Vitamin D deficiency in children with severe disabilities under limited ultraviolet exposure.

INTRODUCTION: Nutritional prevention of osteoporosis management is an important issue for children with severe disabilities. Due to the coronavirus disease 2019 (COVID-19) pandemic that started in 2020, children admitted to institutions had fewer opportunities for ultraviolet (UV) exposure owing to restrictions on attending school and going out. Hence, the vitamin D (VD) status of these children has been a cause of concern. This study aimed to assess the correlation between VD intake and VD status among children with severe disabilities who had limited UV exposure. MATERIALS AND METHODS: This research included patients admitted to Iwate Prefectural Rehabilitation and Nursery Center for Disabled Children. Serum 25-hydroxyvitamin D [25(OH)D] levels were assessed during school/outing restriction periods and after restriction removal and the introduction of sunbathing periods. The trends in 25(OH)D levels and oral VD intake before the two measurements were analyzed. RESULTS: Although 17 of 32 patients had VD intake above the recommended level of Dietary Reference Intakes for Japanese during the first measurement, 31 patients had VD deficiency. The 25(OH)D levels of 13 patients without UV exposure before the first evaluation and those with UV exposure before the second evaluation were 2.03 times higher, despite of constant VD intakes. In contrast, there were no remarkable changes in both VD intakes and 25(OH)D levels in five patients without UV exposure before both assessments. CONCLUSION: Japanese children with severe disabilities who consume the recommended oral VD intake but who have limited UV exposure can still present VD deficiency.

Vitamin D Supplementation at a Dose of 10 µg/Day in Institutionalized Children with Severe Motor and Intellectual Disabilities.

Vitamin D (VD) deficiency can lead to health-related consequences. This study determined the effects of VD administration in VD-deficient children with severe motor and intellectual disabilities (SMID). Twenty-eight subjects were included. Among them, 25 subjects with parental consent for VD administration were given 10 µg/day (400 IU/day) of VD in April 2021. Serum 25-hydroxyvitamin D [25(OH)D] levels were measured at least 30 days after the start of VD administration. The total VD intake, serum 25(OH)D levels, and ultraviolet (UV) exposure before the blood tests were investigated. The results showed that the median serum 25(OH)D levels were 8.7 ng/mL (4.3-17.2) and 24.0 ng/mL (7.8-39 ng/mL) from March to May in 2020 and 2021, respectively. Among the 25 subjects, 22 with UV exposure had >20 ng/mL serum 25(OH)D level, and 2 without UV exposure had <20 ng/mL serum 25(OH)D level. Three subjects who did not receive VD supplementation had <20 ng/mL serum 25(OH)D level. Taken together, VD supplementation (10 µg/day) is effective in children with SMID in institutional care. Moreover, it may be sufficient for children with UV exposure, but not for those without.

Efficacy of long-term adrenocorticotropic hormone therapy for West syndrome: A retrospective multicenter case series.

OBJECTIVES: Long-term adrenocorticotropic therapy (LT-ACTH), which consisted of 2-4 weeks of daily injections of adrenocorticotropic hormone (ACTH) and subsequent months of weekly injections, was tried for relapsed West syndrome (WS) or other intractable epilepsies in small case reports. Our aim was to explore the efficacy of LT-ACTH for preventing WS relapse, as well as the prevalence of its adverse events. METHODS: This is a retrospective, nationwide, multicenter case series of patients with WS who underwent LT-ACTH. Clinical information of the patients and protocol of LT-ACTH were collected from participating institutes in this study. We defined clinical response to ACTH as achievement of hypsarrhythmia and epileptic spasms resolution. Patients who responded to daily ACTH injections were identified and assessed whether they experienced WS relapse during/after the weekly ACTH injection period. The outcome was measured by the nonrelapse rate at 24 months after daily ACTH injections using the Kaplan-Meier method. RESULTS: Clinical information of 16 children with WS was analyzed. The median age at LT-ACTH initiation was 14.5 months (range: 7-68 months). Thirteen (81%) patients had previously undergone conventional ACTH treatment. The LT-ACTH regimens comprised a median of 16 days of daily injections (range: 11-28 days) and 10 months of weekly injections (range: 3-22 months). Seven patients experienced WS relapse during/after subsequent weekly ACTH period, and the nonrelapse rate at 24 months after daily injections was estimated at 60.6% (95% confidence interval: 32.3%-80.0%). Height stagnation, hypertension, and irritability were observed; lethal adverse events were not reported. SIGNIFICANCE: Our study firstly explored the efficacy of LT-ACTH for preventing WS relapse. LT-ACTH might be a treatment option for patients with relapsed or intractable WS; however, we note that our study is limited by its small sample size and the lack of an appropriate control group.

