Hypoxic-ischemic brain damage presents a significant neurological challenge, often manifesting during the perinatal period. Specifically, periventricular leukomalacia (PVL) is emerging as a notable contributor to cerebral palsy and intellectual disabilities. It compromises cerebral microcirculation, resulting in insufficient oxygen or blood flow to the periventricular region of the brain. As widely documented, these pathological conditions can be caused by several factors encompassing preterm birth (4-5% of the total cases), as well single cotwin abortion and genetic variants such as those associated with GTPase pathways. Whole exome sequencing (WES) analysis identified a de novo causative variant within the pleckstrin homology domain-containing family G member 1 (PLEKHG1) gene in a patient presenting with PVL. The PLEKHG1 gene is ubiquitously expressed, showing high expression patterns in brain tissues. PLEKHG1 is part of a family of Rho guanine nucleotide exchange factors, and the protein is essential for cell division control protein 42 (CDC42) activation in the GTPase pathway. CDC42 is a key small GTPase of the Rho-subfamily, regulating various cellular functions such as cell morphology, migration, endocytosis, and cell cycle progression. The molecular mechanism involving PLEKHG1 and CDC42 has an intriguing role in the reorientation of cells in the vascular endothelium, thus suggesting that disruption responses to mechanical stress in endothelial cells may be involved in the formation of white matter lesions. Significantly, CDC42 association with white matter abnormalities is underscored by its MIM phenotype number. In contrast, although PLEKHG1 has been recently associated with patients showing white matter hyperintensities, it currently lacks a MIM phenotype number. Additionally, in silico analyses classified the identified variant as pathogenic. Although the patient was born prematurely and subsequently to dichorionic gestation, during which its cotwin died, we suggest that the variant described can strongly contribute to PVL. The aim of the current study is to establish a plausible association between the PLEKHG1 gene and PVL.

UNASSIGNED: Congenital heart disease (CHD) is the most common birth defect, affecting 1% of children who are born in the United States each year. Children with hypoplastic left heart syndrome, a type of critical CHD, are at high risk for neurodevelopmental disabilities, which are conditions that can affect motor, language, and cognitive development. In children with critical CHD, the severity and prevalence of their motor delays is most pronounced in infancy.
UNASSIGNED: We present a case of a former late preterm male with hypoplastic left heart syndrome and history of hypoxic ischemic encephalopathy, who was diagnosed with spastic diplegic cerebral palsy in the setting of periventricular leukomalacia. Like many children with critical CHD, this child had gross motor delays and tone abnormalities in infancy. However, unlike many children with CHD, he continued to have neurologic differences that prompted additional evaluation through a Cardiac Neurodevelopmental Program. He was diagnosed with spastic diplegic cerebral palsy based upon clinical history and physical examination. Ancillary testing showed periventricular leukomalacia on brain magnetic resonance imaging (MRI); this finding was consistent with his clinical diagnosis.
UNASSIGNED: This is an interesting case report of spastic diplegic cerebral palsy in a late preterm infant with critical CHD. When making a diagnosis of cerebral palsy, it is important to consider the etiology of the motor impairment. Selective vulnerability may have played a factor in this child\'s condition. The most vulnerable part of the neonatal brain is the periventricular white matter; cerebral hypoxia can lead to periventricular leukomalacia. Children with CHD have brain dysmaturity beginning in-utero. Thus, it is possible that this child\'s brain dysmaturity may have increased his susceptibility to periventricular leukomalacia. Because most children with CHD have gross motor delays in infancy, it may be challenging to make a definitive diagnosis of cerebral palsy in an infant with critical CHD. Children with cerebral palsy have early motor delays that persist throughout life. It is the identification of persistent motor impairments through repeat evaluations that enabled this child\'s cerebral palsy diagnosis. This illustrates the importance of developmental surveillance in children with critical CHD.

Intrapartum fetal heart rate monitoring abnormalities had been reported to correlate with decreased umbilical artery base excess associated with neonatal seizures. However, we present an infant born at 35 weeks of gestation diagnosed with cerebral palsy associated with periventricular leukomalacia (PVL) without fetal heart rate (FHR) monitoring abnormalities, According to the summary reports of PVL cases published on the home page of the Japan Obstetric Compensation System for Cerebral Palsy (JOCSC)), the percentage of placenta previa without FHR monitoring abnormalities in the cases of PVL was 5.7% (12/209), which seemed to be higher than the total percentage of placenta previa reported in Japan (0.3-0.5%).

