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.

Restricted Ketogenic Diet Therapy for Primary Lung Cancer With Metastasis to the Brain: A Case Report.

A high-fat and low-carbohydrate diet was administered as a complementary and alternative therapy to a 54-year-old man suffering from non-small-cell lung cancer (NSCLC) with brain metastasis. Three months after the cessation of chemotherapy and radiotherapy, a ketogenic diet (KD) was initiated. This approach was an attempt to stabilize the disease progression after chemotherapy and radiotherapy. Computed tomography following radiation and chemotherapy showed a reduction in the right frontal lobe lesion from 5.5 cm × 6.2 cm to 4 cm × 2.7 cm, while the mass in the upper-right lung lobe reduced from 6.0 cm × 3.0 cm to 2.0 × 1.8 cm. Two years after KD initiation and without any other therapeutic intervention, the right frontal lobe lesion calcified and decreased in size to 1.9 cm × 1.0 cm, while the size of the lung mass further decreased to 1.7 cm × 1.0 cm. The size of the brain and lung lesion remained stable after nine years of KD therapy. However, dyslipidemia developed after this time which led to the discontinuation of the diet. No tumor relapse or health issues occurred for two years after the discontinuation of the diet. This case report indicates that the inclusion of ketogenic metabolic therapy following radiation and chemotherapy is associated with better clinical and survival outcomes for our patient with metastatic NSCLC.

Efficacy of a Robot-Assisted Intervention in Improving Learning Performance of Elementary School Children with Specific Learning Disorders.

(1) Background: There has been significant recent interest in the potential role of social robots (SRs) in special education. Specific Learning Disorders (SpLDs) have a high prevalence in the student population, and early intervention with personalized special educational programs is crucial for optimal academic achievement. (2) Methods: We designed an intense special education intervention for children in the third and fourth years of elementary school with a diagnosis of a SpLD. Following confirmation of eligibility and informed consent, the participants were prospectively and randomly allocated to two groups: (a) the SR group, for which the intervention was delivered by the humanoid robot NAO with the assistance of a special education teacher and (b) the control group, for which the intervention was delivered by the special educator. All participants underwent pre- and post-intervention evaluation for outcome measures. (3) Results: 40 children (NAO = 19, control = 21, similar baseline characteristics) were included. Pre- and post-intervention evaluation showed comparable improvements in both groups in cognition skills (decoding, phonological awareness and reading comprehension), while between-group changes favored the NAO group only for some phonological awareness exercises. In total, no significant changes were found in any of the groups regarding the emotional/behavioral secondary outcomes. (4) Conclusion: NAO was efficient as a tutor for a human-supported intervention when compared to the gold-standard intervention for elementary school students with SpLDs.

Ketogenic therapy for Parkinson's disease: A systematic review and synthesis without meta-analysis of animal and human trials.

OBJECTIVE: The aim of the present systematic review was to assess the efficacy of ketogenic therapy in Parkinson's disease (PD), using all available data from randomized controlled trials (RCTs) on humans and animal studies with PD models. DESIGN: Systematic review of in vivo studies. METHODS: Studies related to the research question were identified through searches in PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, clinicaltrials.gov and the gray literature, from inception until November 2021. Rayyan was employed to screen and identify all studies fulfilling the inclusion criteria. Cochrane's revised Risk of Bias 2.0 and SYRCLE tools evaluated bias in RCTs and animal studies, respectively. An effect direction plot was developed to synthesize the evidence of the RCTs. RESULTS: Twelve studies were identified and included in the qualitative synthesis (4 RCTs and 8 animal trials). Interventions included ketogenic diets (KDs), supplementation with medium-chain triglyceride (MCT) oil, caprylic acid administration and ketone ester drinks. The animal research used zebrafish and rodents, and PD was toxin-induced. Based on the available RCTs, ketogenic therapy does not improve motor coordination and functioning, cognitive impairment, anthropometrics, blood lipids and glycemic control, exercise performance or voice disorders in patients with PD. The evidence is scattered and heterogenous, with single trials assessing different outcomes; thus, a synthesis of the evidence cannot be conclusive regarding the efficacy of ketogenic therapy. On the other hand, animal studies tend to demonstrate more promising results, with marked improvements in locomotor activity, dopaminergic activity, redox status, and inflammatory markers. CONCLUSIONS: Although animal studies indicate promising results, research on the effect of ketogenic therapy in PD is still in its infancy, with RCTs conducted on humans being heterogeneous and lacking PD-specific outcomes. More studies are required to recommend or refute the use of ketogenic therapy in PD.

A Pediatric Patient With Autism Spectrum Disorder and Comorbid Compulsive Behaviors Treated With Robot-Assisted Relaxation: A Case Report.

