Brain Anomalies Research Articles

Loss of tissue-type plasminogen activator causes multiple developmental anomalies

Abstract Hydrocephalus and Dandy-Walker malformation are among the most common congenital brain anomalies. We identified three consanguineous families with both obstructive hydrocephalus and Dandy-Walker malformation. To understand the molecular basis of these anomalies, we conducted genome-wide sequencing in these families. We identified three homozygous truncating variants in the PLAT gene in the four affected family members. All of them showed tetraventricular hydrocephalus. In two individuals, a membrane at the inferior aspect of the fourth ventricle was likely the cause of their hydrocephalus. Three cases exhibited Dandy-Walker malformation whereas the two oldest individuals displayed intellectual disability. PLAT encodes the tissue-type plasminogen activator, a serine protease whose main function is to cleave the proenzyme plasminogen to produce active plasmin. Interestingly, plasminogen deficiency has also been shown to cause obstructive hydrocephalus and Dandy-Walker malformation, suggesting that loss of PLAT causes these defects by disrupting plasmin production. In summary, we describe a recessive disorder characterized by obstructive hydrocephalus, Dandy-Walker malformation and intellectual disability in individuals with loss-of-function variants in PLAT. This discovery further strengthens the involvement of the plasminogen pathway in the pathogenesis of these developmental disorders.

Inpp5e Is Critical for Photoreceptor Outer Segment Maintenance.

In humans, inositol polyphosphate-5-phosphatase e (INPP5E) mutations cause retinal degeneration as part of Joubert and MORM syndromes and can also cause non-syndromic blindness. In mice, mutations cause a spectrum of brain, kidney, and other anomalies and prevent the formation of photoreceptor outer segments. To further explore the function of Inpp5e in photoreceptors, we generated conditional and inducible knockouts of mouse Inpp5e where the gene was deleted either during outer segment formation or after outer segments were fully formed. In both cases, the loss of Inpp5e led to severe defects in photoreceptor outer segment morphology and ultimately photoreceptor cell loss. The primary morphological defect consisted of outer segment shortening and reduction in the number of newly forming discs at the outer segment base. This was accompanied by structural abnormalities of the Golgi apparatus, mislocalized rhodopsin, and an accumulation of extracellular vesicles. In addition, knockout cells showed a reduction in the size and prevalence of the actin network at the site of new disc morphogenesis and the occasional formation of membrane whorls instead of discs in a subset of cells. Together, these data demonstrate that Inpp5e plays a critical role in maintaining the outer segment and the normal process of outer segment renewal depends on the activity of this enzyme.

Extracutaneous Lesions in Patients with Focal Scleroderma of Craniofacial Localization: a Retrospective Cross-Sectional Study

Background. Focal scleroderma is rare, acquired disease characterized by inflammation, sclerosis, skin and underlying tissues atrophy, with no lesions to internal organs. However, craniofacial localized scleroderma (CLS) can lead to neurological, ophthalmic, and maxillofacial changes. Extracutaneous lesions at limited scleroderma remain poorly studied despite its high prevalence. Objective. The aim of the study is to characterize brain anomalies revealed at neuroimaging and to analyze their incidence in pediatric patients with focal scleroderma, as well as to describe comorbid neurological and ophthalmic disorders. Methods. Descriptive retrospective cross-sectional study included 33 pediatric patients who underwent hospital treatment at dermatology and allergology department of National Medical Research Center of Children’s Health with diagnosis of focal scleroderma from 2016 to 2024. All patients were examined by neurologist and ophthalmologist during hospitalization, as well as magnetic resonance imaging (MRI) was performed. The incidence of neurological, ophthalmic, and radiological signs was evaluated in the studied patients as well as their correlations within the data analysis. Results. 33 pediatric patients from 3 to 17 years old were studied. The number of boys and girls was not significantly different (p=0.46). MRI neuroimaging changes were revealed in 17 of 33 patients (51.5%). 12 patients (36.4%) had isolated disorders, 5 (15.1%) — multiple (two or more types) according to MRI data. Neurological disorders were reported in 8 out of 33 patients (24%). Ophthalmic disorders — in 10 out of 33 (30.3%). The study has revealed correlation indicating that the presence of epilepsy in CLS is associated with changes in the brain structure according to MRI (hyperintensive signal at T2-weighted image and FLAIR) (p=0,022). Also, such changes as hypointense signal during T2-VI are correlated with tension headache (p=0.03). No correlation between ophthalmic changes and neuroimaging changes was revealed. Conclusion. Significant number of pediatric patients with CLS have wide range of ophthalmic and neurological manifestations, including neuroimaging abnormalities. Precise and timely diagnosis of these symptoms is crucial for determining treatment intervention.

