Prenatal clinical manifestations in individuals with COL4A1/2 variants.

BACKGROUND: Variants in the type IV collagen gene (COL4A1/2) cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with COL4A1/2 variants remain unclear. METHODS: We examined COL4A1/2 in 218 individuals with suspected COL4A1/2-related brain defects. Among those arising from COL4A1/2 variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail. RESULTS: Pathogenic COL4A1/2 variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with COL4A1/2 variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly. CONCLUSIONS: Prenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and COL4A1/2 gene testing should be considered when pathogenic variants are strongly suspected.

[Long-term outcome of childhood hypoxic-ischemic encephalopathy].

OBJECTIVE: To propose an adequate rehabilitation program for children suffering from hypoxic-ischemic encephalopathy (HIE) based on estimated outcomes. METHODS: Participants were 42 children, 28 boys and 14 girls, who suffered from HIE after neonatal period. We divided them into three groups; favorable (GMFCS level 1 or 2), moderate (level 3 or 4), and unfavorable (level 5), and compared the extent of brain lesions on MRI, age of onset, and complications among the groups. RESULTS: The number of children in favorable, moderate, and unfavorable groups was 10, 10 and 22, respectively. All children in favorable and moderate groups showed focal cerebral lesions on MRI. In contrast, most children in unfavorable group (19/22) had diffuse brain damage and the rest were infantile onset with focal cerebral lesions. The etiology and situation of HIE did not differ among three groups. Three children in moderate group whose onsets were earlier than 5 months showed lesions similar to those in neonatal HIE; in bilateral basal ganglia, thalamus, and perirolandic cortex. In favorable group, 7 children were able to walk independently within 5 months after the insult, but 9 had moderate or severe mental retardation and 3 showed severe visual impairment. A majority of unfavorable group developed scoliosis or hip dislocation, and underwent tracheostomy or gastrostomy. Five children who had stayed acute hospitals for longer than 6 months developed irreversible complications such as joint contractures before discharge. CONCLUSIONS: Children with focal cerebral lesions need continual rehabilitation and education for mental retardation and visual impairment, even if they can walk within several months after HIE. Those with diffuse brain damage need sufficient rehabilitation as early as possible to avoid developing secondary complications. MR image, age of onset, and clinical course were of great prognostic value to make appropriate long-term rehabilitation and education programs.

Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly.

OBJECTIVE: Recently, COL4A1 mutations have been reported in porencephaly and other cerebral vascular diseases, often associated with ocular, renal, and muscular features. In this study, we aimed to clarify the phenotypic spectrum and incidence of COL4A1 mutations. METHODS: We screened for COL4A1 mutations in 61 patients with porencephaly and 10 patients with schizencephaly, which may be similarly caused by disturbed vascular supply leading to cerebral degeneration, but can be distinguished depending on time of insult. RESULTS: COL4A1 mutations were identified in 15 patients (21%, 10 mutations in porencephaly and 5 mutations in schizencephaly), who showed a variety of associated findings, including intracranial calcification, focal cortical dysplasia, pontocerebellar atrophy, ocular abnormalities, myopathy, elevated serum creatine kinase levels, and hemolytic anemia. Mutations include 10 missense, a nonsense, a frameshift, and 3 splice site mutations. Five mutations were confirmed as de novo events. One mutation was cosegregated with familial porencephaly, and 2 mutations were inherited from asymptomatic parents. Aberrant splicing was demonstrated by reverse transcriptase polymerase chain reaction analyses in 2 patients with splice site mutations. INTERPRETATION: Our study first confirmed that COL4A1 mutations are associated with schizencephaly and hemolytic anemia. Based on the finding that COL4A1 mutations were frequent in patients with porencephaly and schizencephaly, genetic testing for COL4A1 should be considered for children with these conditions.

Childhood-onset epilepsy in patients with dyskinetic cerebral palsy caused by basal ganglia and thalamic lesions.

