CLINICAL REPORT
Cerebral Palsy, Epilepsy, and Severe Intellectual Disability in a Patient With 3q29 Microduplication Syndrome Alberto Ferna´ndez-Jae´n,1* Marı´a del Carmen Castellanos,2 Ana Laura Ferna´ndez-Perrone,1 Daniel Martı´n Ferna´ndez-Mayoralas,1 Alberto Gonza´lez de la Vega,3 Beatriz Calleja-Pe´rez,4 Ester Corbacho Ferna´ndez,3 Jacobo Albert,5 and Marı´a Carmen Sa´nchez Hombre3 1
Pediatric Neurology Unit, Quiron University Hospital, Madrid, Spain
2
Genetics Department, Gemolab, Quiron University Hospital, Madrid, Spain
3
CGC Genetics Laboratory, Madrid, Spain Pediatric Primary Care, Doctor Cirajas Healthcare Center, Madrid, Spain
4 5
Human Brain Mapping Unit, Pluridisciplinary Institute, Complutense University of Madrid, Madrid, Spain
Manuscript Received: 20 September 2013; Manuscript Accepted: 10 March 2014
Interstitial microduplication of 3q29 has been recently described. Individuals with this syndrome have widely variable phenotypes. We describe the first clinical case with a 1.607 Mb duplication at 3q29 (chr3: 195,731,956–197,339,329), accompanied by severe intellectual disability, epilepsy, and cerebral palsy. This duplication involves 22 genes; PAK2, DLG1, BDH1, and FBXO45 are implicated in neuronal development and synaptic function and could play an important role in this syndrome. We propose considering genetic studies, particularly array comparative genomic hybridization, in patients with epilepsy and/or cerebral palsy of unknown etiology when dysmorphic features are present. Ó 2014 Wiley Periodicals, Inc.
Key words: 3q29 microduplication; epilepsy; cerebral palsy; p21-activated kinases; membrane proteins
INTRODUCTION High resolution microarray analysis has facilitated the identification of multiple new microdeletion/microduplication syndromes in individuals with idiopathic intellectual disability, autism, congenital malformations, and/or dysmorphic features. Recent array comparative genomic hybridization (a-CGH) studies demonstrated cryptic imbalances in about 15–25% of patients with these characteristics [Krepischi-Santos et al., 2006; Rosenberg et al., 2006]. Microdeletion syndromes tend to be more severe than reciprocal microduplication syndromes; patients with microdeletion syndromes exhibit more severe cognitive disability, more patent dysmorphic features, and/or antagonistic physical characteristics [Dolan et al., 2010; Rosenfeld et al., 2013]. Cerebral palsy (CP) has been occasionally described in patients with microdeletion [Peredo et al., 2013; Zahanova et al., 2012] and microduplication syndromes [Degerliyurt et al., 2012]. A recent study of 50 cases with CP revealed
Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article: Ferna´ndez-Jae´n A, Castellanos MDC, Ferna´ndez-Perrone AL, Ferna´ndezMayoralas DM, de la Vega AG, CallejaPe´rez B, Ferna´ndez EC, Albert J, Hombre MCS. 2014. Cerebral palsy, epilepsy, and severe intellectual disability in a patient with 3q29 microduplication syndrome. Am J Med Genet Part A 164A:2043–2047.
the presence of rare copy number variants (CNVs) of potential relevance to CP [McMichael et al., 2014]. Accordingly, rare CNVs with probable causative roles have been identified in up to 19% of patients with Lennox–Gastaut syndrome, a severe epileptic encephalopathy [Lund et al., 2013]; thus, a-CGH has been suggested as the first-line genetic analysis for West syndrome [Hansen et al., 2012]. Interstitial deletions and duplications of 3q29 have recently been described as new syndromes [Willatt et al., 2005; Ballif et al., 2008]. Deletion and duplication size is the same in most of the cases studied (1.5–1.6 Mb). They have widely heterogeneous clinical syndromes but mild to moderate cognitive disabilities are frequently exhibited. As with other syndromes, clinical manifestations tend to be more Conflict of interest: none. Correspondence to: Alberto Fernandez Jae´n, Head of Pediatric Neurology, Hospital University Quiro´n Madrid, C/Diego de Velazquez 1, Pozuelo de Alarco´n, Madrid 28024, Spain. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 16 May 2014 DOI 10.1002/ajmg.a.36559
2043
2044 severe in 3q29 microdeletion than in 3q29 microduplication syndrome [Ballif et al., 2008]. Because this is a milder phenotype, it may be subject to less frequent detection. In this paper, we describe the first case published in literature, with a de novo chromosome 3q29 microduplication, epilepsy, and CP.
