNH), subcortical heterotopia and leptomeningeal heterotopia1.
infections or other prenatal insults or by genetic mutations.
RI PT
Periventricular nodular heterotopia can be caused either by extrinsic factors such as
The most frequent genetic cause of periventricular nodular heterotopia is the mutation in the filamin A2 gene, which has an X-linked autosomal dominant pattern of inheritance.
SC
New genes for PNH have been recently discovered which are often associated with more seriously affected individuals.
M AN U
We report the cases of two siblings, a boy and a girl, with periventricular nodular heterotopia. They have severe psychomotor retardation, microcephaly and a major movement disorder that resembled an athetoid-dystonic cerebral palsy.
CASE:
TE D
We have followed a girl, full-term newborn, with ventriculomegaly diagnosed with a routine ultrasound at 32 weeks of gestation. She was born by normal delivery with normal birth weight 3,250 g and head circumference of 35 cm (p75). Her neurological examination at birth was normal and her ventriculomegaly was confirmed by
EP
transfontanellar ultrasound, presenting also a thin corpus callosum, TORCH infections were discarded. About family history, their father and their maternal grandfather are
AC C
cousins.
Since the first months her development was delayed. At 10 months head circumference was 42 cm (< 2 SD) and she had variable muscle tone, alternating low axial tone with jerking movements of the extremities exacerbated by the emotions. She had not sitting ability and tended to lingual protrusion. Deep tendon reflexes were normal and she had difficulties for grasping, holding on objects just for a few seconds, due to dystonia. Development quotient score was performed, resulting in 4-month in movement, posture and in language and 3 ½ months in cognition, coordination and use of objects as well as in socialization.
ACCEPTED MANUSCRIPT At 12 months brain MRI showed enlarged lateral ventricles; periventricular nodular heterotopia along the ependyma and a thin corpus callosum, although completely formed. It was also observed a T2-hyperintensity of the putamen and the thalamus, with a lost of volume of lenticular nucleus. Metabolic testing was normal. She was diagnosed of dyskinetic cerebral palsy
RI PT
secondary to cerebral malformation.
At 18 months, the patient developed sporadic myoclonic seizures consisting on a widespread increase in muscle tone preceded by crying that lasted about 2 minutes.
SC
During the episodes, she was lying in the prone position and she raised her legs. The EEG demonstrated a bitemporal slow background with diffuse epileptiform activity in both hemispheres. Involuntary movements were seen in EEG-video that could
M AN U
correspond to myoclonus. Also slowing diffuse background overlapping with spikewave complexes during sleep. The seizures were controlled with valproic.
Nowadays, at the age of 3.5 years, she is not able to sit down and has a dystonic
TE D
extrapiramidal movement disorder.
Her younger brother, born 2 years later, had normal transfontanellar ultrasound at birth and he had no incidents during the neonatal period. However, progressive microcephaly began to be observed at six months, being one month later the head circumference less
EP
than the 3rd percentile.
In his physical examination at this age was already observed an axial hypotonia with fluctuating limbs tone, tending to wrists overpronation and important dystonic-athetoid
AC C
component. At nine months his psychomotor delay was important and his development quotient score corresponded to 4 months. MRI was performed at 15 months showing asymmetric ventriculomegaly (right ventricle 18 mm and left 14 mm) plus diffuse nodules lining the temporal horns, which seemed consistent with bilateral periventricular nodular heterotopia. It associates a thin corpus callosum mainly in the posterior half and a loss of volume of the lenticular nuclei with hyperintensity signal in putamens (Figure 1). Unlike her sister this patient had not presented seizures until now.
ACCEPTED MANUSCRIPT He and his sister are attending to early care programs and physiotherapy since the begginning. They actually have no feeding problems although they have low weight percentiles.
With the clinical picture composed by acquired microcephaly, development delay with
RI PT
important dystonic movements, the imaging results and the probable autosomal recessive inheritance, genetic analisis is requested, detecting a homozygous nonsense mutation in ARFGEF2 gene, at the DNA level c.388C>T in exon 4.
