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ATRX mutations are commonly associated with alpha-thalassaemia mental retardation syndrome (ATR-X syndrome) with a notable variable expressivity. This X-linked disorder is characterized by intellectual disability (ID) in a higher or lesser degree, in which the alpha-thalassaemia feature is not always present. Other phenotypic manifestations like facial dimorphism, hypotonia, microcephaly, skeletal abnormalities or urogenital malformations have been frequently observed in ATR-X syndrome. Herein, we report a missense ATRX mutation (Thr1621Met) in a patient with an autism spectrum disorder (ASD) diagnosis. Except for ID, no typical signs of ATR-X syndrome were found in the patient. These results confirm the extensive phenotypic variability associated to ATRX mutations and show the involvement of this gene in the ASD., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

A twelve-year-old patient with a previous clinical diagnosis of spondylocostal skeletal dysplasia and moderate intellectual disability was genetically analyzed through next generation sequencing of a targeted gene panel of 179 genes associated to skeletal dysplasia and mucopolysaccharidosis in order to stablish a precision diagnosis. A homozygous nonsense [c.62C>G; p.(Ser21Ter)] mutation in DYM gene was identified in the patient. Null mutations in DYM have been associated to Dyggve-Melchior-Clausen syndrome, which is a rare autosomal-recessive disorder characterized by skeletal dysplasia and mental retardation, compatible with the patient´s phenotype. To confirm the pathogenicity of this mutation, a segregation analysis was carried out, revealing that the mutation p(Ser21Ter) was solely inherited from the father, who is a carrier of the mutation, while the mother does not carry the mutation. With the suspicion that a paternal disomy could be causing the disease, a series of microsatellite markers in chromosome 18, where the DYM gene is harbored, was analyzed in all the members of the family. Haplotype analysis provided strong evidence of paternal isodisomy and heterodisomy in that chromosome, confirming the pathological effect of this mutation. Furthermore, the patient may have a compromised expression of the ELOA3 gene due to modifications in the genomic imprinting that may potentially increase the risk of digestive cancer. All these results highlight the importance of obtaining a precision diagnosis in rare diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 López-Garrido, Carrascosa-Romero, Montero-Hernández, Serrano-Martínez and Sánchez-Sánchez.)

Introduction: The different types of viral meningitis constitute a condition that is relatively frequent in newborn infants, although in many cases they are underdiagnosed due to the absence of pleocytosis in the cerebrospinal fluid (CSF)., Aims: To describe the clinical features and laboratory findings of newborn infants with viral meningitis and to highlight the importance of the polymerase chain reaction (PCR) in the CSF to diagnose this condition., Patients and Methods: A retrospective review of the medical records of newborn infants hospitalised in the neonatology section who had been diagnosed with viral meningitis between May 2014 and May 2017., Results: Altogether 17 cases of viral meningitis were registered (15 caused by enterovirus and two due to parechovirus), which accounts for 14.8% of all newborns hospitalised owing to febrile symptoms. All of them had fever (100%), and other notable symptoms were irritability (76%) and rejection of feeding (65%). Normal cellularity was found in the CSF without high protein levels in 88% of them, and without hypoglycorrhachia in all of them (100%), which meant that many of these children had previously been left with a diagnosis of a febrile syndrome with no focus. These data stress the need to perform the PCR in the CSF of newborn infants who have a fever without a focus, due to the normal status of the results of the complementary tests in most cases. Subsequent neurological follow-up was performed in 64.7% of the children in the neurology service, without any neurological sequelae being found, except in one case., Conclusions: Multiple PCR in the CSF has become an essential diagnostic technique in cases of newborn infants with a suspected infection, and replaces viral culture as the reference test due its being quicker and more sensitive.