TARS2 c.470 C > G is a chinese-specific founder mutation in three unrelated families with mitochondrial encephalomyopathy

Biallelic pathogenic variants in TARS2 lead to combined oxidative phosphorylation deficiency, subtype 21 (COXPD21, MIM #615918), which is a rare mitochondrial encephalomyopathy (ME) characterized by early-onset severe axial hypotonia, limb hypertonia, psychomotor developmental delay, epilepsy and brain anomalies. To date, approximately 28 individuals with COXPD21 and 28 TARS2 variants have been identified. In this study, we reported additional four individuals from three unrelated Chinese families with mitochondrial encephalomyopathy caused by pathogenic variants in TARS2, and described the novel clinical phenotypes and genotypic information. In addition to two novel variants (c.512G > A, p.Arg171Lys; c.988dup, p.Arg330Lysfs*4), one previously reported variant (c.470 C > G, p.Thr157Arg) recurred in six Chinese individuals with COXPD21 but was not present in populations of other races. Our findings expanded the mutation spectrum of TARS2 and confirmed that c.470 C > G is a Chinese-specific founder mutation. The novel phenotypes, including reduced fetal movement, eye anomalies and sleep irregularities, observed in our patients enriched the clinical characteristics of COXPD21.

Particularities of spasticity in myelomeningocele patients.

Myelomeningocele (MMC), a congenital neural tube defect, is the most common developmental anomaly of the central nervous system (CNS). Spasticity is among the main disabling factors in these patients, affecting up to 1/5 of children. The purpose of this article is to review the current knowledge regarding spasticity in MMC patients, mainly focusing on its manifestations and management. A literature search was conducted using the PubMed database for the terms "myelomeningocele" and "spasticity." Data were collected by 5 independent investigators and then synthesized in a scoping format. Causes of spasticity in these patients include hydrocephalus, tethered cord syndrome (TCS), syringomyelia, CNS infection, and associated congenital brain and spine anomalies. Clinical manifestations include limb spasticity and neurogenic bladder. Spasticity primarily affects muscles below the neurological level and contributes to gait impairment. Besides walking ability, spasticity also severely affects functional mobility in general, self-care, and quality of life. The majority of MMC patients experience neurogenic bladder. Treatment of spasticity can be symptomatic or target its cause. Medical and surgical options are available for both limb and bladder spasticity. Regular physiotherapy and orthotics are used to prevent contractures and the early introduction of orthoses is the cornerstone of a gait training program. Neurosurgical treatment options for spasticity include nonablative and ablative procedures such as selective dorsal rhizototmy. The urodynamic pattern guides treatment strategies, with intermittent catheterization being the best treatment option for patients with underactive detrusor and overactive sphincter muscles. Given the particularities of spasticity in MMC patients, a multidisciplinary team approach and early rehabilitation programs are keys for their optimal management.

Cardiovascular Ultrasound Predictors for Brain Alterations in Fetuses With Heart Disease: An Exploratory Review of the Literature.

To identify cardiovascular ultrasound predictors for brain anomalies in fetuses with heart disease. A literature search was performed in the following databases: MEDLINE through OVID, EMBASE, Cochrane Registry Center for Controlled Trials (CENTRAL), and LILACS, from their inception until May 2023. Clinical studies, cross-sectional studies, case-control studies, cohorts, and systematic reviews were included. Data extraction was performed, and the risk of bias was assessed using the QUADAS-2 tool. Among 2705 studies evaluated, after filtering information, 10 articles were selected that met the inclusion criteria. These studies noted the following outcomes: a decrease in fetal head circumference, changes in brain maturation measured in days, decreased depth of brain fissures, and a decrease in total brain volume. The studies show a statistically significant correlation with the presence of the following cardiovascular predictors: low or mixed oxygen content in the ascending aorta (p < 0.001), retrograde flow in the aortic arch (p < 0.001), lower z values of the MCA-PI (p < 0.05), higher UA-PI z values (p < 0.01), and lower CPR (p < 0.05). In addition, lower values of left ventricular flow (p < 0.01), ductus arteriosus (p < 0.0001), and combined cardiac output index (p < 0.01) were reported. This review describes the most relevant evidence correlating the effects of hemodynamic changes that lead to states of chronic hypoxia related to the aforementioned changes in the central nervous system.

