N. Boddaert

The first founder DGUOK mutation associated with hepatocerebral mitochondrial DNA depletion syndrome

Deoxyguanosine kinase (dGK) deficiency is a frequent cause of mitochondrial DNA depletion associated with a hepatocerebral phenotype. In this study, we describe a new splice site mutation in the DGUOK gene and the clinical, radiologic, and genetic features of these DGUOK patients. This new DGUOK homozygous mutation (c.444-62C>A) was identified in three patients from two North-African consanguineous families with combined respiratory chain deficiencies and mitochondrial DNA depletion in the liver. Brain MRIs are normal in DGUOK patients in the literature. Interestingly, we found subtentorial abnormal myelination and moderate hyperintensity in the bilateral pallidi in our patients. This new mutation creates a cryptic splice site in intron 3 (in position -62) and is predicted to result in a larger protein with an in-frame insertion of 20 amino acids. In silico analysis of the putative impact of the insertion shows serious clashes in protein conformation: this insertion disrupts the alpha5 helix of the dGK kinase domain, rendering the protein unable to bind purine deoxyribonucleosides. In addition, a common haplotype that segregated with the disease in both families was detected by haplotype reconstruction with 10 markers (microsatellites and SNPs), which span 4.6 Mb of DNA covering the DGUOK locus. In conclusion, we report a new DGUOK splice site mutation that provide insight into a critical protein domain (dGK kinase domain) and the first founder mutation in a North-African population.

Mise au pointMaladies héréditaires du métabolisme : signes anténatals et diagnostic biologiquePrenatal symptoms and diagnosis of inherited metabolic diseases☆

Inherited metabolic diseases are mostly due to enzyme deficiency in one of numerous metabolic pathways, leading to absence of a compound downstream from and the accumulation of a compound upstream from the deficient metabolite(s). Diseases of intoxication by proteins (aminoacidopathies, organic acidurias, urea cycle defects) and by sugars (galactosemia, fructosemia) usually do not give prenatal symptoms since mothers protect their fetuses from pathological metabolite accumulation. A well-known exception is hypoplasia of corpus callosum, as is sometimes observed in nonketotic hyperglycinemia and sulfite oxidase deficiency. Conversely, women with phenylketonuria poison their fetus if they are not treated (spontaneous abortions, intrauterine growth restriction [IUGR], cardiac malformations, and brain disease). Amino acid synthesis defects can lead to prenatal symptoms: microcephaly in serine deficiency (detectable by amino acid analysis in fetal cord blood), and brain malformations in glutamine synthetase deficiency. Impaired folate metabolism is involved in a large fraction of neurodevelopmental defects referred to as spina bifida, yet the underlying genetic component(s) are largely unknown. Energy metabolism diseases caused by defects in the synthesis or utilization of relevant metabolites lead to organ dysfunctions or malformations, but prenatal diagnosis is usually impossible unless genetic analysis can rely on a previously affected child in the family. A somewhat intermediate condition is defects of mitochondrial beta-oxidation of fatty acids, as they may sometimes be symptomatic prenatally (notably the HELLP syndrome or other presentations), and in this case, organic acid and acylcarnitine analysis in amniotic fluid can be informative in the absence of an index case. In contrast, complex molecule diseases commonly give prenatal symptoms that may permit the diagnosis even in the absence of index cases: hydrops fetalis and skeletal anomalies in lysosomal storage diseases, hydrops fetalis in congenital disorders of glycosylation (CDG) and transaldolase deficiency, brain malformations in O-glycosylation defects, brain malformations, kidney cysts and skeletal anomalies in peroxysomal diseases (Zellweger syndrome), syndactyly, genitalia malformations, and IUGR in Smith-Lemli-Opitz (SLO) syndrome. Although many metabolic disorders show biochemical abnormalities during fetal development that are informative for prenatal diagnosis, only a fraction of them are clinically/sonographically symptomatic before birth, thus allowing for prenatal diagnosis in the absence of an index case, i.e., serine deficiency, some fatty acid beta-oxidation defects, transaldolase deficiency, lysosomal diseases, CDG, Zellweger syndrome, and SLO syndrome.

