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1.
AJNR Am J Neuroradiol ; 43(1): 132-138, 2022 01.
Article in English | MEDLINE | ID: mdl-34949593

ABSTRACT

BACKGROUND AND PURPOSE: Prognosis of isolated short corpus callosum is challenging. Our aim was to assess whether fetal DTI tractography can distinguish callosal dysplasia from variants of normal callosal development in fetuses with an isolated short corpus callosum. MATERIALS AND METHODS: This was a retrospective study of 37 cases referred for fetal DTI at 30.4 weeks (range, 25-34 weeks) because of an isolated short corpus callosum less than the 5th percentile by sonography at 26 weeks (range, 22-31 weeks). Tractography quality, the presence of Probst bundles, dysmorphic frontal horns, callosal length (internal cranial occipitofrontal dimension/length of the corpus callosum ratio), and callosal thickness were assessed. Cytogenetic data and neurodevelopmental follow-up were systematically reviewed. RESULTS: Thirty-three of 37 fetal DTIs distinguished the 2 groups: those with Probst bundles (Probst bundles+) in 13/33 cases (40%) and without Probst bundles (Probst bundles-) in 20/33 cases (60%). Internal cranial occipitofrontal dimension/length of the corpus callosum was significantly higher in Probst bundles+ than in Probst bundles-, with a threshold value determined at 3.75 for a sensitivity of 92% (95% CI, 77%-100%) and specificity of 85% (95% CI, 63%-100%). Callosal lipomas (4/4) were all in the Probst bundles- group. More genetic anomalies were found in the Probst bundles+ than in Probst bundles- group (23% versus 10%, P = .08). CONCLUSIONS: Fetal DTI, combined with anatomic, cytogenetic, and clinical characteristics could suggest the possibility of classifying an isolated short corpus callosum as callosal dysplasia and a variant of normal callosal development.


Subject(s)
Agenesis of Corpus Callosum , Corpus Callosum , Agenesis of Corpus Callosum/diagnostic imaging , Corpus Callosum/diagnostic imaging , Feasibility Studies , Fetus , Humans , Retrospective Studies
2.
Arch Pediatr ; 28(5): 374-380, 2021 Jul.
Article in English | MEDLINE | ID: mdl-33994267

ABSTRACT

AIM: Little is known about the clinical profile of COVID-19 infection in polyhandicapped persons. This study aimed to describe the characteristics of this infection among individuals with polyhandicap. METHOD: This was a retrospective observational study. Polyhandicap was defined by the combination of motor deficiency, profound mental retardation, and age at onset of cerebral lesion younger than 6 years. A positive COVID-19 status was considered for patients with a positive COVID-19 laboratory test result, or patients presenting with compatible symptoms and living in an institution or at home with other patients or relatives who had laboratory-confirmed COVID-19 infection. Data collection included sociodemographic data, clinical and paraclinical characteristics, as well as the management and treatment for COVID-19 infection. RESULTS: We collected 98 cases, with a sex ratio of 0.98 and a mean age of 38.5 years (3 months to 73 years). COVID-19 infection was paucisymptomatic in 46% of patients, 20.6% of patients presented with dyspnea, while the most frequent extra-respiratory symptoms were digestive (26.5%) and neurological changes (24.5%); 18 patients required hospital admission, four adults died. The mean duration of infection was longer for adults than for children, and the proportion of taste and smell disorders was higher in older patients. CONCLUSION: These findings suggest that PLH persons often develop paucisymptomatic forms of COVID-19 infection, although they may also experience severe outcomes, including death. Clinicians should be aware that COVID-19 symptoms in PLH persons are often extra-respiratory signs, mostly digestive and neurologic, which may help in the earlier identification of COVID-19 infection in this particular population of patients.


Subject(s)
COVID-19/complications , COVID-19/diagnosis , Intellectual Disability/complications , Motor Disorders/complications , Adolescent , Adult , Aged , Child , Child, Preschool , Female , France , Humans , Infant , Male , Middle Aged , Retrospective Studies , Young Adult
3.
Clin Neurophysiol ; 132(5): 1126-1137, 2021 05.
Article in English | MEDLINE | ID: mdl-33773177

