ABSTRACT
Autism Spectrum Disorder (ASD) is a complex neurodevelopmental trouble characterized by deficits in communication and social interactions associated with restricted and repetitive behaviour, interests and activities. Given the heterogeneity of the disorder and the absence of biomarker, its diagnostic approach must be comprehensive and multidisciplinary, according to international classifications. The aetiology of ASDs remains mostly unknown and results from a multifactorial model. This document offers guidelines to standardize practices and optimize the exploration of children with autism.
Le trouble du spectre de l'autisme (TSA) est une pathologie neurodéveloppementale complexe, caractérisée par des déficits de la communication et des interactions sociales associés à un caractère restreint et répétitif des comportements, des intérêts et des activités. Etant donné le caractère très hétérogène du trouble et l'absence de biomarqueur, son approche diagnostique doit être globale, multidisciplinaire, et répondre aux critères des classifications internationales. Par ailleurs, les TSA résultent d'un modèle multifactoriel dont l'étiologie demeure inconnue dans la majorité des cas. Afin d'optimiser le rendement exploratoire et d'homogénéiser les pratiques, ce document propose un cadre pour la mise au point des TSA en pédiatrie.
Subject(s)
Autism Spectrum Disorder , Autism Spectrum Disorder/diagnosis , Child , Communication , Family , HumansABSTRACT
Global developmental delay (GDD) and intellectual development disorder (IDD) are common but heterogeneous pediatric conditions. Guided by a rigorous clinical and anamnestic examination, the diagnostic approach is a dynamic process which is not limited to the intelligence quotient measurement. A large panel of paraclinical tests allows etiological exploration; this generally includes biological, genetic, metabolic and iconographic examinations. To maximize therapeutic efficiency and standardize practices, this document provides a guideline for the management of pediatric GDD/IDD.
Le retard global du développement (RGD) et le trouble du développement intellectuel (TDI) forment un groupe hétérogène de pathologies pédiatriques relativement fréquentes. Orientée par un examen clinique et anamnestique rigoureux, la démarche diagnostique est un processus dynamique qui ne se limite pas au quotient intellectuel. Son exploration étiologique est menée à travers un large panel d'examens paracliniques qui comprend généralement des examens biologiques, génétiques, métaboliques et iconographiques. Afin d'optimiser le rendement thérapeutique et d'homogénéiser les pratiques, ce document propose un cadre pour la mise au point des RGD/TDI en pédiatrie.
Subject(s)
Developmental Disabilities , Intellectual Disability , Child , Cognition , Developmental Disabilities/diagnosis , Developmental Disabilities/etiology , Family , Humans , Intellectual Disability/diagnosis , Intellectual Disability/etiologyABSTRACT
Inborn errors of metabolism (IEM) represent a vast group of orphan genetic disorders associated with enzyme deficiencies, substrates accumulation and products depletion. For several decades, the cornerstone of life-saving therapies in IEM was based on extreme manipulations of the nutritional intakes. Such outstanding dietary engineering is still relevant today, but new therapeutic avenues have emerged last years, based on better pathophysiological understanding and technological advances. In this paper, we summarize current and new therapeutic options in the field of IEM.
Les erreurs innées du métabolisme (EIM) représentent un groupe de conditions génétiques associées à une déficience enzymatique causant une accumulation du substrat en amont de la réaction et une déficience du produit en aval. Pendant des décennies, la pierre angulaire du traitement de ces affections a été basée sur des régimes drastiquement restrictifs. Ces manipulations diététiques extrêmes sont encore aujourd'hui d'actualité, mais l'arsenal thérapeutique s'est considérablement élargi ces dernières années, basé sur de meilleures connaissances physiopathologiques et sur des progrès technologiques et pharmacologiques. Dans cet article, nous résumons les différentes stratégies et nouveautés thérapeutiques dans le domaine des erreurs innées du métabolisme.
Subject(s)
Metabolism, Inborn Errors , Humans , Metabolism, Inborn Errors/therapy , Rare DiseasesABSTRACT
Psychiatric disorders in children may be the expression of underlying organic conditions. These are numerous and varied. The clinical presentation is often frustrating : psychiatric signs can remain isolated for years before other more specific organic signs appear. More recently, new treatments have been developed, making it possible to improve the prognosis of some of these organic diseases; screening them is therefore a daily concern for the child psychiatrist. This literature review discusses various paediatric treatable organic disorders that may have an isolated psychiatric presentation, to finally propose a decision tree algorithm based on somatic and psychiatric complaints reported.
