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1.
N Engl J Med ; 384(25): 2406-2417, 2021 06 24.
Article in English | MEDLINE | ID: mdl-34161705

ABSTRACT

BACKGROUND: Autophagy is the major intracellular degradation route in mammalian cells. Systemic ablation of core autophagy-related (ATG) genes in mice leads to embryonic or perinatal lethality, and conditional models show neurodegeneration. Impaired autophagy has been associated with a range of complex human diseases, yet congenital autophagy disorders are rare. METHODS: We performed a genetic, clinical, and neuroimaging analysis involving five families. Mechanistic investigations were conducted with the use of patient-derived fibroblasts, skeletal muscle-biopsy specimens, mouse embryonic fibroblasts, and yeast. RESULTS: We found deleterious, recessive variants in human ATG7, a core autophagy-related gene encoding a protein that is indispensable to classical degradative autophagy. Twelve patients from five families with distinct ATG7 variants had complex neurodevelopmental disorders with brain, muscle, and endocrine involvement. Patients had abnormalities of the cerebellum and corpus callosum and various degrees of facial dysmorphism. These patients have survived with impaired autophagic flux arising from a diminishment or absence of ATG7 protein. Although autophagic sequestration was markedly reduced, evidence of basal autophagy was readily identified in fibroblasts and skeletal muscle with loss of ATG7. Complementation of different model systems by deleterious ATG7 variants resulted in poor or absent autophagic function as compared with the reintroduction of wild-type ATG7. CONCLUSIONS: We identified several patients with a neurodevelopmental disorder who have survived with a severe loss or complete absence of ATG7, an essential effector enzyme for autophagy without a known functional paralogue. (Funded by the Wellcome Centre for Mitochondrial Research and others.).


Subject(s)
Abnormalities, Multiple/genetics , Ataxia/genetics , Autophagy-Related Protein 7/genetics , Autophagy/genetics , Developmental Disabilities/genetics , Mutation, Missense , Adolescent , Adult , Autophagy/physiology , Autophagy-Related Protein 7/physiology , Cells, Cultured , Cerebellum/abnormalities , Computer Simulation , Face/abnormalities , Female , Fibroblasts , Genes, Recessive , Humans , Infant , Male , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Nervous System Malformations/genetics , Pedigree , Phenotype
2.
Dev Med Child Neurol ; 65(2): 215-222, 2023 02.
Article in English | MEDLINE | ID: mdl-35765978

ABSTRACT

AIM: To compare paediatric patients with cerebral sinovenous thrombosis (CSVT) with and without head/neck infection to improve management of the condition. METHOD: We conducted a bicentric retrospective study of consecutive children (neonates excluded) with radiologically confirmed CSVT, comparing children with a concurrent head/neck infection and children with other causes. RESULTS: A total of 84 consecutive patients (46 males and 38 females) with a median age of 4 years 6 months (range 3 months-17 years 5 months) were included. Associated head/neck infection was identified in 65.4% of cases and represented the main identified CSVT aetiology. Children in the head/neck infection group displayed a milder clinical presentation and less extensive CSVT. Median time to complete recanalization was significantly shorter in this group (89 days [interquartile range 35-101] vs 112.5 days [interquartile range 83-177], p = 0.005). These findings were even more pronounced in the subgroup of patients with otogenic infection and no neurological sign. INTERPRETATION: As CSVT in the setting of an otogenic infection and no neurological sign seems to represent a milder condition with a shorter course, these results suggest adapting current recommendations: consider earlier control imaging in paediatric otogenic CSVT, and shorter anticoagulant treatment if recanalization is obtained. WHAT THIS PAPER ADDS: Children with cerebral sinovenous thrombosis related to head/neck infections have a milder clinical presentation. They also have a shorter recanalization time, especially if there is otogenic infection without neurological symptoms.