Diseases of the primary cilia: a clinical characteristics review.

Ciliopathies encompass a broad spectrum of diseases stemming from dysfunction of the primary (non-motile) cilia, present on almost all cells in the human body. These disorders include autosomal dominant and recessive polycystic kidney diseases, nephronophthisis, and multisystem ciliopathies such as Joubert, Meckel, Bardet-Biedl, Alström, oral-facial-digital syndromes, and skeletal ciliopathies. The majority of these ciliopathies are associated with fibrocystic kidney disease resulting in progressive kidney dysfunction. In addition, many ciliopathies are associated with extra-renal manifestations including congenital hepatic fibrosis, retinal dystrophy, obesity, and brain and skeletal anomalies. The diagnoses may be challenging due to their overlapping clinical features and molecular heterogeneity. To date, over 190 genes encoding proteins that localize to the primary cilia have been identified as disease-causing. This review will discuss the clinical features of the most frequently encountered disorders of primary cilia.

Routine whole spine magnetic resonance imaging for patients with anorectal malformations.

To evaluate the necessity of performing whole spine magnetic resonance imaging (MRI) as opposed to solely lumbosacral MRI for detecting high-level spinal lesions (in the brain, cervical, or thoracic spine) in patients with anorectal malformations (ARM). This retrospective cohort study included 69 patients treated for ARM at a medical center between January 2011 and January 2022. Before March 2021, lumbosacral MRI was used for patients with ARM. Since March 2021, anomalies in the posterior cranial fossa and whole spine were assessed using routine MRI. Both male (n = 30, 43.4%) and female patients were included in the study. Out of the 69 patients, 19 (27.5%) underwent whole spine MRI, and 50 (72.5%) underwent lumbosacral MRI. In the whole spine group, 4 patients had anomalies beyond the lumbosacral area. In the lumbosacral group, 4 patients subsequently underwent whole spine MRI due to symptoms, with 3 revealing higher-level anomalies.High-level spinal and brain anomalies, although infrequent, are present in patients with ARM. The findings suggest considering routine whole spine MRI in screening ARM patients to avoid missing high-level anomalies.

Parental or Trio Magnetic Resonance Imaging to Improve Prenatal Counseling in Brain Anomalies.

To assess whether targeted magnetic resonance of one or both of the progenitors could refine the diagnosis in cases of fetal brain anomalies with uncertain prognosis. Single-center retrospective case series, where targeted magnetic resonance was performed on one or both of progenitors after a suspicion of fetal complex brain anomalies, and prognosis was unclear based solely on fetal tests (neurosonogram, fetal magnetic resonance, and genetic testing). Seven women were included. Results were relevant for prenatal counseling in five cases, with a definitive diagnosis in three: one periventricular nodular heterotopia, one mild tubulinopathy, and one dynein-associated neurodevelopmental disorder. Median gestational age at referral was 28.3weeks (range, 20.7-34.9). Neurosonogram findings were inconclusive in all cases. Exome sequencing in amniotic fluid was conducted for all cases. Fetal magnetic resonance was performed at a median gestational age of 34.4weeks (range, 29.3-35.7), confirming ultrasound diagnosis in all cases, and providing substantial additional information in two (2/7, 28.6%). Parental magnetic resonance findings aligned with fetal findings in 5/7 cases (71.4%). DUO or TRIO magnetic resonance, involving both progenitors and the fetus, could play a significant role in prenatal diagnosis of selected brain anomalies with uncertain prognosis.

Bridging Prenatal Diagnostics and AI: A Systematic Review and Meta-Analysis of the Efficacy of Advanced Algorithms in Identifying Congenital Fetal Abnormalities