ABSTRACT

OBJECTIVE: We aimed to describe epilepsy and EEG patterns related to vigilance states and age, in chromosome15-long-arm-duplication-syndrome (dup15q) children with epilepsy, in both duplication types: interstitial (intdup15) and isodicentric (idic15). METHODS: Clinical data and 70 EEGs of 12 patients (5 intdup15, 7 idic15), followed from 4.5 m.o to 17y4m (median follow-up 8y3m), were retrospectively reviewed. EEGs were analyzed visually and using power spectrum analysis. RESULTS: Seventy video-EEGs were analyzed (1-16 per patient, median 6), follow-up lasting up to 8y10m (median 4y2m): 25 EEGs in intdup15 (8 m.o to 12y.o, median 4y6m) and 45 EEGs in idic15 (7 m.o to 12 y.o, median 15 m). Epilepsy: 6 West syndrome (WS) (2intdup15, 4idic15); 4 Lennox-Gastaut syndromes (LGS) (1 intdup15, 3 idic15), 2 evolving from WS; focal epilepsy (3 intdup15). In idic15, WS displayed additional myoclonic seizures (3), atypical (4) or no hypsarrhythmia (2) and posterior predominant spike and polyspike bursts (4). Beta-band rapid-rhythms (RR): present in 11 patients, power decreased during non-REM-sleep, localization shifted from diffuse to anterior, peak frequency increased with age. CONCLUSION: WS with peculiar electro-clinical features and LGS, along with beta-band RR decreasing in non-REM-sleep and shifting from diffuse to anterior localization with age are recognizable features pointing towards dup15q diagnosis in children with autism spectrum disorder and developmental delay. SIGNIFICANCE: This study describes electroclinical features in both interstitial and isodicentric duplications of chromosome 15q, in epileptic children, including some recent extensions regarding sleep features; and illustrates how the temporo-spatial organization of beta oscillations can be of significant help in directing towards dup15q diagnosis hypothesis.


Subject(s)
Beta Rhythm , Chromosome Disorders/physiopathology , Epilepsy/physiopathology , Intellectual Disability/physiopathology , Trisomy/physiopathology , Adolescent , Child , Child, Preschool , Chromosome Aberrations , Chromosomes, Human, Pair 15 , Epilepsy/genetics , Female , Humans , Infant , Male , Sleep , Wakefulness
4.
Clin Exp Immunol ; 203(2): 247-266, 2021 02.
Article in English | MEDLINE | ID: mdl-32954498

ABSTRACT

Chronic granulomatous disease (CGD) is a rare inherited disorder in which phagocytes lack nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The most common form is the X-linked CGD (X91-CGD), caused by mutations in the CYBB gene. Clinical, functional and genetic characterizations of 16 CGD cases of male patients and their relatives were performed. We classified them as suffering from different variants of CGD (X910 , X91- or X91+ ), according to NADPH oxidase 2 (NOX2) expression and NADPH oxidase activity in neutrophils. Eleven mutations were novel (nine X910 -CGD and two X91- -CGD). One X910 -CGD was due to a new and extremely rare double missense mutation Thr208Arg-Thr503Ile. We investigated the pathological impact of each single mutation using stable transfection of each mutated cDNA in the NOX2 knock-out PLB-985 cell line. Both mutations leading to X91- -CGD were also novel; one deletion, c.-67delT, was localized in the promoter region of CYBB; the second c.253-1879A>G mutation activates a splicing donor site, which unveils a cryptic acceptor site leading to the inclusion of a 124-nucleotide pseudo-exon between exons 3 and 4 and responsible for the partial loss of NOX2 expression. Both X91- -CGD mutations were characterized by a low cytochrome b558 expression and a faint NADPH oxidase activity. The functional impact of new missense mutations is discussed in the context of a new three-dimensional model of the dehydrogenase domain of NOX2. Our study demonstrates that low NADPH oxidase activity found in both X91- -CGD patients correlates with mild clinical forms of CGD, whereas X910 -CGD and X91+ -CGD cases remain the most clinically severe forms.


Subject(s)
Granulomatous Disease, Chronic/genetics , Mutation, Missense/genetics , NADPH Oxidase 2/genetics , Adult , Cell Line , Exons/genetics , Female , Granulomatous Disease, Chronic/metabolism , Humans , Male , Membrane Glycoproteins/genetics , Neutrophils/metabolism , Young Adult
5.
Ultrasound Obstet Gynecol ; 58(1): 11-18, 2021 07.
Article in English | MEDLINE | ID: mdl-32798278