Les troubles psychiatriques chez l'enfant peuvent être l'expression d'affections organiques sous-jacentes. Celles-ci sont nombreuses et variées avec une expression clinique souvent fruste, les signes psychiatriques pouvant rester isolés pendant des années avant que d'autres signes organiques plus spécifiques n'apparaissent. Plus récemment, de nouveaux traitements ont été développés, permettant d'améliorer le pronostic de certaines de ces maladies organiques; le dépistage de celles-ci constitue, dès lors, une préoccupation quotidienne pour le pédopsychiatre. Cette revue de littérature discute des différentes affections organiques traitables chez l'enfant pouvant avoir une présentation psychiatrique isolée. Elle propose, par la suite, un algorithme décisionnel orienté en fonction des plaintes somatiques et psychiatriques rapportées.
Subject(s)
Medically Unexplained Symptoms , Mental Disorders , Child , Humans , Mental Disorders/complicationsABSTRACT
The range of applications performed on dried blood spots (DBS) widely broadened during the past decades to now include next-generation sequencing (NGS). Previous publications provided a general overview of NGS capacities on DBS-extracted DNA but did not focus on the identification of specific disorders. We thus aimed to demonstrate that NGS was reliable for detecting pathogenic mutations on genomic material extracted from DBS. Assuming the future implementation of NGS technologies into newborn screening (NBS), we conducted a pilot study on fifteen patients with inherited metabolic disorders. Blood was collected from DBS. Whole-exome sequencing was performed, and sequences were analyzed with a specific focus on genes related to NBS. Results were compared to the known pathogenic mutations previously identified by Sanger sequencing. Causal mutations were readily characterized, and multiple polymorphisms have been identified. According to variant database prediction, an unexplained homozygote pathogenic mutation, unrelated to patient's disorder, was also found in one sample. While amount and quality of DBS-extracted DNA are adequate to identify causal mutations by NGS, bioinformatics analysis revealed critical drawbacks: coverage fluctuations between regions, difficulties in identifying insertions/deletions, and inconsistent reliability of database-referenced variants. Nevertheless, results of this study lead us to consider future perspectives regarding "next-generation" NBS.
Subject(s)
Dried Blood Spot Testing/methods , Genotype , Metabolic Diseases/genetics , Mutation/genetics , Computational Biology , Genetic Predisposition to Disease , High-Throughput Nucleotide Sequencing , Humans , Infant, Newborn , Neonatal Screening , Pilot Projects , Polymorphism, Single Nucleotide , Reproducibility of Results , Exome SequencingABSTRACT
We report the case of a 26-year-old man who initiated a limb girdle muscular dystrophy (lgmd2b). It is a rare and slowly progressive autosomal recessive dysferlinopathy occurring in young adults and for which no treatment is currently known.
Nous rapportons le cas clinique d'un homme de 26 ans présentant une dystrophie musculaire des ceintures de type 2b (lgmd2b). Il s'agit d'une dysferlinopathie autosomique récessive, pathologie rare, lentement progressive, survenant chez de jeunes adultes et pour laquelle aucun traitement n'est actuellement connu.
Subject(s)
Muscle Weakness/etiology , Muscular Dystrophies, Limb-Girdle/diagnosis , Adult , Dysferlin/genetics , Humans , Male , Muscular Dystrophies, Limb-Girdle/genetics , MutationABSTRACT
Carnitine palmitoyltransferase II (CPT2) deficiency is a rare inborn error of mitochondrial fatty acid metabolism associated with various phenotypes. Whereas most patients present with postnatal signs of energetic failure affecting muscle and liver, a small subset of patients presents antenatal malformations including brain dysgenesis and neuronal migration defects. Here, we report recurrence of severe cerebral dysgenesis with Dandy-Walker malformation in three successive pregnancies and review previously reported antenatal cases. Interestingly, we also report that acylcarnitines profile, tested retrospectively on the amniotic fluid of last pregnancy, was not sensitive enough to allow reliable prenatal diagnosis of CPT2 deficiency. Finally, because fetuses affected by severe cerebral malformations are frequently aborted, CPT2 deficiency may be underestimated and fatty acid oxidation disorders should be considered when faced with a fetus with Dandy-Walker anomaly or another brain dysgenesis.