GNAO1 mutation-related severe involuntary movements treated with gabapentin.

BACKGROUND: Mutations in GNAO1 typically result in neurodevelopmental disorders, including involuntary movements. They may be improved using calcium-channel modulators. CASE: The patient visited our hospital at age 2 years because of moderate global developmental delay. Her intermittent, generalized involuntary movements started at age 8 years. A de novo GNAO1 mutation, NM_020988.2:c.626G > A, (p.Arg209Cys), was identified by whole exome sequencing. At age 9 years, she experienced severe, intermittent involuntary movements, which led to rhabdomyolysis. She needed intensive care with administration of midazolam, dantrolene sodium hydrate, and plasma exchange. We started treating her with gabapentin (GBP), after which she recovered completely. At age 11 years, she developed continuous, generalized involuntary movements. This prompted us to increase the GBP dose, which again resolved the involuntary movements completely. CONCLUSION: In the case of movement disorders associated with GNAO1 mutations, GBP treatment may be attempted before more invasive procedures are performed.

Turner Syndrome Associated With Refractory Seizures and Intellectual Disability: A Case Study.

Turner syndrome (TS) is the most frequent sex abnormality in women. The physical features include short stature, webbing of the neck, and gonadal dysgenesis. Typically, patients with Turner syndrome exhibit no intellectual disability, and a few cases of TS have been associated with epilepsy. Herein, we present a case of TS with intractable epilepsy. The patient presented with global developmental delay at the age of two and karyotyping revealed mosaicism [45, X/46, X del (X) (q21.1)]. At the age of seven, she had generalized tonic epilepsy as well as several focal-onset seizures. She developed daily seizures, which were refractory to several antiepileptic drugs. Interictal electroencephalography (EEG) revealed multifocal spikes, and ictal EEG revealed shifting foci. She visited our hospital at the age of 13. Her peripheral white blood cells G-band and fluorescence in situ hybridization (FISH) method chromosome with cheek swab examinations revealed 45, X. Her peripheral white blood cell mosaic pattern may have disappeared over time or become indetectable. We treated her with clobazam, and then lamotrigine and valproic acid combination therapy, which resulted in a reduction in the frequency of seizures by approximately 50%. Epilepsy and intellectual disability in this case may be due to the mosaic deletion at Xq21.1. Further analysis of similar cases may provide valuable information for effective therapeutic strategies.

Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases.

Proteins anchored to the cell surface via glycosylphosphatidylinositol (GPI) play various key roles in the human body, particularly in development and neurogenesis. As such, many developmental disorders are caused by mutations in genes involved in the GPI biosynthesis and remodeling pathway. We describe ten unrelated families with bi-allelic mutations in PIGB, a gene that encodes phosphatidylinositol glycan class B, which transfers the third mannose to the GPI. Ten different PIGB variants were found in these individuals. Flow cytometric analysis of blood cells and fibroblasts from the affected individuals showed decreased cell surface presence of GPI-anchored proteins. Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy. Eight children passed away before four years old. Two of them had a clinical diagnosis of DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures), a condition that includes sensorineural deafness, shortened terminal phalanges with small finger and toenails, intellectual disability, and seizures; this condition overlaps with the severe phenotypes associated with inherited GPI deficiency. Most individuals tested showed elevated alkaline phosphatase, which is a characteristic of the inherited GPI deficiency but not DOORS syndrome. It is notable that two severely affected individuals showed 2-oxoglutaric aciduria, which can be seen in DOORS syndrome, suggesting that severe cases of inherited GPI deficiency and DOORS syndrome might share some molecular pathway disruptions.

Successful Management of Fulminant Guillain-Barré Syndrome and Its Complications.

A 3-year-old girl presented with muscle weakness of her limbs and trunk 6 days after developing symptoms of common cold. Two days later, she experienced respiratory arrest with a Glasgow Coma Scale score of 3, necessitating endotracheal intubation. Therefore, she was transferred to our hospital with suspected acute encephalopathy. Although no abnormalities were observed on brain and spinal magnetic resonance imaging and electroencephalography, peripheral nerve conduction velocity tests failed to evoke motor and sensory nerve action potentials. Thus, we gave a diagnosis of fulminant Guillain-Barré syndrome and initiated immunoglobulin therapy. On day 3 of admission, she developed sinus tachycardia that induced circulatory failure and oliguria, which was successfully treated with landiolol. Subsequently, we performed plasmapheresis followed by immunoglobulin and steroid pulse therapies. She was weaned off the mechanical ventilator by day 20 of admission, was ambulatory by day 44, and had completely recovered without any adverse sequelae by day 55. In conclusion, landiolol was effective for treating acute sinus tachycardia-induced circulatory failure and played a key role in saving the life of this patient.