ABSTRACT

OBJECTIVE: Fetal anomalies of the corpus callosum (CC) have been reported in the prenatal imaging literature since 1985, and, especially when isolated, pose challenges for both the patient and fetal medicine specialist. The purpose of this study was to review systematically the literature on prenatally diagnosed abnormalities of the CC, focusing on the terminology used to describe abnormalities other than complete agenesis of the CC, and to assess the heterogeneity of the nomenclature and definitions used. METHODS: This study was conducted in accordance with the PRISMA statement for reporting systematic reviews. A literature search was performed to identify prospective or retrospective case series or cohort studies, published in English, French, Italian, German or Spanish, reporting fetal imaging findings and describing anomalies of the CC. Quality and risk of bias of the studies were evaluated using the Newcastle-Ottawa scale and a modification of the scale developed by Conde-Agudelo et al. for other fetal imaging studies. The data extracted included the number of patients, the number of different anomalies identified, the descriptive names of the anomalies, and, where applicable, the definitions of the anomalies, the number of cases of each type of anomaly and the biometric charts used. Secondary tests used to confirm the diagnosis, as well as the postnatal or post-termination tests used to ascertain the diagnosis, were also recorded. RESULTS: The search identified 998 records, and, after review of titles and abstracts and full review of 45 papers, 27 studies were included initially in the review, of which 24 were included in the final analysis. These 24 studies had a broad range of quality and risk of bias and represented 1135 cases of CC anomalies, of which 49% were complete agenesis and the remainder were described using the term partial agenesis or nine other terms, of which five had more than one definition. CONCLUSIONS: In comparison to the postnatal literature, in the prenatal literature there is much greater heterogeneity in the nomenclature and definition of CC anomalies other than complete agenesis. This heterogeneity and lack of standard definitions in the prenatal literature make it difficult to develop large multicenter pooled cohorts of patients who can be followed in order to develop a better understanding of the genetic associations and neurodevelopmental and psychological outcomes of patients with CC anomalies. As this information is important to improve counseling of these patients, a good first step towards this goal would be to develop a simpler categorization of prenatal CC anomalies that matches better the postnatal literature. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.


Subject(s)
Agenesis of Corpus Callosum/embryology , Corpus Callosum/embryology , Fetus/diagnostic imaging , Prenatal Diagnosis , Terminology as Topic , Agenesis of Corpus Callosum/diagnostic imaging , Corpus Callosum/diagnostic imaging , Female , Fetus/embryology , Humans , Pregnancy , Prospective Studies , Retrospective Studies
6.
AJNR Am J Neuroradiol ; 41(5): 844-851, 2020 05.
Article in English | MEDLINE | ID: mdl-32327435

ABSTRACT

BACKGROUND AND PURPOSE: During thyroidectomy incomplete resection of the thyroid gland may occur. This complicates the imaging surveillance of these patients as residual thyroid needs to be distinguished from local recurrence. Therefore, the purpose of this study was to determine if multiphasic multi-detector computed tomography (4D-MDCT) can differentiate residual nonmalignant thyroid tissue and recurrent thyroid carcinoma after thyroidectomy. MATERIALS AND METHODS: In this retrospective study, Hounsfield unit values on multiphasic multidetector CT in precontrast, arterial (25 seconds), venous (55 seconds), and delayed (85 seconds) phases were compared in 29 lesions of recurrent thyroid cancer, 29 with normal thyroid, and 29 with diseased thyroid (thyroiditis/multinodular thyroid). The comparison of Hounsfield unit values among lesion types by phase was performed using ANOVA. The performance of Hounsfield unit values to predict recurrence was evaluated by logistic regression and receiver operating characteristic analysis. RESULTS: All 3 tissue types had near-parallel enhancement characteristics, with a wash-in-washout pattern. Statistically different Hounsfield unit density was noted between the recurrence (lowest Hounsfield unit), diseased (intermediate Hounsfield unit), and normal (highest Hounsfield unit) thyroid groups throughout all 4 phases (P < .001 for each group and in each phase). Dichotomized recurrence-versus-diseased/normal thyroid tissue with univariate logistic regression analysis demonstrated that the area under the receiver operating characteristic curve for differentiating benign from malignant thyroid for the various phases of enhancement was greatest in the precontrast phase at 0.983 (95% CI, 0.954-1), with a cutoff value of ≤62 (sensitivity/specificity, 0.966/0.983) followed by the arterial phase. CONCLUSIONS: Recurrent thyroid carcinoma can be distinguished from residual nonmalignant thyroid tissue using multiphasic multidetector CT with high accuracy. The maximum information for discrimination is in the precontrast images, then the arterial phase. An optimal clinical protocol could be built from any number of phases but should include a precontrast phase.


Subject(s)
Four-Dimensional Computed Tomography/methods , Neoplasm Recurrence, Local/diagnostic imaging , Thyroid Gland/diagnostic imaging , Thyroid Neoplasms/diagnostic imaging , Adult , Aged , Aged, 80 and over , Female , Humans , Logistic Models , Male , Middle Aged , ROC Curve , Retrospective Studies , Sensitivity and Specificity , Thyroid Neoplasms/pathology , Young Adult
7.
Eur J Med Genet ; 61(12): 773-782, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30391507

