Brainstem Auditory Evoked Potentials in Boys with Autism: Still Searching for the Hidden Truth

How to Cite This Article: Ververi A, Vargiami E, V Papadopoulou V, Tryfonas D, Zafeiriou DI. Brainstem Auditory Evoked Potentials inBoys with Autism: Still Searching for the Hidden Truth. Iran J Child Neurol. Spring 2015;9(2):21-28.Abstract Objective Brainstem auditory evoked potentials (BAEPs) have long been utilized in the investigation of auditory modulation and, more specifically, auditory brainstem functions in individuals with autism. Although most investigators have reported significant abnormalities, no single BAEPs pattern has yet been identified. The present study further delineates the BAEPs deficits among subjects with autism. Materials & Methods BAEPs were recorded in 43 male patients, aged 35–104 months, who underwent standard evaluations after receiving a diagnosis of autism. The control group consisted of 43 age-matched typically developing boys. The study took place in a tertiary neurodevelopmental center over a period of two years. Results The mean values of all absolute and/or interpeak latencies were longer in patients when compared to controls, albeit the differences were not significant for any of the parameters. Prolonged or shortened absolute/interpeak latencies (control group mean ± 2.5SD) were unilaterally or bilaterally identified in 33% of patients, compared to 9% of controls. The most frequent findings included prolongation of absolute latencies I, V and III, followed by shortening of interpeak latency I-V. In addition, abnormalities (either shortening or prolongation) of absolute latencies I and V, as well as interpeak latency I-V, were significantly more common among patients. Taken together, BAEPs in 23% of patients were indicative of a clinically abnormal response in 32% of patients. Conclusion As can be easily concluded, BAEPs abnormalities characterize only a subset of subjects with autism, who may be important to identify clinically. The latter individuals may benefit from targeted intervention to utilize brainstem plasticity

Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis

Tyrosine hydroxylase deficiency is an autosomal recessive disorder resulting from cerebral catecholamine deficiency. Tyrosine hydroxylase deficiency has been reported in fewer than 40 patients worldwide. To recapitulate all available evidence on clinical phenotypes and rational diagnostic and therapeutic approaches for this devastating, but treatable, neurometabolic disorder, we studied 36 patients with tyrosine hydroxylase deficiency and reviewed the literature. Based on the presenting neurological features, tyrosine hydroxylase deficiency can be divided in two phenotypes: an infantile onset, progressive, hypokinetic-rigid syndrome with dystonia (type A), and a complex encephalopathy with neonatal onset (type B). Decreased cerebrospinal fluid concentrations of homovanillic acid and 3-methoxy-4-hydroxyphenylethylene glycol, with normal 5-hydroxyindoleacetic acid cerebrospinal fluid concentrations, are the biochemical hallmark of tyrosine hydroxylase deficiency. The homovanillic acid concentrations and homovanillic acid/5-hydroxyindoleacetic acid ratio in cerebrospinal fluid correlate with the severity of the phenotype. Tyrosine hydroxylase deficiency is almost exclusively caused by missense mutations in the TH gene and its promoter region, suggesting that mutations with more deleterious effects on the protein are incompatible with life. Genotype-phenotype correlations do not exist for the common c.698G>A and c.707T>C mutations. Carriership of at least one promotor mutation, however, apparently predicts type A tyrosine hydroxylase deficiency. Most patients with tyrosine hydroxylase deficiency can be successfully treated with l-dop

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 analysed brain MRIs in order to characterize and better understand neuroimaging changes and to re-evaluate the diagnostic role of brain MRI in iMNDs

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.Dietmar Hopp Stiftung (DE); Medical Faculty of the University of Heidelberg

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.We thank all patients and their families for their contributions to this study and for their trust. T.H. and J.K. were supported the grant from the Ministry of Health of the Czech Republic RVO-VFN 64165 GJIH-0599-00-7-846 and ProgresQ26/LF1. A.G.C. and N.J.P. are supported by FIS P118/00111 “Instituto de Salud Carlos III (ISCIII)” and “Fondo Europeo de desarrollo regional (FEDER)”. T.O., K.J., G.F.H. and O.K.H. were supported in parts by the Dietmar Hopp Foundation, St. Leon-Rot, Germany. M.A.K. is funded by an NIHR Professorship, the Sir Jules Thorn Award for Biomedical Research and the Rosetrees trust. M.V. is supported by Stichting Stofwisselkracht Grant. D.H. acknowledges funding by the Molecular Diagnostics Program of the National Center for Tumor Diseases (NCT) Heidelberg.Peer reviewe