CLINICAL REPORT This 11-year-old female patient was the only child of nonconsanguineous parents who were healthy. There was no family history of known physical malformations, epilepsy, or intellectual disability. She was the product of a 39-week pregnancy via uncomplicated vaginal delivery to her 29-year-old primigravida mother. Apgar scores were 9 at both 1 and 5 min. Birth weight was 2,760 g (10th centile), length was 48 cm (25th centile), and occipital frontal diameter (OFD) was 34 cm (45th centile). The patient was evaluated by us on the first day of life because of recurring focal clonic seizures involving superior limbs, with a poor response to common doses of phenobarbital and phenytoin. Seizures completely disappeared after introduction of carbamazepine. Physical and neurological examinations identified moderate axial hypotonia, brachicephaly, and up-slanting palpebral fissures. Results of a cranial ultrasound, karyotyping, cerebrospinal fluid analyses, and urine/plasma metabolic screens were normal. Heart ultrasound revealed the presence of a mild interauricular communication. An electroencephalogram (EEG) with neonatal montage showed evolving spike-wave activity with maximal negativity at C4. Clinically, the patient demonstrated rhythmic clonic jerks of the left arm. At the age of 2 months, a brain 1.5T MRI revealed no significant abnormal findings.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A During the first months of life, the patient showed a severe psychomotor delay; she developed distal spasticity in her limbs. Her spasticity was treated with physiotherapy and botulinum toxin infiltrations; however, she was never able to sit or stand without support. Epileptiform discharges over the right temporal region were frequently shown on EEGs. At the ages of 5 and 10 years, we unsuccessfully tried to withdraw the antiepileptic treatment; on both occasions, the patient suffered secondary generalized seizures. Now at 11 years old, she is fully wheelchair dependent and voluntary movements of the hands are hampered by sudden hyperextension or myoclonic jerks. She has never achieved bowel or bladder control. Her verbal communication is absent, but she can communicate through gestures, of which she has few. Vision and hearing have remained within the normal ranges and she remains seizure-free. Physical examination reveals mild truncular obesity with a weight of 32 kg (20th centile) and a height of 122 cm (
Cerebral Palsy, Epilepsy, and Severe Intellectual Disability in a Patient With 3q29 Microduplication Syndrome Alberto Ferna´ndez-Jae´n,1* Marı´a del Carmen Castellanos,2 Ana Laura Ferna´ndez-Perrone,1 Daniel Martı´n Ferna´ndez-Mayoralas,1 Alberto Gonza´lez de la Vega,3 Beatriz Calleja-Pe´rez,4 Ester Corbacho Ferna´ndez,3 Jacobo Albert,5 and Marı´a Carmen Sa´nchez Hombre3 1
Pediatric Neurology Unit, Quiron University Hospital, Madrid, Spain
2
Genetics Department, Gemolab, Quiron University Hospital, Madrid, Spain
3
CGC Genetics Laboratory, Madrid, Spain Pediatric Primary Care, Doctor Cirajas Healthcare Center, Madrid, Spain
4 5
Human Brain Mapping Unit, Pluridisciplinary Institute, Complutense University of Madrid, Madrid, Spain
Manuscript Received: 20 September 2013; Manuscript Accepted: 10 March 2014
Interstitial microduplication of 3q29 has been recently described. Individuals with this syndrome have widely variable phenotypes. We describe the first clinical case with a 1.607 Mb duplication at 3q29 (chr3: 195,731,956–197,339,329), accompanied by severe intellectual disability, epilepsy, and cerebral palsy. This duplication involves 22 genes; PAK2, DLG1, BDH1, and FBXO45 are implicated in neuronal development and synaptic function and could play an important role in this syndrome. We propose considering genetic studies, particularly array comparative genomic hybridization, in patients with epilepsy and/or cerebral palsy of unknown etiology when dysmorphic features are present. Ó 2014 Wiley Periodicals, Inc.