Congenital myasthenic syndromes are a group of genetically determined rare diseases resulting from ultrastructural alterations in synaptic proteins. Up to 32 genes are known to be involved in those syndromes and many mutations have been reported, of which less than 8% affect the presynaptic complex. One of these syndromes is caused by the impairment of the presynaptic sodium-dependent high-affinity choline transporter 1, as a result of a mutation of the SCL5A7 gene associated with congenital myasthenic syndrome type 20 (MIM # 617143). We present a new case of this syndrome, caused by a mutation not previously described. A full term infant presented with acute respiratory failure and generalized weakness. The genetic analysis revealed the patient to be compound heterozygous for a new mutation of the SCL5A7 gene. The genetic analysis of congenital myasthenic syndromes provide information on the ultrastructural underlying mechanisms, which is valuable for differential diagnosis and specific treatments., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Leucinosis is a severe neonatal metabolic disease. It is the consequence of the genetically determined enzyme deficiency of the complex formed by decarboxylase-dihydrolipoyl transacylase and dihydrolipoyl dehydrogenase, and of the subsequent accumulation of precursor metabolites, long branched-chain amino acids and their alpha ketoacids. They are powerful neurotoxins, responsible for the swift onset of oedema and diffuse cerebral demyelination. Delays in its diagnosis usually result in severe psychomotor sequelae or even death., Case Report: We report the case of a newborn female patient with severe neonatal encephalopathy, epileptic seizures and an electroencephalogram (EEG) with certain special characteristics that guided the diagnosis towards that of possible leucinosis. Early diagnosis makes it possible to establish specific treatment and achieve a favourable patient outcome., Conclusions: An EEG in patients with suspected neonatal encephalopathy offers highly cost-effective functional information at a low cost, especially because it promotes early diagnoses and treatments. In cases of leucinosis, EEG presents peculiar signs that are easily recognisable in early periods in most patients, as occurred in the case reported here. We believe EEG should be included in screening for neonatal encephalopathies because it is a valuable, innocuous and generally accessible diagnostic technique. It is especially helpful in treatable metabolic diseases, such as leucinosis.

Antiepileptic drugs may occasionally increase seizure frequency or eliciting de novo seizure occurrence; the underlying mechanism of these effects is not known. The potential adverse effects of valproic acid in myoclonic astatic epilepsy have been noted by experienced clinicians in various different regions of the world, but this important observation has not been sufficiently reported. We present the case of tonic status epilepticus in an 8-year-old boy with Doose syndrome related to valproic acid. Valproic acid, such as others antiepileptic drugs, is liable to produce paradoxical effects such as the atypical seizures we report. We emphasize the importance for the management of acute seizures in an intensive care unit setting and increase awareness of the acute toxic effects of antiepileptic drugs., (Georg Thieme Verlag KG Stuttgart · New York.)

Spinal muscular atrophy and progressive myoclonic epilepsy (SMAPME, OMIM#159950) is a rare autosomal recessive disorder characterized by the combination of progressive myoclonic epilepsy and muscular weakness due to lower motor neuron disease. Mutations in ASAH1, previously associated only to Farber disease, have been recently described in seven patients with SMAPME. A homozygous c.125C>T mutation was initially found in six patients with a clinical homogeneous phenotype. A heterozygous compound mutation found in an additional patient has broadened the clinical and genetic spectrum of clinical SMAPME. We report a new case of a 13-year-old girl with SMAPME with the homozygous ASAH1 c.125C>T mutation, unique in that it is due to paternal uniparental disomy. She experienced muscle weakness from the age of three due to lower motor neuron involvement that lead to severe handicap and onset in late childhood of a progressive myoclonic epilepsy. This clinical picture fully overlaps with that of previously reported patients with this mutation and supports our view that the clinical phenotype associated with the homozygous c.125C>T mutation constitutes a clinically homogenous and recognizable disease., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Septo-optic dysplasia (SOD)[MIM182230] consisting of a heterogeneous and uncommon condition characterised by the classictriad: optic nerve hypoplasia, abnormalities of pituitary hormone, and defects of thebrain midline (including agenesis of the septum pellucidum and/or the corpus callosum; ithas also been described associated cortical malformations, it was referred to as SOD plus syndrome).We report the first known case in which the initial diagnostic sign of SOD was a bilateralmydriasis as a manifestation ofhypoplasia of both optic nerves, pituitary hypoplasia andcerebral dysgenesis with neuronal migration disorder.We discuss thedifferential diagnosis of congenital mydriasis., (Copyright © 2010 Sociedad Española de Oftalmología. Published by Elsevier Espana. All rights reserved.)

