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European Journal of Paediatric... Nov 2021Lissencephaly represents a spectrum of rare malformations of cortical development including agyria, pachygyria and subcortical band heterotopia. The progress in... (Review)
Review
Lissencephaly represents a spectrum of rare malformations of cortical development including agyria, pachygyria and subcortical band heterotopia. The progress in molecular genetics has led to identification of 31 lissencephaly-associated genes with the overall diagnostic yield over 80%. In this review, we focus on clinical and molecular diagnosis of lissencephaly and summarize the current knowledge on histopathological changes and their correlation with the MRI imaging. Additionally we provide the overview of clinical follow-up recommendations and available data on epilepsy management in patients with lissencephaly.
Topics: Cerebral Cortex; Classical Lissencephalies and Subcortical Band Heterotopias; Epilepsy; Humans; Lissencephaly; Magnetic Resonance Imaging; Mutation
PubMed: 34731701
DOI: 10.1016/j.ejpn.2021.09.013 -
American Journal of Obstetrics and... Dec 2020
Review
Topics: Abnormalities, Multiple; Aortic Coarctation; Cerebellar Vermis; Cerebellum; Chromosome Aberrations; Ciliary Motility Disorders; Cranial Fossa, Posterior; Craniofacial Abnormalities; Dandy-Walker Syndrome; Dura Mater; Encephalocele; Eye Abnormalities; Female; Fourth Ventricle; Heart Defects, Congenital; Humans; Kidney Diseases, Cystic; Neurocutaneous Syndromes; Polycystic Kidney Diseases; Pregnancy; Prognosis; Retina; Retinitis Pigmentosa; Transverse Sinuses; Trisomy 18 Syndrome; Ultrasonography, Prenatal; Walker-Warburg Syndrome
PubMed: 33168220
DOI: 10.1016/j.ajog.2020.08.184 -
Seminars in Cell & Developmental Biology Mar 2023Mutations causing dysfunction of tubulins and microtubule-associated proteins, also known as tubulinopathies, are a group of recently described entities that lead to... (Review)
Review
Mutations causing dysfunction of tubulins and microtubule-associated proteins, also known as tubulinopathies, are a group of recently described entities that lead to complex brain malformations. Anatomical and functional consequences of the disruption of tubulins include microcephaly, combined with abnormal corticogenesis due to impaired migration or lamination and abnormal growth cone dynamics of projecting and callosal axons. Key imaging features of tubulinopathies are characterized by three major patterns of malformations of cortical development (MCD): lissencephaly, microlissencephaly, and dysgyria. Additional distinctive MRI features include dysmorphism of the basal ganglia, midline commissural structure hypoplasia or agenesis, and cerebellar and brainstem hypoplasia. Tubulinopathies can be diagnosed as early as 21-24 gestational weeks using imaging and neuropathology, with possible extreme microlissencephaly with an extremely thin cortex, lissencephaly with either thick or thin/intermediate cortex, and dysgyria combined with cerebellar hypoplasia, pons hypoplasia and corpus callosum dysgenesis. More than 100 MCD-associated mutations have been reported in TUBA1A, TUBB2B, or TUBB3 genes, whereas fewer than ten are known in other genes such TUBB2A, TUBB or TUBG1. Although these mutations are scattered along the α- and β-tubulin sequences, recurrent mutations are consistently associated with almost identical cortical dysgenesis. Much of the evidence supports that these mutations alter the dynamic properties and functions of microtubules in several fashions. These include diminishing the abundance of functional tubulin heterodimers, altering GTP binding, altering longitudinal and lateral protofilament interactions, and impairing microtubule interactions with kinesin and/or dynein motors or with MAPs. In this review we discuss the recent advances in our understanding of the effects of mutations of tubulins and microtubule-associated proteins on human brain development and the pathogenesis of malformations of cortical development.
Topics: Humans; Developmental Disabilities; Lissencephaly; Microcephaly; Microtubule-Associated Proteins; Mutation; Tubulin
PubMed: 35915025
DOI: 10.1016/j.semcdb.2022.07.009 -
Orphanet Journal of Rare Diseases Feb 2019The TUBA1A-associated tubulinopathy is clinically heterogeneous with brain malformations, microcephaly, developmental delay and epilepsy being the main clinical... (Review)
Review
BACKGROUND
The TUBA1A-associated tubulinopathy is clinically heterogeneous with brain malformations, microcephaly, developmental delay and epilepsy being the main clinical features. It is an autosomal dominant disorder mostly caused by de novo variants in TUBA1A.
