Branched-chain amino acids as adjunctive-alternative treatment in patients with autism: a pilot study.

The branched-chain amino acid (BCAA) is a group of essential amino acids that are involved in maintaining the energy balance of a human being as well as the homoeostasis of GABAergic, glutamatergic, serotonergic and dopaminergic systems. Disruption of these systems has been associated with the pathophysiology of autism while low levels of these amino acids have been discovered in patients with autism. A pilot open-label, prospective, follow-up study of the use of BCAA in children with autistic behaviour was carried out. Fifty-five children between the ages of 6 and 18 participated in the study from May 2015 to May 2018. We used a carbohydrate-free BCAA-powdered mixture containing 45·5 g of leucine, 30 g of isoleucine and 24·5 g of valine in a daily dose of 0·4 g/kg of body weight which was administered every morning. Following the initiation of BCAA administration, children were submitted to a monthly psychological examination. Beyond the 4-week mark, BCAA were given to thirty-two people (58·18 %). Six of them (10·9 %) discontinued after 4-10 weeks owing to lack of improvement. The remaining twenty-six children (47·27 %) who took BCAA for longer than 10 weeks displayed improved social behaviour and interactions, as well as improvements in their speech, cooperation, stereotypy and, principally, their hyperactivity. There were no adverse reactions reported during the course of the treatment. Although these data are preliminary, there is some evidence that BCAA could be used as adjunctive treatment to conventional therapeutic methods for the management of autism.

Blood pressure in children with sickle cell disease is higher than in the general pediatric population.

BACKGROUND: Sickle cell disease (SCD) is associated with an increased risk of cardiovascular disease that may be due to a variety of possible risk factors, including abnormal blood pressure. Blood pressure (BP) of children and adolescents with SCD has been reported to be lower compared to the BP of the general pediatric population. METHODS: To confirm this prior observation, we compared reference BP values for children with SCD with reference BP values of the general pediatric population. We hypothesized that children with SCD do not have lower BPs than children without SCD. RESULTS: Systolic BP differed for both males and females, over the different age groups between pediatric subjects with and without SCD. Systolic BP was higher in children with SCD, in both obese and non-obese populations. Diastolic BP did not differ between the groups. CONCLUSIONS: Our analysis demonstrated that systolic BP values are indeed higher in children with SCD than in the general pediatric population. This finding is consistent with the most recent literature showing abnormal BP patterns in the SCD pediatric population utilizing 24-hour BP monitoring devices. This is an important step for recognizing abnormal BP as a risk factor for cardio- and neurovascular events in SCD.

Integrative Approach to Predict Severity in Nonketotic Hyperglycinemia.

OBJECTIVE: Glycine encephalopathy, also known as nonketotic hyperglycinemia (NKH), is an inherited neurometabolic disorder with variable clinical course and severity, ranging from infantile epileptic encephalopathy to psychiatric disorders. A precise phenotypic characterization and an evaluation of predictive approaches are needed. METHODS: Longitudinal clinical and biochemical data of 25 individuals with NKH from the patient registry of the International Working Group on Neurotransmitter Related Disorders were studied with in silico analyses, pathogenicity scores, and molecular modeling of GLDC and AMT variants. RESULTS: Symptom onset (p < 0.01) and diagnosis occur earlier in life in severe NKH (p < 0.01). Presenting symptoms affect the age at diagnosis. Psychiatric problems occur predominantly in attenuated NKH. Onset age ≥ 3 months (66% specificity, 100% sensitivity, area under the curve [AUC] = 0.87) and cerebrospinal fluid (CSF)/plasma glycine ratio ≤ 0.09 (57% specificity, 100% sensitivity, AUC = 0.88) are sensitive indicators for attenuated NKH, whereas CSF glycine concentration ≥ 116.5µmol/l (100% specificity, 93% sensitivity, AUC = 0.97) and CSF/plasma glycine ratio ≥ 0.15 (100% specificity, 64% sensitivity, AUC = 0.88) are specific for severe forms. A ratio threshold of 0.128 discriminates the overlapping range. We present 10 new GLDC variants. Two mild variants resulted in attenuated, whereas 2 severe variants or 1 mild and 1 severe variant led to severe phenotype. Based on clinical, biochemical, and genetic parameters, we propose a severity prediction model. INTERPRETATION: This study widens the phenotypic spectrum of attenuated NKH and expands the number of pathogenic variants. The multiparametric approach provides a promising tool to predict disease severity, helping to improve clinical management strategies. ANN NEUROL 2022;92:292-303.

Insights into the expanding phenotypic spectrum of inherited disorders of biogenic amines.