We present a girl with the characteristic clinical picture associated with Marden-Walker syndrome (MWS; OMIM 248700), including mask-like face with blepharophimosis, joint contractures, intellectual disability, a multicystic dysplastic kidney and cerebral dysgenesis. The long-term follow-up allowed us to monitor the evolution of the phenotype in this patient, and among the main findings we highlight the following: demyelination of the pyramidal tract demonstrated by transcranial magnetic stimulation and the involvement of the levator muscles of angle of mouth in fixed facial expression with relative integrity of the rest of the facial expression muscles. A 244 k array comparative genomic hybridization (aCGH) was carried out and showed a de novo interstitial deletion of approximately 2.84 Mb affecting only the cytoband 21q22.11 (genome coordinates chr21:31,874,016-34,711,763). We selected 10 of the most recent published cases with either total or partial deletions of cytoband 21q22.11 that provided good characterization of the genomic size or the genes in the deleted regions. We observed that in nine of the 10 cases the deleted regions included the RUNX1 gene in 21q22.12, which is not affected in the current patient's deletion or in that of Patient 3 from Roberson et al. [2011]. After a comparison of shared deleted genes between cases, and correlation of their potential phenotypes, we concluded that the pattern of defects considered for a diagnosis of MWS may represent part of the phenotypic expression of a partial or total deletion of 21q22.11., (Copyright © 2013 Wiley Periodicals, Inc.)

Pneumococcal meningoencephalitis (PME) is a life-threatening condition of the central nervous system (CNS), and is often the result of a complicated upper airway infection. Periodic Lateralized Epileptiform Discharges (PLEDs) are a typical electroencephalographic (EEG) pattern found in some acutely acquired brain insults. Within the pediatric population they are frequently seen in association with herpetic encephalitis, a CNS infection with a high morbidity and mortality rate. We report the case of a 3-year-old girl with a bilateral ear infection who developed convulsions and coma. She had early PLEDs lateralized to the right on the EEG and microbiological criteria for Streptococcus pneumoniae infection. Concomitant herpetic encephalitis was ruled out. Intensive antibiotic and antiepileptic treatment resulted in a remarkable improvement, with the patient being able to resume her normal activities within months. To our knowledge, the association of PME and PLEDs has not been previously described in children. On the other hand, EEG has scarcely been used in the management of acute CNS infections. Hence, non-herpetic CNS encephalitis with potentially more favorable outcomes ought to be considered in the differential diagnosis of PLEDs. Continuous EEG monitoring should be considered in children with CNS infections presenting with altered sensorium, independent of the presence of seizures., (Copyright © 2012 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

A newborn boy with broad forehead, mild microretrognathia, large hands and feet, arachnodactyly and a cortical thumb also had left renal agenesis, dysgenesis of corpus callosum with psychomotor delay. After olignucleotide array comparative genomic hybridization (array-CGH) analysis, we detected a 900 kb duplication in cytoband 5p13.2, apperently a first clinical description., (Copyright © 2012 Wiley Periodicals, Inc.)

X-chromosome-linked ichthyosis is caused by mutation or deletion of the STS gene associated with a deficiency of the enzyme steroid sulphatase, located in the distal part of the short arm of the X chromosome (Xp22.3-pter), close to the pseudo-autosomal region. Depending on its size, it can present as an isolated entity or combined with a syndrome caused by neighbouring genes, thus associating itself with other monogenic diseases as well as other mental disorders. The most relevant findings from the literature review are the importance of the Xp22.3-pter region and the higher incidence of neurological disorders among males (attention deficit hyperactivity disorder, autism and X-linked mental retardation). The role and implication of these genes in the disease are discussed and the authors suggest a possible contribution of the gene PNPLA4, which was originally described as GS2 and codes for calcium-independent phospholipase A2 beta, involved in lipoprotein metabolism, as one of the causes of autism. Improvements have been observed following treatment with citicoline, thanks to the role this nootropic plays in the biosynthesis of structural phospholipids involved in the formation and repair of the neuronal membrane.

We present the clinical course and EEG evolution of an extreme low birth weight preterm neonate with an uncommon type of glycine encephalopathy. The patient presented with myoclonic jerks, apnea and encephalopathy three months after birth without satisfactory therapeutic response. During the first days of clinical symptoms the patient presented a paroxystic burst-attenuation EEG pattern which progressively evolved into an established typical burst-suppression pattern within a few days. West syndrome occurred four weeks later and the patient died at seven months of extra-uterine life due to a serious respiratory infection with cardio-respiratory arrest. Genetic analysis showed a non-previously described mutation affecting a consensus splice site (IVS2-1G > C 3) in the AMT gene encoding the T protein of the glycine cleavage system.