Subject(s)
Carnitine O-Palmitoyltransferase/deficiency , Metabolism, Inborn Errors/diagnosis , Adult , Fatal Outcome , Female , Humans , Infant, Newborn , Male , PregnancyABSTRACT
Phenylketonuria is a metabolic disease caused by phenylalanine hydroxylase deficiency. Treatment is based on a strict natural protein-restricted diet that is associated with the risk of malnutrition and severe psychosocial burden. Oral administration of tetrahydrobiopterin can increase residual enzyme activity, but most patients with severe clinical phenotypes are nonresponders. We performed liver cell transplantation in a 6-year-old boy with severe tetrahydrobiopterin nonresponsive phenylketonuria who failed to comply with diet prescriptions. The transplanted hepatocytes were obtained in part from an explanted glycogen storage type 1b liver. Following two infusions, blood phenylalanine levels returned within the therapeutic target while the phenylalanine half-life assessed by loading tests decreased from 43 to 19 h. However, 3 months later, blood phenylalanine concentrations increased and the phenylalanine intake had to be reduced. Cell-based therapy is a promising therapeutic option in phenylketonuria, and the domino concept may solve the issue of cell sources for hepatocyte transplantation.
Subject(s)
Hepatocytes/transplantation , Phenylketonurias/therapy , Cell- and Tissue-Based Therapy , Child , Female , Glycogen Storage Disease Type I/therapy , Half-Life , Hepatocytes/cytology , Humans , Infant , Liver Function Tests , Male , Phenylalanine/blood , Phenylalanine Hydroxylase/genetics , Phenylalanine Hydroxylase/metabolism , Phenylketonurias/diagnosisABSTRACT
Congenital Isolated hypogonadotropic hypogonadism (CIHH) is caused by an inherited mechanism of impairment of the pituitary-gonadal axis, interfering with gonads' control. Currently, different forms of HHCI with (Kallmann syndrome or KS) or without anosmia-hyposmia are known. There are six forms of KS already described but in several cases no genetic mutation is found. The genetic anomalies already described are: KAL1 (locus Xp23) coding for anosmine-1, KAL-2 or FGFRI (8p11. locus 2 - p11.1) coding for Fibroblast Growth Factor Receptor 1 (FGFR1), KAL4 or PROk2 (locus 3p21.1) and KAL3 or ProKR2 (locus 20p13) coding respectively for the Prokinecitin-2 and its receptor, KAL5 or CHD7 (locus_8q12.1) coding for a chromodomain helicase DNA-binding protein-7 gene (CHD7) and lastly KAL6 or FGF8 (10Q 24 loci) coding for Fibroblast Growth Factor 8. The other genetic anomalies without anosmia are less frequent. These are associated either with Gnrhl gene (8p2-11. 2), GnRHR (4q21.2), GPR54 (19p13),TAC3R or neurokinine receptor 3 (4 q 25), LH (19q13.32) or FSH (11p13). The isolated congenital hypogonadotrophic hypogonadism phenotype is variable depending on gender, the importance of the deficit, and ultimately, according to a specific regulatory mechanism of the axis, affected by an inherited genetic anomaly. In this review, we describe the essential aspects of the different phenotypes and genotypes of HHCI, in order to assess clinicians an early disease's diagnosis and management.
Subject(s)
Hypogonadism/congenital , Hypogonadism/genetics , Diagnosis, Differential , Genetic Counseling , Humans , Hypogonadism/diagnosis , Hypogonadism/therapyABSTRACT
We report the case of a young boy who had had multiple bone fractures (more than 10) since the age of 19 months. The father had the same clinical history. The clinical examination was normal for his age except blue sclera. The bone densitometry showed a severe osteoporosis for his age. Biological exam swere correct. The genetic exploration revealed mutation of COL1A2 gene. With this clinical history, the diagnosis of Osteogenesis imperfecta (OI) was retained. OI is a hereditary dystrophy with abnormal synthesis or metabolism of collagen with, often, mutation of COL1A1 or COL1A2 genes. There are 7 different forms. We consider the possible differential diagnoses. The goal of any treatment is to promote bone remineralisation and to decrease the fracture frequency. The treatment includes calcium and vitamin D, and in the presence of some precise criteria, biphosphonate therapy.