Congenital fetal abnormalities have emerged as a major cause of infant mortality globally. About 3% of pregnancies are reported as fetal structural anomaly through ultrasound, ranging from minor defect to severe organ system anomalies. Our study aimed to evaluate effectiveness of Artificial intelligence (AI) algorithms in prediction of fetal heart and brain abnormalities by using meta-analysis approach. In this study, the “Reporting Items for Systematic Review and Meta-Analysis (PRISMA)" guidelines were applied for screening and selection of research articles. We searched the research articles according to research aims from Google scholar, PubMed, and Ovid MEDLINE. The data search was limited to January 2015 to May 2024. Two researchers independently screened the studies to detect research aim oriented studies. After screening of titles, those researchers assessed all abstract for eligibility. The risk bias of included studies was assessed by two researchers who used Cochrane library tool (version 5.4.0). Using the DerSimonian-Laird technique, a bivariate random effect model that generated SROC plots, we pooled test estimates. This method is particularly helpful in visualizing variability in the sensitivity and specificity across studies, accounting for the heterogeneity. This improves the reliability of the SROC plot, offering a clear summary of diagnostic performance Using the software RevMan 5.4, we carried out every statistical analysis, particularly heterogeneity through the Q test. About 243,456 screened fetus or pregnant women of 11-32 gestational weeks through 10 studies based on AI algorithms (machine learning, deep learning and AI diagnostic tool). The imaging protocols including ultrasound and MRI were used to take visuals of fetal brain and heart abnormalities in all of including studies. DL and ML algorithms provided high-performance diagnostic predictions, mostly include CNN models that assist in providing accurate diagnostic results with high sensitivity and specificity. The AI algorithm model showed a generally good accuracy scores for detection of brain and heart abnormalities and reference machine learning findings, with sensitivity ranging from 82 to 99% and specificity from 78 to 99%. Fig. 5's area under the SROC curve was 0.960. In contrast to the general detection, ML and DL seems to be more sensitive in diagnosing fetal brain and heart abnormalities. Our study provided the scientific evidence that AI models including deep learning and Machine learning are effective in generating highly reliable detection or classification results for diagnosis of fetal brain and heart anomalies. These strategies can help in reducing infant mortalities, improving treatment outcomes, and postpartum outcomes among women.

Parental magnetic resonance imaging for the evaluation of fetuses with brain anomalies.

To evaluate the role of parental magnetic resonance imaging (MRI) in assessing fetuses with suspected brain anomalies and its use in prenatal counselling. A retrospective, multicentre chart review was conducted on fetuses who underwent brain MRI because of suspected brain abnormalities between January 2008 and December 2022, with one or both parents who underwent brain MRI (MRI-Trio) as part of prenatal counselling. Clinical and demographic data were collected, including fetal and parental MRI findings, prenatal counselling outcomes, genetic testing results, family and previous pregnancy history, neurological examinations of the born children up to 24 months of age, and autopsy reports of fetuses from terminated pregnancies. MRI-Trio concordance was defined as at least one abnormal brain feature identified with similarity in the fetus and the parents. The live-born children were assessed postnatally through either neurodevelopmental evaluations or telephone interviews. Sixty pregnancies were included (41.7% with concordant and 58.3% with discordant MRI-Trio). Forty-two children were born (70%) and 17 pregnancies were terminated (28.3%). One case of in utero fetal death (1.7%) was reported. The most common brain findings were multiple anomalies (n = 26, 43.3%), isolated disorders of the corpus callosum (n = 17, 28.3%), atypical periventricular pseudocysts (n = 6, 10%), and anomalies of the anterior complex (n = 4, 6.7%). MRI-Trio enabled better prognostication. When MRI-Trio was concordant, counselling was more favourable (n = 22, 36.6%) and the majority of live-born children exhibited typical development (p < 0.001). MRI-Trio is a valuable tool for identifying dominantly inherited brain anomalies that may not hold developmental significance or are associated with favourable outcomes, acknowledging the potential for variable penetrance, which may result in more severe presentations. Concordant MRI-Trio findings can enhance the accuracy of prenatal counselling, potentially reducing the incidence of termination of pregnancy.

Effects of growth hormone and sex steroid therapy on brain structure and pituitary function in turner syndrome