Biallelic Mutations in LIPT2 Cause a Mitochondrial Lipoylation Defect Associated with Severe Neonatal Encephalopathy

Lipoate serves as a cofactor for the glycine cleavage system (GCS) and four 2-oxoacid dehydrogenases functioning in energy metabolism (α-oxoglutarate dehydrogenase [α-KGDHc] and pyruvate dehydrogenase [PDHc]), or amino acid metabolism (branched-chain oxoacid dehydrogenase, 2-oxoadipate dehydrogenase). Mitochondrial lipoate synthesis involves three enzymatic steps catalyzed sequentially by lipoyl(octanoyl) transferase 2 (LIPT2), lipoic acid synthetase (LIAS), and lipoyltransferase 1 (LIPT1). Mutations in LIAS have been associated with nonketotic hyperglycinemia-like early-onset convulsions and encephalopathy combined with a defect in mitochondrial energy metabolism. LIPT1 deficiency spares GCS deficiency and has been associated with a biochemical signature of combined 2-oxoacid dehydrogenase deficiency leading to early death or Leigh-like encephalopathy. We report on the identification of biallelic LIPT2 mutations in three affected individuals from two families with severe neonatal encephalopathy. Brain MRI showed major cortical atrophy with white matter abnormalities and cysts. Plasma glycine was mildly increased. Affected individuals fibroblasts showed reduced oxygen consumption rates, PDHc, α-KGDHc activities, leucine catabolic flux, and decreased protein lipoylation. A normalization of lipoylation was observed after expression of wild-type LIPT2, arguing for LIPT2 requirement in intramitochondrial lipoate synthesis. Lipoic acid supplementation did not improve clinical condition nor activities of PDHc, α-KGDHc, or leucine metabolism in fibroblasts and was ineffective in yeast deleted for the orthologous LIP2.

Mitochondrial ND5 mutations mimicking brainstem tectal glioma

We report MRI periaqueductal T2 hypersignal suggestive of tectal glioma in 3 unrelated children with reduced vision and normal mental development (figure). Increased CSF lactate and optic atrophy in the first case suggested …

Moyamoya syndrome in children with neurofibromatosis type 1: Italian-French experience

Moyamoya syndrome (MMS) is the most common cerebral vasculopathy among children with neurofibromatosis type 1 (NF1). In this study, we clinically, radiologically, and genetically examined a cohort that was not previously described, comprising European children with NF1 and MMS. The NF1 genotyping had been registered. This study included 18 children. The mean age was 2.93u2009±u20093.03 years at the NF1 diagnosis and 7.43u2009±u20094.27 years at the MMS diagnosis. In seven patients, MMS was diagnosed before or at the same time as NF1. Neuroimaging was performed in 10 patients due to clinical symptoms, including headache (nu2009=u20096), cerebral infarction (nu2009=u20092), and complex partial seizures (nu2009=u20092). The remaining eight children (47%) had MMS diagnosed incidentally. Sixteen children were characterized molecularly. The features of MMS were similar between patients with and without NF1. Additionally, the NF1 phenotype and genotype were similar between children with and without MMS. Interestingly, three children experienced tumors with malignant histology or behavior. The presence of two first cousins in our cohort suggested that there may be potential genetic factors, not linked to NF1, with an additional role respect of NF1 might play a role in MMS pathogenesis. The incidental diagnosis of MMS, and the observation that, among children with NF1, those with MMS were clinically indistinguishable from those without MMS, suggested that it might be worthwhile to add an angiographic sequence to brain MRIs requested for children with NF1. A MMS diagnosis may assist in properly addressing an NF1 diagnosis in very young children who do not fulfill diagnostic criteria.

Imaging features of medulloblastoma: Conventional imaging, diffusion-weighted imaging, perfusion-weighted imaging, and spectroscopy: From general features to subtypes and characteristics

Medulloblastoma is a frequent high-grade neoplasm among pediatric brain tumours. Its classical imaging features are a midline tumour growing into the fourth ventricle, hyperdense on CT-scan, displaying a hypersignal when using diffusion-weighted imaging, with a variable contrast enhancement. Nevertheless, atypical imaging features have been widely reported, varying according to the age of the patient, and histopathological subtype. In this study, we review the classical and atypical imaging features of medulloblastomas, with emphasis on advanced MRI techniques, histopathological and molecular subtypes and characteristics, and follow-up modalities.

Diffusion tensor imaging (DTI) and Tractography of the spinal cord in pediatric population with spinal lipomas: preliminary study

