RESUMEN
Doublecortin, encoded by the DCX gene, plays a crucial role in the neuronal migration process during brain development. Pathogenic variants of the DCX gene are the major causes of the "lissencephaly (LIS) spectrum", which comprehends a milder phenotype like Subcortical Band Heterotopia (SBH) in heterozygous female subjects. We performed targeted sequencing in three unrelated female cases with SBH. We identified three DCX-related variants: a novel missense (c.601A>G: p.Lys201Glu), a novel nonsense (c.210C>G: p.Tyr70*), and a previously identified nonsense (c.907C>T: p.Arg303*) variant. The novel c.601A>G: p.Lys201Glu variant shows a mother-daughter transmission pattern across four generations. The proband exhibits focal epilepsy and achieved seizure freedom with a combination of oxcarbazepine and levetiracetam. All other affected members have no history of epileptic seizures. Brain MRIs of the affected members shows predominant fronto-central SBH with mixed pachygyria on the overlying cortex. The two nonsense variants were identified in two unrelated probands with SBH, severe drug-resistant epilepsy and intellectual disability. These novel DCX variants further expand the genotypic-phenotypic correlations of lissencephaly spectrum disorders. Our documented phenotypic descriptions of three unrelated families provide valuable insights and stimulate further discussions on DCX-SBH cases.
Asunto(s)
Lisencefalias Clásicas y Heterotopias Subcorticales en Banda , Proteína Doblecortina , Fenotipo , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lisencefalias Clásicas y Heterotopias Subcorticales en Banda/genética , Lisencefalias Clásicas y Heterotopias Subcorticales en Banda/patología , Codón sin Sentido/genética , Imagen por Resonancia Magnética , Mutación MissenseRESUMEN
The ILAE Neuroimaging Task Force publishes educational case reports that highlight basic aspects of neuroimaging in epilepsy consistent with the ILAE's educational mission. Subcortical laminar heterotopia, also known as subcortical band heterotopia (SBH) or "double cortex," is an intriguing and rare congenital malformation of cortical development. SBH lesions are part of a continuum best designated as agyria-pachygyria-band-spectrum. The malformation is associated with epilepsy that is often refractory, as well as variable degrees of developmental delay. Moreover, in an increasing proportion of cases, a distinct molecular-genetic background can be found. Diagnosing SBH can be a major challenge for many reasons, including more subtle lesions, and "non-classic" or unusual MRI-appearances. By presenting an illustrative case, we address the challenges and needs of diagnosing and treating SBH patients in epilepsy, especially the value of high-resolution imaging and specialized MRI-protocols.
Asunto(s)
Lisencefalias Clásicas y Heterotopias Subcorticales en Banda , Epilepsia , Humanos , Lisencefalias Clásicas y Heterotopias Subcorticales en Banda/diagnóstico por imagen , Corteza Cerebral/patología , Epilepsia/etiología , Neuroimagen , Imagen por Resonancia MagnéticaRESUMEN
Subcortical band heterotopia (SHB) is a rare severe brain developmental malformation caused by deficient neuronal migration during the development of cerebral cortex. Here, a human induced pluripotent stem cell (iPSCs) line was established from a 4-year-1-month-old girl with SHB carrying a heterozygous mutation (c.568A > G, p.K190E) in DCX. The generated iPSC line showed the ability to differentiate into three lineages in vitro and was confirmed by pluripotency markers and the original gene mutation.