ABSTRACT

OBJECTIVES: Periventricular nodular heterotopia (PNH) is a malformation of cortical development which presents with heterogeneous imaging, neurological phenotype and outcome. There is a paucity of comprehensive description detailing the prenatal diagnosis of PNH. The aim of this study is to report neuroimaging features and correlated outcomes in order to delineate the spectrum of prenatally diagnosed PNH. METHODS: It was a retrospective study over 15 years in five tertiary centers. All fetuses with prenatally diagnosed PNH were collected. Fetal ultrasound and MRI were reviewed and genetic screening collected. Prenatal findings were analyzed in correlation to fetopathological analyses and post-natal follow up. RESULTS: Thirty fetuses (22 females and 8 males) with PNH were identified. The two major ultrasound signs were ventriculomegaly associated with dysmorphic frontal horns (60%) and posterior fossa anomalies (73.3%). On MRI, two groups of PNH were identified: the contiguous and diffuse PNH (n = 15, 50%), often associated with megacisterna magna, and the non-diffuse, either anterior, posterior or unilateral PNH. FLNA mutations were found in 6/11 cases with diffuse PNH. Additional cortical malformations were exclusively observed in non diffuse PNH (9/15; 60%). Twenty-four pregnancies (80%) were terminated. Six children aged 6 months to 5 years are alive. Five have normal neurodevelopment (all had diffuse PNH) whereas one case with non diffuse PNH has developmental delay and epilepsy. CONCLUSION: PNH is heterogeneous but patients with diffuse PNH are a common subgroup with specific findings on prenatal imaging and implications for prenatal counseling.


Subject(s)
Brain/diagnostic imaging , Epilepsy/diagnosis , Periventricular Nodular Heterotopia/genetics , Prenatal Diagnosis , Brain/physiopathology , Child , Child, Preschool , Epilepsy/diagnostic imaging , Epilepsy/genetics , Epilepsy/physiopathology , Female , Humans , Infant , Magnetic Resonance Imaging , Male , Periventricular Nodular Heterotopia/diagnosis , Periventricular Nodular Heterotopia/diagnostic imaging , Periventricular Nodular Heterotopia/physiopathology , Phenotype , Pregnancy , Retrospective Studies
8.
Acta Neurol Scand ; 137(5): 452-461, 2018 May.
Article in English | MEDLINE | ID: mdl-29635721

ABSTRACT

OBJECTIVES: Rhabdomyolysis and myalgia are common conditions, and mutation in the ryanodine receptor 1 gene (RYR1) is suggested to be a common cause. Due to the large size of RYR1, however, sequencing has not been widely accessible before the recent advent of next-generation sequencing technology and limited phenotypic descriptions are therefore available. MATERIAL & METHODS: We present the medical history, clinical and ancillary findings of patients with RYR1 mutations and rhabdomyolysis and myalgia identified in Denmark, France and The Netherlands. RESULTS: Twenty-two patients with recurrent rhabdomyolysis (CK > 10 000) or myalgia with hyperCKemia (>1.5 × ULN) and a RYR1 mutation were identified. One had mild wasting of the quadriceps muscle, but none had fixed weakness. Symptoms varied from being restricted to intense exercise to limiting ADL function. One patient developed transient kidney failure during rhabdomyolysis. Two received immunosuppressants on suspicion of myositis. None had episodes of malignant hyperthermia. Muscle biopsies were normal, but CT/MRI showed muscle hypertrophy in most. Delay from first symptom to diagnosis was 12 years on average. Fifteen different dominantly inherited mutations were identified. Ten were previously described as pathogenic and 5 were novel, but rare/absent from the background population, and predicted to be pathogenic by in silico analyses. Ten of the mutations were reported to give malignant hyperthermia susceptibility. CONCLUSION: Mutations in RYR1 should be considered as a significant cause of rhabdomyolysis and myalgia syndrome in patients with the characteristic combination of rhabdomyolysis, myalgia and cramps, creatine kinase elevation, no weakness and often muscle hypertrophy.


Subject(s)
Myalgia/genetics , Rhabdomyolysis/genetics , Ryanodine Receptor Calcium Release Channel/genetics , Adolescent , Adult , Child , Denmark , Female , France , Genotype , Humans , Male , Middle Aged , Mutation , Myalgia/physiopathology , Netherlands , Phenotype , Rhabdomyolysis/physiopathology , Syndrome , Young Adult
9.
BJOG ; 125(9): 1186-1191, 2018 Aug.
Article in English | MEDLINE | ID: mdl-27348600

ABSTRACT

OBJECTIVE: To describe the incidence and nature of prenatal brain damage following fetoscopic laser selective coagulation (FLSC) of placental vessels for twin-to-twin transfusion syndrome (TTTS). DESIGN: Retrospective observational study. SETTING: Single center cohort. POPULATION: All consecutive cases referred for TTTS treated by FLSC between 2003 and 2015. METHODS: After the FLSC, patients were followed weekly by ultrasound. Fetal magnetic resonance imaging (MRI) scans were systematically planned at 30-32 weeks of gestation. MAIN OUTCOME MEASURES: Brain damage diagnosed prenatally by ultrasound or MRI. RESULTS: In total, 1023 cases were reviewed. Brain damage was diagnosed prenatally in 22/1023 (2.1%) cases. Diagnosis was performed by ultrasound prior to MRI in 18 (82%) cases. All lesions were within the spectrum of ischaemic haemorrhagic lesions. Postoperative twin anaemia polycythaemia sequence and recurrence of TTTS were significantly associated with brain damage. CONCLUSION: The incidence of prenatal brain damage is low following FSLC, and is strongly associated with incomplete surgery. TWEETABLE ABSTRACT: Following FSLC for TTTS, prenatal brain damage occurs in 2% of cases and is associated with incomplete surgery.