Inherited disorders of neurotransmitter metabolism are rare neurodevelopmental diseases presenting with movement disorders and global developmental delay. This study presents the results of the first standardized deep phenotyping approach and describes the clinical and biochemical presentation at disease onset as well as diagnostic approaches of 275 patients from the registry of the International Working Group on Neurotransmitter related Disorders. The results reveal an increased rate of prematurity, a high risk for being small for gestational age and for congenital microcephaly in some disorders. Age at diagnosis and the diagnostic delay are influenced by the diagnostic methods applied and by disease-specific symptoms. The timepoint of investigation was also a significant factor: delay to diagnosis has decreased in recent years, possibly due to novel diagnostic approaches or raised awareness. Although each disorder has a specific biochemical pattern, we observed confounding exceptions to the rule. The data provide comprehensive insights into the phenotypic spectrum of neurotransmitter disorders.

The Complex Interplay of Cortex, Cerebellum, and Age in a Cohort of Pediatric Patients With Tuberous Sclerosis Complex.

BACKGROUND: The neurodevelopmental impairment in tuberous sclerosis complex (TSC) has a multifactorial origin. Various factors have been proposed as predictors of neurological outcome such as tuber load, seizure onset, and TSC2 mutation. Cerebellar lesions have been associated with worse neuroradiological phenotype, but their contribution is not well understood. METHODS: A partly retrospective and partly prospective pediatric cohort study was conducted at three hospitals in Greece between 2015 and 2020. Patients aged ≤ 18 years with a confirmed TSC daignosis were included and underwent brain imaging, a semistructured interview (authorized Greek version of the tuberous sclerosis-associated neuropsychiatric disorders, or TAND, checklist), and intellectual ability assessment. RESULTS: The study populations consisted of 45 patients with TSC (22 females, 23 males; mean age 9.53 years). Twenty patients (44.4%) had cerebellar lesions. Cerebellar involvement was the most powerful predictor of tuber load (P = 0.03). Cerebellar lesions were associated with giant cell astrocytomas (SEGAs) (P = 0.01) and severe neurological outcome (P = 0.01). Even though in the univariate analysis early seizure onset, tuber load, and cerebellar involvement were associated with intellectual impairment and neurological severity, none of them was an independent predictor of cognitive outcome and neurological severity. CONCLUSIONS: Cerebellar lesions are common among individuals with TSC. Cerebellar involvement correlates with supratentorial derangement and the development of SEGAs, which is suggestive of a more severe clinical and neuroradiological phenotype. Cerebellar involvement and early seizure onset were not independent predictors of either neurological severity or intellectual disability or neurobehavioral outcome; their role in TSC clinical phenotype should be further investigated.

Assessment of intellectual impairment, health-related quality of life, and behavioral phenotype in patients with neurotransmitter related disorders: Data from the iNTD registry.

Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport, or degradation of neurotransmitters or cofactors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry of the International Working Group on Neurotransmitter Related Disorders (iNTD) was evaluated using results from standardized age-adjusted tests and questionnaires. Patients with a primary disorder of monoamine metabolism had lower IQ scores (mean IQ 58, range 40-100) within the range of cognitive impairment (<70) compared to patients with a BH4 deficiency (mean IQ 84, range 40-129). Short attention span and distractibility were most frequently mentioned by parents, while patients reported most frequently anxiety and distractibility when asked for behavioral traits. In individuals with succinic semialdehyde dehydrogenase deficiency, self-stimulatory behaviors were commonly reported by parents, whereas in patients with dopamine transporter deficiency, DNAJC12 deficiency, and monoamine oxidase A deficiency, self-injurious or mutilating behaviors have commonly been observed. Phobic fears were increased in patients with 6-pyruvoyltetrahydropterin synthase deficiency, while individuals with sepiapterin reductase deficiency frequently experienced communication and sleep difficulties. Patients with BH4 deficiencies achieved significantly higher quality of life as compared to other groups. This analysis of the iNTD registry data highlights: (a) difference in IQ and subdomains of quality of life between BH4 deficiencies and primary neurotransmitter-related disorders and (b) previously underreported behavioral traits.

Brain MR patterns in inherited disorders of monoamine neurotransmitters: An analysis of 70 patients.