Asunto(s)
Lisencefalias Clásicas y Heterotopias Subcorticales en Banda , Células Madre Pluripotentes Inducidas , Femenino , Humanos , Lactante , Lisencefalias Clásicas y Heterotopias Subcorticales en Banda/genética , Lisencefalias Clásicas y Heterotopias Subcorticales en Banda/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Mutación/genética , Heterocigoto , Corteza CerebralRESUMEN
BACKGROUND AND HYPOTHESIS: A double cortical button technique for ulnar collateral ligament reconstruction (UCLR) has advantages including significant control over graft tensioning, less concern about graft length, and minimized risk of bone tunnel fracture compared with traditional UCLR techniques. This double cortical button technique was recently found to be noninferior in mechanical performance to the traditional docking technique regarding joint strength, joint stiffness, and graft strain. However, clinical outcomes have not been compared between these UCLR techniques. Therefore, the purpose of this study was to determine whether baseball players who underwent UCLR with a double cortical button (double button) technique have similar return-to-sport (RTS) outcomes to baseball players who underwent UCLR with the traditional docking (docking) technique. MATERIALS AND METHODS: Baseball players who underwent primary UCLR from 2011 to 2020 across 2 institutions were identified. Included patients were contacted to complete a follow-up survey evaluating reoperations, RTS, and functional outcome scores. Functional outcome surveys include the Kerlan-Jobe Orthopaedic Clinic score, the Conway-Jobe score, the Andrews-Timmerman elbow score, and the Single Assessment Numeric Evaluation score. RESULTS: Overall, 78 male baseball players (age: 18.9 ± 2.4 years) with an average follow-up of 3.1 ± 2.4 years were evaluated, with 73 of the players being baseball pitchers. Players in the double button group more frequently received palmaris longus autografts (78% vs. 30%) and less frequently received gracilis autografts (22% vs. 58%) compared with players in the docking group (P = .001); however, all other demographic factors were similar between the groups. All players in the double button group were able to RTS in 11.1 ± 2.6 months, whereas 96% of players in the docking group were able to RTS in 13.5 ± 3.4 months (P > .05). All postoperative outcomes and patient-reported outcomes were statistically similar between the groups and remained similar after isolating pitchers only and after separating partial-thickness from full-thickness UCL tears (all P > .05). CONCLUSION: RTS and other postoperative outcomes may be similar between baseball players who underwent UCLR with the double button technique and the docking technique. Although future research may be necessary to strengthen clinical recommendations, these findings provide the first clinical outcomes in light of a recent cadaveric study finding similar elbow strength, joint stiffness, and graft strain compared with the docking technique.
Asunto(s)
Béisbol , Lisencefalias Clásicas y Heterotopias Subcorticales en Banda , Ligamento Colateral Cubital , Ligamentos Colaterales , Articulación del Codo , Reconstrucción del Ligamento Colateral Cubital , Humanos , Masculino , Adolescente , Adulto Joven , Adulto , Volver al Deporte , Reconstrucción del Ligamento Colateral Cubital/métodos , Ligamento Colateral Cubital/cirugía , Codo/cirugía , Articulación del Codo/cirugía , Ligamentos Colaterales/cirugíaRESUMEN
Second-generation headless compression screws (HCSs) are commonly used for the fixation of small bones and articular fractures. However, there is a lack of biomechanical data regarding the application of such screws to radial head fractures. This study evaluated the mechanical properties of the fixation of radial head fractures using a single oblique HCS compared with those obtained using a standard locking radial head plate (LRHP) construct and a double cortical screw (DCS) construct. Radial synbone models were used for biomechanical tests of HCS, LRHP, and DCS constructs. All specimens were first cyclically loaded and then loaded to failure. The stiffness for the LRHP group was significantly higher than that for the other two groups, and that for the HCS group was significantly higher than that for the DCS group. The LRHP group had the greatest strength, followed by the HCS group and then the DCS group. The HCS construct demonstrated greater fixation strength than that of the commonly used cortical screws, although the plate group was the most stable. The present study revealed the feasibility of using a single oblique HCS, which has the advantages of being buried, requiring limited wound exposure, and having relatively easy operation, for treating simple radial head fractures.
