Serum brain-type creatine kinase increases in children with osteogenesis imperfecta during neridronate treatment.

BACKGROUND: Creatine kinase (Ck) catalyzes the reversible transfer of high-energy phosphate groups between adenosine triphosphate and phosphocreatine. The brain isoform (Ckbb) is greatly induced in mature osteoclasts, playing an important role in bone-resorbing function during osteoclastogenesis. High Ckbb serum level has been found in patients with osteopetrosis and in patients with bisphosphonate (BP)-induced osteopetrosis. BPs are considered the treatment of choice for children with osteogenesis imperfecta (OI), acting as potent inhibitors of bone resorption by suppressing the activity of osteoclasts. METHODS: We determined total serum Ck and isoform activity in 18 prepubertal children with type I OI, before and during treatment with the BP neridronate infusions. RESULTS: Basal serum Ckbb levels were slightly elevated with respect to controls (mean ± SD = 3.0 ± 2.7 vs. 2.0 ± 2.2) and progressively increased after neridronate treatment (t0 vs. t4: mean ± SD = 3.0 ± 2.7 to 10.8 ± 8.1), with significant increment after first, second, and fourth infusions (P < 0.01). An inverse correlation was found between serum Ckbb and serum CTx at basal level. CONCLUSION: Our results support previous observations that increased serum Ckbb reflects failure of osteoclasts or, at least, suppression of osteoclasts. Upon considering that BPs are long acting, this information could be useful to prevent the risk of overtreatment after long-term BP exposure in pediatric patients with OI.

Evaluation of the basal ganglia in neurofibromatosis type 1.

PURPOSE: Alterations of the brain microstructure and metabolism have been identified in patients with neurofibromatosis type 1 (NF1). In this study, we analyzed the basal ganglia of NF1 subjects without cognitive delay throughout a combined approach with magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) in order to better define the metabolic and microstructural characteristics of these regions and, furthermore, to verify if metabolic and microstructural abnormalities may be present in normally developed NF1 patients. METHODS: A 3-T MRI with multivoxel MRS and DTI was performed in 14 NF1 patients and eight controls. N-acetyl-aspartate (NAA), choline (Cho), creatine (Cr) values and ratios, fractional anisotropy, and apparent diffusion coefficient (ADC) were calculated, for a total of four regions of interest (ROI) for each hemisphere. RESULTS: NF1 patients, compared to healthy controls, showed (a) decreased NAA in all the four ROI, (b) increased Cho and decreased Cr in three of the four ROI, (c) decreased NAA/Cho ratio in three ROI, and (d) increased ADC in all the four ROI. A trend of increased ADC was present in three of the four ROI of NF1 patients with unidentified bright objects (UBOs) and younger than 18 years. CONCLUSION: These data confirm the presence of neuroaxonal damage with myelin disturbances in NF1 patients. We showed that metabolic and microstructural anomalies can be present in the same time in NF1 patients without developmental delay or cognitive deficits. Relations between brain anomalies, UBOs, and cognitive functions need further studies.

Chilblain-like lesions onset during SARS-CoV-2 infection in a COVID-19-vaccinated adolescent: case report and review of literature.

BACKGROUND: COVID toes or chilblain-like skin lesions have been widely reported during COVID-19 pandemic. Most cases were described in patients with negative microbiological tests for SARS-CoV-2, therefore the possible relationship with SARS-CoV-2 infection, as well as with the nowadays broadly available mRNA-based vaccination, has not been fully elucidated.  CASE PRESENTATION: We here describe the case of a 14-year-old male who developed chilblain-like skin eruptions during SARS-CoV-2 infection despite two mRNA-based vaccine doses and review the clinical and epidemiological characteristics of chilblain-like lesions as a cutaneous presentation of COVID-19 in children. CONCLUSIONS: Most children and adolescent with COVID toes have a mild or asymptomatic SARS-CoV-2 infection. Our report aims to highlight the possible onset of these skin lesions in vaccinated children, if infection has occurred, and the potential use of systemic corticosteroids as a first line treatment. Additional evidence is required to better understand SARS-CoV-2 infection and cutaneous manifestations in children and determine the relationship between chilblain-like lesions and COVID-19 vaccination.