SC
Discussion:
Periventricular nodular heterotopia is a cerebral malformation characterized by the presence of neuronal nodules along the lateral ventricles. It can be uni or bilateral and
M AN U
the nodules can be positioned anterior, posterior or along the surface of the ventricles. It can occur singly or in combination with other malformations of the nervous system (polymicrogyria, microcephaly, hydrocephalus) or extra-neurological (cardiac or limbs abnormalities).
TE D
Traditionally, it was included in the malformations due to abnormal neuronal migration. However, in the updated classification for malformations of cortical development, made by Barkovich in 20123, he included periventricular heterotopia in a subcategory of malformations resulting from abnormalities of the neuroependyma, that affect
EP
postmitotic neurons preventing them to join properly to radial glial cells and avoiding the onset of the migration process.
AC C
Ferland 20094 showed that injury to, or denudation of, the neuroependyma could be linked to the formation of periventricular nodular heterotopia, because it causes disengagement of radial glia, resulting in an inability of neurons to migrate away. Periventricular nodular heterotopia can be found as an incidental finding on imaging studies of asymptomatic patients5. However, more frequently are discovered after diagnostic tests done to a patient with developmental delay or epilepsy.
Most causes of family periventricular nodular heterotopia are linked to FLNA mutations,
located
on
chromosome
Xq28,
with
an
X-linked
inheritance.
ACCEPTED MANUSCRIPT Characteristically nodules appear along the frontal horns, bodies and trigones of the lateral ventricles without affecting the temporal horns. Women who have this mutation usually have seizures in the second or third decade of life and a normal intelligence. It is believed that this mutation is lethal for hemizygous
RI PT
males, although there are some cases described in the literature.
The mutation in the filamin A has been associated with classic bilateral nodular periventricular heterotopia, rarely with unilateral and also with the Ehlers-Danlos syndrome6. Filamin A, a protein binded to actin, has an important role in regulating cell
SC
migration and cell shape. This protein interacts with actin mediating adhesion through interactions with integrins. Filamin A appears not only in the central nervous system but also its mutation produces extraneuronal significant pathology. It seems to play a role in
M AN U
the vasculature development and its mutation has been associated with an increased frequency of stroke and heart defects, such as, persistent ductus arteriosus and bicuspid aortic valve7.
In 2004, Sheen et al.8 reported two cases of periventricular nodular heterotopia with an
TE D
autosomal inheritance pattern due to a mutation in ARGEF-2 gene (ADP ribosylation factor guanine exchange factor-2), located in 20q13.13. This gene codifies for BIG-2, a protein expressed in neural progenitors of the ventricular and subventricular zones9.
EP
BIG-2 protein regulates the vesicle trafficking and possibly the transport of adhesion molecules such as β- catenin and E-cadherin. Its inhibition causes suppression of axonal
AC C
and dendritic growth.
Once seen that FLNA or ARGEF-2 mutation produce similar nodular heterotopia, some studies were carried to look for a functional relationship between both genes. It was found a co-expression between FLNA and BIG-2 proteins in the neuroependymal cells along the lateral ventricles. Besides, Jie Lu et al2 observed that supression of ARFGEF2 in neuroblastoma cells partially blocked FLNA transport from the Golgi to the cell membrane.
Until now, there are thirteen patients with ARGEF-2 mutation described (seven of them were Turkish and five of Palestinian origin)10,11. All of them have a similar phenotype to
ACCEPTED MANUSCRIPT our two patients with acquired microcephaly, delayed development, low axial tone and tetraparesia. Not so consistent is the movement disorder which is only described in three cases besides our patients in the literature10,13. Seizures are also common in cerebral heterotopias, sometimes with hypsarrhythmia or refractory epilepsy11.
RI PT
In five cases patients associated recurrent infections, especially of the respiratory tract, even being the cause of death in some of them. Feeding problems are also common, some cases even requering to perform a gastrostomy for maintaining optimal nutrition. As extraneurological manifestations, it is reported one patients who was affected with
SC
obstructive cardiomyopathy which was controlled with medical treatment. The mortality of the reported cases in the literature is currently of 50%, during the first and second decade of life.
M AN U
MRI images in patients with the ARFGEF2 gene mutation showed a cortico-subcortical atrophy with periventricular heterotopia. The existance of hyperintensity of the putamen is only described in four patients that also showed severe motor impairment. This alteration could be related to the dyskinetic problems of these patients, appearing as a dyskinetic cerebral palsy.