BACKGROUND: The thalamus L-sign, characterized by damage to the lateral and posterior parts of the thalamus, has recently been identified as a potential marker of partial prolonged hypoxic-ischemic injury (HII). Although prematurity-related thalamic injury is well documented, its association with the thalamus L-sign is infrequently described.
OBJECTIVE: The primary objective of this study was to further investigate the thalamus L-sign in premature birth and white matter injury.
METHODS: A retrospective analysis of 246 brain magnetic resonance imaging (MRI) scans from preterm infants born before 37 weeks of gestation was conducted to explore the occurrence, characteristics, and associations of the thalamus L-sign with white matter injury.
RESULTS: The L-sign was detected in 12.6% of patients with periventricular leukomalacia (PVL), primarily in severe cases (57.9% of severe PVL). All cases were associated with posterior parieto-occipital PVL. Four patients exhibited unilateral or asymmetric L-signs, which were linked to high-grade intraventricular hemorrhage (IVH) or periventricular hemorrhagic infarction on the ipsilateral side, with the most severe white matter injury occurring on that side. No significant differences were observed regarding gestational age at birth, duration of neonatal intensive care unit hospitalization, percentage of IVH, hypoglycemia, or jaundice between patients with moderate-to-severe PVL with and without the thalamus L-sign.
CONCLUSIONS: The thalamus L-sign may serve as a marker for severe parieto-occipital PVL and may be exacerbated and appear asymmetric in cases of ipsilateral IVH or periventricular hemorrhagic infarction.

Pontocerebellar hypoplasia type 9 (PCH9) is a rare, autosomal, recessive, neurodevelopmental disorder caused by a mutation in the AMPD2 gene. Despite its rarity, it presents distinctive clinical and neuroradiological features. Diagnosing it is challenging yet crucial for appropriate management. We describe a 21-month-old boy with clinical and neuroradiological manifestations of the diagnosis, including characteristic signs such as an eight-configured midbrain and hypoplasia of the brainstem and cerebellar structures. Genetic evaluation confirmed homozygous missense mutations in the AMPD2 gene. This case highlights the pathognomonic neuroradiological features of pontocerebellar hypoplasia type 9 that point toward diagnosis.

Neonatal brain injury (NBI) is a critical condition for preterm neonates with potential long-term adverse neurodevelopmental outcomes. This prospective longitudinal case-control study aimed at investigating the levels and prognostic value of serum neuron-specific enolase (NSE) during the first 3 days of life in preterm neonates (<34 weeks) that later developed brain injury in the form of either periventricular leukomalacia (PVL) or intraventricular hemorrhage (IVH) during their hospitalization. Participants were recruited from one neonatal intensive care unit, and on the basis of birth weight and gestational age, we matched each case (n = 29) with a neonate who had a normal head ultrasound scan (n = 29). We report that serum NSE levels during the first three days of life do not differ significantly between control and preterm neonates with NBI. Nevertheless, subgroup analysis revealed that neonates with IVH had significantly higher concentrations of serum NSE in comparison to controls and neonates with PVL on the third day of life (p = 0.014 and p = 0.033, respectively). The same pattern on the levels of NSE on the third day of life was also observed between (a) neonates with IVH and all other neonates (PVL and control; p = 0.003), (b) neonates with II-IV degree IVH and all other neonates (p = 0.003), and (c) between control and the five (n = 5) neonates that died from the case group (p = 0.023). We conclude that NSE could be an effective and useful biomarker on the third day of life for the identification of preterm neonates at high risk of developing severe forms of IVH.

UNASSIGNED: Weaver syndrome (WS) is a rare autosomal dominant disorder characterized by distinctive facial features, pre- and post-natal overgrowth, macrocephaly, and variable developmental delay. The characteristic facial features are ocular hypertelorism, a broad forehead, almond-shaped palpebral fissures and, in early childhood, large, fleshy ears, a pointed \"stuck-on\" chin with horizontal skin creases, and retrognathia. Heterozygous pathogenic/likely pathogenic variants in the enhancer of zeste homolog 2 (EZH2) gene are responsible for WS.
UNASSIGNED: Here, we report a male patient with a heterozygous likely pathogenic variant in EZH2 gene who has tall stature, distinctive facial features, mild development delay, hypoxic-ischemic encephalopathy with a MRI finding of periventricular leukomalacia, gingival hypertrophy, and early onset high hypermetropia.
UNASSIGNED: This case demonstrates the importance of reporting detailed molecular and clinical findings in patients to expand the genotypic and phenotypic findings of this rare syndrome.