MTHFR homozygous mutation and additional risk factors for cerebral infarction in a large Italian family.

Several cases with cerebral infarctions associated with the C677T mutation in the methylenetetrahydrofolate reductase gene (MTHFR) have been reported. Given the large number of asymptomatic individuals with the MTHFR mutation, additional risk factors for cerebral infarction should be considered. This study describes a large family with the MTHFR mutation and a combination of heterozygous factor V Leiden mutations and different additional exogenous and endogenous thrombogenic risk factors. Psychomotor retardation and a left fronto-insular infarct associated with the MTHFR mutation together with diminished factor VII and low level of protein C was documented in the first patient. In the second patient, generalized epilepsy and a malacic area in the right nucleus lenticularis was associated with the MTHFR mutation and a low level of protein C. In the third patient, right hemiparesis and a left fronto-temporal porencephalic cyst were documented, together with the MTHFR mutation and hyperhomocysteinemia. An extensive search of additional circumstantial and genetic thrombogenic risk factors should be useful for prophylaxis and prognosis of infants with cerebral infarctions associated with the MTHFR mutation and of their related family members.

Stroke in children: inherited and acquired factors and age-related variations in the presentation of 48 paediatric patients.

AIM: Stroke is relatively rare in children and the clinical presentation of paediatric stroke is often subtle. Numerous predisposing risk factors are known, and these can be both inherited and acquired. They include cardiac disease, vascular abnormalities, endothelial damage, infectious diseases, collagen tissue diseases, certain inborn errors of metabolism and anticardiolipin antibody, lupus anticoagulant and deficiencies of protein C, protein S, antithrombin or plasminogen. In addition, abnormal activated protein C resistance (or Factor V Leiden), Factor II G20219A variant, and the thermolabile variant of methylenetetrahydrofolate reductase (MTHFR C677T) need to be considered. METHODS: To explore the prevalence of different predisposing conditions in paediatric stroke patients, we evaluated 48 patients, including subjects with ischaemic and haemorrhagic stroke subtypes. RESULTS: Only 7 out of 48 (14.5%) had no recognizable risk factors: the majority of paediatric stroke patients had pre-existing risk factors that predisposed to the condition. The major genetic risk factor in our series of patients was homozygosity for the MTHFR C677T mutation (7 out of 48 patients); three more patients were found to be heterozygous for the Factor V Leiden mutation. Acquired predisposing conditions were present in 23 out of 48 patients and included pulmunar stenosis, head trauma, hyperlipidaemia and varicella infection. A total of 17 patients had both genetic and acquired predisposing factors. CONCLUSION: Our results emphasize that multiple predisposing risk factors commonly predispose to paediatric stroke. In addition, the primary clinical presentation appeared to differ between the older and younger children: hemiparesis was the typical presentation in children <1 year of age while seizure predominated in older children.

Three-dimensional echocardiography in various types of heart disease: a comparison study of magnetic resonance imaging and 64-slice computed tomography in a real-world population.

