Abstract
In 2018, I was honored to receive the Bernard Sachs Award for a lifetime of work expanding
knowledge of diverse neurodevelopmental disorders. Summarizing work over more than
30 years is difficult but is an opportunity to chronicle the dramatic changes in the
medical and scientific world that have transformed the field of Child Neurology over
this time, as reflected in my own work. Here I have chosen to highlight five broad
themes of my research beginning with my interest in descriptive terms that drive wider
understanding and my choice for the title of this review. From there I will go on
to contrast the state of knowledge as I entered the field with the state of knowledge
today for four human brain malformations–lissencephaly, megalencephaly, cerebellar
malformations, and polymicrogyria. For all, the changes have been dramatic.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Pediatric NeurologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- James Harold Dobyns, MD.J Hand Surg Am. 2011; 36: 1877-1878
- William B. Dobyns, MD.CNS Connections. 2018; 26: 20-21
- Further comments on the lissencephaly syndromes.Am J Med Genet. 1985; 22: 197-211
- Causal heterogeneity in isolated lissencephaly.Neurology. 1992; 42: 1375-1388
- Lissenzephalie beim Menschen.Monatsschr Psychiatr Neurol. 1939; 101: 350-381
- Proceedings of the 27th ENMC sponsored workshop on congenital muscular dystrophy. 22-24 April 1994, The Netherlands.Neuromuscul Disord. 1995; 5: 253-258
- Cobblestone lissencephaly with normal eyes and muscle.Neuropediatrics. 1996; 27: 70-75
- A classification scheme for malformations of cortical development.Neuropediatrics. 1996; 27: 59-63
- Classification system for malformations of cortical development: update 2001.Neurology. 2001; 57: 2168-2178
- A developmental and genetic classification for malformations of cortical development.Neurology. 2005; 65: 1873-1887
- A developmental and genetic classification for malformations of cortical development: update 2012.Brain. 2012; 135: 1348-1369
- A developmental and genetic classification for midbrain-hindbrain malformations.Brain. 2009; 132: 3199-3230
- A developmental classification of malformations of the brainstem.Ann Neurol. 2007; 62: 625-639
- Cerebello-oculo-renal syndromes including Arima, Senior-Loken and COACH syndromes: more than just variants of Joubert syndrome.Am J Med Genet. 1999; 86: 459-469
- Primary microcephaly: new approaches for an old disorder.Am J Med Genet. 2002; 112: 315-317
- Human malformations of the midbrain and hindbrain: review and proposed classification scheme.Mol Genet Metab. 2003; 80: 36-53
- Overlapping cortical malformations and mutations in TUBB2B and TUBA1A.Brain. 2013; 136: 536-548
- De novo mutations in the beta-tubulin gene TUBB2A cause simplified gyral patterning and infantile-onset epilepsy.Am J Hum Genet. 2014; 94: 634-641
- Recognizable cerebellar dysplasia associated with mutations in multiple tubulin genes.Hum Mol Genet. 2015; 24: 5313-5325
- Tubulinopathies continued: refining the phenotypic spectrum associated with variants in TUBG1.Eur J Hum Genet. 2018; 26: 1132-1142
- Epilepsy surgery in children with focal cortical dysplasia (FCD): results of long-term seizure outcome.Neuropediatrics. 2002; 33: 21-26
- Disorders of microtubule function in neurons: imaging correlates.AJNR Am J Neuroradiol. 2016; 37: 528-535
- Why West? Comparisons of clinical, genetic and molecular features of infants with and without spasms.PLoS One. 2018; 13: e0193599
- Novel mutations in ATP1A3 associated with catastrophic early life epilepsy, episodic prolonged apnea, and postnatal microcephaly.Epilepsia. 2015; 56: 422-430
- Phenotype differentiation of FOXG1 and MECP2 disorders: a new method for characterization of developmental encephalopathies.J Pediatr. 2016; 178: 233-240 e210
- Loss of function mutation in glutamic pyruvate transaminase 2 (GPT2) causes developmental encephalopathy.J Inherit Metab Dis. 2015; 38: 941-948
- Epilepsy, Infantile Spasms, and Developmental Encephalopathy. 49. Academic Press, San Diego2002
- Subcortical heterotopic gray matter brain malformations: classification study of 107 individuals.Neurology. 2019; 93: e1360-e1373
- Syndromes with lissencephaly. I: Miller-Dieker and Norman-Roberts syndromes and isolated lissencephaly.Am J Med Genet. 1984; 18: 509-526
- Syndromes with lissencephaly. II: Walker-Warburg and cerebro-oculo-muscular syndromes and a new syndrome with type II lissencephaly.Am J Med Genet. 1985; 22: 157-195