Introduction: Turner syndrome (TS) is a chromosomal disorder affecting approximately 1 in 2,500 live female births, characterized by the partial or complete absence of one X chromosome. This genetic anomaly leads to physical, cognitive, and endocrine abnormalities, including short stature, gonadal dysgenesis, and structural brain anomalies. Cognitive deficits in TS involve visuospatial processing, memory, and executive function, often linked to structural brain changes. Magnetic resonance imaging (MRI) has revealed significant alterations in gray and white matter volumes in various brain regions. Growth hormone (GH) and sex steroid therapies, such as estrogen and progesterone, are used to address growth and developmental delays in TS. However, their impact on brain structure and pituitary function remains an area of active research. Aim of the Review: To systematically review and synthesize findings on the effects of GH and sex steroid therapy on brain structure and pituitary function in patients with Turner syndrome. Methods: A comprehensive literature review was conducted to identify studies examining the effects of GH and sex steroid therapy on brain structure and pituitary function in TS. Data from various sources were compiled, focusing on MRI-based structural brain changes. Key parameters analyzed included sample size, findings from MRI and fMRI studies, and clinical associations. Studies were summarized and presented in a structured table format. Results: Estrogen-progesterone treatment was found to suppress pituitary gonadotropin release more effectively than estrogen alone, indicating a feedback interaction between pituitary gonadotropin release and sex steroids. MRI studies showed that TS patients exhibit smaller volumes in the hippocampus, caudate, lenticular, thalamic nuclei, and parieto-occipital brain matter, correlating with cognitive deficits. GH-IGF axis abnormalities are modulated by body composition and physical fitness, with sex hormone replacement normalizing the GH-IGF axis and improving body composition. Although GH therapy alone did not significantly improve cognitive functions, the combination of GH with oxandrolone improved working memory. Estrogen deficiency and TS are associated with slower growth in parieto-occipital regions and enhanced volume growth in basal ganglia and cerebellar areas during adolescence, underscoring the importance of estrogen replacement in brain development. Discussion: GH and sex steroid therapies significantly impact brain structure, pituitary function, and clinical outcomes in TS. GH therapy, often combined with sex steroids, improves growth and cognitive functions, particularly working memory. However, GH alone does not significantly impact overall cognitive function. The timing and combination of these therapies are crucial for optimizing outcomes. Regular monitoring and individualized treatment plans are essential to address the complex needs of TS patients. Further research is needed to explore the long-term impacts of these therapies and develop optimal treatment regimens. Conclusion: GH and sex steroid therapies are vital in managing TS contributing to improved growth, body composition, and cognitive enhancements. A multifaceted therapeutic approach and regular monitoring are crucial for optimizing treatment outcomes and quality of life for TS patients.

Multimodal abnormalities of brain structures in adolescents and young adults with major depressive disorder: An activation likelihood estimation meta-analysis.

Major depressive disorder (MDD) in adolescents and young adults contributes significantly to global morbidity, with inconsistent findings on brain structural changes from structural magnetic resonance imaging studies. Activation likelihood estimation (ALE) offers a method to synthesize these diverse findings and identify consistent brain anomalies. To identify consistent brain structural changes in adolescents and young adults with MDD using ALE meta-analysis. We performed a comprehensive literature search in PubMed, Web of Science, Embase, and Chinese National Knowledge Infrastructure databases for neuroimaging studies on MDD among adolescents and young adults published up to November 19, 2023. Two independent researchers performed the study selection, quality assessment, and data extraction. The ALE technique was employed to synthesize findings on localized brain function anomalies in MDD patients, which was supplemented by sensitivity analyses. Twenty-two studies comprising fourteen diffusion tensor imaging (DTI) studies and eight voxel-based morphometry (VBM) studies, and involving 451 MDD patients and 465 healthy controls (HCs) for DTI and 664 MDD patients and 946 HCs for VBM, were included. DTI-based ALE demonstrated significant reductions in fractional anisotropy (FA) values in the right caudate head, right insula, and right lentiform nucleus putamen in adolescents and young adults with MDD compared to HCs, with no regions exhibiting increased FA values. VBM-based ALE did not demonstrate significant alterations in gray matter volume. Sensitivity analyses highlighted consistent findings in the right caudate head (11 of 14 analyses), right insula (10 of 14 analyses), and right lentiform nucleus putamen (11 of 14 analyses). Structural alterations in the right caudate head, right insula, and right lentiform nucleus putamen in young MDD patients may contribute to its recurrent nature, offering insights for targeted therapies.

Multicenter retrospective study of patients with PCDH19-related epilepsy: The first Hungarian cohort.