OBJECTIVE: To elucidate the incidence and outcomes of childhood-onset epilepsy and associated factors in term-born patients with basal ganglia and thalamic lesion (BGTL)-induced dyskinetic cerebral palsy (DCP) caused by perinatal hypoxic-ischemic encephalopathy (HIE). METHODS: We studied 104 term-born patients with BGTL-induced DCP (63 males and 41 females, aged 2-22 years) to investigate the incidence of epilepsy and the factors related to its development. We used multivariate analysis to assess perinatal factors, gross motor function, and the extent of brain lesions. We also investigated the seizure onset, clinical course, and electroencephalography (EEG) characteristics. RESULTS: The cumulative epilepsy incidence was 36%. Multiple logistic regression analysis revealed that deep white matter lesions were the only independent risk factor for epilepsy. The confirmed seizure types included epileptic spasms (ES, n = 13), myoclonic seizures (MS, n = 6), and focal-onset seizures (FS, n = 24). Only patients with deep white matter lesions exhibited ES or MS. The symptoms of FS resembled those of self-limited epilepsy with centrotemporal spikes; however, only half of the patients reached remission by the time of investigation, and four patients had more than one seizure per month despite appropriate drug therapy. Focal spikes in the peri-rolandic area were detected not only in patients with FS but also in half of the patients without epilepsy. CONCLUSIONS: One-third of term-born patients with BGTL-induced DCP caused by perinatal HIE develop epilepsy, and deep white matter lesions increase the likelihood of epilepsy. Preparation for early-onset ES, MS, and subsequent FS is beneficial.

Leigh-like syndrome with progressive cerebellar atrophy caused by novel HIBCH variants.

Pathogenic variants in the HIBCH gene cause HIBCH deficiency, leading to mitochondrial disorders associated with valine metabolism. Patients typically present with symptoms such as developmental regression/delay, encephalopathy, hypotonia and dystonia. Brain magnetic resonance imaging (MRI) shows bilateral lesions in the basal ganglia with/without brainstem involvement. Here, we report a case of a Japanese patient with Leigh-like syndrome caused by novel HIBCH variants. Long-term follow-up MRI revealed progressive cerebellar atrophy, which expands the phenotypic spectrum of HIBCH deficiency.

Functional outcomes of children with dyskinetic cerebral palsy depend on etiology and gestational age.

OBJECTIVE: To elucidate the differences in etiology of dyskinetic cerebral palsy (DCP) between term-born and preterm-born children and its relationship to functional outcomes. METHODS: We determined the etiology of DCP based on the clinical course and brain MRI of 163 term-born and 136 preterm-born children. Information about genetic abnormality was also collected if available. Functional outcomes were compared between the two major etiologies in each group, i.e., hypoxic ischemic encephalopathy (HIE) and bilirubin encephalopathy (BE), using four standardized classification systems, i.e., Gross Motor Function Classification System (GMFCS), Manual Ability Classification System (MACS), Communication Function Classification System (CFCS), and Eating and Drinking Ability Classification System (EDACS). RESULTS: The most common etiologies were HIE (123/163) in term-born and BE (93/136) in preterm-born children. Genetic mutations were identified in 14 of 30 term-born children with no other known etiology. GMFCS levels of the preterm children with BE were significantly poorer than those of term children with HIE (p < 0.01). Both the CFCS and EDACS levels were significantly better in preterm children with BE than in term children with HIE (p < 0.01). CONCLUSION: The most common etiology of DCP is different between term-born and preterm-born children, and the distribution of functional impairment is significantly influenced by etiology and gestational age. The difference should be taken into consideration to allow the provision of adequate interventions.

Vibrational dynamics of hydrogen-bonded complexes in solutions studied with ultrafast infrared pump-probe spectroscopy.