- MECP2 mutation in a boy with severe neonatal encephalopathy: clinical, neuropathological and molecular findings.Neuropediatrics. 2002; 33: 33-36
- Interstitial deletion of (17)(p11.2p11.2): report of six additional patients with a new chromosome deletion syndrome.Am J Med Genet. 1986; 24: 421-432
- Rapid-onset dystonia-parkinsonism.Neurology. 1993; 43: 2596-2602
- Mutation of the PAX2 gene in a family with optic nerve colobomas, renal anomalies and vesicoureteral reflux.Nat Genet. 1995; 9: 358-364
- Autosomal dominant optic nerve colobomas, vesicoureteral reflux, and renal anomalies.Am J Med Genet. 1995; 59: 204-208
- Macrocephaly-cutis marmorata telangiectatica congenita: a distinct disorder with developmental delay and connective tissue abnormalities.Am J Med Genet. 1997; 70: 67-73
- Megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes: two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis.Am J Med Genet A. 2012; 158A: 269-291
- X-linked lissencephaly with absent corpus callosum and ambiguous genitalia.Am J Med Genet. 1999; 86: 331-337
- Megalencephaly and perisylvian polymicrogyria with postaxial polydactyly and hydrocephalus: a rare brain malformation syndrome associated with mental retardation and seizures.Neuropediatrics. 2004; 35: 353-359
- Association of MTOR mutations with developmental brain disorders, including megalencephaly, focal cortical dysplasia, and pigmentary mosaicism.JAMA Neurol. 2016; 73: 836-845
- MACF1 mutations encoding highly conserved zinc-binding residues of the GAR domain cause defects in neuronal migration and axon guidance.Am J Hum Genet. 2018; 103: 1009-1021
- A dyadic approach to the delineation of diagnostic entities in clinical genomics.Am J Hum Genet. 2021; 108: 8-15
- Miller-Dieker syndrome: lissencephaly and monosomy 17p.J Pediatr. 1983; 102: 552-558
- New chromosomal syndrome: Miller-Dieker syndrome and monosomy 17p13.Hum Genet. 1984; 67: 193-200
- Molecular detection of microscopic and submicroscopic deletions associated with Miller-Dieker syndrome.Am J Hum Genet. 1988; 43: 587-596
- Molecular dissection of a contiguous gene syndrome: frequent submicroscopic deletions, evolutionarily conserved sequences, and a hypomethylated “island” in the Miller-Dieker chromosome region.Proc Natl Acad Sci U S A. 1989; 86: 5136-5140
- Rapid diagnosis of Miller-Dieker syndrome and isolated lissencephaly sequence by the polymerase chain reaction.Hum Genet. 1990; 85: 555-559
- Clinical and molecular diagnosis of Miller-Dieker syndrome.Am J Hum Genet. 1991; 48: 584-594
- Detection of deletions and cryptic translocations in Miller-Dieker syndrome by in situ hybridization.Am J Hum Genet. 1991; 49: 707-714
- Isolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like repeats.Nature. 1993; 364: 717-721
- LIS1 and XLIS (DCX) mutations cause most classical lissencephaly, but different patterns of malformation.Hum Mol Genet. 1998; 7: 2029-2037
- A revision of the lissencephaly and Miller-Dieker syndrome critical regions in chromosome 17p13.3.Hum Mol Genet. 1997; 6: 147-155
- Point mutations and an intragenic deletion in LIS1, the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome.Hum Mol Genet. 1997; 6: 157-164
- Mutations in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly in humans.Cell. 2007; 128: 45-57
- Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans.Nat Genet. 2002; 32: 359-369
- Mutations in the murine homologue of TUBB5 cause microcephaly by perturbing cell cycle progression and inducing p53-associated apoptosis.Development. 2016; 143: 1126-1133
- Mutations in the beta-tubulin gene TUBB2B result in asymmetrical polymicrogyria.Nat Genet. 2009; 41: 746-752
- Mutations in the neuronal ss-tubulin subunit TUBB3 result in malformation of cortical development and neuronal migration defects.Hum Mol Genet. 2010; 19: 4462-4473
- Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with a loss-of-function mutation in CDK5.Hum Genet. 2015; 134: 305-314
- Deletion 16p13.11 uncovers NDE1 mutations on the non-deleted homolog and extends the spectrum of severe microcephaly to include fetal brain disruption.Am J Med Genet A. 2013; 161A: 1523-1530
- Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations.Nat Genet. 2000; 26: 93-96
- Mutations in VLDLR as a cause for autosomal recessive cerebellar ataxia with mental retardation (dysequilibrium syndrome).J Child Neurol. 2009; 24: 1310-1315
- Mutations in CRADD result in reduced caspase-2-mediated neuronal apoptosis and cause megalencephaly with a rare lissencephaly variant.Am J Hum Genet. 2016; 99: 1117-1129