Subject(s)
Fetofetal Transfusion/surgery , Fetoscopy/adverse effects , Hypoxia, Brain/diagnostic imaging , Laser Coagulation/adverse effects , Postoperative Complications/diagnostic imaging , Prenatal Injuries/diagnostic imaging , Brain/diagnostic imaging , Brain/embryology , Female , Fetoscopy/methods , Fetus/diagnostic imaging , Fetus/embryology , Humans , Hypoxia, Brain/embryology , Hypoxia, Brain/etiology , Laser Coagulation/methods , Neuroimaging/methods , Postoperative Complications/etiology , Pregnancy , Prenatal Injuries/etiology , Retrospective Studies
10.
JIMD Rep ; 38: 53-59, 2018.
Article in English | MEDLINE | ID: mdl-28510035

ABSTRACT

OBJECTIVE: Ketogenic diet is the first line therapy for neurological symptoms associated with pyruvate dehydrogenase deficiency (PDHD) and intractable seizures in a number of disorders, including GLUT1 deficiency syndrome (GLUT1-DS). Because high-fat diet raises serious compliance issues, we investigated if oral L,D-3-hydroxybutyrate administration could be as effective as ketogenic diet in PDHD and GLUT1-DS. METHODS: We designed a partial or total progressive substitution of KD with L,D-3-hydroxybutyrate in three GLUT1-DS and two PDHD patients. RESULTS: In GLUT1-DS patients, we observed clinical deterioration including increased frequency of seizures and myoclonus. In parallel, ketone bodies in CSF decreased after introducing 3-hydroxybutyrate. By contrast, two patients with PDHD showed clinical improvement as dystonic crises and fatigability decreased under basal metabolic conditions. In one of the two PDHD children, 3-hydroxybutyrate has largely replaced the ketogenic diet, with the latter that is mostly resumed only during febrile illness. Positive direct effects on energy metabolism in PDHD patients were suggested by negative correlation between ketonemia and lactatemia (r 2 = 0.59). Moreover, in cultured PDHc-deficient fibroblasts, the increase of CO2 production after 14C-labeled 3-hydroxybutyrate supplementation was consistent with improved Krebs cycle activity. However, except in one patient, ketonemia tended to be lower with 3-hydroxybutyrate administration compared to ketogenic diet. CONCLUSION: 3-hydroxybutyrate may be an adjuvant treatment to ketogenic diet in PDHD but not in GLUT1-DS under basal metabolic conditions. Nevertheless, ketogenic diet is still necessary in PDHD patients during febrile illness.

12.
Epilepsy Behav ; 69: 161-169, 2017 04.
Article in English | MEDLINE | ID: mdl-28256379

ABSTRACT

This is the second of three papers that summarize the second symposium on Transition in Epilepsies held in Paris in June 2016. This paper addresses the outcome for some particularly challenging childhood-onset epileptic disorders with the goal of recommending the best approach to transition. We have grouped these disorders in five categories with a few examples for each. The first group includes disorders presenting in childhood that may have late- or adult-onset epilepsy (metabolic and mitochondrial disorders). The second group includes disorders with changing problems in adulthood (tuberous sclerosis complex, Rett syndrome, Dravet syndrome, and autism). A third group includes epilepsies that change with age (Childhood Absence Epilepsy, Juvenile Myoclonic Epilepsy, West Syndrome, and Lennox-Gastaut syndrome). A fourth group consists of epilepsies that vary in symptoms and severity depending on the age of onset (autoimmune encephalitis, Rasmussen's syndrome). A fifth group has epilepsy from structural causes that are less likely to evolve in adulthood. Finally we have included a discussion about the risk of later adulthood cerebrovascular disease and dementia following childhood-onset epilepsy. A detailed knowledge of each of these disorders should assist the process of transition to be certain that attention is paid to the most important age-related symptoms and concerns.


