Pediatric Neurology 52 (2015) e7ee8
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Letter to the Editor
Primary Microcephaly With Anterior Predominant Pachygyria Caused by Novel Compound Heterozygous Mutations in ASPM To the Editor: Autosomal recessive primary microcephaly (MCPH) is a genetically heterogeneous disorder. Abnormal spindle-like microcephaly-associated (ASPM), categorized as MCPH5, plays a preferential role in regulating neurogenesis before and after birth. ASPM mutations lead primarily to reductions in cerebral cortex size and are found in approximately 40% of patients with MCPH.1 Most MCPH5 patients show normal to severe intellectual disability, normal to mild motor developmental delay, and normal or less severe
cortical malformations.2 Here, we report a more severe form of primary microcephaly, exhibiting novel compound heterozygous ASPM mutations and pachygyria with anterior predominance. An 8-year-old boy was born to nonconsanguineous parents. His birth weight was 3160 g ( 1.0 standard deviation [SD]), height 48 cm ( 0.9 SD), and head circumference 29.5 cm ( 2.7 SD). At 4 years of age, he exhibited daily tonic seizures that were refractory to anticonvulsant drugs. Brain magnetic resonance imaging at 5 years of age (Figure A, B)
FIGURE. Brain magnetic resonance image at 5 years of age. Scale bars, 10 mm. (A) Axial T2-weighted image showing thickened cortex compatible with pachygyria. Cortical thickness is 5 mm (normal, 2e3 mm). Both lateral ventricles are enlarged with posterior dominance. (B) Sagittal T1-weighted image showing slightly thickened corpus callosum, and normal appearance of the brainstem and cerebellum. (C) Family pedigree of the patient (II-4). Samples of three unaffected siblings were not available (N/A). WT, wild-type. (D) Compound heterozygous ASPM mutations in the patient (II-4). The mother (I-1) and father (I-2) have the c.3055C>T (p.R1019*) and c.6750delT (p.F2250Lfs*10) mutations, respectively. 0887-8994/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2015.01.019
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Letter to the Editor / Pediatric Neurology 52 (2015) e7ee8
revealed frontal-dominant pachygyria with enlarged lateral ventricles and a slightly thickened corpus callosum. At 8 years of age, his head circumference was 41 cm ( 7.6 SD). He exhibited increased muscle tone and mild spasticity in the arms and severe spasticity in the legs. He was unable to walk or speak coherently. To determine the genetic background of his disorder, we performed targeted capture and sequencing of 284 genes related to neural development using the Illumina HiSeq 2000 sequencer (San Diego, CA, USA). We identified compound heterozygous mutations in ASPM (NM_018136): c.3055C>T (p.R1019*) and c.6750delT (p.F2250Lfs*10). Sanger sequencing confirmed both mutations (Figure C, D). Neither mutation was present in the public databases or our control in-house samples. The c.3055C>T (p.R1019*) mutation has been already reported,1 whereas the c.6750delT (p.F2250Lfs*10) mutation is novel. The p.F2250Lfs*10 mutation is predicted to cause premature termination in the repeated calmodulinbinding IQ domain of ASPM. More than 20 truncating mutations within this domain have been identified,1 suggesting that p.F2250Lfs*10 is highly pathogenic for MCPH. Fourteen patients with MCPH5 show simplified gyral patterns, whereas temporal pachygyria has been reported in only one patient with MCPH5.3 Interestingly, 7 of the 14 MCPH5 patients had more severe gyral formation in the frontal lobe than the occipital lobe.2,4,5 Frontal dominancy of cortical malformations may be a characteristic finding of MCPH5, suggesting involvement of ASPM mutations. Our patient experienced severe neurological symptoms, although typically patients with ASPM mutations exhibit less severe phenotypes, with normal to severe intellectual disability, normal to mild motor delay, and mild language delay.2 Several MCPH5 patients have epilepsy, which usually responds to monotherapy of an anticonvulsant drug. The more severe phenotype of our patient is likely related to the pachygyria, which is more pronounced and epileptogenic than simplified gyral patterns. In conclusion, pachygyria is rare for MCPH5, but frontal lesion predominance may be characteristic. Our findings expand the variable severity of cortical malformations in patients with ASPM mutations. This study was approved by the Institutional Review Board for Ethical Issues at the Yamagata University Faculty of Medicine.