Inherited monoamine neurotransmitter disorders (iMNDs) are rare disorders with clinical manifestations ranging from mild infantile hypotonia, movement disorders to early infantile severe encephalopathy. Neuroimaging has been reported as non-specific. We systematically analyzed brain MRIs in order to characterize and better understand neuroimaging changes and to re-evaluate the diagnostic role of brain MRI in iMNDs. 81 MRIs of 70 patients (0.1-52.9 years, 39 patients with tetrahydrobiopterin deficiencies, 31 with primary disorders of monoamine metabolism) were retrospectively analyzed and clinical records reviewed. 33/70 patients had MRI changes, most commonly atrophy (n = 24). Eight patients, six with dihydropteridine reductase deficiency (DHPR), had a common pattern of bilateral parieto-occipital and to a lesser extent frontal and/or cerebellar changes in arterial watershed zones. Two patients imaged after acute severe encephalopathy had signs of profound hypoxic-ischemic injury and a combination of deep gray matter and watershed injury (aromatic l-amino acid decarboxylase (AADCD), tyrosine hydroxylase deficiency (THD)). Four patients had myelination delay (AADCD; THD); two had changes characteristic of post-infantile onset neuronal disease (AADCD, monoamine oxidase A deficiency), and nine T2-hyperintensity of central tegmental tracts. iMNDs are associated with MRI patterns consistent with chronic effects of a neuronal disorder and signs of repetitive injury to cerebral and cerebellar watershed areas, in particular in DHPRD. These will be helpful in the (neuroradiological) differential diagnosis of children with unknown disorders and monitoring of iMNDs. We hypothesize that deficiency of catecholamines and/or tetrahydrobiopterin increase the incidence of and the CNS susceptibility to vascular dysfunction.

Hemimegalencephaly and tuberous sclerosis complex: A rare yet challenging association.

Hemimegalencephaly is a rare malformation of cortical development characterised by enlargement of one cerebral hemisphere. The association between hemimegalencephaly and tuberous sclerosis complex, an autosomal dominant genetic disorder, is uncommon and has so far been reported only in a few cases. Intractable epilepsy and severe developmental delay are typical clinical manifestations. Aberrant activation of the mTOR signalling pathway is considered to be the hallmark of the pathogenesis of these two disorders. Thus, mTOR inhibitors such as everolimus represent a promising therapeutic approach to mTOR-associated manifestations. We present a thorough literature review of the association between hemimegaloencephaly and tuberous sclerosis complex.

Hypertension and childhood stroke.

Cerebrovascular disease (stroke) is one of the ten leading causes of death in children and adolescents. Multiple etiologies, from arteriopathies to prothrombic states, can cause stroke in youth. In adult stroke, hypertension has been shown to be the single most important modifiable risk factor. Although hypertension has not been strongly identified as a risk factor in childhood stroke to date, there is preliminary evidence that suggests that hypertension may also be associated with stroke in children. In this review, we summarize the literature that may link hypertension to stroke in the young. We have identified a series of barriers and limitations in the fields of pediatric hypertension and pediatric neurology that might explain why hypertension has been overlooked in childhood stroke. We suggest that hypertension may be a relevant risk factor that, alone or in combination with other multiple factors, contributes to the development of stroke in children. Currently, there are no consensus guidelines for the management of post-stroke hypertension in children. Thus, we recommend that blood pressure be assessed carefully in every child presenting with acute stroke in order to better understand the effects of hypertension in the development and the outcome of childhood stroke. We suggest a treatment algorithm to help practitioners manage hypertension after a stroke.

Neurological complications in childhood nephrotic syndrome: A systematic review.

BACKGROUND AND OBJECTIVE: Nephrotic syndrome (NS) in childhood can be accompanied by serious neurological complications increasing the morbidity of disease. The study aimed to assess the spectrum of neurological complications in children with in terms of clinical presentation, contributory risk factors, and outcome. METHODS: In this systematic review, we searched for articles in PubMed, providing individual patient-level data for any neurological complication in children and adolescents with primary NS, between January 1, 1990 and April 30, 2018. FINDINGS: The search yielded 63 articles, involving 103 patients. Events occurred more frequently during nephrotic state relapses; 71.6% of cerebral thromboembolic (TE) events and 81.2% of posterior reversible encephalopathy (PRES) cases. Median duration of disease before a cerebral TE event was 3 months (IQR 0-27), and 18 months (IQR 1-37.5) for PRES. Among cases with TE, 73.1% presented with cerebral sinovenous thrombosis (CSVT), and 16.9% parenchymal lesions. 70% of patients had a risk factor for neurological complication including NS-associated thrombophilia, hypertension, and treatment with immunosuppressive agents. Outcome was favorable in 93.8% of the patients with PRES. In patients with cerebral TE outcome was favorable in 95.8% of the cases with CSVT only, and in 64.7% of the cases with parenchymal lesions. CONCLUSIONS: Neurological complications may occur in children with primary NS and risk factors during nephrotic state relapses. The outcome for PRES has been reported favorable. Outcome in cerebral TE events may differ by the presence of venous or artery infarct. Recognition of additional protrombotic state risk factors may help to lower the incidence of neurological complications.

Diagnosis of tuberous sclerosis complex in the fetus.