Intellectual outcomes of extremely preterm infants at school age.

BACKGROUND: The survival rate of extremely preterm (EP) infants (<28 weeks of gestation) has improved dramatically, and there is great interest in the long-term prognosis. The aim of this study was to elucidate the influence of prenatal and postnatal care on long-term intellectual outcome in EP infants. METHODS: Subjects were EP infants admitted to the neonatal intensive care unit from 1982 to 2005. The survival rate and neurodevelopmental outcomes at 6 years of age were analyzed for the periods 1982-1991 (period 1) and 1992-2005 (period 2). Logistic regression analysis was performed to examine risk factors for intellectual impairment. RESULTS: Survival rate improved significantly from 84.5% (period 1) to 92.4% (period 2; P = 0.007). Follow-up data were obtained from 92 children in period 1 (69.7% of survivors) and from 245 in period 2 (72.3% of survivors). The incidence of intellectual impairment increased from 16.3% (period 1) to 31.0% (period 2). Significant factors associated with intellectual impairment were period 2 (OR, 3.53; P = 0.007), supplemental oxygen at 36 weeks' corrected age (OR, 2.22; P = 0.012), number of days in the hospital (OR, 1.01; P = 0.012), intraventricular hemorrhage (IVH; OR, 3.05; P = 0.024), and later tube-feeding commencement date (OR, 1.10; P = 0.032). CONCLUSIONS: Despite an increase in survival rate, the rate of intellectual impairment increased in period 2. According to risk factor analysis, reducing the incidence of chronic lung disease and/or apnea, IVH, and nutritional deprivation is a key factor in improving the intellectual outcomes of EP infants.

Temporal brain metabolite changes in preterm infants with normal development.

OBJECTIVE: Preterm infants are at high risk for developmental delay, epilepsy, and autism spectrum disorders. Some reports have described associations between these conditions and gamma-aminobutyric acid (GABA) dysfunction; however, no study has evaluated temporal changes in GABA in preterm infants. Therefore, we assessed temporal changes in brain metabolites including GABA using single-voxel 3-Tesla (T) proton magnetic resonance spectroscopy (1H-MRS) in preterm infants with normal development. METHODS: We performed 3T 1H-MRS at 37-46 postmenstrual weeks (PMWs, period A) and 64-73PMWs (period B). GABA was assessed with the MEGA-PRESS method. N-acetyl aspartate (NAA), glutamate-glutamine complex (Glx), creatine (Cr), choline (Cho), and myo-inositol (Ins) were assessed with the PRESS method. Metabolite concentrations were automatically calculated using LCModel. RESULTS: Data were collected from 20 preterm infants for periods A and B (medians [ranges], 30 [24-34] gestational weeks, 1281 [486-2030]g birth weight). GABA/Cr ratio decreased significantly in period B (p=0.03), but there was no significant difference in GABA/Cho ratios (p=0.58) between the two periods. In period B, NAA/Cr, Glx/Cr, NAA/Cho, and Glx/Cho ratios were significantly increased (p<0.01), whereas Cho/Cr, Ins/Cr, and Ins/Cho ratios were significantly decreased (p<0.01). There was no significant difference for GABA or Cho concentrations (p=0.52, p=0.22, respectively). NAA, Glx, and Cr concentrations were significantly increased (p<0.01), whereas Ins was significantly decreased (p<0.01). CONCLUSIONS: Our results provide new information on normative values of brain metabolites in preterm infants.

Asymptomatic congenital cytomegalovirus infection with neurological sequelae: A retrospective study using umbilical cord.

BACKGROUND: Congenital cytomegalovirus (CMV) infection causes various neurological sequelae. However, most infected infants are asymptomatic at birth, and retrospective diagnosis is difficult beyond the neonatal period. OBJECTIVE: This study aimed to investigate the aspects of neurological sequelae associated with asymptomatic congenital CMV infection. METHODS: We retrospectively analyzed 182 patients who were suspected of having asymptomatic congenital CMV infection with neurological symptoms in Japan. Congenital CMV infection was diagnosed by quantitative polymerase chain reaction amplification of CMV from dried umbilical cord DNA. RESULTS: Fifty-nine patients (32.4%) who tested positive for CMV were confirmed as having congenital CMV infection. Among 54 congenital CMV patients, major neurological symptoms included intellectual disability (n=51, 94.4%), hearing impairment (n=36, 66.7%) and cerebral palsy (n=21, 38.9%), while microcephaly (n=16, 29.6%) and epilepsy (n=14, 25.9%) were less common. In a brain magnetic resonance imaging (MRI) study, cortical dysplasia was observed in 27 CMV-positive patients (50.0%), and all patients (100%) had cerebral white matter (WM) abnormality. Intracranial calcification was detected by CT in 16 (48.5%) of 33 CMV-positive patients. Cerebral palsy, cortical dysplasia and a WM abnormality with a diffuse pattern were associated with marked intellectual disability. CONCLUSIONS: Brain MRI investigations are important for making a diagnosis and formulating an intellectual prognosis. Analysis of umbilical cord tissue represents a unique and useful way to retrospectively diagnose congenital CMV infection.