The nature of autism spectrum disorders (ASDs) presents significant challenges, especially with regard to comorbidities and drug treatments. Parents and caregivers are often hesitant towards psychotropic medications, mainly due to the fear of side effects. Problems arise when comorbid symptomatology reaches extreme levels, leading to functional decline in the patients. We discuss the case of a 13-year-old girl diagnosed with autism disorder who presented with a long history of social, interpersonal, and academic challenges. The patient was hospitalized with the complaint of a persistent, non-painful, and unpleasant sensation in the perineal area that eventually resulted in repetitive and compulsive behaviors. Robot-enhanced relaxation training was introduced to support the patient since she declined to undergo any form of talk therapy. The aim of the intervention was to prevent the irritation from escalating and promote self-regulation skills. The results, based on parent reporting, indicated that the patient acquired relaxation skills, experienced some positive effects on emotional regulation, and showed a decrease in the duration of her disruptive behaviors upon completing the relaxation training. This case report provides evidence that robot-assisted relaxation training may be effective in dealing with ASD-related behavioral disturbances and comorbid anxiety.

Cerebral folate deficiency in two siblings caused by biallelic variants including a novel mutation of FOLR1 gene: Intrafamilial heterogeneity following early treatment and the role of ketogenic diet.

Mutations in the FOLR1 gene, encoding for the folate alpha receptor (FRa), represent a rare recessive genetic cause of cerebral folate deficiency (CFD), a potentially reversible neurometabolic condition. Patients typically present with developmental delay, seizures, abnormal movements, and delayed myelination. We hereby expand the phenotypic and genotypic spectrum of the disease with the report of the first two Greek siblings that were found compound heterozygous for one known FOLR1 gene mutation (p.Cys65Trp) and a mutation (p.Trp143Arg) that has not yet been reported in the literature (class 3 variant according to ASHG classification). A distinguishing feature of the older sibling is the manifestation of drug-resistant epileptic spasms beyond infancy. These had a relatively good response to a ketogenic diet, as an additional treatment to topiramate and valproate. A further clinical improvement was observed when folinic acid was combined with the above treatment. While a response to folinic acid is well established in the disorder, the efficacy of its combination with the ketogenic diet needs further evaluation, but we suggest considering it early in the course of drug resistant epilepsy in the setting of CFD. The younger sibling was diagnosed and treated with folinic acid at an early-symptomatic stage. Both patients had moderately low age-related CSF 5-methyltetrahydrofolate levels at diagnosis with the older sibling (that was already treated at base line collection) averaging 19 nmol/L (normal range: 44-122 nmol/L) and the younger one 49 nmol/L (normal range 63-122 nmol/L). These levels were restored to normal limits after folinic supplementation.

Truncated prelamin A expression in HGPS-like patients: a transcriptional study.

Premature aging syndromes are rare genetic disorders mimicking clinical and molecular features of aging. A recently identified group of premature aging syndromes is linked to mutation of the LMNA gene encoding lamins A and C, and is associated with nuclear deformation and dysfunction. Hutchinson-Gilford progeria syndrome (HGPS) was the first premature aging syndrome linked to LMNA mutation and its molecular bases have been deeply investigated. It is due to a recurrent de novo mutation leading to aberrant splicing and the production of a truncated and toxic nuclear lamin A precursor (prelamin AΔ50), also called progerin. In this work and based on the literature data, we propose to distinguish two main groups of premature aging laminopathies: (1) HGPS and HGP-like syndromes, which share clinical features due to hampered processing and intranuclear toxic accumulation of prelamin A isoforms; and (2) APS (atypical progeria syndromes), due to dominant or recessive missense mutations affecting lamins A and C. Among HGPS-like patients, several deleted prelamin A transcripts (prelamin AΔ50, AΔ35 and AΔ90) have been described. The purpose of this work was to characterize those transcripts in eight patients affected with HGP-like rare syndromes. When fibroblasts were available, the relationships between the presence and ratios of these transcripts and other parameters were studied, aiming to increase our understanding of genotype-phenotype relationships in HGPS-like patients. Altogether our results evidence that progerin accumulation is the major pathogenetic mechanism responsible for HGP-like syndromes due to mutations near the donor splice site of exon 11.

Evaluation of Oral Glucose Tolerance Test in Children With Epilepsy.

Glucose metabolism of children with drug-resistant epilepsy, controlled by antiepileptic drugs epilepsy, and first-time nonfebrile seizures was studied through the performance of an oral glucose tolerance test and through insulin, C-peptide, and glycosylated hemoglobin measurements. In the refractory epilepsy group, there were more abnormal oral glucose tolerance test results (62.07%) in comparison to the controlled epilepsy group (25%) and the group of first-time seizures (21.21%). There was a significant difference between the group of refractory epilepsy and every other group concerning the abnormality of the oral glucose tolerance test (P < .05). The mean values of insulin, HbA1c, and C-peptide levels were normal for all groups. The results of the present study suggest that there is a distinction of refractory epilepsies from the drug-controlled ones and the first-induced seizures relating to their metabolic profile, regardless of the type of seizures.