Asunto(s)
Lisencefalias Clásicas y Heterotopias Subcorticales en Banda , Fracturas Radiales de Cabeza y Cuello , Fracturas del Radio , Humanos , Fijación Interna de Fracturas , Tornillos Óseos , Fracturas del Radio/cirugía , Placas Óseas , Fenómenos BiomecánicosRESUMEN
About 50% of individuals with developmental and epileptic encephalopathies (DEEs) are unsolved following genetic testing. Deep intronic variants, defined as >100 bp from exon-intron junctions, contribute to disease by affecting the splicing of mRNAs in clinically relevant genes. Identifying deep intronic pathogenic variants is challenging and resource intensive, and interpretation is difficult due to limited functional annotations. We aimed to identify deep intronic variants in individuals suspected to have unsolved single gene DEEs. In a research cohort of unsolved cases of DEEs, we searched for children with a DEE syndrome predominantly caused by variants in specific genes in >80% of described cases. We identified two children with Dravet syndrome and one individual with classic lissencephaly. Multiple sequencing and bioinformatics strategies were employed to interrogate intronic regions in SCN1A and PAFAH1B1. A novel de novo deep intronic 12 kb deletion in PAFAH1B1 was identified in the individual with lissencephaly. We showed experimentally that the deletion disrupts mRNA splicing, which results in partial intron retention after exon 2 and disruption of the highly conserved LisH motif. We demonstrate that targeted interrogation of deep intronic regions using multiple genomics technologies, coupled with functional analysis, can reveal hidden causes of unsolved monogenic DEE syndromes. PLAIN LANGUAGE SUMMARY: Deep intronic variants can cause disease by affecting the splicing of mRNAs in clinically relevant genes. A deep intronic deletion that caused abnormal splicing of the PAFAH1B1 gene was identified in a patient with classic lissencephaly. Our findings reinforce that targeted interrogation of deep intronic regions and functional analysis can reveal hidden causes of unsolved epilepsy syndromes.
Asunto(s)
Lisencefalias Clásicas y Heterotopias Subcorticales en Banda , Epilepsias Mioclónicas , Niño , Humanos , Intrones/genética , Lisencefalias Clásicas y Heterotopias Subcorticales en Banda/genética , Pruebas Genéticas , Mutación , Epilepsias Mioclónicas/genéticaRESUMEN
Cytoplasmic dynein-1 transports intracellular cargo towards microtubule minus ends. Dynein is autoinhibited and undergoes conformational changes to form an active complex that consists of one or two dynein dimers, the dynactin complex, and activating adapter(s). The Lissencephaly 1 gene, LIS1, is genetically linked to the dynein pathway from fungi to mammals and is mutated in people with the neurodevelopmental disease lissencephaly. Lis1 is required for active dynein complexes to form, but how it enables this is unclear. Here, we present a structure of two yeast dynein motor domains with two Lis1 dimers wedged in-between. The contact sites between dynein and Lis1 in this structure, termed 'Chi,' are required for Lis1's regulation of dynein in Saccharomyces cerevisiae in vivo and the formation of active human dynein-dynactin-activating adapter complexes in vitro. We propose that this structure represents an intermediate in dynein's activation pathway, revealing how Lis1 relieves dynein's autoinhibited state.
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Lisencefalias Clásicas y Heterotopias Subcorticales en Banda , Dineínas Citoplasmáticas , Animales , Humanos , Dineínas Citoplasmáticas/genética , Dineínas , Transporte Biológico , Citoesqueleto , Complejo Dinactina , Oligonucleótidos , MamíferosRESUMEN
Lissencephaly type 10 is a recently reported condition characterized by posterior predominant abnormalities in gyration with associated seizures, developmental delays or intellectual disability. We report a boy who presented at 5 years of age with epilepsy and developmental delays. His family history was notable for epilepsy in two prior generations associated with variable developmental and cognitive impact. Exome sequencing identified a novel missense variant in CEP85L [NM_001042475.2; c.196A>G, p.(Thr66Ala)] which segregated in four affected family members across three generations. Brain imaging of the proband demonstrated a posterior lissencephaly pattern with pachygyria, while other affected family members demonstrated a similar subcortical band heterotopia. This report expands the phenotypic spectrum of this rare disorder by describing a novel variant in CEP85L in a family with variable clinical and neuroimaging findings.