TE D
Recently a terminal deletion on chromosome 6q27 in 12 patients with periventricular nodular heterotopia, corpus callosum dysgenesis, colpocephaly, cerebellar hypoplasia, ataxia and cognitive impairment has been described by Conti et al12. These authors suggest that C6orf70 gene, located in the critical deleted region, plays an important role
CONCLUSION:
EP
in neuronal migration control.
AC C
At the present time there are few data on the clinical course of patients with this type of nodular heterotopia linked to ARFGEF-2 gene mutation. Also it is not clearly known which diseases could they have associated or which tretament could be better to control the seizures. There are no treaments proved for improving the control and the quality of their movements. The assocciation of periventricular nodular heterotopia and dyskinetic movement disorder in patients with acquired microcephaly should make us think of the possibility of an ARGEF2 mutation.
ACCEPTED MANUSCRIPT 1. González G, Vedolin L, Barry B, Poduri A, Walsh C, Barkovich AJ. Location of periventricular nodular heterotopia is related to the malformation phenotype on MRI. AJNR Am J Neuroradiol. 2013;34(4):877-83. 2. Lu J, Tiao G, Folkerth R, Hecht J, Walsh C, Sheen V. Overlapping expression of ARFGEF2 and Filamin A in the neuroependymal lining of the lateral ventricles:
494(3):476-84. 3. Barkovich AJ, Guerrini developmental
R, Kuzniecky
and
RI, Jackson
RI PT
insights into the cause of periventricular heterotopia. J Comp Neurol. 2006;
GD, Dobyns
genetic classification for
WB.
A
malformations
SC
of cortical development: update 2012. Brain 2012 135(Pt 5):1348-69
4. Ferland RJ, Batiz LF, Neal J, Lian G, Bundock E, Lu J, et al. Disruption of neural
progenitors
along
the
ventricular
and
subventricular
zones
M AN U
in periventricular heterotopia. Hum Mol Genet. 2009;18(3):497-516. 5. Sheen VL, Bodell A, Walsh CA. X-Linked Periventricular Heterotopia. 2002 Oct 8 [Updated 2009 Jun 4]. In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013.
TE D
6. Gómez-Garre P, Seijo M, Gutiérrez-Delicado E, Castro del Río M, de la Torre C, Gómez-Abad C et al. Ehlers-Danlos syndrome and periventricular nodular heterotopia in a Spanish family with a single FLNA mutation. J Med Genet.
EP
2006;43(3):232-7.
7. Liu JS. Molecular genetics of neuronal migration disorders. Curr Neurol Neurosci Rep. 2011;11(2):171-8
AC C
8. Sheen VL, Topçu M, Berkovic S, Yalnizoglu D, Blatt I, Bodell A, et al. Autosomal recessive form of periventricular heterotopia. Neurology. 2003;60(7):1108-12.
9. Zhang J, Neal J, Lian G, Hu J, Lu J, Sheen V. Filamin A regulates neuronal migration through brefeldin A-inhibited guanine exchange factor 2-dependent Arf1 activation. J Neurosci. 2013;33(40):15735-46 10. Tanyalçin I, Verhelst H, Halley DJ, Vanderhasselt T, Villard L, Goizet C, et al. Elaborating the phenotypic spectrum associated with mutations in ARFGEF2: Case study and literature review. Eur J Paediatr Neurol. 2013;17(6):666-70.
ACCEPTED MANUSCRIPT 11. Banne E, Atawneh O, Henneke M, Brockmann K, Gärtner J, Elpeleg O, et al. West syndrome, microcephaly, grey matter heterotopia and hypoplasia of corpus callosum due to a novel ARFGEF2 mutation. J Med Genet. 2013;50(11):772-5. 12. Conti V, Carabalona A, Pallesi-Pocachard E, Parrini E, Leventer RJ, Buhler E et al. Periventricular heterotopia in 6q terminal deletion syndrome: role of the
13. de
Wit
MC,
de
Coo
IF, Halley
DJ, Lequin
RI PT
C6orf70 gene. Brain. 2013;136(Pt 11):3378-94. MH, Mancini
GM.
Movement disorder and neuronal migration disorder due to ARFGEF2 mutation.