Assessing Temporal Brain Metabolite Changes in Preterm Infants Using Multivoxel Magnetic Resonance Spectroscopy.

PURPOSE: To investigate temporal changes in brain metabolites during the first year of life in preterm infants using multivoxel proton magnetic resonance spectroscopy ((1)H-MRS). METHODS: Seventeen infants born at 29 (25-33) gestational week (median, range) weighing 1104 (628-1836) g underwent 1.5-T multivoxel (1)H-MRS at 42 postconceptional week (PCW) and at 3, 6, 9, and 12 months after. We measured N-acetyl aspartate (NAA)/creatine (Cr), choline (Cho)/Cr, myo-inositol (Ins)/Cr, NAA/Cho, and Ins/Cho ratios in the frontal lobe (FL) and basal ganglia and thalamus (BG + Th). Linear regression analyses were performed to identify longitudinal changes in infants showing normal imaging findings and normal development. We also evaluated ratios of subjects with abnormal imaging findings and/or development using the 95% confidence intervals (CIs) of regression equations in normal subjects. RESULTS: In the 13 infants with normal development, NAA/Cr and NAA/Cho ratios showed significant positive correlations with PCWs in the FL (r = 0.64 and 0.83, respectively, both P < 0.01) and BG + Th (r = 0.79 and 0.87, respectively, both P < 0.01), while Cho/Cr and Ins/Cr ratios revealed significant negative correlations with PCWs in the FL (r =-0.69 and -0.58, respectively, both P < 0.01) and BG + Th (r =-0.74 and -0.72, respectively, both P < 0.01). Ins/Cho ratios in the FL did not significantly correlate with PCWs (r =-0.19, P = 0.18), while those in the BG + Th showed significant negative correlation with PCWs (r =-0.44, P < 0.01). The metrics in the abnormal group were within the normal group 95% CIs in all periods except a few exceptions. CONCLUSIONS: Longitudinal multivoxel MRS is able to detect temporal changes in major brain metabolites during the first year of life in preterm infants.

Hypofibrinogenemia caused by adrenocorticotropic hormone for infantile spasms: a case report.

We report the case of a 7-month-old boy who developed hypofibrinogenemia (66.6 mg/dL; reference value, 170-405 mg/dL) during adrenocorticotropic hormone (ACTH) therapy for infantile spasms. Although the patient showed no clinical signs of a bleeding diathesis, we recommend that plasma fibrinogen levels should be monitored during ACTH therapy, which should be discontinued when fibrinogen levels fall below hemostatic levels (60.0mg/dL) or when bleeding tendencies are recognized.

Clinical and genetic features of acute encephalopathy in children taking theophylline.

BACKGROUND: Theophylline has recently been suspected as a risk factor of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), although there has been no systematic study on the relationship between acute encephalopathy in children taking theophylline (AET) and AESD. METHODS: We recruited 16 Japanese patients (11 male and 5 female, median age of 2 years and 7 months) with AET from 2008 to 2013. We evaluated their clinical features, such as the duration of first seizure, biphasic clinical course and cranial CT/MRI imaging and compared them with those of AESD. We analyzed the polymorphisms or mutations of genes which are associated with AESD. RESULTS: Clinically, 12 patients had neurological and/or radiological features of AESD. Only one patient died, whereas all 15 surviving patients were left with motor and/or intellectual deficits. Genetically, 14 patients had at least one of the following polymorphisms or mutations associated with AESD: thermolabile variation of the carnitine palmitoyltransferase 2 (CPT2) gene, polymorphism causing high expression of the adenosine receptor A2A (ADORA2A) gene, and heterozygous missense mutation of the voltage gated sodium channel 1A (SCN1A) and 2A (SCN2A) gene. CONCLUSIONS: Our results demonstrate that AET overlaps with AESD, and that AET is a multifactorial disorder sharing a genetic background with AESD.