Subject(s)
Sinus Thrombosis, Intracranial , Venous Thrombosis , Child , Female , Humans , Infant , Infant, Newborn , Male , Retrospective Studies , Risk Factors , Sinus Thrombosis, Intracranial/complications , Sinus Thrombosis, Intracranial/diagnostic imaging , Thrombosis/complications
3.
Eur J Neurol ; 29(11): 3229-3242, 2022 11.
Article in English | MEDLINE | ID: mdl-36200804

ABSTRACT

BACKGROUND AND PURPOSE: HIBCH and ECHS1 genes encode two enzymes implicated in the critical steps of valine catabolism, 3-hydroxyisobutyryl-coenzyme A (CoA) hydrolase (HIBCH) and short-chainenoyl-CoA hydratase (ECHS1), respectively. HIBCH deficiency (HIBCHD) and ECHS1 deficiency (ECHS1D) generate rare metabolic dysfunctions, often revealed by neurological symptoms. The aim of this study was to describe movement disorders spectrum in patients with pathogenic variants in ECHS1 and HIBC. METHODS: We reviewed a series of 18 patients (HIBCHD: 5; ECHS1D: 13) as well as 105 patients from the literature. We analysed the detailed phenotype of HIBCHD (38 patients) and ECHS1D (85 patients), focusing on MDs. RESULTS: The two diseases have a very similar neurological phenotype, with an early onset before 10 years of age for three clinical presentations: neonatal onset, Leigh-like syndrome (progressive onset or acute neurological decompensation), and isolated paroxysmal dyskinesia. Permanent or paroxysmal MDs were recorded in 61% of HIBCHD patients and 72% of ECHS1D patients. Patients had a variable combination of either isolated or combined MD, and dystonia was the main MD. These continuous MDs included dystonia, chorea, parkinsonism, athetosis, myoclonus, tremors, and abnormal eye movements. Patients with paroxysmal dyskinesia (HIBCHD: 4; ECHS1D: 9) usually had pure paroxysmal dystonia with normal clinical examination and no major impairment in psychomotor development. No correlation could be identified between clinical pattern (especially MD) and genetic pathogenic variants. CONCLUSIONS: Movement disorders, including abnormal ocular movements, are a hallmark of HIBCHD and ECHS1D. MDs are not uniform; dystonia is the most frequent, and various types of MD are combined in single patient.


Subject(s)
Chorea , Dystonia , Dystonic Disorders , Enoyl-CoA Hydratase/metabolism , Leigh Disease , Movement Disorders , Abnormalities, Multiple , Amino Acid Metabolism, Inborn Errors , Coenzyme A , Dystonic Disorders/genetics , Humans , Leigh Disease/diagnosis , Leigh Disease/genetics , Movement Disorders/genetics , Thiolester Hydrolases/deficiency , Valine/metabolism
4.
Am J Hum Genet ; 102(5): 744-759, 2018 05 03.
Article in English | MEDLINE | ID: mdl-29656859

ABSTRACT

RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D. rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome.


Subject(s)
Autistic Disorder/genetics , Cerebellar Ataxia/genetics , Genes, Dominant , Intellectual Disability/genetics , Mutation, Missense/genetics , Nuclear Receptor Subfamily 1, Group F, Member 1/genetics , Adolescent , Adult , Aged, 80 and over , Alleles , Animals , Autistic Disorder/complications , Brain/pathology , Cerebellar Ataxia/complications , Child , Child, Preschool , DNA Copy Number Variations/genetics , Disease Models, Animal , Female , Genetic Complementation Test , Humans , Intellectual Disability/complications , Larva/genetics , Magnetic Resonance Imaging , Male , Middle Aged , Purkinje Cells/metabolism , Purkinje Cells/pathology , Syndrome , Zebrafish/genetics
5.
Neuropediatrics ; 52(5): 410-414, 2021 10.
Article in English | MEDLINE | ID: mdl-33506479