SC
Neurogenetics. 2009;10(4):333-6.
M AN U
Figure legends:
Figure 1: Brain MRI of the younger brother made at the age of one year and 3 months. (a) Axial T2-weighted TSE images and (b) coronal T2-weighted TSE show asimetrical ventriculomegaly and bilateral periventricular nodular heterotopia with the same signal intensity of gray matter (white arrows). Images also reveal bilateral loss of volumen of
AC C
EP
TE D
the lenticular nucleus an hiperintensity of the putamen (black arrowheads).
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S0887-8994(14)00284-7
DOI:
10.1016/j.pediatrneurol.2014.05.008
Reference:
PNU 8362
To appear in:
Pediatric Neurology
Received Date: 26 March 2014 Revised Date:
11 May 2014
Accepted Date: 12 May 2014
Please cite this article as: Bardón-Cancho EJ, Muñoz-Jiménez L, Vázquez-López M, Ruíz-Martín Y, García-Morín M, Barredo-Valderrama E, Dyskinetic cerebral palsy- like due to ARFGEF-2 mutation, Pediatric Neurology (2014), doi: 10.1016/j.pediatrneurol.2014.05.008. 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
Title: Dyskinetic cerebral palsy- like due to ARFGEF-2 mutation Short title: Cerebral palsy and ARFGEF2 mutation
Authors:
RI PT
- Bardón-Cancho, Eduardo Jesúsa - Muñoz-Jiménez, Lucíaa - Vázquez-López, Maríaa,b - Ruíz-Martín, Yolandac
SC
- García-Morín, Marinaa
a
M AN U
- Barredo-Valderrama, Estíbaliza,b
Department of Pediatrics, Hospital General Universitario Gregorio Marañón, Madrid,
Spain. b
Section of Neuropediatrics, Hospital General Universitario Gregorio Marañón,
Madrid, Spain.
Section of Pediatric Radiology, Hospital General Universitario Gregorio Marañón,
Madrid, Spain.
Corresponding author: María Vázquez López
TE D
c
EP
Section of Neuropediatrics. Department of Pediatrics. Hospital Materno-Infantil Gregorio Marañón.
AC C
C/ Doctor Castelo nº 47, 28009, Madrid, Spain. email: [email protected]
Word Count: 1968 words
ACCEPTED MANUSCRIPT ABSTRACT
BACKGROUND: Heterotopias are a neuronal migration disorder caused by extrinsic factors or by genetic mutations. When the location is periventricular the most frequent genetic cause is the mutation in the filamin A2 gene, which an X-linked inheritance.
RI PT
New genes for periventricular nodular heterotopia (PNH) with an autosomal inheritance pattern have been recently discovered.
PATIENTS: We introduce the cases of two siblings. The girl, who was prenatally
SC
diagnosed ventriculomegaly, had delayed development. At six months she had no head control and variable muscle tone, alternating low axial tone with jerking movements. She became microcephalic. Her MRI at 12 months showed enlarged lateral ventricles;
M AN U
periventricular nodular heterotopia, thin corpus callosum, a T2-hyperintensity of the putamen and the thalamus and a lost of volume of lenticular nucleus. At 18 months, she developed sporadic myoclonic seizures that were well controlled with valproic acid. Her younger brother also developed progressive microcephaly and psychomotor delay by 6 months. He associated axial hypotonia with important dystonic-athetoid
TE D
component. MRI performed at 15 months showed asymmetric ventriculomegaly plus diffuse nodules lining the temporal horns, a thin corpus callosum and hyperintensity signal in putamens. He had no seizures.
EP
RESULTS: Because of the association of microcephaly, development delay with important dystonic movements, the imaging results and the probable autosomal recessive inheritance, genetic analisis was requested, detecting a homozygous nonsense
AC C
mutation in ARFGEF2 gene, at the DNA level c.388C>T in exon 4.
CONCLUSIONS: The presence of dyskinetic movements in patients with acquired microcephaly could be the manifestations of PNH due to ARFGEF2 mutation.
Key words: cerebral palsy, dyskinesia, periventricular, heterotopia, ARFGEF2 mutation, psychomotor delay, extrapiramidal, putamen.