PurposeDiffusion tensor imaging (DTI) allows studying the micro and macro architecture. One of the major challenges in dysraphism is to know the morphologic organization of the spinal cord. In a preliminary work, spinal lipoma was chosen for analyzing the micro-architecture parameters and fiber morphology of the spinal cord by DTI with tractography.MethodsTwelve patients (0–8xa0years) related to spinal lipomas treated between May 2017 and March 2018 were included. Tractography reconstruction of the conus medullaris of 12 patients were obtained using the MedINRIA software. The diffusion parameters have been calculated by Osirix DTImap plugin.ResultsWe found a significant difference in the FA (pu2009=u20090.024) between two age groups (<u200924xa0months old and >u200924xa0months old). However, no significant differences in the mean values of FA, RD, and MD between the level of the lipoma and the level above were noted. The tractography obtained in each case was coherent with morphologic sequences and reproducible. The conus medullaris was deformed and shifted. Destruction or disorganization of fibers and any passing inside the lipomas was not observed.ConclusionsTractography of the conus medullaris in a very young pediatric population (0–8xa0years old) with a spinal lipoma is possible, reproductive, and allows visualization of the spinal cord within the dysraphism. Analysis of the FA shows that the presence of a lipoma seems to have an effect on the myelination of the conus medullaris. It is during the probable myelination phase that the majority of symptoms appear. Is the myelination per se the cause?

Deficits en creatine : a propos de 10 cas pediatriques

Objectifs Les deficits en creatine constituent un nouveau groupe de maladies hereditaires du metabolisme responsable de 1% de retard mental chez le garcon. Ils rassemblent le deficit en guanidinoacetate-methyltransferase (GAMT), le deficit en arginine-glycine-amidino-transferase (AGAT) et le deficit en transporteur membranaire de la creatine. Nous decrivons ici, la presentation clinique, les donnees de l’IRM cerebrale et le traitement de 10 enfants porteurs d’un deficit en creatine. Materiels et methodes Dix enfants (âge-moyen 9 ans) avec deficit en creatine confirme sur le plan enzymatique et moleculaire (deficit en GAMT nxa0=xa04, anomalie du transporteur de la creatine nxa0=xa06) sont inclus. Tous ont eu une IRM cerebrale avec spectroscopie. Resultats Les enfants presentent un retard mental et du langage (nxa0=xa010), une epilepsie (nxa0=xa06), des troubles du comportement (nxa0=xa07). Sept sur 10 enfants ont ete depistes par la spectroscopie qui a montre une absence totale de creatine/phosphocreatine intra-cerebrale (nxa0=xa08) ou une nette diminution de la creatine (2 filles avec deficit-du-trans-porteur). Les deficits en GAMT sont traites de facon efficace par la creatine orale alors que le deficit-en-transporteur ne semble pas repondre aux traitements par creatine, arginine et lysine (precurseurs de la creatine). Conclusion Devant tout retard mental non specifique, il faudrait faire une IRM-spectroscopie de depistage le plus tot possible.

O6-6 Acute neurovascular events in children with ornithine transcarbamylase (OTC) deficiency: a retrospective review

O6-6 Acute neurovascular events in children with ornithine transcarbamylase (OTC) deficiency: a retrospective review A. Brassier2, N. Boddaert3, J.P. Bonnefont4, I. Desguerre1, M. Kossorotoff1 *, P. De Lonlay2,4. 1Neuropediatrics, Necker Enfants Malades, Paris, France; 2Metabolic Disease, Necker Enfants Malades, Paris, France; 3Pediatric Radiology, Necker Enfants Malades, Paris, France; 4Genetics, Necker Enfants Malades, Paris, France

Correlations radiologiques et genetiques chez 36 enfants porteurs d’une cytopathie mitochondriale avec mutation genetique identifiee

Objectifs Dans le cadre des cytopathies mitochondriales (CM), nous avons recherche en imagerie cerebrale un profil lesionnel commun en fonction du type de mutation identifiee. Materiels et methodes Nous avons realise une analyse retrospective de l’imagerie cerebrale de 36 patients vus dans le service de radiologie pediatrique de l’Hopital Necker-Enfants-Malades. Ces patients avec CM presentaient un deficit isole ou multiple de la chaine respiratoire et une mutation genetique identifiee. Resultats Pour un meme groupe de mutations, le profil lesionnel en imagerie etait tres souvent commun. Nous avons mis en evidence chez les patients avec deficit en complexe 1 (nxa0=xa011), des anomalies du tronc et des noyaux gris centraux (10/11). Les deficits en complexe V (nxa0=xa05) avaient des anomalies des noyaux gris centraux (4/5) et une atrophie cerebelleuse (4/5). Les deficits en quinone (nxa0=xa03) avaient une atrophie cerebelleuse (3/3) et des strokes-like sus-tentoriels (2/3). Les mutations MELAS (nxa0=xa05) avaient des anomalies des noyaux gris centraux et cerebelleuses (5/5). L’imagerie etait normale chez les patients avec deficit en complexe III (nxa0=xa04,4/4) et tres souvent normale chez les patients avec mutations POLG (nxa0=xa08,6/8). Conclusion En cas de suspicion de CM, l’imagerie cerebrale peut contribuer a l’identification de la mutation en cause dans la maladie.