Tuberous sclerosis complex is a dominantly inherited genetic disorder of striking clinical variability. It is caused by mutations in either TSC1 or TSC2 gene, which regulate cell growth and proliferation by inhibition of mTORC1 signaling. TS is characterized by the development of benign tumors in many tissues and organs and its neurological manifestations include epilepsy, autism, cognitive and behavioral dysfunction, and giant cell tumors. With mechanism-based mTOR inhibitors therapy now available for many of its manifestations, early diagnosis of TSC is very important in order to offer appropriate care, long-term surveillance and parental counseling. Fetal ultrasound and MRI imaging techniques have evolved and may capture even earlier the following TSC-associated lesions: cardiac rhabdomyomas, subependymal nodules, cortical tubers and renal cysts. Often these represent an incidental finding during a routine ultrasound. Furthermore, in the past decades prenatal molecular diagnosis of TSC has emerged as an important option for families with a known affected member; however, the existing evidence with regards to the clinical characteristics and long-term outcome of babies diagnosed prenatally with TSC is yet limited and the path that follows early TSC detection merits further research.

Stroke and Hypertension in Children and Adolescents.

Hypertension is the single most important modifiable risk factor for adult stroke. Stroke mortality has significantly decreased over the last 5 decades; this decline has been mainly associated to improved blood pressure control. Though much less prevalent than in adults, stroke is an increasingly recognized cause of morbidity and mortality in children. Although hypertension has not been strongly identified as a risk factor in childhood stroke yet, there is preliminary evidence that suggests that elevated blood pressure may be associated with stroke in children. This review summarizes the literature that may link elevated blood pressure to the development of childhood ischemic and hemorrhagic stroke. The authors suggest that elevated blood pressure may be a significant risk factor that, alone or in combination with other multiple risk factors, leads to the development of stroke in childhood. It is therefore recommend that blood pressure be measured and assessed carefully in every child presenting with acute stroke.

Multiple Coronary Artery Microfistulas in a Girl with Kleefstra Syndrome.

Kleefstra syndrome is characterized by hypotonia, developmental delay, dysmorphic features, congenital heart defects, and so forth. It is caused by 9q34.3 microdeletions or EHMT1 mutations. Herein a 20-month-old girl with Kleefstra syndrome, due to a de novo subterminal deletion, is described. She exhibits a rare and complex cardiopathy, encompassing multiple coronary artery microfistulas, VSD/ASD, and PFO.

Nephrocalcinosis and Renal Failure in Lesch-Nyhan Syndrome: Report of Two Familial Cases and Review of the Literature.

Lesch-Nyhan syndrome is an X-linked recessive inborn error of purine metabolism, due to deficiency of the enzyme HPRT (hypoxanthine-guanine phosphoribosyl transferase) and underlying HPRT gene mutations (over 300 mutations identified up to date). It is characterized by a wide range of neurological symptoms and signs (mainly a combination of spastic diplegia with choreoathetosis and an overall psychomotor redardation). Herein, we report of two cousins with Lesch-Nyhan syndrome and a confirmed novel HPRT gene mutation: c.65T>C, who both developed nephrocalcinosis and renal failure, findings not been previously published in children with HPRT deficiency.

Association between iron deficiency and febrile seizures.

OBJECTIVE: The relationship between iron status and febrile seizures has been examined in various settings, mainly in the Developing World, with conflicting results. The aim of this study was to investigate any association between iron deficiency and febrile seizures (FS) in European children aged 6-60 months. DESIGN: Prospective, case-control study. SETTING: Greek population in Thessaloniki. PATIENTS: 50 patients with febrile seizures (cases) and 50 controls (children presenting with fever, without seizures). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Haematologic parameters (haemoglobin concentration, haematocrit, mean corpuscular volume, red cell distribution width), plasma iron, total iron-binding capacity, plasma ferritin, transferrin saturation and soluble transferrin receptors were compared in cases and controls. RESULTS: Plasma ferritin was lower (median [range]: 42.8 (3-285.7) vs 58.3 (21.4-195.3 ng/ml; p = 0.02) and Total Iron Binding Capacity (TIBC) higher (mean [Standard Deviation] 267 [58.9] vs 243 [58.45] µg/dl, p = 0.04) in cases than in controls. Results were similar for 12 complex FS cases (ferritin 30 (3-121 vs 89 (41.8-141.5ng/lL; TIBC 292.92 [68.0] vs 232.08 [36.27] µg/dL). Iron deficiency, defined as ferritin <30 ng/ml, was more frequent in cases (24%) than controls (4%; p = 0.004). Ferritin was lower and TIBC higher in 18 with previous seizures than in 32 with a first seizure although haemoglobin and mean cell haemoglobin concentration were higher. CONCLUSIONS: European children with febrile seizures have lower Ferritin than those with fever alone, and iron deficiency, but not anaemia, is associated with recurrence. Iron status screening should be considered as routine for children presenting with or at high risk for febrile seizures.