BACKGROUND: Accurate quantification of left ventricular (LV) volumes [end-diastolic volume (EDV) and end-systolic volume (ESV)] and ejection fraction (EF) is of critical importance. The development of real-time three-dimensional echocardiography (RT3DE) has shown better correlation than two-dimensional (2D) echocardiography with magnetic resonance imaging (MRI) measurements. The aim of our study was to assess the accuracy of RT3DE and 64-slice computed tomography (CT) in the evaluation of LV volumes and function using MRI as the reference standard in a real-world population with various types of heart disease with different chamber geometry. METHODS: The study population consisted of 66 patients referred for cardiac MRI for various pathologies. All patients underwent cardiac MRI, and RT3DE and 64 slices CT were then performed on a subsequent day. The study population was then divided into 5 clinical groups depending on the underlying heart disease. RESULTS: RT3DE volumes correlated well with MRI values (R 2 values: 0.90 for EDV and 0.94 for ESV). RT3DE measurements of EF correlated well with MRI values (R 2 = 0.86). RT3DE measurements resulted in slightly underestimated values of both EDV and ESV, as reflected by biases of -9.18 and -4.50 mL, respectively. Comparison of RT3DE and MRI in various types of cardiomyopathies showed no statistical difference between different LV geometrical patterns. CONCLUSION: These results confirm that RT3DE has good accuracy in everyday clinical practice and can be of clinical utility in all types of cardiomyopathy independently of LV geometric pattern, LV diameter or wall thickness, taking into account a slight underestimation of LV volumes and EF compared to MRI.

Stroke and migraine is there a possible comorbidity?

The association between migraine and stroke is still a dilemma for neurologists. Migraine is associated with an increased stroke risk and it is considered an independent risk factor for ischaemic stroke in a particular subgroup of patients. The pathogenesis is still unknown even if several studies report some common biochemical mechanisms between these two diseases. A classification of migraine-related stroke that encompasses the full spectrum of the possible relationship between migraine and stroke includes three main entities: coexisting stroke and migraine, stroke with clinical features of migraine, and migraine-induced stroke. The concept of migraine-induced stroke is well represented by migrainous infarction and it is described in the revised classification of the International Headache Society (IHS), representing the strongest demonstration of the relationship between ischaemic stroke and migraine. A very interesting common condition in stroke and migraine is patent foramen ovale (PFO) which could play a pathogenetic role in both disorders. The neuroradiological evidence of subclinical lesions most typical in the white matter and in the posterior artery territories in patients with migraine, opens a new field of research. In conclusion the association between migraine and stroke remains an open question. Solving the above mentioned issues is fundamental to understand the epidemiologic, pathogenetic and clinical aspects of migraine-related stroke.

Intravenous immunoglobulin and interferon: successful treatment of optic neuritis in pediatric multiple sclerosis.

Optic neuritis is a common clinical condition that causes loss of vision. It can be clinically isolated or can occur as one of the manifestations of multiple sclerosis. Multiple sclerosis is a severe disabling demyelinating disease of the central nervous system, which is rare among children. The treatment of optic neuritis has been investigated in several trials, the results of which have shown that corticosteroids speed up the recovery of vision without affecting the final visual outcome. Treatment of neurologic disorders with intravenous immunoglobulin is an increasing feature of our practice for an expanding range of indications, including multiple sclerosis. Owing to its anti-inflammatory properties, intravenous immunoglobulin can be beneficial in the treatment of acute relapses and in the prevention of new relapses of multiple sclerosis. To our knowledge, there is only one experience of treatment of optic neuritis with intravenous immunoglobulin in multiple sclerosis, even if therapeutic trials are used in the therapy of multiple sclerosis. We report on a girl with optic neuritis and multiple sclerosis in whom treatment with intravenous immunoglobulin at first alone and subsequently associated with interferon achieved great improvement in visual acuity.

Electroencephalogram and magnetic resonance imaging comparison as a predicting factor for neurodevelopmental outcome in hypoxic ischemic encephalopathy infant treated with hypothermia.

Hypoxic-ischemic encephalopathy (HIE) is an important cause of acute neurological damage in newborns at (or near) term. Several trials in recent years have shown that moderate hypothermia by total body cooling or selective head is an effective intervention to reduce mortality and major disability in infants survived a perinatal hypoxic-ischemic attack. Follow-up in these patients is very important to establish neurodevelopmental outcome, and specific markers can lead us to detect predicting sign for good or poor outcome. We reported a few cases of newborn with HIE treated with hypothermia, in whom the comparison between electroencephalogram (EEG) and magnetic resonance imaging (MRI) represents the first marker for neurodevelopment outcome prediction. The continuous EEG monitoring showed a depressed EEG activity with diffuse burst depression in 7 patients. No epileptic abnormalities were registered. In 10 out of 20 patients no abnormalities of the background activity and no epileptic abnormalities were observed. We found that a depressed EEG activity during the first 72 h of life and a diffused alteration of basal ganglia at MRI were correlated with a poor neurodevelopmental outcome at 18 months of follow-up.