Subject(s)
Congresses as Topic , Epilepsy/diagnosis , Epilepsy/therapy , Transition to Adult Care/trends , Adolescent , Adult , Child , Child, Preschool , Encephalitis/diagnosis , Encephalitis/therapy , Epilepsy, Absence/diagnosis , Epilepsy, Absence/therapy , Hashimoto Disease/diagnosis , Hashimoto Disease/therapy , Humans , Infant , Myoclonic Epilepsy, Juvenile/diagnosis , Myoclonic Epilepsy, Juvenile/therapy , Rett Syndrome/diagnosis , Rett Syndrome/therapy , Spasms, Infantile/diagnosis , Spasms, Infantile/therapy , Treatment Outcome , Tuberous Sclerosis/diagnosis , Tuberous Sclerosis/therapy , Young Adult
13.
Clin Genet ; 91(1): 126-130, 2017 01.
Article in English | MEDLINE | ID: mdl-27030002

ABSTRACT

Left ventricular noncompaction cardiomyopathy (LVNC) is a clinically heterogeneous disorder characterized by a trabecular meshwork and deep intertrabecular myocardial recesses that communicate with the left ventricular cavity. Several genetic causes of LVNC have been reported, with variable modes of inheritance, including autosomal dominant and X-linked inheritance, but relatively few responsible genes have been identified. A NGS workflow, based on a panel of 95 genes developed for sequencing most prevalent sudden cardiac death-causing genes, was used to make a rapid and costless molecular diagnosis in two siblings with a severe noncompaction cardiomyopathy starting prenatally and leading to rapid cardiac failure. For the first time, a total homozygous PKP2 deletion was identified. This molecular defect was further confirmed by MLPA and array-comparative genomic hybridization (CGH). Heterozygous PKP2 mutations are usually reported in a significant proportion of Arrhythmogenic Right Ventricular Cardiomyopathy cases. Our results show, for the first time, the involvement of PKP2 in severe cardiomyopathy with ventricular non compaction.


Subject(s)
Cardiomyopathies/genetics , Gene Deletion , Genetic Predisposition to Disease/genetics , Plakophilins/genetics , Cardiomyopathies/pathology , Comparative Genomic Hybridization/methods , Consanguinity , Family Health , Female , Heart Ventricles/abnormalities , High-Throughput Nucleotide Sequencing/methods , Homozygote , Humans , Infant, Newborn , Male , Pedigree , Siblings
15.
Eur J Paediatr Neurol ; 20(1): 53-60, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26610677

ABSTRACT

OBJECTIVE AND PATIENTS: We report on two new cases of serine deficiency due respectively to 3-phosphoglycerate dehydrogenase (PHGDH) deficiency (Patient 1) and phosphoserine aminotransferase (PSAT1) deficiency (Patient 2), presenting with congenital microcephaly (<3rd centile at birth) and encephalopathy with spasticity. Patient 1 had also intractable seizures. A treatment with oral l-serine was started at age 4.5 years and 3 months respectively. RESULTS: Serine levels were low in plasma and CSF relative to the reference population, for which we confirm recently redefined intervals based on a larger number of samples. l-Serine treatment led in patient 1 to a significant reduction of seizures after one week of treatment and decrease of electroencephalographic abnormalities within one year. In patient 2 treatment with l-serine led to an improvement of spasticity. However for both patients, l-serine failed to improve substantially head circumference (HC) and neurocognitive development. In a couple related to patient's 2 family, dosage of serine was performed on fetal cord blood when the fetus presented severe microcephaly, showing reduced serine levels at 30 weeks of pregnancy. CONCLUSIONS: l-Serine treatment in patients with 2 different serine synthesis defects, led to a significant reduction of seizures and an improvement of spasticity, but failed to improve substantially neurocognitive impairment. Therefore, CSF and plasma serine levels should be measured in all cases of severe microcephaly at birth to screen for serine deficiency, as prompt treatment with l-serine may significantly impact the outcome of the disease. Reduced serine levels in fetal cord blood may also be diagnostic as early as 30 weeks of pregnancy.


Subject(s)
Amino Acid Metabolism, Inborn Errors/drug therapy , Carbohydrate Metabolism, Inborn Errors/drug therapy , Microcephaly/drug therapy , Phosphoglycerate Dehydrogenase/deficiency , Psychomotor Disorders/drug therapy , Seizures/drug therapy , Serine/deficiency , Serine/therapeutic use , Transaminases/deficiency , Adult , Amino Acid Metabolism, Inborn Errors/genetics , Amino Acids/cerebrospinal fluid , Carbohydrate Metabolism, Inborn Errors/genetics , Child, Preschool , Cognition Disorders/drug therapy , Cognition Disorders/etiology , Drug Resistant Epilepsy/etiology , Electroencephalography , Female , Head/growth & development , Humans , Infant , Infant, Newborn , Male , Microcephaly/etiology , Microcephaly/genetics , Muscle Spasticity/etiology , Phosphoglycerate Dehydrogenase/genetics , Pregnancy , Psychomotor Disorders/genetics , Seizures/etiology , Seizures/genetics , Serine/blood , Transaminases/genetics , Treatment Outcome
16.
Neuromuscul Disord ; 25(6): 461-73, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25817838