PCDH19-related epilepsy occurs predominantly in girls and is caused by pathogenic variant of the protocadherin-19 gene. The initial seizures usually develop in association with fever, begin on average at 15 months of age, and often occur in clusters. Autistic symptoms, intellectual disability, and sleep disturbance are often associated. In our retrospective, multicenter study, we reviewed clinical data of nine children with epilepsy genetically confirmed to be associated with PCDH19. In the Hungarian patient population aged 0-18 years, the prevalence of PCDH19-related epilepsy was found to be lower (1/100000 live births in females) than the reported international data (4-5/100000 live births in females). Four of our nine patients had positive family history of epilepsy (cousins, sister, and mother). We assessed brain anomalies in three patients (in one patient focal cortical dysplasia and left anterior cingulate dysgenesis, and in two children right or left hippocampal sclerosis) and in another three cases incidentally identified benign alterations on brain MRI were found. The first seizure presented as a cluster in seven out of nine children. In seven out of nine cases occurred status epilepticus. Six out of nine children had autistic symptoms and only one child had normal intellectual development. Seven of our patients were seizure free with combined antiseizure medication (ASM). The most effective ASMs were levetiracetam, valproate, and clobazam. The prevalence of PCDH19-related epilepsy is presumably underestimated because of the lack of widely performed molecular genetic evaluations. Molecular genetic testing including PCDH19 pathogenic variants is recommended for female patients with an onset of seizures before the age of 3 years.

Identification of novel variants in BRF1 gene from patient with developmental delay, hearing abnormality, and nervous system anomalies.

Cerebellofaciodental syndrome characterized with dysmorphic features, intellectual disability, and brain anomalies. Now its clinical spectrum expanded more manifestations including bilateral sensorineural hearing impairment and inner ear malformation. Here, we report a 14-month-old boy with global developmental delay and hearing disorder. Whole exome sequencing (WES) revealed the compound heterozygous variants [NM_001519.4: c.652 T > G (p.W218G); c.915 + 1G > T] in the BRF1 gene which inherited from his parents, respectively. The MRI results showed hypoplastic cerebellar vermis, enlarged cisterna magna, and prominent fourth ventricle, the rehabilitation therapy failed to improve the symptoms for our patient. Our finding expands the genetic spectrum of BRF1 variants, which indicates patients with the developmental delay caused by BRF1 variants require other treatments instead of rehabilitation.

From Theory to Therapy: A Review of Anti-Social Personality Disorder

Treatment of anti-social personality disorder in clinical practice is difficult because of the condition's complex etiology, enduring nature, and significant societal impact. This review summarizes evidence-based therapy approaches, comorbidities, and biopsychosocial variables related to ASPD, by indicating the state of the field. Twin studies and neuroimaging research arguing for structural brain anomalies provide clear evidence that genetic predispositions and neurobiological abnormalities play a role in ASPD. Psycho-social variables also participate in the development and characteristics of the condition, such as maltreatment in childhood and disturbed family relationships. Emerging therapeutic approaches such as Mentalization-Based Treatment, Psychodynamic Art Psychotherapy, Transference-Focused Psychotherapy, Schema Therapy, and Mindfulness-Based Interventions show promise, though their efficacy varies and requires further investigation.

Cerebellar atrophy in genetic epileptic encephalopathies: A cohort study and a systematic review

ObjectiveTo analyze cerebellar atrophy in genetic epileptic encephalopathies (EEs). MethodsThis research included a retrospective cohort study conducted from January 2016 to December 2023 and a systematic review on cerebellar atrophy in genetic EEs. Pediatric individuals who were diagnosed with EEs based on electroclinical features, carried causative gene variants, and exhibited cerebellar atrophy were recruited. Electroclinical features, neuroimaging findings, and causative variants of eligible individuals were analyzed. ResultsThe cohort study showed 10 of 67 pediatric individuals (10/67; 15 %) who were diagnosed with genetic EEs had cerebellar atrophy; and 6 of the 10 individuals (6/10; 60 %) exhibited cerebellar signs. Diagnostic delay between the detection of cerebellar atrophy and the identification of genetic diagnosis existed in 6 individuals (6/10; 60 %) and the median duration was 4.4 years. A total of 32 genes, including 31 genes from the literature review and a newly identified SCN2A gene in this cohort, were reported associated with cerebellar atrophy in genetic EEs. Twenty-six genes (26/32; 81 %) accounted for cerebellar atrophy associated with other brain anomalies and 6 genes (6/32; 19 %) caused isolated cerebellar atrophy. Twenty-five genes (25/32; 78 %) showed late-onset cerebellar atrophy identified after the age of 1 year old. ConclusionCerebellar atrophy is not uncommon in genetic EEs and may serve as an indicator for molecular diagnosis in clinical practice. To shorten the diagnostic delay, follow-up neuroimaging study is crucial because of high rate of clinico-radiological dissociation and late-onset cerebellar atrophy in this patient group.