References 1. Nicholas AK, Swanson EA, Cox JJ, et al. The molecular landscape of ASPM mutations in primary microcephaly. J Med Genet. 2009;46: 249-253. 2. Passemard S, Titomanlio L, Elmaleh M, et al. Expanding the clinical and neuroradiologic phenotype of primary microcephaly due to ASPM mutations. Neurology. 2009;73:962-969. 3. Ariani F, Mari F, Amitrano S, et al. Exome sequencing overrides formal genetics: ASPM mutations in a case study of apparent X-linked microcephalic intellectual deficit. Clin Genet. 2013;83:288-290. 4. Saadi A, Borck G, Boddaert N, et al. Compound heterozygous ASPM mutations associated with microcephaly and simplified cortical
gyration in a consanguineous Algerian family. Eur J Med Genet. 2009; 52:180-184. 5. Desir J, Cassart M, David P, Van Bogaert P, Abramowicz M. Primary microcephaly with ASPM mutation shows simplified cortical gyration with antero-posterior gradient pre- and post-natally. Am J Med Genet A. 2008;146A:1439-1443.
Kazuyuki Nakamura, MD Department of Pediatrics Yamagata University Faculty of Medicine Yamagata, Japan Takehiko Inui, MD Department of Pediatric Neurology Takuto Rehabilitation Center for Children Sendai, Japan Fuyuki Miya, MD, PhD Laboratory for Medical Science Mathematics Center for Integrative Medical Sciences, RIKEN Yokohama, Japan Yonehiro Kanemura, MD, PhD Division of Regenerative Medicine, Institute for Clinical Research Osaka National Hospital, National Hospital Organization Osaka, Japan Department of Neurosurgery Osaka National Hospital, National Hospital Organization Osaka, Japan Nobuhiko Okamoto, MD, PhD Department of Medical Genetics Osaka Medical Center and Research Institute for Maternal and Child Health Osaka, Japan Shinji Saitoh, MD, PhD Department of Pediatrics and Neonatology Nagoya City University Graduate School of Medical Sciences Nagoya, Japan Mami Yamasaki, MD, PhD Department of Pediatric Neurosurgery Takatsuki General Hospital Osaka, Japan Tatsuhiko Tsunoda, MD, PhD Laboratory for Medical Science Mathematics Center for Integrative Medical Sciences, RIKEN Yokohama, Japan Kenjiro Kosaki, MD, PhD Center for Medical Genetics Keio University School of Medicine Tokyo, Japan Soichiro Tanaka, MD, PhD Department of Pediatric Neurology Takuto Rehabilitation Center for Children Sendai, Japan Mitsuhiro Kato, MD, PhD Department of Pediatrics Yamagata University Faculty of Medicine Yamagata, Japan E-mail address: [email protected]
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Letter to the Editor
Primary Microcephaly With Anterior Predominant Pachygyria Caused by Novel Compound Heterozygous Mutations in ASPM To the Editor: Autosomal recessive primary microcephaly (MCPH) is a genetically heterogeneous disorder. Abnormal spindle-like microcephaly-associated (ASPM), categorized as MCPH5, plays a preferential role in regulating neurogenesis before and after birth. ASPM mutations lead primarily to reductions in cerebral cortex size and are found in approximately 40% of patients with MCPH.1 Most MCPH5 patients show normal to severe intellectual disability, normal to mild motor developmental delay, and normal or less severe
cortical malformations.2 Here, we report a more severe form of primary microcephaly, exhibiting novel compound heterozygous ASPM mutations and pachygyria with anterior predominance. An 8-year-old boy was born to nonconsanguineous parents. His birth weight was 3160 g ( 1.0 standard deviation [SD]), height 48 cm ( 0.9 SD), and head circumference 29.5 cm ( 2.7 SD). At 4 years of age, he exhibited daily tonic seizures that were refractory to anticonvulsant drugs. Brain magnetic resonance imaging at 5 years of age (Figure A, B)
FIGURE. Brain magnetic resonance image at 5 years of age. Scale bars, 10 mm. (A) Axial T2-weighted image showing thickened cortex compatible with pachygyria. Cortical thickness is 5 mm (normal, 2e3 mm). Both lateral ventricles are enlarged with posterior dominance. (B) Sagittal T1-weighted image showing slightly thickened corpus callosum, and normal appearance of the brainstem and cerebellum. (C) Family pedigree of the patient (II-4). Samples of three unaffected siblings were not available (N/A). WT, wild-type. (D) Compound heterozygous ASPM mutations in the patient (II-4). The mother (I-1) and father (I-2) have the c.3055C>T (p.R1019*) and c.6750delT (p.F2250Lfs*10) mutations, respectively. 0887-8994/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2015.01.019
e8
Letter to the Editor / Pediatric Neurology 52 (2015) e7ee8