Haemophagocytic syndrome is a disease diagnosed according to clinical and analytical criteria, related to many infectious diseases. It is exceptionally described in patients infected with Leishmania. Visceral leishmaniasis is an uncommon disease in our country except in some areas where it is endemic. Its diagnosis is sometimes difficult and the use of other methods currently available is needed. Haemophagocytic syndrome treatment is based on established chemotherapy protocols, but when it is secondary to Visceral Leishmaniasis, it may be an exception, since the abnormalities can be resolved by treatment of the infection itself. This treatment has improved recently as Liposomal Amphotericin B has replaced classic antimonials, being more beneficial due to less adverse effects and a shorter treatment time.

The partial trisomy 4q is a strange chromosomal illness. This illness is caused by the duplication of a portion of chromosome 4. In most of the cases, it is the result of a balanced translocation in one of the progenitors. The "de novo" appearance is less common. We present a patient with a partial "de novo" duplication in the distal segment of the long arm of chromosome 4 (q31, q35), in association with Robertsonian translocation between chromosomes 14 and 21. This association has not been described previously. In the 4q duplication, the relationship between the phenotype and the parts of the duplicated segment is not well defined, although it seems clear that the renal anomalies and/or thumbs abnormalities are a characteristic manifestation. We have reviewed the literature and, of the cases previously described with trisomy q31-35, we came to the conclusion that this region of chromosome 4 may also be involved in constituting the "Syndrome of partial trisomy 4q" or Auriculo-acro-renal Syndrome".

Introduction: Hirschsprung's disease (HD), or aganglionic megacolon, is a congenital disorder that is characterised by the absence of ganglion cells in the submucosal and myenteric plexuses of the intestine, which is caused by the failure of these cells to migrate from the neural crest (neurocristopathy). Cerebral dysgenesis and polymalformation syndromes have been reported in association with HD, thus suggesting an abnormal morphogenesis., Aim: To study the frequency of cerebral malformations in patients with HD in our environment., Patients and Methods: We conducted a retrospective study of 41,666 live newborn infants, over the period 1993-2003, and 17 cases of HD where identified., Results: The incidence of HD in the health district of the province of Albacete is 1.68 per 5,000 live newborn infants. Of the 17 patients with HD who were studied, 10 were isolated (58.8%) and seven (41.1%) were associated to other structural abnormalities and psychomotor retardation. Three of the cases in this latter group were due to chromosome pathology (trisomy 21, Down syndrome), two were caused by specific polymalformation syndromes (one Mowat-Wilson syndrome and one possible FG syndrome), one was due to a pattern of abnormalities that did not fit any known syndrome, and one had a normal phenotype and isolated cerebral dysgenesis. In all of cases the neuroimaging studies identified cerebral dysgenesis that was compatible with neuronal migration disorders., Conclusions: The frequency of association of HD, either isolated or within the context of a specific malformation syndrome, with neuronal migration disorders is high (23.5%). We suggest a full genetic and neurological evaluation should be carried out in patients with HD, together with brain imaging studies in order to rule out the possibility of cerebral dysgenesis.

There are several causes of gingival hyperplasia and one of the most well-known is drug-induced gingival enlargement. Nevertheless, causes of congenital gingival enlargement include only hereditary and metabolic disorders. Only one case of drug-induced congenital gingival hyperplasia has been reported. We present the second neonate with gingival hyperplasia in the context of foetal valproate syndrome and review the literature.

Introduction: In 1974 Pena and Shokeir described an early lethal disorder (OMIM 208150) that was characterised by neurogenic arthrogryposis, facial abnormalities and pulmonary hypoplasia. It has recently been suggested that it is secondary to the reduction of movements in the uterus due to an intrinsic pathology regardless of the cause (FADS, foetal akinesia deformation sequence). Klippel-Feil (K-F) syndrome (OMIM 118100) is defined by the congenital fusion of one or two cervical vertebrae, and clinically manifests as a shortened neck, with limited head movements, and may also be associated to other malformations., Case Reports: We report the case of a family diagnosed with K-F syndrome type II. It was observed in the father and one daughter; another child presented Pena-Shokeir type I and died during the neonatal period. Both siblings presented anomalies in the central nervous system., Conclusions: The incidence of FADS syndrome is 1/10,000 deliveries and that of K-F syndrome is between 1/35,000 and 1/42,000 births. We reviewed the literature on FADS syndrome and no familiar association with K-F syndrome was found among its causes. Our aim is to report that an association between the two conditions is possible, which is very important for establishing suitable genetic counselling.