RESULTS
In three individuals with developmental delay we identified heterozygous de novo missense variants in TUBA1A using exome sequencing. While the c.1307G > A, p.(Gly436Asp) variant was novel, the two variants c.518C > T, p.(Pro173Leu) and c.641G > A, p.(Arg214His) were previously described. We compared the variable phenotype observed in these individuals with a carefully conducted review of the current literature and identified 166 individuals, 146 born and 20 fetuses with a TUBA1A variant. In 107 cases with available clinical information we standardized the reported phenotypes according to the Human Phenotype Ontology. The most commonly reported features were developmental delay (98%), anomalies of the corpus callosum (96%), microcephaly (76%) and lissencephaly (agyria-pachygyria) (70%), although reporting was incomplete in the different studies. We identified a total of 121 specific variants, including 15 recurrent ones. Missense variants cluster in the C-terminal region around the most commonly affected amino acid position Arg402 (13.3%). In a three-dimensional protein model, 38.6% of all disease-causing variants including those in the C-terminal region are predicted to affect the binding of microtubule-associated proteins or motor proteins. Genotype-phenotype analysis for recurrent variants showed an overrepresentation of certain clinical features. However, individuals with these variants are often reported in the same publication.
CONCLUSIONS
With 166 individuals, we present the most comprehensive phenotypic and genotypic standardized synopsis for clinical interpretation of TUBA1A variants. Despite this considerable number, a detailed genotype-phenotype characterization is limited by large inter-study variability in reporting.
Topics: Adolescent; Child; Corpus Callosum; Female; Genotype; Humans; Lissencephaly; Male; Microcephaly; Mutation, Missense; Phenotype; Tubulin
PubMed: 30744660
DOI: 10.1186/s13023-019-1020-x -
Frontiers in Genetics 2018Chromosome 17p13.3 is a region of genomic instability that is linked to different rare neurodevelopmental genetic diseases, depending on whether a deletion or... (Review)
Review
Chromosome 17p13.3 is a region of genomic instability that is linked to different rare neurodevelopmental genetic diseases, depending on whether a deletion or duplication of the region has occurred. Chromosome microdeletions within 17p13.3 can result in either isolated lissencephaly sequence (ILS) or Miller-Dieker syndrome (MDS). Both conditions are associated with a smooth cerebral cortex, or lissencephaly, which leads to developmental delay, intellectual disability, and seizures. However, patients with MDS have larger deletions than patients with ILS, resulting in additional symptoms such as poor muscle tone, congenital anomalies, abnormal spasticity, and craniofacial dysmorphisms. In contrast to microdeletions in 17p13.3, recent studies have attracted considerable attention to a condition known as a 17p13.3 microduplication syndrome. Depending on the genes involved in their microduplication, patients with 17p13.3 microduplication syndrome may be categorized into either class I or class II. Individuals in class I have microduplications of the gene encoding 14-3-3ε, as well as other genes in the region. However, the gene encoding LIS1 is never duplicated in these patients. Class I microduplications generally result in learning disabilities, autism, and developmental delays, among other disorders. Individuals in class II always have microduplications of the gene, which may include and other genetic microduplications. Class II microduplications generally result in smaller body size, developmental delays, microcephaly, and other brain malformations. Here, we review the phenotypes associated with copy number variations (CNVs) of chromosome 17p13.3 and detail their developmental connection to particular microdeletions or microduplications. We also focus on existing single and double knockout mouse models that have been used to study human phenotypes, since the highly limited number of patients makes a study of these conditions difficult in humans. These models are also crucial for the study of brain development at a mechanistic level since this cannot be accomplished in humans. Finally, we emphasize the usefulness of the CRISPR/Cas9 system and next generation sequencing in the study of neurodevelopmental diseases.
PubMed: 29628935
DOI: 10.3389/fgene.2018.00080 -
Brain : a Journal of Neurology Sep 2022Reelin, a large extracellular protein, plays several critical roles in brain development and function. It is encoded by RELN, first identified as the gene disrupted in...