revealed frontal-dominant pachygyria with enlarged lateral ventricles and a slightly thickened corpus callosum. At 8 years of age, his head circumference was 41 cm ( 7.6 SD). He exhibited increased muscle tone and mild spasticity in the arms and severe spasticity in the legs. He was unable to walk or speak coherently. To determine the genetic background of his disorder, we performed targeted capture and sequencing of 284 genes related to neural development using the Illumina HiSeq 2000 sequencer (San Diego, CA, USA). We identified compound heterozygous mutations in ASPM (NM_018136): c.3055C>T (p.R1019*) and c.6750delT (p.F2250Lfs*10). Sanger sequencing confirmed both mutations (Figure C, D). Neither mutation was present in the public databases or our control in-house samples. The c.3055C>T (p.R1019*) mutation has been already reported,1 whereas the c.6750delT (p.F2250Lfs*10) mutation is novel. The p.F2250Lfs*10 mutation is predicted to cause premature termination in the repeated calmodulinbinding IQ domain of ASPM. More than 20 truncating mutations within this domain have been identified,1 suggesting that p.F2250Lfs*10 is highly pathogenic for MCPH. Fourteen patients with MCPH5 show simplified gyral patterns, whereas temporal pachygyria has been reported in only one patient with MCPH5.3 Interestingly, 7 of the 14 MCPH5 patients had more severe gyral formation in the frontal lobe than the occipital lobe.2,4,5 Frontal dominancy of cortical malformations may be a characteristic finding of MCPH5, suggesting involvement of ASPM mutations. Our patient experienced severe neurological symptoms, although typically patients with ASPM mutations exhibit less severe phenotypes, with normal to severe intellectual disability, normal to mild motor delay, and mild language delay.2 Several MCPH5 patients have epilepsy, which usually responds to monotherapy of an anticonvulsant drug. The more severe phenotype of our patient is likely related to the pachygyria, which is more pronounced and epileptogenic than simplified gyral patterns. In conclusion, pachygyria is rare for MCPH5, but frontal lesion predominance may be characteristic. Our findings expand the variable severity of cortical malformations in patients with ASPM mutations. This study was approved by the Institutional Review Board for Ethical Issues at the Yamagata University Faculty of Medicine.
References 1. Nicholas AK, Swanson EA, Cox JJ, et al. The molecular landscape of ASPM mutations in primary microcephaly. J Med Genet. 2009;46: 249-253. 2. Passemard S, Titomanlio L, Elmaleh M, et al. Expanding the clinical and neuroradiologic phenotype of primary microcephaly due to ASPM mutations. Neurology. 2009;73:962-969. 3. Ariani F, Mari F, Amitrano S, et al. Exome sequencing overrides formal genetics: ASPM mutations in a case study of apparent X-linked microcephalic intellectual deficit. Clin Genet. 2013;83:288-290. 4. Saadi A, Borck G, Boddaert N, et al. Compound heterozygous ASPM mutations associated with microcephaly and simplified cortical
gyration in a consanguineous Algerian family. Eur J Med Genet. 2009; 52:180-184. 5. Desir J, Cassart M, David P, Van Bogaert P, Abramowicz M. Primary microcephaly with ASPM mutation shows simplified cortical gyration with antero-posterior gradient pre- and post-natally. Am J Med Genet A. 2008;146A:1439-1443.
Kazuyuki Nakamura, MD Department of Pediatrics Yamagata University Faculty of Medicine Yamagata, Japan Takehiko Inui, MD Department of Pediatric Neurology Takuto Rehabilitation Center for Children Sendai, Japan Fuyuki Miya, MD, PhD Laboratory for Medical Science Mathematics Center for Integrative Medical Sciences, RIKEN Yokohama, Japan Yonehiro Kanemura, MD, PhD Division of Regenerative Medicine, Institute for Clinical Research Osaka National Hospital, National Hospital Organization Osaka, Japan Department of Neurosurgery Osaka National Hospital, National Hospital Organization Osaka, Japan Nobuhiko Okamoto, MD, PhD Department of Medical Genetics Osaka Medical Center and Research Institute for Maternal and Child Health Osaka, Japan Shinji Saitoh, MD, PhD Department of Pediatrics and Neonatology Nagoya City University Graduate School of Medical Sciences Nagoya, Japan Mami Yamasaki, MD, PhD Department of Pediatric Neurosurgery Takatsuki General Hospital Osaka, Japan Tatsuhiko Tsunoda, MD, PhD Laboratory for Medical Science Mathematics Center for Integrative Medical Sciences, RIKEN Yokohama, Japan Kenjiro Kosaki, MD, PhD Center for Medical Genetics Keio University School of Medicine Tokyo, Japan Soichiro Tanaka, MD, PhD Department of Pediatric Neurology Takuto Rehabilitation Center for Children Sendai, Japan Mitsuhiro Kato, MD, PhD Department of Pediatrics Yamagata University Faculty of Medicine Yamagata, Japan E-mail address: [email protected]