ABSTRACT

Paroxysmal dyskinesias (PD) are rare movement disorders characterized by recurrent attacks of dystonia, chorea, athetosis, or their combination, with large phenotypic and genetic heterogeneity. 3-Hydroxy-isobutyryl-CoA hydrolase (HIBCH) deficiency is a neurodegenerative disease characterized in most patients by a continuous decline in psychomotor abilities or a secondary regression triggered by febrile infections and metabolic crises.We describe two PD patients from two pedigrees, both carrying a homozygous c.913A > G, p.Thr305Ala mutation in the HIBCH gene, associated with an unusual clinical presentation. The first patient presented in the second year of life with right paroxysmal hemidystonia lasting for 30 minutes, without any loss of consciousness and without any triggering factor. The second patient has presented since the age of 3 recurrent exercise-induced PD episodes which have been described as abnormal equinovarus, contractures of the lower limbs, lasting for 1 to 4 hours, associated with choreic movements of the hands. Their neurological examination and metabolic screening were normal, while brain magnetic resonance imaging showed abnormal signal of the pallidi.We suggest that HIBCH deficiency, through the accumulation of metabolic intermediates of the valine catabolic pathway, leads to a secondary defect in respiratory chain activity and pyruvate dehydrogenase (PDH) activity and to a broad phenotypic spectrum ranging from Leigh syndrome to milder phenotypes. The two patients presented herein expand the spectrum of the disease to include unusual paroxysmal phenotypes and HIBCH deficiency should be considered in the diagnostic strategy of PD to enable adequate preventive treatment.


Subject(s)
Abnormalities, Multiple , Amino Acid Metabolism, Inborn Errors , Chorea , Neurodegenerative Diseases , Thiolester Hydrolases/deficiency , Abnormalities, Multiple/enzymology , Abnormalities, Multiple/pathology , Amino Acid Metabolism, Inborn Errors/enzymology , Amino Acid Metabolism, Inborn Errors/pathology , Chorea/enzymology , Chorea/pathology , Humans , Neurodegenerative Diseases/enzymology , Neurodegenerative Diseases/pathology
6.
Neuropediatrics ; 50(4): 244-247, 2019 08.
Article in English | MEDLINE | ID: mdl-31170735

ABSTRACT

INTRODUCTION: Migraine is the most common neurological disorder and the third most common disease worldwide. However, the underlying mechanisms contributing to its development are not completely understood. Symptoms may arise from a combination of dilation-independent vascular events and neurogenic mechanisms interacting throughout the brain and within the trigeminovascular system in the meninges MATERIALS AND METHOD: We report here a case of a patient with a suspected familial hemiplegic migraine who presented an increased recurrence of events from one per month to one every other day. Three magnetic resonance imaging (MRI) acquisitions were performed after the appearance of a strong crisis which included a paresthesia and aphasia along with headaches. Two MRIs were performed close to the crisis, while the last one was done 1 month later. RESULTS: During the crisis, cerebral perfusion exhibits incoherent results. Blood velocity measurements highlight a strong phase lag between left internal carotid artery (ICA) and basilar artery and more importantly right ICA. After a month, parameters came back to standard values. CONCLUSION: The transitory nature of the observed modifications suggests a reversible alteration of the vascular tone of the ICA in patients with migraine. This alteration seems to follow recovery pattern of the patient.


Subject(s)
Carotid Artery, Internal/diagnostic imaging , Cerebrovascular Circulation/physiology , Magnetic Resonance Imaging/methods , Migraine Disorders/diagnostic imaging , Adolescent , Female , Humans
7.
BMC Pediatr ; 18(1): 351, 2018 11 09.
Article in English | MEDLINE | ID: mdl-30413155

ABSTRACT

BACKGROUND: Congenital bilateral vocal cord paralysis is a rare occurrence. Approximately half the cases are associated with a major comorbidity, usually neurological, neuromuscular or malformative. CASE PRESENTATION: In a male newborn, respiratory distress syndrome and stridor were observed immediately following birth. The cause was bilateral vocal cord paralysis in the adducted position. Neuroradiological investigation revealed a unilateral discontinuity between the upper pons and the right medulla oblongata. Hypoplasia of the right posterior hemiarches of C1-C2 and the right exo-occipital bone was observed, as was a small clivus. MR angiography showed the absence of the distal right vertebral artery, with hypoplasia and parietal irregularities of the proximal segments. Respiratory autonomy was not obtained despite endoscopic laser cordotomy, corticosteroid therapy and nasal continuous positive airway pressure. The infant died at the age of 4 weeks after treatment was limited to comfort care. CONCLUSIONS: A medullary lesion is an exceptional cause of congenital bilateral vocal cord paralysis. The strictly unilateral neurological and vascular defect and the absence of associated intracranial or extracranial malformation make this clinical case unique and suggest a disruptive mechanism. This case also highlights the help provided by advanced neuroimaging techniques, i.e. fibre tracking using diffusion tensor imaging, in the decision-making process.