Introduction: Embryogenetic disorders are one of the most serious problems in the life of an epileptic. Over the last few decades many antiepileptic drugs, including valproic acid, have been shown to have teratogenic properties. Embryopathy due to valproate, also known as fetal valproate syndrome, is a well-known and documented example of these conditions., Case Report: We report the case of a preterm newborn infant who, at birth, exhibited a syndrome characterised by facial dysmorphia, gingival hyperplasia, neurological hyperexcitability and multiple malformations, the most striking of which was the presence of predominantly temporal atrophy in the left brain hemisphere. The most significant event in the medical history of the case was the mother's taking valproate in monotherapy throughout the entire period of gestation as treatment for generalised idiopathic epilepsy that was diagnosed during adolescence. Screening precluded the most common metabolic, hereditary or infectious causes that can cause embryopathies., Conclusions: The mother's history of taking valproic acid and the specific findings that coincided in the peculiar embryopathy of this patient enabled us to link them.

Glutaric aciduria type I is an autosomal recessive metabolic disease (1 case/30,000) characterized by a progressive dystonic-diakinetic syndrome in children. Pathologic examination reveals striatal degeneration of the caudate and putamen nucleus and biochemical analysis shows glutaryl CoA dehydrogenase deficiency. Values of glutaric and -hydroxyglutaric acids in urine are usually increased. Currently, the disease is considered untreatable since there are usually irreversible lesions in the central nervous system at diagnosis. However, treatment can be provided to pre-symptomatic children and usually to the siblings of patients with this diagnosis. We present the case of a 23-month-old boy, with macrocephaly and minimal neurologic manifestations at diagnosis, which were attributed to his semivegetarian diet. A dietary regimen and vitamin supplementation halted and even improved symptomatic progression of the disease. We conclude that amino and organic acids in urine should be investigated in all children with progressive macrocephaly of unknown etiology to rule out glutaric aciduria type I.

Aims: In this paper we review the main publications on incontinentia pigmenti (IP) and the current knowledge of the etiopathogenesis of the disease and of the convulsions in the neonatal period, by considering a clear case of neonatal IP, with skin, eye, brain and bone lesions., Case Report: Our patient, a female, started with clonic seizures in the right half of the body at the age of three days. Method. IP, or Bloch Sulzberger syndrome, is a genetic multisystemic neuroectodermic disorder. It is a disease of low incidence (1% of all neuroectodermic disorders) which is transmitted by means of a pattern of dominant inheritance linked to X, and is lethal in males, except in rare cases of somatic mosaicism and Klinefelter. In the family forms the gene is located in the p11 (IP 1) and q28 (IP 2) regions of the X chromosome. It has recently been discovered that the cause lies in a mutation of a gene called NEMO (IKK gamma). Together with Bourneville s tuberous sclerosis it is the only neurocutaneous syndrome that can begin with neonatal convulsions. The convulsions start on the second or third day of life and are often limited to a single side of the body, although it can also appear as encephalitis. The origin of the convulsions has been linked with recurring encephalomyelitis, or with an alteration of the neuronal migration., Conclusions: The cause of the early convulsions in our patient, which we put down to a left perisylvian focal dysgenesia (unilateral opercular syndrome) observed in the computerised axial tomography (CAT scan), has not been reported up to the present associated with IP.

Eighteen catheterizations were attempted in 17 patients catheters (Arrow 3ChFr and 4ChFr), between january of 1996 and december of 1997. The patients ranged in age from 3 to 148 days (mean of 43.3 and standard deviation of 47.5) and in weight from 1110 to 4000 grams (mean of 3182 grams and standard deviation 767.2 grams). Overall successful catheterization rate was 94.5%. Complications included a pneumothorax that needed pleural drainage, one self-limited femoral artery spasm and one stenosis of femoral vein that did not require any treatment. The mean catheterism time was 6.64 days (deviation of 3.84 days), and the causes of removal were end of treatment in 8 patients, accidental removal in 5, infectious suspicion in 2 and limb edema in 2. Seldinger technique may be a useful approach for central venous catheterization in neonates. Careful catheterization, extensive experience and appropriate selection of material, help to keep the risk of complications low.