Subject(s)
Collagen Type I/genetics , Collagen/genetics , Osteogenesis Imperfecta/genetics , Bone Density/drug effects , Calcium/therapeutic use , Chromosome Mapping , Collagen Type I, alpha 1 Chain , Diagnosis, Differential , Diphosphonates/therapeutic use , Drug Therapy, Combination , Humans , Infant , Male , Mutation , Osteogenesis Imperfecta/diagnosis , Osteogenesis Imperfecta/drug therapy , Pedigree , Treatment Outcome , Vitamin D/therapeutic useABSTRACT
BACKGROUND: Hyperornithinaemia-hyperammonaemia-homocitrullinuria (HHH) syndrome (OMIM 238970) is caused by impaired ornithine transport across the inner mitochondrial membrane due to mutations in SLC25A15. To date, 22 different mutations of the SLC25A15 gene have been described in 49 patients belonging to 31 unrelated families. OBJECTIVE: To further delineate the phenotypic spectrum of HHH syndrome from a description of a genetically homogeneous cohort of patients and identify prognostic factors based on long-term follow-up. METHODS: Sixteen French-Canadian patients were retrospectively and prospectively clinically assessed. RESULTS: Owing to a founder effect, 15 of the 16 patients were homozygous for the F188del mutation in the SLC25A15 gene. The main clinical features at presentation were liver dysfunction (6/16) and neurological disease (9/16), including chronic neurological symptoms (6/9) and acute encephalopathy (3/9). Hyperammonaemia was not constant and usually mild and uncommon after start of treatment. Long-term follow-up showed that variable intellectual impairment and lower limb spasticity often occur, together or separately, with no obvious relationship to age at diagnosis and compliance with treatment. CONCLUSION: We report the largest known cohort to date of patients with HHH syndrome. A similar range of severity occurred in the clinical course and outcome of patients homozygous for delF188 and in the 33 other reported patients compiled from the literature. The poor clinical outcome of some patients with HHH syndrome despite early treatment and repeatedly normal plasma ammonia levels emphasises the need to better understand the pathophysiology and to reconsider the therapeutic goals for HHH.
Subject(s)
Amino Acid Metabolism, Inborn Errors , Amino Acid Transport Systems, Basic/genetics , Citrulline/analogs & derivatives , Homozygote , Hyperammonemia/genetics , Mutation , Ornithine/blood , Adolescent , Amino Acid Metabolism, Inborn Errors/genetics , Amino Acid Metabolism, Inborn Errors/physiopathology , Child , Child, Preschool , Citrulline/blood , Citrulline/urine , Founder Effect , Humans , Hyperammonemia/blood , Hyperammonemia/complications , Hyperammonemia/urine , Infant , Phenotype , SyndromeABSTRACT
OBJECTIVE: To investigate whether secondary impairment of the transmethylation pathway is a mechanism underlying the neurologic involvement in homocystinuria due to remethylation defects. METHODS: Twelve patients with neurologic disease due to remethylation defects were examined by brain magnetic resonance spectroscopic imaging ((1)H MRSI). Brain N-acetylaspartate, choline-containing compounds (Cho), and creatine (Cr) were quantified and compared to with controls. Metabolites of remethylation cycle and creatine biosynthesis pathway were measured in plasma and urine. RESULTS: MRSI revealed isolated Cho deficiency in all regions examined (mean concentration units +/- SD, patients vs controls): frontal white matter (0.051 +/- 0.010 vs 0.064 +/- 0.010; p = 0.001), lenticular nucleus (0.056 +/- 0.011 vs 0.069 +/- 0.009; p < 0.001), and thalamus (0.063 +/- 0.010 vs 0.071 +/- 0.007; p = 0.006). In contrast to controls, the Cho/Cr ratio decreased with age in patients in the three brain regions examined. Low creatine urinary excretion (p < 0.005), normal urine and plasma guanidinoacetate, and a paradoxical increase in plasma S-adenosylmethionine (p < 0.005) concentrations were observed. CONCLUSION: Patients with homocystinuria due to remethylation defects have an isolated brain choline deficiency, probably secondary to depletion of labile methyl groups produced by the transmethylation pathway. Although biochemical studies suggest mild peripheral creatine deficiency, brain creatine is in the reference range, indicating a possible compartmentation phenomenon. Paradoxical increase of S-adenosylmethionine suggests that secondary inhibition of methylases contributes to the transmethylation defect in these conditions.