Subject(s)
Medulla Oblongata/abnormalities , Vocal Cord Paralysis/congenital , Vocal Cord Paralysis/diagnostic imaging , Diffusion Tensor Imaging , Fatal Outcome , Humans , Infant, Newborn , Magnetic Resonance Angiography , Male , Medulla Oblongata/diagnostic imaging , Neuroradiography , Pons/abnormalities , Pons/diagnostic imaging , Tomography, X-Ray Computed
8.
Hum Mol Genet ; 24(14): 3948-55, 2015 Jul 15.
Article in English | MEDLINE | ID: mdl-25901006

ABSTRACT

Mitochondrial complex I (CI) deficiencies are causing debilitating neurological diseases, among which, the Leber Hereditary Optic Neuropathy and Leigh Syndrome are the most frequent. Here, we describe the first germinal pathogenic mutation in the NDUFA13/GRIM19 gene encoding a CI subunit, in two sisters with early onset hypotonia, dyskinesia and sensorial deficiencies, including a severe optic neuropathy. Biochemical analysis revealed a drastic decrease in CI enzymatic activity in patient muscle biopsies, and reduction of CI-driven respiration in fibroblasts, while the activities of complex II, III and IV were hardly affected. Western blots disclosed that the abundances of NDUFA13 protein, CI holoenzyme and super complexes were drastically reduced in mitochondrial fractions, a situation that was reproduced by silencing NDUFA13 in control cells. Thus, we established here a correlation between the first mutation yet identified in the NDUFA13 gene, which induces CI instability and a severe but slowly evolving clinical presentation affecting the central nervous system.


Subject(s)
Apoptosis Regulatory Proteins/genetics , Dyskinesias/genetics , Electron Transport Complex I/deficiency , Mitochondrial Diseases/genetics , Muscle Hypotonia/genetics , NADH, NADPH Oxidoreductases/genetics , Apoptosis Regulatory Proteins/metabolism , Child , Child, Preschool , Electron Transport Complex I/genetics , Female , Follow-Up Studies , Humans , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Mutation , NADH, NADPH Oxidoreductases/metabolism , Open Reading Frames , Pedigree
9.
J Am Acad Dermatol ; 76(3): 478-487, 2017 Mar.
Article in English | MEDLINE | ID: mdl-27742172

ABSTRACT

BACKGROUND: Hair collar sign (HCS) and hair tuft of the scalp (HTS) are cutaneous signs of an underlying neuroectodermal defect, but most available data are based on case reports. OBJECTIVE: We sought to define the clinical spectrum of HCS and HTS, clarify the risk for underlying neurovascular anomalies, and provide imaging recommendations. METHODS: A 10-year multicenter retrospective and prospective analysis of clinical, radiologic, and histopathologic features of HCS and HTS in pediatric patients was performed. RESULTS: Of the 78 patients included in the study, 56 underwent cranial and brain imaging. Twenty-three of the 56 patients (41%) had abnormal findings, including the following: (1) cranial/bone defect (30.4%), with direct communication with the central nervous system in 28.6%; (2) venous malformations (25%); or (3) central nervous system abnormalities (12.5%). Meningeal heterotopia in 34.6% (9/26) was the most common neuroectodermal association. Sinus pericranii, paraganglioma, and combined nevus were also identified. LIMITATIONS: The partial retrospective design and predominant recruitment from the dermatology department are limitations of this study. CONCLUSIONS: Infants with HCS or HTS are at high risk for underlying neurovascular anomalies. Magnetic resonance imaging scans should be performed in order to refer the infant to the appropriate specialist for management.