Asunto(s)
Lisencefalias Clásicas y Heterotopias Subcorticales en Banda , Epilepsia , Lisencefalia , Masculino , Humanos , Lisencefalia/diagnóstico por imagen , Lisencefalia/genética , Encéfalo/diagnóstico por imagen , Mutación Missense , Proteínas del Citoesqueleto/genética , Proteínas de Fusión OncogénicaRESUMEN
Miller-Dieker syndrome (MDS) is a rare disease characterized by type I lissencephaly, craniofacial dysmorphisms, intellectual disability, seizures, and death in early childhood. We report a case of a premature infant with MDS with an anomalous right coronary artery from the pulmonary artery who developed sudden bowel ischemia. This case prompts the reconsideration of cardiovascular involvement in patients with MDS. In addition, this review highlights key clinical features and reviews the critical manifestations of MDS that persist into childhood. [Pediatr Ann. 2023;52(8):e283-e291.].
Asunto(s)
Anomalías Múltiples , Lisencefalias Clásicas y Heterotopias Subcorticales en Banda , Lactante , Recién Nacido , Humanos , Preescolar , Anomalías Múltiples/diagnóstico , Arteria Pulmonar , Vasos Coronarios , IsquemiaAsunto(s)
Lisencefalias Clásicas y Heterotopias Subcorticales en Banda , Sustancia Blanca , Humanos , Sustancia Blanca/diagnóstico por imagen , Lisencefalias Clásicas y Heterotopias Subcorticales en Banda/diagnóstico por imagen , Lisencefalias Clásicas y Heterotopias Subcorticales en Banda/genética , Corteza Cerebral , Imagen de Difusión Tensora , Encéfalo/diagnóstico por imagenRESUMEN
OBJECTIVE: To explore the clinical characteristics and genetic basis for a child with X-linked lissencephaly with abnormal genitalia (XLAG). METHODS: A child with XLAG who had presented at the Third Affiliated Hospital of Zhengzhou University in May 2021 was selected as the study subject. Peripheral blood samples of the child and his parents were collected and subjected to high-throughput sequencing. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the result was analyzed by using bioinformatic software. RESULTS: The child was found to have harbored a hemizygous c.945_948del variant in exon 2 of the ARX gene, which as a frameshifting variant has resulted in a truncated protein. His mother was found to be heterozygous for the variant, whilst his father was of wild type. The variant was unreported previously. CONCLUSION: The hemizygous c.945_948del variant of the ARX gene probably underlay the XLAG in this patient. Above finding has provided a basis for the diagnosis and genetic counseling for this family.
Asunto(s)
Lisencefalias Clásicas y Heterotopias Subcorticales en Banda , Humanos , Niño , Exones , Biología Computacional , Asesoramiento Genético , Genitales , Factores de Transcripción , Proteínas de HomeodominioRESUMEN
17p13 is a chromosomal region characterized by genomic instability due to high gene density leading to multiple deletion and duplication events. 17p13.3 microduplication syndrome is a rare condition, reported only in 40 cases worldwide, which is found in the Miller-Dieker chromosomal region, presenting a wide range of phenotypic manifestations. Usually, the duplicated area is de novo and varies in size from 1.8 to 4.0 Mbp. Critical genes for this region are PAFAH1B1 (#601545), YWHAE (#605066), and CRK (#164762). 17p13.3 microduplication syndrome can be categorized into two classes (Class I and Class II) based on the genes that are present in the duplicated area, which lead to different phenotypes. In this report, we present a new case of Class I 17p13.3 microduplication syndrome that presents with unilateral sensorineural hearing loss. Oligonucleotide and SNP array comparative genomic hybridization (a-CGH) analysis revealed a duplication of approximately 121 Kbp on chromosome 17p13.3, which includes YWHAE and CRK genes. Whole-exome sequencing (WES) analysis confirmed the duplication. Our patient has common clinical symptoms of Class I 17p13.3 microduplication syndrome, and in addition, she has unilateral sensorineural hearing loss. Interestingly, WES analysis did not detect any mutations in genes that are associated with hearing loss. The above findings lead us to propose that hearing loss is a manifestation of 17p13.3 duplication syndrome.