Reelin, a large extracellular protein, plays several critical roles in brain development and function. It is encoded by RELN, first identified as the gene disrupted in the reeler mouse, a classic neurological mutant exhibiting ataxia, tremors and a 'reeling' gait. In humans, biallelic variants in RELN have been associated with a recessive lissencephaly variant with cerebellar hypoplasia, which matches well with the homozygous mouse mutant that has abnormal cortical structure, small hippocampi and severe cerebellar hypoplasia. Despite the large size of the gene, only 11 individuals with RELN-related lissencephaly with cerebellar hypoplasia from six families have previously been reported. Heterozygous carriers in these families were briefly reported as unaffected, although putative loss-of-function variants are practically absent in the population (probability of loss of function intolerance = 1). Here we present data on seven individuals from four families with biallelic and 13 individuals from seven families with monoallelic (heterozygous) variants of RELN and frontotemporal or temporal-predominant lissencephaly variant. Some individuals with monoallelic variants have moderate frontotemporal lissencephaly, but with normal cerebellar structure and intellectual disability with severe behavioural dysfunction. However, one adult had abnormal MRI with normal intelligence and neurological profile. Thorough literature analysis supports a causal role for monoallelic RELN variants in four seemingly distinct phenotypes including frontotemporal lissencephaly, epilepsy, autism and probably schizophrenia. Notably, we observed a significantly higher proportion of loss-of-function variants in the biallelic compared to the monoallelic cohort, where the variant spectrum included missense and splice-site variants. We assessed the impact of two canonical splice-site variants observed as biallelic or monoallelic variants in individuals with moderately affected or normal cerebellum and demonstrated exon skipping causing in-frame loss of 46 or 52 amino acids in the central RELN domain. Previously reported functional studies demonstrated severe reduction in overall RELN secretion caused by heterozygous missense variants p.Cys539Arg and p.Arg3207Cys associated with lissencephaly suggesting a dominant-negative effect. We conclude that biallelic variants resulting in complete absence of RELN expression are associated with a consistent and severe phenotype that includes cerebellar hypoplasia. However, reduced expression of RELN remains sufficient to maintain nearly normal cerebellar structure. Monoallelic variants are associated with incomplete penetrance and variable expressivity even within the same family and may have dominant-negative effects. Reduced RELN secretion in heterozygous individuals affects only cortical structure whereas the cerebellum remains intact. Our data expand the spectrum of RELN-related neurodevelopmental disorders ranging from lethal brain malformations to adult phenotypes with normal brain imaging.
Topics: Adult; Cerebellum; Child; Developmental Disabilities; Humans; Lissencephaly; Mutation; Nervous System Malformations; Reelin Protein
PubMed: 35769015
DOI: 10.1093/brain/awac164 -
Clinical Genetics Jul 2017Baraitser-Winter cerebrofrontofacial syndrome (BWCFF) (BRWS; MIM #243310, 614583) is a rare developmental disorder affecting multiple organ systems. It is characterised... (Review)
Review
Baraitser-Winter cerebrofrontofacial syndrome (BWCFF) (BRWS; MIM #243310, 614583) is a rare developmental disorder affecting multiple organ systems. It is characterised by intellectual disability (mild to severe) and distinctive facial appearance (metopic ridging/trigonocephaly, bilateral ptosis, hypertelorism). The additional presence of cortical malformations (pachygyria/lissencephaly) and ocular colobomata are also suggestive of this syndrome. Other features include moderate short stature, contractures, congenital cardiac disease and genitourinary malformations. BWCFF is caused by missense mutations in the cytoplasmic beta- and gamma-actin genes ACTB and ACTG1. We provide an overview of the clinical characteristics (including some novel findings in four recently diagnosed patients), diagnosis, management, mutation spectrum and genetic counselling.
Topics: Abnormalities, Multiple; Actins; Craniofacial Abnormalities; Developmental Disabilities; Facies; Genetic Counseling; Growth Disorders; Humans; Hydrocephalus; Mental Retardation, X-Linked; Mutation, Missense; Obesity
PubMed: 27625340
DOI: 10.1111/cge.12864