- De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome.Nat Genet. 2012; 44 (S1-2): 440-444
- Bi-allelic loss of human APC2, encoding adenomatous polyposis coli protein 2, leads to lissencephaly, subcortical heterotopia, and global developmental delay.Am J Hum Genet. 2019; 105: 844-853
- Pathogenic variants in CEP85L cause sporadic and familial posterior predominant lissencephaly.Neuron. 2020; 106: 237-245 e238
- Biallelic loss of human CTNNA2, encoding alphaN-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration.Nat Genet. 2018; 50: 1093-1101
- Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly.Nat Genet. 2013; 45: 639-647
- Mutations in MAST1 cause mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations.Neuron. 2018; 100: 1354-1368.e5
- De novo TUBB2A variant presenting with anterior temporal pachygyria.J Child Neurol. 2017; 32: 127-131
- Mutations in citron kinase cause recessive microlissencephaly with multinucleated neurons.Am J Hum Genet. 2016; 99: 511-520
- DMRTA2 (DMRT5) is mutated in a novel cortical brain malformation.Clin Genet. 2016; 89: 724-727
- Mutations in KATNB1 cause complex cerebral malformations by disrupting asymmetrically dividing neural progenitors.Neuron. 2015; 85: 228
- Biallelic mutations in the death domain of PIDD1 impair caspase-2 activation and are associated with intellectual disability.Transl Psychiatry. 2021; 11: 1
- A homozygous mutation in RNU4ATAC as a cause of microcephalic osteodysplastic primordial dwarfism type I (MOPD I) with associated pigmentary disorder.Am J Med Genet A. 2011; 155A: 2885-2896
- Bi-allelic pathogenic variants in TUBGCP2 cause microcephaly and lissencephaly spectrum disorders.Am J Hum Genet. 2019; 105: 1005-1015
- Lissencephaly: expanded imaging and clinical classification.Am J Med Genet A. 2017; 173: 1473-1488
- Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly.Genet Med. 2018; 20: 1354-1364
- Epidermal nevus syndrome: a neurologic variant with hemimegalencephaly, gyral malformation, mental retardation, seizures, and facial hemihypertrophy.Neurology. 1991; 41: 266-271
- De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes.Nat Genet. 2012; 44: 934-940
- De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome.Nat Genet. 2014; 46: 510-515
- Characterisation of mutations of the phosphoinositide-3-kinase regulatory subunit, PIK3R2, in perisylvian polymicrogyria: a next-generation sequencing study.Lancet Neurol. 2015; 14: 1182-1195
- PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution.JCI Insight. 2016; 1: e87623
- Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly.Brain. 2017; 140: 2610-2622
- Subtelomeric deletions of chromosome 6p: molecular and cytogenetic characterization of three new cases with phenotypic overlap with Ritscher-Schinzel (3C) syndrome.Am J Med Genet A. 2005; 134A: 3-11
- Heterozygous deletion of the linked genes ZIC1 and ZIC4 is involved in Dandy-Walker malformation.Nat Genet. 2004; 36: 1053-1055
- FOXC1 is required for normal cerebellar development and is a major contributor to chromosome 6p25.3 Dandy-Walker malformation.Nat Genet. 2009; 41: 1037-1042
- Both rare and de novo copy number variants are prevalent in agenesis of the corpus callosum but not in cerebellar hypoplasia or polymicrogyria.PLoS Genet. 2013; 9: e1003823
- Mutations in the oligophrenin-1 gene (OPHN1) cause X linked congenital cerebellar hypoplasia.J Med Genet. 2003; 40: 441-446
- Phenotypic spectrum associated with CASK loss-of-function mutations.J Med Genet. 2011; 48: 741-751
- Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum.Nat Genet. 2008; 40: 1065-1067
- A Golgi analysis of unlayered polymicrogyria.Acta Neuropathol. 1984; 65: 69-76
- Porencephaly with microgyria: a pathologic study.Acta Neuropathol. 1974; 29: 99-113
- Cerebral microgyria in a 27-week fetus: an architectonic and topographic analysis.J Neuropathol Exp Neurol. 1974; 33: 374-384
- Syndromes of bilateral symmetrical polymicrogyria.AJNR Am J Neuroradiol. 1999; 20: 1814-1821
- Bilateral generalized polymicrogyria (BGP): a distinct syndrome of cortical malformation.Neurology. 2004; 62: 1722-1728
- Bilateral parasagittal parietooccipital polymicrogyria and epilepsy.Ann Neurol. 1997; 41: 65-73
- Multilobar polymicrogyria, intractable drop attack seizures, and sleep- related electrical status epilepticus.Neurology. 1998; 51: 504-512
- Bilateral frontal polymicrogyria: a newly recognized brain malformation syndrome.Neurology. 2000; 54: 909-913
- The congenital bilateral perisylvian syndrome: study of 31 patients. The congenital bilateral perisylvian syndrome multicenter collaborative study.Lancet. 1993; 341: 608-612