ACCEPTED MANUSCRIPT
Dyskinetic cerebral palsy- like due to ARFGEF-2 mutation Heterotopias are a neuronal migration disorder characterized by the placement of a subset of neurons in an abnormal location. They are classified into three groups, depending on the location of the aberrant neurons: periventricular nodular heterotopia (PNH), subcortical heterotopia and leptomeningeal heterotopia1.
infections or other prenatal insults or by genetic mutations.
RI PT
Periventricular nodular heterotopia can be caused either by extrinsic factors such as
The most frequent genetic cause of periventricular nodular heterotopia is the mutation in the filamin A2 gene, which has an X-linked autosomal dominant pattern of inheritance.
SC
New genes for PNH have been recently discovered which are often associated with more seriously affected individuals.
M AN U
We report the cases of two siblings, a boy and a girl, with periventricular nodular heterotopia. They have severe psychomotor retardation, microcephaly and a major movement disorder that resembled an athetoid-dystonic cerebral palsy.
CASE:
TE D
We have followed a girl, full-term newborn, with ventriculomegaly diagnosed with a routine ultrasound at 32 weeks of gestation. She was born by normal delivery with normal birth weight 3,250 g and head circumference of 35 cm (p75). Her neurological examination at birth was normal and her ventriculomegaly was confirmed by
EP
transfontanellar ultrasound, presenting also a thin corpus callosum, TORCH infections were discarded. About family history, their father and their maternal grandfather are
AC C
cousins.
Since the first months her development was delayed. At 10 months head circumference was 42 cm (< 2 SD) and she had variable muscle tone, alternating low axial tone with jerking movements of the extremities exacerbated by the emotions. She had not sitting ability and tended to lingual protrusion. Deep tendon reflexes were normal and she had difficulties for grasping, holding on objects just for a few seconds, due to dystonia. Development quotient score was performed, resulting in 4-month in movement, posture and in language and 3 ½ months in cognition, coordination and use of objects as well as in socialization.
ACCEPTED MANUSCRIPT At 12 months brain MRI showed enlarged lateral ventricles; periventricular nodular heterotopia along the ependyma and a thin corpus callosum, although completely formed. It was also observed a T2-hyperintensity of the putamen and the thalamus, with a lost of volume of lenticular nucleus. Metabolic testing was normal. She was diagnosed of dyskinetic cerebral palsy
RI PT
secondary to cerebral malformation.
At 18 months, the patient developed sporadic myoclonic seizures consisting on a widespread increase in muscle tone preceded by crying that lasted about 2 minutes.
SC
During the episodes, she was lying in the prone position and she raised her legs. The EEG demonstrated a bitemporal slow background with diffuse epileptiform activity in both hemispheres. Involuntary movements were seen in EEG-video that could
M AN U
correspond to myoclonus. Also slowing diffuse background overlapping with spikewave complexes during sleep. The seizures were controlled with valproic.
Nowadays, at the age of 3.5 years, she is not able to sit down and has a dystonic
TE D
extrapiramidal movement disorder.
Her younger brother, born 2 years later, had normal transfontanellar ultrasound at birth and he had no incidents during the neonatal period. However, progressive microcephaly began to be observed at six months, being one month later the head circumference less
EP
than the 3rd percentile.
In his physical examination at this age was already observed an axial hypotonia with fluctuating limbs tone, tending to wrists overpronation and important dystonic-athetoid
AC C
component. At nine months his psychomotor delay was important and his development quotient score corresponded to 4 months. MRI was performed at 15 months showing asymmetric ventriculomegaly (right ventricle 18 mm and left 14 mm) plus diffuse nodules lining the temporal horns, which seemed consistent with bilateral periventricular nodular heterotopia. It associates a thin corpus callosum mainly in the posterior half and a loss of volume of the lenticular nuclei with hyperintensity signal in putamens (Figure 1). Unlike her sister this patient had not presented seizures until now.
ACCEPTED MANUSCRIPT He and his sister are attending to early care programs and physiotherapy since the begginning. They actually have no feeding problems although they have low weight percentiles.
With the clinical picture composed by acquired microcephaly, development delay with
RI PT
important dystonic movements, the imaging results and the probable autosomal recessive inheritance, genetic analisis is requested, detecting a homozygous nonsense mutation in ARFGEF2 gene, at the DNA level c.388C>T in exon 4.