In aqueous solution, the basis of all living processes, hydrogen bonding exerts a powerful effect on chemical reactivity. The vibrational energy relaxation (VER) process in hydrogen-bonded complexes in solution is sensitive to the microscopic environment around the oscillator and to the geometrical configuration of the hydrogen-bonded complexes. In this Account, we describe the use of time-resolved infrared (IR) pump-probe spectroscopy to study the vibrational dynamics of (i) the carbonyl CO stretching modes in protic solvents and (ii) the OH stretching modes of phenol and carboxylic acid. In these cases, the carbonyl group acts as a hydrogen-bond acceptor, whereas the hydroxyl group acts as a hydrogen-bond donor. These vibrational modes have different properties depending on their respective chemical bonds, suggesting that hydrogen bonding may have different mechanisms and effects on the VER of the CO and OH modes than previously understood. The IR pump-probe signals of the CO stretching mode of 9-fluorenone and methyl acetate in alcohol, as well as that of acetic acid in water, include several components with different time constants. Quantum chemical calculations indicate that the dynamical components are the result of various hydrogen-bonded complexes that form between solute and solvent molecules. The acceleration of the VER is due to the increasing vibrational density of states caused by the formation of hydrogen bonds. The vibrational dynamics of the OH stretching mode in hydrogen-bonded complexes were studied in several systems. For phenol-base complexes, the decay time constant of the pump-probe signal decreases as the band peak of the IR absorption spectrum shifts to lower wavenumbers (the result of changing the proton acceptor). For phenol oligomers, the decay time constant of the pump-probe signal decreases as the probe wavenumber decreases. These observations show that the VER time strongly correlates with the strength of hydrogen bonding. This acceleration may be due to increased coupling between the OH stretching mode and the accepting mode of the VER, because the low-frequency shift caused by hydrogen bond formation is very large. Unlike phenol oligomers, however, the pump-probe signals of phenol-base complexes did not exhibit probe frequency dependence. For these complexes, rapid interconversion between different conformations causes rapid fluctuations in the vibrational frequency of the OH stretching modes, and these fluctuations level the VER times of different conformations. For the benzoic acid dimer, a quantum beat at a frequency of around 100 cm(-1) is superimposed on the pump-probe signal. This result indicates the presence of strong anharmonic coupling between the intramolecular OH stretching and the intermolecular stretching modes. From a two-dimensional plot of the OH stretching wavenumber and the low-frequency wavenumber, the wavenumber of the low-frequency mode is found to increase monotonically as the probe wavenumber is shifted toward lower wavenumbers. Our results represent a quantitative determination of the acceleration of VER by the formation of hydrogen bonds. Our studies merit further evaluation and raise fundamental questions about the current theory of vibrational dynamics in the condensed phase.

A questionnaire survey on the efficacy of various treatments for dyskinetic cerebral palsy due to preterm bilirubin encephalopathy.

OBJECTIVES: Preterm children with severe dyskinetic cerebral palsy due to bilirubin encephalopathy often suffer from marked generalised hypertonus as they age. We performed a questionnaire survey to investigate patient-reported outcomes of treatments for improving their activities of daily life. METHODS: A mail questionnaire was administered to the caregivers of 67 children with preterm bilirubin encephalopathy aged >4 years. We asked about the type of treatments they received and their efficacy using a five-point subjective scale for the following five domains: motor function, postural stability, sleep, pain, and care burden. The names of oral drugs and their efficacies were also explored. RESULTS: The response rate of the questionnaires was 62.7% (42/67), and we analysed the results from 41 validated cases. All children underwent rehabilitation. A total of 30 children received oral drugs, 22 botulinum toxin, 12 orthopaedic surgery, and 3 intrathecal baclofen. Each of these treatments was subjectively reported to be effective in more than half of the recipients for each of the five domains, whereas 23 (56%) required more than two types of treatments other than rehabilitation. Chlordiazepoxide was the most commonly used oral drug, by 28 children (68%), and was discontinued in 7 patients (25%) only. In the sleep domain, the rate of a positive effect was significantly higher for oral drugs (92.7%) than the other treatments (p < 0.01). CONCLUSION: All treatments were partially effective, but their appropriate combination based on a multidisciplinary approach is essential for muscle tone management in children with preterm bilirubin encephalopathy.

Diagnosis of Bilirubin Encephalopathy in Preterm Infants with Dyskinetic Cerebral Palsy.

INTRODUCTION: Very preterm infants are susceptible to bilirubin neurotoxicity, the signs of which are unclear during early infancy. We investigated children born preterm and later diagnosed with bilirubin encephalopathy (BE) to gain insights into accurate early diagnosis. METHODS: We identified 93 children born preterm and clinically diagnosed with BE who visited our hospital between 2006 and 2018. Perinatal history, findings of auditory brainstem response (ABR), brain magnetic resonance imaging (MRI), and functional outcomes were investigated retrospectively based on chart review. RESULTS: The mean gestational age and birth weights were 27.2 weeks and 991 g, respectively. During the neonatal period, only 3% (2/71) had exchange transfusions, and none were diagnosed with acute BE. ABR was abnormal in 64% (51/80), but the majority (34/51) required no hearing aids. Brain MRI taken between 6 and 18 months of age revealed bilateral T2 hyperintensity of the globi pallidi in 91% (60/66); subsequently, the rate decreased with age. Functional communication outcomes were markedly superior to gross motor and hand function outcomes. CONCLUSION: For early diagnosis of BE, brain MRI is recommended at a corrected age of between 6 and 18 months, especially for those with abnormal ABR during early infancy, and even with no apparent history of marked neonatal hyperbilirubinemia.