Asunto(s)
Trastornos de los Cromosomas , Lisencefalias Clásicas y Heterotopias Subcorticales en Banda , Pérdida Auditiva Sensorineural , Pérdida Auditiva Unilateral , Femenino , Humanos , Pérdida Auditiva Unilateral/genética , Hibridación Genómica Comparativa , Duplicación Cromosómica/genética , Trastornos de los Cromosomas/genética , Deleción Cromosómica , Pérdida Auditiva Sensorineural/genéticaRESUMEN
BACKGROUND AND PURPOSE: Subcortical band heterotopia (SBH) is a malformation of cortical development diagnosed via MRI. Currently, patients with SBH are classified according to Di Donato's classification. We aimed to show a variation of SBH and the usefulness of double inversion recovery (DIR) images. METHODS: We retrospectively reviewed the MRI findings of 28 patients with SBH. The patients were classified according to Donato's classification by using conventional MR images, and their DIR findings were reviewed. RESULTS: Of 28 patients, 20 were grade 1 and 8 were grade 2 according to Di Donato's classification. In 15 of 28 patients, the following four types of atypical MRI findings were detected: asymmetry distribution (four cases), coexistence of thin and thick SBH (five cases), and DIR faint abnormal signal intensity in subcortical white matter (five cases) and in deep white matter (five cases). The latter two types were detected on DIR alone and have not been reported. Additionally, these were identified only in the mild group (Di Donato's classification 1-1 or 1-2). CONCLUSION: DIR is a useful MRI sequence for detecting faint white matter signal abnormalities, and it can aid in the accurate classification of SBH and identification of its variations, which may reflect the pathology of SBH.
Asunto(s)
Lisencefalias Clásicas y Heterotopias Subcorticales en Banda , Humanos , Lisencefalias Clásicas y Heterotopias Subcorticales en Banda/diagnóstico por imagen , Estudios Retrospectivos , Imagen por Resonancia Magnética/métodosAsunto(s)
Lisencefalias Clásicas y Heterotopias Subcorticales en Banda , Espasmos Infantiles , Humanos , Lactante , 1-Alquil-2-acetilglicerofosfocolina Esterasa/genética , Deleción Cromosómica , Lisencefalias Clásicas y Heterotopias Subcorticales en Banda/genética , Eliminación de Gen , Proteínas Asociadas a Microtúbulos/genética , Espasmos Infantiles/genéticaRESUMEN
OBJECTIVE: To explore the genetic basis for fetus with bilateral lateral ventriculomegaly. METHODS: Fetus umbilical cord blood and peripheral blood samples of its parents were collected. The fetus was subjected to chromosomal karyotyping, whilst the fetus and its parents were subjected to array comparative genomic hybridization (aCGH). The candidate copy number variation (CNV) were verified by qPCR, Application goldeneye DNA identification system was used to confirm the parental relationship. RESULTS: The fetus was found to have a normal karyotype. aCGH analysis indicated that it has carried a 1.16 Mb deletion at 17p13.3, which partially overlapped with the critical region of Miller-Dieker syndrome (MDS), in addition with a 1.33 Mb deletion at 17p12 region, which is associated with hereditary stress-susceptible peripheral neuropathy (HNPP). Its mother was also found to harbor the 1.33 Mb deletion at 17p12. qPCR analysis confirmed that the expression levels of genes from the 17p13.3 and 17p12 regions were about the half of that in the normal control, as well as the maternal peripheral blood sample. Parental relationship was confirmed between the fetus and its parents. Following genetic counseling, the parents has chosen to continue with the pregnancy. CONCLUSION: The fetus was diagnosed with Miller-Dieker syndrome due to the de novo deletion at 17p13.3. Ventriculomegaly may be an important indicator for prenatal ultrasonography in fetuses with MDS.