SC
Discussion:
Periventricular nodular heterotopia is a cerebral malformation characterized by the presence of neuronal nodules along the lateral ventricles. It can be uni or bilateral and
M AN U
the nodules can be positioned anterior, posterior or along the surface of the ventricles. It can occur singly or in combination with other malformations of the nervous system (polymicrogyria, microcephaly, hydrocephalus) or extra-neurological (cardiac or limbs abnormalities).
TE D
Traditionally, it was included in the malformations due to abnormal neuronal migration. However, in the updated classification for malformations of cortical development, made by Barkovich in 20123, he included periventricular heterotopia in a subcategory of malformations resulting from abnormalities of the neuroependyma, that affect
EP
postmitotic neurons preventing them to join properly to radial glial cells and avoiding the onset of the migration process.
AC C
Ferland 20094 showed that injury to, or denudation of, the neuroependyma could be linked to the formation of periventricular nodular heterotopia, because it causes disengagement of radial glia, resulting in an inability of neurons to migrate away. Periventricular nodular heterotopia can be found as an incidental finding on imaging studies of asymptomatic patients5. However, more frequently are discovered after diagnostic tests done to a patient with developmental delay or epilepsy.
Most causes of family periventricular nodular heterotopia are linked to FLNA mutations,
located
on
chromosome
Xq28,
with
an
X-linked
inheritance.
ACCEPTED MANUSCRIPT Characteristically nodules appear along the frontal horns, bodies and trigones of the lateral ventricles without affecting the temporal horns. Women who have this mutation usually have seizures in the second or third decade of life and a normal intelligence. It is believed that this mutation is lethal for hemizygous
RI PT
males, although there are some cases described in the literature.
The mutation in the filamin A has been associated with classic bilateral nodular periventricular heterotopia, rarely with unilateral and also with the Ehlers-Danlos syndrome6. Filamin A, a protein binded to actin, has an important role in regulating cell
SC
migration and cell shape. This protein interacts with actin mediating adhesion through interactions with integrins. Filamin A appears not only in the central nervous system but also its mutation produces extraneuronal significant pathology. It seems to play a role in
M AN U
the vasculature development and its mutation has been associated with an increased frequency of stroke and heart defects, such as, persistent ductus arteriosus and bicuspid aortic valve7.
In 2004, Sheen et al.8 reported two cases of periventricular nodular heterotopia with an
TE D
autosomal inheritance pattern due to a mutation in ARGEF-2 gene (ADP ribosylation factor guanine exchange factor-2), located in 20q13.13. This gene codifies for BIG-2, a protein expressed in neural progenitors of the ventricular and subventricular zones9.
EP
BIG-2 protein regulates the vesicle trafficking and possibly the transport of adhesion molecules such as β- catenin and E-cadherin. Its inhibition causes suppression of axonal
AC C
and dendritic growth.
Once seen that FLNA or ARGEF-2 mutation produce similar nodular heterotopia, some studies were carried to look for a functional relationship between both genes. It was found a co-expression between FLNA and BIG-2 proteins in the neuroependymal cells along the lateral ventricles. Besides, Jie Lu et al2 observed that supression of ARFGEF2 in neuroblastoma cells partially blocked FLNA transport from the Golgi to the cell membrane.
Until now, there are thirteen patients with ARGEF-2 mutation described (seven of them were Turkish and five of Palestinian origin)10,11. All of them have a similar phenotype to
ACCEPTED MANUSCRIPT our two patients with acquired microcephaly, delayed development, low axial tone and tetraparesia. Not so consistent is the movement disorder which is only described in three cases besides our patients in the literature10,13. Seizures are also common in cerebral heterotopias, sometimes with hypsarrhythmia or refractory epilepsy11.
RI PT
In five cases patients associated recurrent infections, especially of the respiratory tract, even being the cause of death in some of them. Feeding problems are also common, some cases even requering to perform a gastrostomy for maintaining optimal nutrition. As extraneurological manifestations, it is reported one patients who was affected with
SC
obstructive cardiomyopathy which was controlled with medical treatment. The mortality of the reported cases in the literature is currently of 50%, during the first and second decade of life.