Aicardi-Goutières syndrome with systemic lupus erythematosus and hypothyroidism.

We report a case of Aicardi-Goutières syndrome with systemic lupus erythematosus and hypothyroidism. A 3-year-old girl, diagnosed with Aicardi-Goutières syndrome at 9 months, was transferred to our hospital for fever of unknown origin. Severe spasticity with dystonic posturing and flexion contracture of the limbs were noted. Interstitial pneumonia with pleural effusion was evident. Immunological investigations revealed positive antinuclear antibodies and reduced thyroid function. Prompt treatment with steroids, cyclophosphamide, and levothyroxine sodium hydrate elicited a good response. It is necessary to emphasize that its possible relationship between Aicardi-Goutières syndrome and systemic lupus erythematosus and/or hypothyroidism.

Use of magnetic resonance imaging to identify the edge of a dural tear in an infant with growing skull fracture: a case study.

PURPOSE: Growing skull fractures can be a challenging surgical problem facing pediatric neurosurgeons. The goal of this manuscript was to describe an effective surgical method used to treat a growing skull fracture. METHODS: We present a case study of a 2-month-old boy who fell from his mother's arms and hit his head on the floor; he underwent X-ray, magnetic resonance (MR), and computed tomography (CT) imaging before cranioplasty with dural plasty. RESULTS: X-ray performed on admission revealed a diastatic fracture with a gap of 8 mm in the right frontal bone and a linear fracture in the right occipital bone. X-ray performed 37 days after injury demonstrated that the gap had increased to 25 mm, and the patient was diagnosed with a growing skull fracture of the right parietal bone. Cranioplasty with dural plasty was performed on day 39. A combination of MR and CT images enabled the edge of the dural tear to be plotted on a three-dimensional image of the skull, and this was used to estimate the location of the edge of the dural tear on the scalp. CONCLUSIONS: We achieved excellent outcomes in terms of bony coverage and dural plasty. The combination of MR and CT images may be recommended for surgical repair of growing skull fracture in children.

Proton magnetic resonance spectroscopic images in preterm infants with bilirubin encephalopathy.

Two preterm infants with athetoid cerebral palsy due to bilirubin encephalopathy were examined by magnetic resonance spectroscopic imaging at age 3 years. An increased glutamate/glutamine complex/creatine ratio was found in the basal ganglia. Chemical metabolic abnormalities of the basal ganglia were clearly demonstrated by color-coded metabolite images.

Unique discrepancy between cerebral blood flow and glucose metabolism in hemimegalencephaly.

Hemimegalencephaly (HME) presents as severe refractory seizures and requires early surgical treatment to prevent progression to catastrophic epilepsy. Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) are useful imaging techniques for the presurgical evaluation of patients with intractable epilepsy. However, the results in HME are variable and no study has compared SPECT and PET performed at around the same time. We performed SPECT and PET for nine patients with HME, which was defined as a whole or part of affected hemisphere enlargement (three males, six females; age range 0.5-20 years). The ictal and interictal states were determined based on the presence or absence of clinical seizures during all PET examinations and majority of SPECT examinations. The perfusion pattern in the malformed hemisphere was increased or equal, despite the reduced glucose metabolism in six out of nine patients. Five of the six patients who underwent early surgical treatment showed this kind of perfusion/metabolism discrepancy. Importantly, even the non-affected hemisphere in early infantile cases already lacked the normal hypoperfusion and hypometabolism patterns of immature frontal lobes, which was most prominent in case with poor surgical prognosis. In all six surgical patients, epileptic seizures appeared before 4 months of age. By contrast, none of the non-surgical patients had seizures before 4 months of age. In conclusion, although the number of patients examined is small and the result is still preliminary, the perfusion/metabolism discrepancy found in this study may show potential characteristic aspect of HME and further study with simultaneous EEG recording will make clear if this finding can be useful indicator for early surgical treatment in HME.

Different effects of novel mtDNA G3242A and G3244A base changes adjacent to a common A3243G mutation in patients with mitochondrial disorders.

Two novel mitochondrial DNA base changes were identified at both sides of the 3243A>G mutation, the most common mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). One was a 3244G>A transition in a girl with MELAS. The other was a 3242G>A transition in a girl with a mitochondrial disorder without a MELAS phenotype. Although the two base changes were adjacent to the 3243A>G mutation, they had different effects on the clinical phenotype, muscle pathology, and respiratory chain enzyme activity. Investigations of the different effects of the 3244G>A and 3242G>A base changes may provide a better understanding of tRNA dysfunction in mitochondrial disorders.