Subject(s)
Abnormalities, Multiple/diagnostic imaging , Brain/diagnostic imaging , Choristoma/diagnostic imaging , Hair/abnormalities , Meninges , Skull/diagnostic imaging , Veins/diagnostic imaging , Brain/abnormalities , False Negative Reactions , False Positive Reactions , Female , Humans , Infant , Infant, Newborn , Magnetic Resonance Imaging , Male , Multimodal Imaging , Neural Plate , Neuroimaging , Prospective Studies , Retrospective Studies , Scalp/pathology , Skull/abnormalities , Tomography, X-Ray Computed , Ultrasonography, Doppler, Color , Veins/abnormalities
10.
Neuropediatrics ; 48(3): 166-184, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28561207

ABSTRACT

We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context.


Subject(s)
Adenosine Deaminase/genetics , Autoimmune Diseases of the Nervous System/genetics , Autoimmune Diseases of the Nervous System/immunology , Interferon Type I/metabolism , Nervous System Malformations/genetics , Nervous System Malformations/immunology , RNA-Binding Proteins/genetics , Adolescent , Adult , Autoimmune Diseases of the Nervous System/diagnostic imaging , Biomarkers/metabolism , Child , Child, Preschool , Female , Humans , Infant , Male , Mutation , Nervous System Malformations/diagnostic imaging , Phenotype , Young Adult
11.
Eur J Pediatr ; 175(8): 1119-22, 2016 Aug.
Article in English | MEDLINE | ID: mdl-26838584

ABSTRACT

UNLABELLED: Hashimoto's thyroiditis is a well-known cause of growth retardation in adolescence. It is less frequently seen in children and rarely seen in infants. A 4-year-old girl was referred to our clinic for a second opinion before starting growth hormone (GH) treatment. Linear growth had markedly declined in the past 2 years, with height -3.4 standard deviations. GH deficiency was complete. She had dry, gray-sallow skin and bloated abdomen, but no goiter. The parents reported fatigue and constipation. Hormonal evaluation revealed TSH 629.5 mIU/ml, free T4 0.08 ng/dl, and prolactin 17.2 ng/ml. Bone age was 2 years. Antibodies to thyroglobulin and thyroid peroxidase were positive, suggesting Hashimoto's thyroiditis. Brain magnetic resonance imaging showed anterior pituitary hyperplasia. After 3 years of L-thyroxine therapy, she was symptomless, her height was -0.6 standard deviations, and the TSH level was normal. Brain magnetic resonance imaging showed regression of the pituitary hyperplasia. CONCLUSIONS: This report describes a patient with Hashimoto's thyroiditis and pituitary hyperplasia, both quite rare in very young children. Acquired hypothyroidism may appear after neonatal screening and therefore should not be overlooked in investigations of short stature, even when clinical signs of hypothyroidism are absent. WHAT IS KNOWN: • Hashimoto's thyroiditis and pituitary hyperplasia are rare in very young children. • Acquired hypothyroidism can appear after negative neonatal screening and should not be overlooked. What is New: • Short children should be evaluated for growth hormone deficiency but only after excluding other causes, particularly hypothyroidism, as we report a child with this disease but no clinical signs of it.


Subject(s)
Growth Hormone/deficiency , Hashimoto Disease/diagnosis , Hypothyroidism/diagnosis , Pituitary Diseases/diagnosis , Pituitary Gland/pathology , Thyroxine/therapeutic use , Brain/diagnostic imaging , Child, Preschool , Female , Growth Disorders/etiology , Growth Disorders/therapy , Hashimoto Disease/complications , Hashimoto Disease/therapy , Humans , Hyperplasia/complications , Magnetic Resonance Imaging , Pituitary Diseases/complications , Pituitary Gland/diagnostic imaging
12.
J Neuroradiol ; 43(3): 176-85, 2016 Jun.
Article in English | MEDLINE | ID: mdl-27126632

ABSTRACT

Hereditary ataxias are a heterogeneous group of neurodegenerative disorders, characterized by cerebellar ataxia as the main clinical feature, and a large spectrum of neurological-associated symptoms and possible multi-organ affection. Image-based approaches to hereditary ataxias in childhood have already been proposed. The aim of this review is to yield the main reports of neuroimaging patterns and diagnostic algorithms and compare them with the results from our study of 23 young patients addressed for ataxia, with subsequent genetic or metabolic diagnosis.