Cluster headache in childhood: case series from a pediatric headache center.

Childhood-onset cluster headache is an excruciatingly painful and distressing condition. A retrospective study was conducted on charts of patients referring to our Headache Center. Those diagnosed as cluster headache were selected. We identified 11 children (6 males and 5 females). The mean age of cluster headache onset was 10 years (range: 5-16). All children had episodic cluster headache. All children had unilateral orbital pain; 7 patients had throbbing pain, whereas 4 children complained stabbing pain. The mean duration of the attack was 86 minutes (ranging from 30 to 180 minutes). The frequency of episodes was between 1 and 4 per day. All children had the typical cluster headache autonomic features, such as lacrimation, conjunctival injection, ptosis, and nostril rhinorrhea. Steroids showed a good clinical efficacy in interrupting cluster headache recurrence. As symptomatic drugs, acetaminophen as well as ibuprofen were ineffective; indomethacin was effective in 1 case.

Scoliosis secondary to ganglioneuroma: a case report and up to date literature review.

Idiopathic scoliosis is the most common form of spinal deformity in children. However, secondary causes of scoliosis, such as ganglioneuroma, should be always considered to avoid wrong diagnosis, and further investigations are required when there are atypical signs. We report a case of ganglioneuroma misdiagnosed as idiopathic scoliosis and review the literature to identify the red flags useful for physicians during the evaluation of a child with scoliosis. On the basis of both clinical and radiographic criteria that emerged from this study, we propose an algorithm that could help in the differential diagnosis, suggesting when to perform an MRI.

Genome characterization through dichotomic classes: an analysis of the whole chromosome 1 of A. thaliana.

In this article we show how dichotomic classes, binary variables naturally derived from a new mathematical model of the genetic code, can be used in order to characterize different parts of the genome. In particular, we analyze and compare different parts of whole chromosome 1 of Arabidopsis thaliana: genes, exons, introns, coding sequences (CDS), intergenes, untranslated regions (UTR) and regulatory sequences. In order to accomplish the task we encode each sequence in the 3 possible reading frames according to the definitions of the dichotomic classes (parity, Rumer and hidden). Then, we perform a statistical analysis on the binary sequences. Interestingly, the results show that coding and non-coding sequences have different patterns and proportions of dichotomic classes. This suggests that the frame is important only for coding sequences and that dichotomic classes can be useful to recognize them. Moreover, such patterns seem to be more enhanced in CDS than in exons. Also, we derive an independence test in order to assess whether the percentages observed could be considered as an expression of independent random processes. The results confirm that only genes, exons and CDS seem to possess a dependence structure that distinguishes them from i.i.d sequences. Such informational content is independent from the global proportion of nucleotides of a sequence. The present work confirms that the recent mathematical model of the genetic code is a new paradigm for understanding the management and the organization of genetic information and is an innovative tool for investigating informational aspects of error detection/correction mechanisms acting at the level of DNA replication.

Pediatric cerebellar stroke associated with elevated titer of antibodies to ß2-glycoprotein.

Antibodies to 2-glycoprotein I (anti-2GPI) have been associated with recurrent thrombosis and pregnancy morbidity. However, the prevalence of anti-2GPI in children suffering from cerebral and cerebellar infarction is unknown. We report on a 10-month-old boy who had an ischemic cerebellar stroke, secondary to antiphospholipid syndrome with high titers of immunoglobulin G anti-2GPI (first titer: 132U) anticardiolipin antibodies and lupus anticoagulant tests were negative. All other causes of infarction were excluded. To our knowledge, this is the first reported case of childhood cerebellar ischemic stroke with only anti-2GPI but no antibodies detectable in standard antiphospholipid assays.