BACKGROUND: Severe brain injury (SBI), including severe intraventricular haemorrhage (sIVH) and cystic periventricular leukomalacia, poses significant challenges for preterm infants, yet recent data and trends are limited.
METHODS: Analyses were conducted using the Australian and New Zealand Neonatal Network data on preterm infants born <32 weeks\' gestation admitted at Monash Children\'s Hospital, Australia, from January 2014 to April 2021. The occurrence and trends of SBI and sIVH among preterm infants, along with the rates and trends of death and neurodevelopmental impairment (NDI) in SBI infants were assessed.
RESULTS: Of 1,609 preterm infants, 6.7% had SBI, and 5.6% exhibited sIVH. A total of 37.6% of infants with SBI did not survive to discharge, with 92% of these deaths occurring following redirection of clinical care. Cerebral palsy was diagnosed in 65.2% of SBI survivors, while 86.4% of SBI survivors experienced NDI. No statistically significant differences were observed in the temporal trends of SBI (adjusted OR [95% CI] 1.08 [0.97-1.20]; p = 0.13) or sIVH (adjusted OR [95% CI] 1.09 [0.97-1.21]; p = 0.11). Similarly, there was no statistically significant difference noted in the temporal trend of the composite outcome, which included death or NDI among infants with SBI (adjusted OR [95% CI] 0.90 [0.53-1.53]; p = 0.71).
CONCLUSIONS: Neither the rates of SBI nor its associated composite outcome of death or NDI improved over time. A notable proportion of preterm infants with SBI faced redirection of care and subsequent mortality, while most survivors exhibited adverse neurodevelopmental challenges. The development of better therapeutic interventions is imperative to improve outcomes for these vulnerable infants.

Dihydropyrimidinase (DHP) deficiency is an autosomal recessive metabolic disorder caused by biallelic pathogenic variants of DPYS Patients with DHP deficiency exhibit a broad spectrum of phenotypes, ranging from severe neurological and gastrointestinal involvement to cases with no apparent symptoms. The biochemical diagnosis of DHP deficiency is based on the detection of a significant amount of dihydropyrimidines in urine, plasma, and cerebrospinal fluid samples. Molecular genetic testing, specifically the identification of biallelic pathogenic variants in DPYS, has proven instrumental in confirming the diagnosis and facilitating family studies. This case study documents the diagnostic journey of an 18-yr-old patient with DHP deficiency, highlighting features at the severe end of the clinical spectrum. Notably, our patient exhibited previously unreported skeletal features that positively responded to bisphosphonate treatment, contributing valuable insights to the clinical characterization of DHP deficiency. Additionally, a novel DPYS variant was identified and confirmed pathogenicity through metabolic testing, further expanding the variant spectrum of the gene. Our case emphasizes the importance of a comprehensive diagnostic approach using genetic sequencing and metabolic testing for accurate diagnosis.

OBJECTIVE: Preterm children with cerebral palsy (CP) often have varying hand dysfunction, while the specific brain injury with periventricular leukomalacia (PVL) cannot quite explain its mechanism. We aimed to investigate glymphatic activity using diffusion tensor image analysis along the perivascular space (DTI-ALPS) method and evaluate its association with brain lesion burden and hand dysfunction in children with CP secondary to PVL.
METHODS: We retrospectively enrolled 18 children with bilateral spastic CP due to PVL and 29 age- and sex-matched typically developing controls. The Manual Ability Classification System (MACS) was used to assess severity of hand dysfunction in CP. A mediation model was performed to explore the relationship among the DTI-ALPS index, brain lesion burden, and the MACS level in children with CP.
RESULTS: There were significant differences in the DTI-ALPS index between children with CP and their typically developing peers. The DTI-ALPS index of the children with CP was lower than that of the controls (1.448 vs. 1.625, P = 0.003). The mediation analysis showed that the DTI-ALPS index fully mediated the relationship between brain lesion burden and the MACS level (c\' = 0.061, P = 0.665), explaining 80% of the effect.
CONCLUSIONS: This study provides new insights into the neural basis of hand dysfunction in children with CP, demonstrating an important role of glymphatic impairment in such patients. These results suggest that PVL might affect hand function in children with CP by disrupting glymphatic drainage.