ABSTRACT

Mutations in the microtubule-associated protein doublecortin (DCX) cause type I (X-linked or XLIS) lissencephaly in hemizygous males and subcortical band heterotopia (SBH) in females, with defects in neuron migration during development affecting cortical lamination. We found that besides its well-established expression in migrating neurons of the brain, doublecortin (Dcx in mice) is also expressed in motor neurons and skeletal muscle in embryonic neuromuscular junctions (NMJs), raising the possibility of a role in synaptogenesis. Studies with whole-mount preparations of embryonic mouse diaphragm revealed that loss of Dcx leads to abnormal presynaptic arborization and a significantly increased incidence of short axonal extensions beyond innervated acetylcholine receptor (AChR) clusters in the developing NMJ. This phenotype, albeit relatively mild, suggests that Dcx contributes to a stop/stabilizing signal at the synapse, which normally limits further axonal growth following establishment of synaptic contact with the postsynaptic element. Importantly, we also identified abnormal and denervated NMJs in a muscle biopsy from a 16-year-old female patient with SBH, showing both profound presynaptic and postsynaptic morphological defects. Overall, these combined results point to a critical role of doublecortin in the formation of the NMJ.


Subject(s)
Classical Lissencephalies and Subcortical Band Heterotopias/pathology , Microtubule-Associated Proteins/metabolism , Neuromuscular Junction/embryology , Neuromuscular Junction/metabolism , Neuropeptides/metabolism , Adolescent , Animals , Axons/metabolism , Brain/embryology , Brain/pathology , Cell Line , Classical Lissencephalies and Subcortical Band Heterotopias/genetics , Doublecortin Domain Proteins , Doublecortin Protein , Female , Humans , Male , Mice , Mice, Knockout , Microtubule-Associated Proteins/genetics , Motor Neurons/metabolism , Motor Neurons/pathology , Muscle, Skeletal/pathology , Neuromuscular Junction/genetics , Neuromuscular Junction/pathology , Neurons/metabolism , Neurons/pathology , Neuropeptides/genetics , Receptors, Cholinergic/metabolism
17.
Arch Pediatr ; 21(11): 1252-61, 2014 Nov.
Article in French | MEDLINE | ID: mdl-25287141

ABSTRACT

CONTEXT AND OBJECTIVES: Guidelines recommend that any epileptic seizure that lasts more than 5 min (prolonged seizures) be treated immediately with benzodiazepines in order to prevent progression to status epilepticus. However, there is very little published information on how such seizures are managed outside of the hospital setting, for example in schools or at home. This paper presents the initial results, specific to France, of the Practices in Emergency and Rescue medication For Epilepsy managed with Community-administered Therapy (PERFECT) Initiative, which was set up in 2011 to gain a better understanding of how prolonged convulsive seizures are managed and rescue medication is administered in out-of-hospital settings across Europe. METHODS: The PERFECT Initiative was conducted in six countries (France, Germany, Italy, Spain, Sweden, the United Kingdom) and consists of three phases. This paper reports on the first two phases of this study and focuses on findings for France. Phase I of the PERFECT initiative consisted of a review of existing clinical guidelines, guidance to schools, and relevant policy and legal frameworks in France, from both published and web-based sources. Phase II consisted in a telephone survey of 20 pediatricians, pediatric neurologists, and neurologists who treat children with prolonged convulsive seizures in France in order to obtain their views on how prolonged seizures are managed outside of hospitals. Phase III is ongoing and consists of a survey of children with prolonged seizures and their caregivers. RESULTS: Existing clinical guidelines pertain mainly to the hospital setting and contain very little informations on how prolonged seizures should be managed outside the hospital. Guidance to schools is unclear as to whether teachers are allowed to administer rescue medication to children and legal frameworks are full of contradictions. As a result, whether or not children who experience prolonged seizures receive their rescue medication during school hours depends mostly on the resources and training available in each school. Healthcare professionals stated that lack of information on prolonged seizures and their management, as well as a lack of up-to-date guidance specific to schools were considerable obstacles to a systematic approach to managing prolonged seizures outside of the hospital. DISCUSSION: In France and elsewhere, there has been growing recognition of substantial gaps in the provision of care to children with epilepsy in recent years. However, the issues that arise for children who require rescue medication for prolonged seizures outside of hospitals are conspicuously absent from policy documents or clinical guidelines. This lack of information, combined with insufficient training in schools on epilepsy, and inadequate guidelines create a situation in which schools are likely to call an ambulance every time a child has a prolonged seizure, therefore risking delays in treatment, and putting the child at risk of status epilepticus and clinical sequelae, not to mention stigmatization at school. CONCLUSION: There is a need for more explicit guidance covering educational and healthcare settings, clearer information to parents and schools, and more systematic training to be made available to caregivers in order to ensure that all children at risk of prolonged seizures receive their prescribed rescue medication as quickly as possible, regardless of where their seizure occurs.