M AN U
MRI images in patients with the ARFGEF2 gene mutation showed a cortico-subcortical atrophy with periventricular heterotopia. The existance of hyperintensity of the putamen is only described in four patients that also showed severe motor impairment. This alteration could be related to the dyskinetic problems of these patients, appearing as a dyskinetic cerebral palsy.
TE D
Recently a terminal deletion on chromosome 6q27 in 12 patients with periventricular nodular heterotopia, corpus callosum dysgenesis, colpocephaly, cerebellar hypoplasia, ataxia and cognitive impairment has been described by Conti et al12. These authors suggest that C6orf70 gene, located in the critical deleted region, plays an important role
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in neuronal migration control.
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At the present time there are few data on the clinical course of patients with this type of nodular heterotopia linked to ARFGEF-2 gene mutation. Also it is not clearly known which diseases could they have associated or which tretament could be better to control the seizures. There are no treaments proved for improving the control and the quality of their movements. The assocciation of periventricular nodular heterotopia and dyskinetic movement disorder in patients with acquired microcephaly should make us think of the possibility of an ARGEF2 mutation.
ACCEPTED MANUSCRIPT 1. González G, Vedolin L, Barry B, Poduri A, Walsh C, Barkovich AJ. Location of periventricular nodular heterotopia is related to the malformation phenotype on MRI. AJNR Am J Neuroradiol. 2013;34(4):877-83. 2. Lu J, Tiao G, Folkerth R, Hecht J, Walsh C, Sheen V. Overlapping expression of ARFGEF2 and Filamin A in the neuroependymal lining of the lateral ventricles:
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in periventricular heterotopia. Hum Mol Genet. 2009;18(3):497-516. 5. Sheen VL, Bodell A, Walsh CA. X-Linked Periventricular Heterotopia. 2002 Oct 8 [Updated 2009 Jun 4]. In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013.
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6. Gómez-Garre P, Seijo M, Gutiérrez-Delicado E, Castro del Río M, de la Torre C, Gómez-Abad C et al. Ehlers-Danlos syndrome and periventricular nodular heterotopia in a Spanish family with a single FLNA mutation. J Med Genet.
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2006;43(3):232-7.
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8. Sheen VL, Topçu M, Berkovic S, Yalnizoglu D, Blatt I, Bodell A, et al. Autosomal recessive form of periventricular heterotopia. Neurology. 2003;60(7):1108-12.
9. Zhang J, Neal J, Lian G, Hu J, Lu J, Sheen V. Filamin A regulates neuronal migration through brefeldin A-inhibited guanine exchange factor 2-dependent Arf1 activation. J Neurosci. 2013;33(40):15735-46 10. Tanyalçin I, Verhelst H, Halley DJ, Vanderhasselt T, Villard L, Goizet C, et al. Elaborating the phenotypic spectrum associated with mutations in ARFGEF2: Case study and literature review. Eur J Paediatr Neurol. 2013;17(6):666-70.
ACCEPTED MANUSCRIPT 11. Banne E, Atawneh O, Henneke M, Brockmann K, Gärtner J, Elpeleg O, et al. West syndrome, microcephaly, grey matter heterotopia and hypoplasia of corpus callosum due to a novel ARFGEF2 mutation. J Med Genet. 2013;50(11):772-5. 12. Conti V, Carabalona A, Pallesi-Pocachard E, Parrini E, Leventer RJ, Buhler E et al. Periventricular heterotopia in 6q terminal deletion syndrome: role of the
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Wit
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IF, Halley
DJ, Lequin
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C6orf70 gene. Brain. 2013;136(Pt 11):3378-94. MH, Mancini
GM.
Movement disorder and neuronal migration disorder due to ARFGEF2 mutation.
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Neurogenetics. 2009;10(4):333-6.
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Figure legends:
Figure 1: Brain MRI of the younger brother made at the age of one year and 3 months. (a) Axial T2-weighted TSE images and (b) coronal T2-weighted TSE show asimetrical ventriculomegaly and bilateral periventricular nodular heterotopia with the same signal intensity of gray matter (white arrows). Images also reveal bilateral loss of volumen of
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the lenticular nucleus an hiperintensity of the putamen (black arrowheads).
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