Chiari type I malformation, syncope, headache, hypoglycemia and hepatic steatosis in an 8-year old girl: a causal association?

Chiari type I malformation (CMI) is a congenital hindbrain anomaly characterized by downward displacement of the cerebellar tonsils through the foramen magnum. Chiari type I malformation often presents with a complex clinical picture and can be sporadic or linked to a variety of genetic conditions. We report on a girl in whom Chiari type I malformation was associated with hypoglycemia, headache, vertigo, syncope and hepatic steatosis. We hypothesize that these symptoms are primarily a consequence of Chiari type I malformation.

Clinical and pharmacological aspects of inflammatory demyelinating diseases in childhood: an update.

Inflammatory demyelinating diseases comprise a spectrum of disorders affecting the myelin of the central and peripheral nervous system. These diseases can usually be differentiated on the basis of clinical, radiological, laboratory and pathological findings. Recent studies have contributed to current awareness that inflammatory demyelinating diseases are not restricted to the adult age group, but are more common in pediatric age than previously believed. Some of pediatric inflammatory demyelinating diseases carry an unfavorable long-term prognosis but appropriate treatments can improve the outcome. The possibility of physical and cognitive disability resulting from these diseases, highlights the urgent need for therapeutic strategies for neurorehabilitation, neuroregeneration, and neurorepair. This review discusses characteristics of primary demyelinating diseases more frequently observed in childhood, focusing on epidemiology, clinical aspects and treatments.

Increased nitric oxide release by neutrophils of a patient with tyrosinemia type III.

Tyrosinemia type III (OMIM 276710) is an autosomal recessive disorder caused by the deficiency of 4-hydroxyphenylpyruvate dioxygenase (4-HPD). Few cases have been described with mental retardation or neurological symptoms. Recently it has been demonstrated that 4-HPD participates to nitric oxide (NO) intracellular sequestration in Pseudomonas aeruginosa. 4-HPD is an ubiquitous enzyme with a prominent expression in neutrophils and neurons. In the nervous system NO has been perceived to be a potential neuromodulator although prolonged excessive generation is detrimental. We analyzed NO release by neutrophils of a patient with tyrosinemia type III in order to evaluate a possible influence of 4-HPD deficiency on this process. Our patient, previously described, is a 30-year-old women with persistent tyrosinemia (450-680 micromol/l) and deficient activity of 4-HPD. At 17 months of age she experienced an acute ataxia and drowsiness lasting for 10 days, but further clinical course showed persistent tyrosinemia with normal growth and psychomotor development. Neutrophils isolated from our patient exhibited a NO release greatly higher in respect to the controls (mean+/-SEM 23.2+/-1.8 micromol/10(6) cells vs 3.5+/-0.5 micromol/10(6) cells). Clinical findings of tyrosinemia type III include neurological symptoms and mental retardation but no consistent phenotype has emerged. Therefore the pathogenesis of neurological involvement is yet not well understood. Our results suggest that an excessive neutrophils of NO release could reflect the lack of scavenging action of 4-HPD. Considering the prominent expression of this enzyme in neurons, we hypothesize that excessive NO release could participate in neuronal damage explaining the neurological involvement described in patients with tyrosinemia type III.

Methylenetetrahydrofolate reductase homozygous mutation in a young boy with cerebellar infarction.

Posterior circulation vascular occlusive disease in children is a rare and uncommonly reported event. Among the numerous risk factors, the methylenetetrahydrofolate reductase (MTHFR) mutation is considered to be a common genetic cause of thrombosis in adults and children. Recently, a link between the MTHFR mutation and cerebrovascular disorders was reported in children. Diffusion tensor imaging (DTI) is a great improvement on magnetic resonance imaging (MRI), making the in vivo anatomical and pathological study of the brain and its fibers possible. In our patient cerebellar infarction was associated with MTHFR mutation and, in a standard neurological examination, DTI revealed normal white matter tracts.