Key words: 3q29 microduplication; epilepsy; cerebral palsy; p21-activated kinases; membrane proteins
INTRODUCTION High resolution microarray analysis has facilitated the identification of multiple new microdeletion/microduplication syndromes in individuals with idiopathic intellectual disability, autism, congenital malformations, and/or dysmorphic features. Recent array comparative genomic hybridization (a-CGH) studies demonstrated cryptic imbalances in about 15–25% of patients with these characteristics [Krepischi-Santos et al., 2006; Rosenberg et al., 2006]. Microdeletion syndromes tend to be more severe than reciprocal microduplication syndromes; patients with microdeletion syndromes exhibit more severe cognitive disability, more patent dysmorphic features, and/or antagonistic physical characteristics [Dolan et al., 2010; Rosenfeld et al., 2013]. Cerebral palsy (CP) has been occasionally described in patients with microdeletion [Peredo et al., 2013; Zahanova et al., 2012] and microduplication syndromes [Degerliyurt et al., 2012]. A recent study of 50 cases with CP revealed
Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article: Ferna´ndez-Jae´n A, Castellanos MDC, Ferna´ndez-Perrone AL, Ferna´ndezMayoralas DM, de la Vega AG, CallejaPe´rez B, Ferna´ndez EC, Albert J, Hombre MCS. 2014. Cerebral palsy, epilepsy, and severe intellectual disability in a patient with 3q29 microduplication syndrome. Am J Med Genet Part A 164A:2043–2047.
the presence of rare copy number variants (CNVs) of potential relevance to CP [McMichael et al., 2014]. Accordingly, rare CNVs with probable causative roles have been identified in up to 19% of patients with Lennox–Gastaut syndrome, a severe epileptic encephalopathy [Lund et al., 2013]; thus, a-CGH has been suggested as the first-line genetic analysis for West syndrome [Hansen et al., 2012]. Interstitial deletions and duplications of 3q29 have recently been described as new syndromes [Willatt et al., 2005; Ballif et al., 2008]. Deletion and duplication size is the same in most of the cases studied (1.5–1.6 Mb). They have widely heterogeneous clinical syndromes but mild to moderate cognitive disabilities are frequently exhibited. As with other syndromes, clinical manifestations tend to be more Conflict of interest: none. Correspondence to: Alberto Fernandez Jae´n, Head of Pediatric Neurology, Hospital University Quiro´n Madrid, C/Diego de Velazquez 1, Pozuelo de Alarco´n, Madrid 28024, Spain. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 16 May 2014 DOI 10.1002/ajmg.a.36559
2043
2044 severe in 3q29 microdeletion than in 3q29 microduplication syndrome [Ballif et al., 2008]. Because this is a milder phenotype, it may be subject to less frequent detection. In this paper, we describe the first case published in literature, with a de novo chromosome 3q29 microduplication, epilepsy, and CP.
CLINICAL REPORT This 11-year-old female patient was the only child of nonconsanguineous parents who were healthy. There was no family history of known physical malformations, epilepsy, or intellectual disability. She was the product of a 39-week pregnancy via uncomplicated vaginal delivery to her 29-year-old primigravida mother. Apgar scores were 9 at both 1 and 5 min. Birth weight was 2,760 g (10th centile), length was 48 cm (25th centile), and occipital frontal diameter (OFD) was 34 cm (45th centile). The patient was evaluated by us on the first day of life because of recurring focal clonic seizures involving superior limbs, with a poor response to common doses of phenobarbital and phenytoin. Seizures completely disappeared after introduction of carbamazepine. Physical and neurological examinations identified moderate axial hypotonia, brachicephaly, and up-slanting palpebral fissures. Results of a cranial ultrasound, karyotyping, cerebrospinal fluid analyses, and urine/plasma metabolic screens were normal. Heart ultrasound revealed the presence of a mild interauricular communication. An electroencephalogram (EEG) with neonatal montage showed evolving spike-wave activity with maximal negativity at C4. Clinically, the patient demonstrated rhythmic clonic jerks of the left arm. At the age of 2 months, a brain 1.5T MRI revealed no significant abnormal findings.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A During the first months of life, the patient showed a severe psychomotor delay; she developed distal spasticity in her limbs. Her spasticity was treated with physiotherapy and botulinum toxin infiltrations; however, she was never able to sit or stand without support. Epileptiform discharges over the right temporal region were frequently shown on EEGs. At the ages of 5 and 10 years, we unsuccessfully tried to withdraw the antiepileptic treatment; on both occasions, the patient suffered secondary generalized seizures. Now at 11 years old, she is fully wheelchair dependent and voluntary movements of the hands are hampered by sudden hyperextension or myoclonic jerks. She has never achieved bowel or bladder control. Her verbal communication is absent, but she can communicate through gestures, of which she has few. Vision and hearing have remained within the normal ranges and she remains seizure-free. Physical examination reveals mild truncular obesity with a weight of 32 kg (20th centile) and a height of 122 cm (