Long-Term Disease Course of Pontocerebellar Hypoplasia Type 10

BackgroundPontocerebellar hypoplasia type 10 (PCH10) due to CLP1 gene mutations is characterized by structural brain anomalies, progressive microcephaly, severe intellectual and physical disabilities, and spasticity. In this follow-up study, evolution of phenotypic and neurological characteristics of patients with PCH10 is discussed. MethodsPhenotype, growth parameters, motor functions, developmental tests, spasticity assessments, functional independence assessments, electroencephalography (EEG), and brain magnetic resonance imaging (MRI) of 10 patients with PCH10 were monitored on separate examinations. Alterations were recorded. ResultsPatients were followed-up for an average of 2.83 years. The tone of the upper extremities was significantly higher than that of the lower extremities, according to Modified Ashworth Scale (MAS) values. Sixty percent of patients could sit unsupported; 20% achieved supported sitting initially but lost the ability during follow-up. Absence of grabbing or sitting was observed in 20% of patients. During follow-up, one person achieved supported sitting and one person achieved head holding. Only one patient was able to speak a few words. Cerebellar atrophy (two of 10), pons hypoplasia (four of 10), cortical atrophy (seven of 10), enlarged ventricles (10 of 10), thinning of the corpus callosum (10 of 10), hypomyelination (six of 10), and increased white matter signal intensity (six of 10) were the observed MRI findings. ConclusionsProgressive cerebral and cerebellar atrophy was demonstrated radiologically for the first time in a PCH10 cohort. It is of crucial importance to identify these patients promptly with the help of dysmorphic findings and spasticity being pronounced in the upper extremities. Furthermore, we note that phenotypic and neurological examination findings tend to change slightly over time.

The postnatal injection of AAV9-FOXG1 rescues corpus callosum agenesis and other brain deficits in the mouse model of FOXG1 syndrome

Heterozygous mutations in the FOXG1 gene manifest as FOXG1 syndrome, a severe neurodevelopmental disorder characterized by structural brain anomalies, including agenesis of the corpus callosum, hippocampal reduction, and myelination delays. Despite the well-defined genetic basis of FOXG1 syndrome, therapeutic interventions targeting the underlying cause of the disorder are nonexistent. In this study, we explore the therapeutic potential of adeno-associated virus 9 (AAV9)-mediated delivery of the FOXG1 gene. Remarkably, intracerebroventricular injection of AAV9-FOXG1 to Foxg1 heterozygous mouse model at the postnatal stage rescues a wide rangeof brain pathologies. This includes the amelioration of corpuscallosum deficiencies, the restoration of dentate gyrus morphology in the hippocampus, the normalization of oligodendrocyte lineage cell numbers, and the rectification of myelination anomalies. Our findings highlight the efficacy of AAV9-based gene therapy as a viable treatment strategy for FOXG1 syndrome and potentially other neurodevelopmental disorders with similar brain malformations, asserting its therapeutic relevance in postnatal stages.

Whole-exome-based single nucleotide variants and copy number analysis for prenatal diagnosis of compound heterozygosity of SMPD4.

Biallelic loss-of-function variants in SMPD4 cause a rare and severe neurodevelopmental disorder. These variants have been identified in a group of children with neurodevelopmental disorders with microcephaly, arthrogryposis, and structural brain anomalies. SMPD4 encodes a sphingomyelinase that hydrolyzes sphingomyelin into ceramide at neutral pH and can thereby affect membrane lipid homeostasis. SMPD4 localizes to the membranes of the endoplasmic reticulum and nuclear envelope and interacts with nuclear pore complexes. For the efficient prenatal diagnosis of rare and undiagnosed diseases, the parallel detection of copy number variants (CNVs) and single nucleotide variants using whole-exome analysis is required. A physical examination of the parents was performed. Karyotype and whole-exome analysis were performed for the fetus and the parents. A fetus with microcephaly and arthrogryposis; biallelic null variants (c.387-1G>A; Chr2[GRCh38]: g.130142742_130202459del) were detected by whole-exome sequencing (WES). We have reported for the first time the biallelic loss-of-function mutations in SMPD4 in patients born to unrelated parents in China. WES could replace chromosomal microarray analysis and copy number variation sequencing as a more cost-effective genetic test for detecting CNVs and diagnosing highly heterogeneous conditions.