Exome Sequencing and the Management of Neurometabolic Disorders

BACKGROUND: Whole-exome sequencing has transformed gene discovery and diagnosis in rare diseases. Translation into disease-modifying treatments is challenging, particularly for intellectual developmental disorder. However, the exception is inborn errors of metabolism, since many of these disorders are responsive to therapy that targets pathophysiological features at the molecular or cellular level. METHODS: To uncover the genetic basis of potentially treatable inborn errors of metabolism, we combined deep clinical phenotyping (the comprehensive characterization of the discrete components of a patient's clinical and biochemical phenotype) with whole-exome sequencing analysis through a semiautomated bioinformatics pipeline in consecutively enrolled patients with intellectual developmental disorder and unexplained metabolic phenotypes. RESULTS: We performed whole-exome sequencing on samples obtained from 47 probands. Of these patients, 6 were excluded, including 1 who withdrew from the study. The remaining 41 probands had been born to predominantly nonconsanguineous parents of European descent. In 37 probands, we identified variants in 2 genes newly implicated in disease, 9 candidate genes, 22 known genes with newly identified phenotypes, and 9 genes with expected phenotypes; in most of the genes, the variants were classified as either pathogenic or probably pathogenic. Complex phenotypes of patients in five families were explained by coexisting monogenic conditions. We obtained a diagnosis in 28 of 41 probands (68%) who were evaluated. A test of a targeted intervention was performed in 18 patients (44%). CONCLUSIONS: Deep phenotyping and whole-exome sequencing in 41 probands with intellectual developmental disorder and unexplained metabolic abnormalities led to a diagnosis in 68%, the identification of 11 candidate genes newly implicated in neurometabolic disease, and a change in treatment beyond genetic counseling in 44%. (Funded by BC Children's Hospital Foundation and others.)

Extracellular matrix components: An intricate network of possible biomarkers for lysosomal storage disorders?

AbstractBiomarkers are extremely important in the case of multisystemic diseases, such as lysosomal storage disorders (LSDs), which are often difficult to assess in clinical practice. Several studies demonstrated significant alterations in the expression of extracellular matrix (ECM) components in LSD patients, raising important questions in relation to their possible involvement in disease pathogenesis and providing evidence for their possible utility as disease biomarkers. This article provides an overview of the possible pathogenic correlations between LSDs and ECM. Data regarding the expression of these molecules are discussed. Finally, the possible implication of ECM components as therapeutic targets in this group of diseases along with the impact of the differential expression of these components in current LSD treatment will be critically addressed

Comparative Study of Refractive Errors, Strabismus, Microsaccades, and Visual Perception Between Preterm and Full-Term Children With Infantile Cerebral Palsy

The purpose of this study was to examine the refractive status, orthoptic status and visual perception in a group of preterm and another of full-term children with cerebral palsy, in order to investigate whether prematurity has an effect on the development of refractive errors and binocular disorders. A hundred school-aged children, 70 preterm and 30 full-term, with congenital cerebral palsy were examined. Differences for hypermetropia, myopia, and emmetropia were not statistically significant between the 2 groups. Astigmatism was significantly increased in the preterm group. The orthoptic status was similar for both groups. Visual perception was markedly reduced in both groups, but the differences were not significant. In conclusion, children with cerebral palsy have impaired visual skills, leading to reading difficulties. The presence of prematurity does not appear to represent an additional risk factor for the development of refractive errors and binocular disorders

Association between iron deficiency and febrile seizures

ObjectiveThe 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.DesignProspective, case–control study.SettingGreek population in Thessaloniki.Patients50 patients with febrile seizures (cases) and 50 controls (children presenting with fever, without seizures).InterventionsNone.Main outcome measuresHaematologic 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.ResultsPlasma 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] ?g/dl, p = 0.04) in cases than in controls. Results were similar for 12 complex FS cases (ferritin 30 (3–121 vs 89 (41.8–141.5 ng/lL; TIBC 292.92 [68.0] vs 232.08 [36.27] ?g/dL). Iron deficiency, defined as ferritin &lt;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.ConclusionsEuropean 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

Hemolytic anemia presenting with idiopathic intracranial hypertension

We report on an 8-year-old girl with hemolytic anemia because of infection with parvovirus B19 and increased intracranial pressure. She presented acutely with headache, vomiting, and mild scleral and mucosal icterus. Upon evaluation, the patient exhibited profound hemolytic anemia, papilledema, and increased intracranial pressure. The patient was treated with intravenous immunoglobulin, prednisone, and packed red blood cells. Concurrent with an improvement of her anemia, she experienced a gradual resolution of her headache, vomiting, and optic-disc swelling. Signs of idiopathic intracranial hypertension may occur as a consequence of severe anemia, and are reversible upon correction of the underlying hematologic disorde