Subject(s)
Benzodiazepines/therapeutic use , Emergency Medical Services , Epilepsy/drug therapy , Guideline Adherence , Child , Cross-Cultural Comparison , Emergency Medical Services/legislation & jurisprudence , Epilepsy/diagnosis , Epilepsy/etiology , France , Health Surveys , Humans , Liability, Legal , School Health Services/legislation & jurisprudence
19.
Mol Genet Metab ; 110(1-2): 106-10, 2013.
Article in English | MEDLINE | ID: mdl-23751327

ABSTRACT

INTRODUCTION: Patients with methylmalonic acidemia (MMA) may develop many complications despite medical treatment, in particular, severe central nervous system damage and chronic kidney disease (CKD). A kidney transplant may partially correct the metabolic dysfunctions. Liver, kidney and combined liver-kidney transplantations have been advocated but no guidelines are available to identify the most suitable organ to transplant. PATIENTS AND METHODS: Four patients with MMA (mut° phenotype) received a kidney graft because of repeated metabolic decompensations, with progression to CKD in 3 patients (end-stage kidney disease in two patients and CKD stage III in one patient with an estimated glomerular filtration rate [eGFR] of 40ml/min/1.73m(2)) but normal renal function in one (eGFR of 93ml/min/1.73m(2)) before transplantation. RESULTS: The medium age at transplantation was 7.9y (5-10.2) and the median follow-up was 2.8years (1.8-4.6). Renal transplantation improved the relevant metabolic parameters in 4/4 patients and renal function in the patients with CKD. Plasma and urinary MMA levels immediately decreased and remained normal or subnormal (mean values of plasma MMA before transplantation 1530µmol/L versus 240µmol/L after transplantation, and mean values of urine MMA before transplantation 4700mmol/mol creatinine versus 2300mmol/mol creatinine after transplantation). No further acute metabolic decompensation was observed and protein-intake was increased from 0.60 to 0.83g/Kg/day. One patient transplanted at age 9.7years developed a hepatoblastoma at age 11years with subsequent neurological complications and eventually died. The three other patients are alive. Two of them remained neurologically stable. The 3rd patient who displayed choreoathetosis transiently improved his neurological condition immediately after transplantation and then remained stable. CONCLUSION: Kidney transplantation represents an interesting alternative therapeutic option in methylmalonic aciduria, for renal complications but also as a "cellular therapy" that may significantly reduce metabolic decompensations and hospitalizations. However, further neurological impairment remains possible.


Subject(s)
Amino Acid Metabolism, Inborn Errors/therapy , Kidney Transplantation , Liver Transplantation , Metabolic Diseases/therapy , Renal Insufficiency, Chronic/therapy , Amino Acid Metabolism, Inborn Errors/blood , Amino Acid Metabolism, Inborn Errors/genetics , Amino Acid Metabolism, Inborn Errors/pathology , Amino Acid Metabolism, Inborn Errors/urine , Cell- and Tissue-Based Therapy , Child , Disease Progression , Female , Glomerular Filtration Rate , Humans , Male , Metabolic Diseases/genetics , Methylmalonic Acid/blood , Methylmalonic Acid/urine , Renal Insufficiency, Chronic/genetics , Renal Insufficiency, Chronic/pathology
20.
Mol Syndromol ; 2(3-5): 153-163, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22670136

ABSTRACT

Rett syndrome (RTT) is a severe neurodevelopmental disease that affects approximately 1 in 10,000 live female births and is often caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MECP2). Mutations in loci other than MECP2 have also been found in individuals that have been labeled as atypical RTT. Among them, a mutation in the gene forkhead box G1 (FOXG1) has been involved in the molecular aetiology of the congenital variant of RTT. The FOXG1 gene encodes a winged-helix transcriptional repressor essential for the development of the ventral telencephalon in embryonic forebrain. Later, FOXG1 continues to be expressed in neurogenetic zones of the postnatal brain. Although RTT affects quasi-exclusively girls, FOXG1 mutations have also been identified in male patients. As far as we know, about 12 point mutations and 13 cases with FOXG1 molecular abnormalities (including translocation, duplication and large deletion on the chromosome 14q12) have been described in the literature. Affected individuals with FOXG1 mutations have shown dysmorphic features and Rett-like clinical course, including normal perinatal period, postnatal microcephaly, seizures and severe mental retardation. Interestingly, the existing animal models of FOXG1 deficiency showed similar phenotype, suggesting that animal models may be a fascinating model to understand this human disease. Here, we describe the impacts of FOXG1 mutations and their associated phenotypes in human and mouse models.

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