Outcome of hemiplegic cerebral palsy born at term depends on its etiology.

OBJECTIVES: To elucidate the etiology and its relationship to the outcomes of hemiplegic cerebral palsy (HCP). PARTICIPANTS AND METHODS: MR images and outcomes of 156 children with HCP born at term and older than three years were investigated in two major centers for cerebral palsy in Japan. Etiologies were classified into perinatal ischemic stroke (PIS), cerebral dysgenesis (CD), and others. PIS was divided into periventricular venous infarction (PVI) and two types of arterial infarction; middle cerebral artery infarction (MCAI) and deep gray matter infarction (DGMI). Initial signs and the time of presentation were investigated among the three types of PIS. As functional outcomes, laterality of paresis, age at initial walk, affected hand's function, intellectual development, and occurrence of epilepsy were compared among all the four types. ETIOLOGY: PIS was found in 106 children (68%), while CD accounted for 28 (18%). Among PIS, venous infarction was more common than arterial infarction (62:44). OUTCOMES: PVI revealed later presentation of motor asymmetry and more involvement of lower extremity as the initial sign among PIS groups. Only MCAI showed right-side predominance in laterality of paresis. DGMI related to better intellectual development and PVI showed lower occurrence of epilepsy, while there was no significant difference in affected hand's function among the four groups. PIS groups showed significantly earlier attainment of independent walk, better intellectual development, and lower occurrence of epilepsy than CD. CONCLUSIONS: PVI was the most common cause of HCP born at term, and the etiology closely related to the initial signs of hemiplegia and overall outcomes.

Cerebellar injury in preterm children with cerebral palsy after intraventricular hemorrhage: Prevalence and relationship to functional outcomes.

OBJECTIVES: To elucidate the prevalence of cerebellar injury and its relationship to functional outcomes in preterm children with cerebral palsy (CP) after intraventricular hemorrhage (IVH). PARTICIPANTS: We selected 69 children (40 males and 29 females, aged between 6 and 13 years) out of 2049 with cerebral palsy who visited Morinomiya Hospital, the regional center hospital for CP in West Japan. The inclusion criteria were (1) gestational age under 36 weeks at birth, (2) clear history of postnatal intraventricular hemorrhage, and (3) age at investigation over 6 years old. Those without sufficient imaging study or functional evaluation were excluded. METHODS: The participants were divided into four groups according to the presence of post-hemorrhagic hydrocephalus (PH) and cerebellar injury (CI): PH+/CI+, PH+/CI-, PH-/CI+, and PH-/CI-. Type of CP, ability to walk, verbal function, the incidence of severe visual impairment, and the complication of epilepsy were investigated and compared among the groups. RESULTS: The gestational ages of the participants were between 22 and 34 weeks, and their birth weight was between 412 and 1788 g. PH and CI were found in 39 (57%) and 40 (58%) children, respectively. Both the PH+/CI+ group (n=31) and the PH-/CI+ group (n=9) showed significantly lower walking and verbal abilities and a higher incidence of epilepsy than the PH-/CI- group (n=21), while the PH+/CI- group showed no significant difference from the PH-/CI- group. Severe visual impairment was found only in the PH+/CI+ group and the PH-/CI+ group. CONCLUSIONS: The prevalence of CI in preterm children with CP after IVH (58%) was almost the same as that of PH. CI is one of the most significant complications in preterm infants, affecting motor and verbal functions and being associated with epilepsy more than PH.

Theoretical and experimental studies on vibrational energy relaxation of the CO stretching mode of acetone in alcohol solutions.

The vibrational energy relaxations (VERs) of the CO stretching mode of acetone and its complexes with alcohols are investigated by sub-picosecond pump-probe spectroscopy and molecular dynamics simulation. The time constants of the vibrational energy relaxation of the free acetone and that of the 1:1 complex are 4.4 and 2.3 ps for methanol solvent and 5.2 and 1.8 ps for 1-proponal solvent, respectively. The VER rate is accelerated a few times by formation of the hydrogen bond. This acceleration of the vibrational energy relaxation is successfully reproduced by the Landau-Teller method calculated from the molecular dynamics simulation. Molecular dynamics simulations reveal that the VER time of acetone with the hydrogen bond is largely affected by the solute polarization induced by solvent molecules.