Evidence for treatable inborn errors of metabolism in a cohort of 187 Greek patients with autism spectrum disorder (ASD).

We screened for the presence of inborn errors of metabolism (IEM) in 187 children (105 males; 82 females, ages 4-14 years old) who presented with confirmed features of autism spectrum disorder (ASD). Twelve patients (7%) manifested increased 3-hydroxyisovaleric acid (3-OH-IVA) excretion in urine, and minor to significant improvement in autistic features was observed in seven patients following supplementation with biotin. Five diagnoses included: Lesch Nyhan syndrome (2), succinic semialdehyde dehydrogenase (SSADH) deficiency (2), and phenylketonuria (1) (2.7%). Additional metabolic disturbances suggestive of IEMs included two patients whose increased urine 3-OH-IVA was accompanied by elevated methylcitrate and lactate in sera, and 30 patients that showed abnormal glucose-loading tests. In the latter group, 16/30 patients manifested increased sera beta hydroxybutyrate (b-OH-b) production and 18/30 had a paradoxical increase of sera lactate. Six patients with elevated b-OH-b in sera showed improved autistic features following implementation of a ketogenic diet (KD). Five patients showed decreased serum ketone body production with glucose loading. Twelve of 187 patients demonstrated non-specific MRI pathology, while 25/187 had abnormal electroencephalogram (EEG) findings. Finally, family history was positive for 22/187 patients (1st or 2nd degree relative with comparable symptomatology) and consanguinity was documented for 12/187 patients. Our data provide evidence for a new biomarker (3-OH-IVA) and novel treatment approaches in ASD patients. Concise 1 sentence take-home message: Detailed metabolic screening in a Greek cohort of ASD patients revealed biomarkers (urine 3-hydroxyisovaleric acid and serum b-OH-b) in 7% (13/187) of patients for whom biotin supplementation or institution of a KD resulted in mild to significant clinical improvement in autistic features.

Acquired toxoplasmosis accompanied by facial nerve palsy in an immunocompetent 5-year-old child.

Acquired toxoplasmosis, although relatively common in children, is usually asymptomatic but can also be clinically manifested by a benign and self-limited infectious mononucleosis-like syndrome. Neurological complications are very rare in immunocompetent children. The authors report a 5-year-old boy who presented with cervical lymphadenopathy because of acquired toxoplasmosis accompanied with unilateral facial nerve paralysis. Toxoplasma gondii DNA detection in blood by polymerase chain reaction, as well as elevated specific immunoglobulin M antibodies against it, established the diagnosis. Characteristic brain lesions on magnetic resonance imaging were absent and ophthalmologic examination revealed no inflammatory lesions in the retina and choroid. Treatment with pyrimethamine, sulfadiazine, and folic acid resulted in a complete recovery after 2 months of therapy. Although rare, acute facial nerve paralysis of unknown origin can be caused by acquired toxoplasmosis even in the immunocompetent pediatric population. Elevated titers of specific antibodies and the presence of parasite's DNA are key findings for the correct diagnosis.

The significance of opthalmologic evaluation in the early diagnosis of inborn errors of metabolism: the Cretan experience.

BACKGROUND: The Inborn Errors of Metabolism (IEM) are far from the rare systemic diseases that mainly affect the neural tissue. There are very few written reports on ocular findings in subjects with IEM, thus it was interesting to study the frequency of ocular findings in the studied population and explore their contribution to the early diagnosis of IEM. METHODS: Our study involved the evaluation of IEM suspected cases, which had been identified in a rural population in Crete, Greece. Over a period of 3 years, 125 patients, who fulfilled the inclusion criteria of this study, were examined. Analytical physical examination, detailed laboratory investigation as well as a thorough ocular examination were made. RESULTS: A diagnosis of IEM was established in 23 of the 125 patients (18.4%). Ten (43.5%) of the diagnosed IEM had ocular findings, while 8 of them (34.8%) had findings which were specific for the diagnosed diseases. One patient diagnosed with glycogenosis type 1b presented a rare finding. Of the 102 non-diagnosed patients, 53 (51.96 %) presented various ophthalmic findings, some of which could be related to a metabolic disease and therefore may be very helpful in the future. CONCLUSIONS: The ocular investigation can be extremely useful for raising the suspicion and the establishment of an early diagnosis of IEM. It could also add new findings related to these diseases. The early management of the ocular symptoms can improve the quality of life to these patients.