- The mechanism of arrest of neuronal migration in the Zellweger malformation: an hypothesis bases upon cytoarchitectonic analysis.Acta Neuropathol. 1978; 41: 109-117
- Cerebro-hepato-renal syndrome of Zellweger: an inherited disorder of neuronal migration.Acta Neuropathol. 1972; 20: 175-198
- Consistent chromosome abnormalities identify novel polymicrogyria loci in 1p36.3, 2p16.1-p23.1, 4q21.21-q22.1, 6q26-q27, and 21q2.Am J Med Genet A. 2008; 146A: 1637-1654
- Clinical and imaging heterogeneity of polymicrogyria: a study of 328 patients.Brain. 2010; 133: 1415-1427
- Polymicrogyria and deletion 22q11.2 syndrome: window to the etiology of a common cortical malformation.Am J Med Genet A. 2006; 140: 2416-2425
- Periventricular nodular heterotopia with overlying polymicrogyria.Brain. 2005; 128: 2811-2821
- The spectrum of brain malformations and disruptions in twins.Am J Med Genet A. 2020;
- Tbx1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice.Nature. 2001; 410: 97-101
- Lack of Cul4b, an E3 ubiquitin ligase component, leads to embryonic lethality and abnormal placental development.PLoS One. 2012; 7: e37070
- PPARgamma is activated during congenital cytomegalovirus infection and inhibits neuronogenesis from human neural stem cells.PLoS Pathog. 2016; 12: e1005547
- Human cytomegalovirus infection is associated with increased expression of the lissencephaly gene PAFAH1B1 encoding LIS1 in neural stem cells and congenitally infected brains.J Pathol. 2021; 254: 92-102
- Prenatal cytomegalovirus disease and cerebral microgyria: evidence for perfusion failure, not disturbance of histogenesis, as the major cause of fetal cytomegalovirus encephalopathy.Neuropediatrics. 1984; 15: 18-24
- Human cytomegalovirus tropism for endothelial cells: not all endothelial cells are created equal.J Virol. 2007; 81: 2095-2101
Article info
Publication history
Published online: June 29, 2021
Accepted:
May 5,
2021
Received:
May 3,
2021
Identification
Copyright
© 2021 Elsevier Inc. All rights reserved.
ScienceDirect
Access this article on ScienceDirectLinked Article
- “The Child Is the Father of the Man”: A Tribute to Ken SwaimanPediatric NeurologyVol. 122
- PreviewMy career path to a richer understanding of fetal and neonatal neurology (FNN) honors Kenneth Swaiman's influence on my training. Our lifelong friendship reinforced a life-course perspective to the neurological care for children across the life span. “The Child is the Father of the Man,” a quote from an 1802 poem by William Wordsworth (“My Heart Leaps Up”) applies a poetic reference to the origins of memory. While self-absorbed academics apply this reference to one's chosen specialty, I was reminded by one colleague that the American rock group “The Beach Boys” also put to music the same ideas!
- Full-Text
- Preview
- Pediatric Neuropsychology and Pediatric Neurology: Kenneth Swaiman's LegacyPediatric NeurologyVol. 122
- PreviewAlthough pediatric neuropsychology and pediatric neurology often collaborate in today's environment, this was not always the case. In many centers providing service to children with neurological disorders in the 1970s, neuropsychologic testing was seen as a laboratory service to diagnose brain damage, and not as a profession that managed the care of children. The idea that understanding children with brain disease required a “developmental” model of brain function did not emerge until the 1980s.
- Full-Text
- Preview
- Post-traumatic Neuroinflammation: Relevance to PediatricsPediatric NeurologyVol. 122
- PreviewBoth detrimental and beneficial effects of post-traumatic neuroinflammation have become a major research focus as they offer the potential for immediate as well as delayed targeted reparative therapies. Understanding the complex interactions of central and peripheral immunocompetent cells as well as their mediators on brain injury and recovery is complicated by the temporal, regional, and developmental differences in their response to injuries. Microglia, the brain-resident macrophages, have become central in these investigations as they serve a major surveillance function, have the ability to react swiftly to injury, recruit various cellular and chemical mediators, and monitor the reparative/degenerative processes.
- Full-Text
- Preview
- Portable Acquisition of Auditory ERPs: A Pilot Study of Premature InfantsPediatric NeurologyVol. 122
- Kenneth Swaiman: A Festschrift to Honor His LegacyPediatric NeurologyVol. 122