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Lisencefalias Clásicas y Heterotopias Subcorticales en Banda , Hidrocefalia , Embarazo , Femenino , Humanos , Hibridación Genómica Comparativa , Variaciones en el Número de Copia de ADN , Feto , Diagnóstico Prenatal , Deleción CromosómicaRESUMEN
PURPOSE: Miller-Dieker syndrome is caused by a multiple gene deletion, including PAFAH1B1 and YWHAE. Although deletion of PAFAH1B1 causes lissencephaly unambiguously, deletion of YWHAE alone has not clearly been linked to a human disorder. METHODS: Cases with YWHAE variants were collected through international data sharing networks. To address the specific impact of YWHAE loss of function, we phenotyped a mouse knockout of Ywhae. RESULTS: We report a series of 10 individuals with heterozygous loss-of-function YWHAE variants (3 single-nucleotide variants and 7 deletions <1 Mb encompassing YWHAE but not PAFAH1B1), including 8 new cases and 2 follow-ups, added with 5 cases (copy number variants) from literature review. Although, until now, only 1 intragenic deletion has been described in YWHAE, we report 4 new variants specifically in YWHAE (3 splice variants and 1 intragenic deletion). The most frequent manifestations are developmental delay, delayed speech, seizures, and brain malformations, including corpus callosum hypoplasia, delayed myelination, and ventricular dilatation. Individuals with variants affecting YWHAE alone have milder features than those with larger deletions. Neuroanatomical studies in Ywhae-/- mice revealed brain structural defects, including thin cerebral cortex, corpus callosum dysgenesis, and hydrocephalus paralleling those seen in humans. CONCLUSION: This study further demonstrates that YWHAE loss-of-function variants cause a neurodevelopmental disease with brain abnormalities.
Asunto(s)
Lisencefalias Clásicas y Heterotopias Subcorticales en Banda , Discapacidad Intelectual , Lisencefalia , Trastornos del Neurodesarrollo , Humanos , Animales , Ratones , Encéfalo/anomalías , Lisencefalia/genética , Discapacidad Intelectual/genética , Proteínas 14-3-3/genéticaRESUMEN
BACKGROUND: Subcortical band heterotopia (SBH) is a rare malformation of the cortical development characterized by a heterotopic band of gray matter between cortex and ventricles. The clinical presentation typically includes intellectual disability and epilepsy. PURPOSE: To evaluate if the Extended Glasgow Outcome Scale-pediatric version (EGOS-ped) is a feasible tool for evaluating the functional disability of patients with (SBH). METHOD: Cross-sectional multicenter study of a cohort of 49 patients with SBH (female n = 30, 61%), recruited from 23 Italian centers. RESULTS: Thirty-nine of 49 (80%) cases showed high functional disability at EGOS-ped assessment. In the poor result subgroup (EGOS-ped >3) motor deficit, language impairment, and lower intelligence quotient were more frequent (P < 0.001, P = 0.02, and P = 0.01, respectively); the age at epilepsy onset was remarkably lower (P < 0.001); and the prevalence of epileptic encephalopathy (West syndrome or Lennox-Gastaut-like encephalopathy) was higher (P = 0.04). The thickness and the extension of the heterotopic band were associated with EGOS-ped score (P < 0.01 and P = 0.02). Pachygyria was found exclusively among patients with poor outcome (P < 0.01). CONCLUSIONS: The EGOS-ped proved to be a reliable tool for stratifying the functional disability of patients with SBH. According to this score, patients could be dichotomized: group 1 (80%) is characterized by a poor overall functionality with early epilepsy onset, thick heterotopic band, and pachygyria, whereas group 2 (20%) is characterized by a good overall functionality with later epilepsy onset and thinner heterotopic band.