Subject(s)
Brain/metabolism , Choline Deficiency/metabolism , Choline/metabolism , Homocysteine S-Methyltransferase/metabolism , Homocystinuria/blood , Homocystinuria/urine , Adolescent , Adult , Aspartic Acid/analogs & derivatives , Aspartic Acid/metabolism , Brain/physiopathology , Brain Chemistry/physiology , Child , Child, Preschool , Choline Deficiency/etiology , Choline Deficiency/physiopathology , Creatine/blood , Creatine/urine , Female , Homocystinuria/physiopathology , Humans , Magnetic Resonance Spectroscopy , Male , Methylation , S-Adenosylmethionine/metabolismABSTRACT
OBJECTIVE: The aim of this study is to report and emphasize unusual presentations of pyruvate dehydrogenase (PDH) deficiency (OMIM 312170). METHODS: PDH activity and PDHA1 gene were studied in two siblings presenting with intermittent ataxia in childhood. Similar presentations in reported PDH-deficient patients were searched for using the Medline database. RESULTS: Both patients had PDH deficiency caused by a new mutation (G585C) in the PDHA1 gene, which is predicted to replace a highly conserved glycine at codon 195 by alanine. Although this mutation lies within the thiamine pyrophosphate binding domain, there was no thiamine responsiveness IN VIVO. The patients presented recurrent episodes of acute isolated ataxia in infancy. Both had normal blood and CSF lactate levels. Although symptoms initially resolved between episodes during the first decade, both patients subsequently worsened and developed progressive and severe encephalopathy, leading to death in their twenties. The spectrum of intermittent presentations in PDH deficiency includes episodic ataxia, intermittent peripheral weakness, recurrent dystonia and extrapyramidal movement disorders. CONCLUSIONS: PDH deficiency should be considered in patients with unexplained intermittent and recurrent acute neurological symptoms. Long-term prognosis and outcome remain uncertain. PDH deficiency can occur even with normal CSF lactate concentration.
Subject(s)
Ataxia/diagnosis , Ataxia/etiology , Pyruvate Dehydrogenase Complex Deficiency Disease/complications , Pyruvate Dehydrogenase Complex Deficiency Disease/diagnosis , Ataxia/genetics , Basal Ganglia Diseases/etiology , Basal Ganglia Diseases/pathology , Binding Sites/genetics , Brain Diseases, Metabolic/etiology , Brain Diseases, Metabolic/pathology , Child , Child, Preschool , Diagnosis, Differential , Dystonia/etiology , Dystonia/pathology , Fatal Outcome , Humans , Infant , Lactic Acid/blood , Lactic Acid/cerebrospinal fluid , Male , Movement Disorders/etiology , Movement Disorders/pathology , Muscle Weakness/etiology , Muscle Weakness/pathology , Mutation , Pyruvate Dehydrogenase (Lipoamide)/genetics , Pyruvate Dehydrogenase Complex/genetics , Pyruvate Dehydrogenase Complex Deficiency Disease/genetics , Thiamine Pyrophosphate/metabolismABSTRACT
We report the case of a 2.5-month-old infant with severe anaemia discovered fortuitously during an acute febrile illness. The patient was admitted because of a septic arthritis of the knee. Initial biology showed a 3.5 g/dl haemoglobin concentration. The anaemia was microcytic and hypochromic, with obvious haemolysis and reticulocytosis. Standard analysis was not contributive. Further investigations allowed the diagnosis of elliptocytosis. The patient was treated by antibiotics, orthopaedic measures and iterative transfusions. Now, 18 months from the initial episode, she is in good health. With this history, we discuss the clinical process facing severe anaemia during infancy and review the particularities of such uncommon congenital anaemia. Elliptocytosis is a haemolytic anaemia caused by congenital anomalies of the erythrocyte membrane. Diagnosis requires morphological studies of the red blood cells on peripheral blood smear. The disease is often overlooked by membrane protein electrophoresis. The condition is heterogeneous concerning clinical, biochemical and genetic aspects. Most of the cases are linked to mutations of the alpha-spectrin gene, in autoassociation regions. Search of spectrin and protein 4.1 genes mutations can confirm the diagnosis but is not routinely performed.