Subject(s)
Brain/diagnostic imaging , Cerebellar Ataxia/diagnostic imaging , Neuroimaging/methods , Spinocerebellar Degenerations/diagnostic imaging , Brain/pathology , Cerebellar Ataxia/genetics , Cerebellar Ataxia/pathology , Child , Diagnosis, Computer-Assisted/methods , Humans , Spinocerebellar Degenerations/genetics , Spinocerebellar Degenerations/pathology
13.
J Neurol Neurosurg Psychiatry ; 86(7): 782-5, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25595153

ABSTRACT

BACKGROUND: Heterozygous dominant mutations of PRRT2 have been associated with various types of paroxysmal neurological manifestations, including benign familial infantile convulsions and paroxysmal kinesigenic dyskinesia. The phenotype associated with biallelic mutations is not well understood as few cases have been reported. METHODS: PRRT2 screening was performed by Sanger sequencing and quantitative multiplex PCR of short fluorescent fragments. A CGH array was used to characterise the size of the deletion at the 16p11.2 locus. RESULTS: Five patients with homozygous or compound heterozygous deleterious PRRT2 gene mutations are described. These patients differ from those with a single mutation by their overall increased severity: (1) the combination of at least three different forms of paroxysmal neurological disorders within the same patient and persistence of paroxysmal attacks; (2) the occurrence of uncommon prolonged episodes of ataxia; and (3) the association of permanent neurological disorders including learning difficulties in four patients and cerebellar atrophy in 2. CONCLUSIONS: Our observations expand the phenotype related to PRRT2 insufficiency, and highlight the complexity of the phenotype associated with biallelic mutations, which represents a severe neurological disease with various paroxysmal disorders and frequent developmental disabilities.


Subject(s)
Membrane Proteins/genetics , Mutation/genetics , Nerve Tissue Proteins/genetics , Adolescent , Adult , Age Factors , Alleles , Ataxia/genetics , Atrophy/genetics , Brain Diseases/genetics , Child , Child, Preschool , Chorea/genetics , Chromosomes, Human, Pair 16/genetics , Female , Gene Deletion , Genes/genetics , Humans , Infant , Learning Disabilities/genetics , Male , Multiplex Polymerase Chain Reaction , Phenotype , Young Adult
14.
BMC Pediatr ; 15: 72, 2015 Jun 27.
Article in English | MEDLINE | ID: mdl-26112048

ABSTRACT

BACKGROUND: Bronchogenic cyst is a congenital malformation, rarely located in the cervical region and almost never involved in a neonate with acute respiratory distress in the delivery room. CASE PRESENTATION: A female newborn with respiratory distress syndrome caused by a large left cervical mass. Intubation was difficult due to tracheal deviation. Magnetic resonance imaging confirmed a left cervical cyst displacing the trachea and esophagus laterally. Surgical excision was performed via a cervical approach on the 5th day, and pathological examination revealed a bronchogenic cyst. The patient's course was complicated by left vocal cord paralysis and necrotic lesions in the glottic and subglottic regions; she required a tracheostomy on the 13th day. Inflammatory stenosis in the subglottic region required balloon dilation once, 20 days later. Proximal esophageal stenosis induced transient upper airway obstruction with salivary stasis. Decannulation was performed at 2 months and the patient was discharged 10 days later. CONCLUSION: A bronchogenic cyst can exceptionally obstruct the airways in the neonatal period. Surgical excision is necessary, but postoperative complications may occur if the cyst is in close contact with the trachea and esophagus, including necrotic and stenotic lesions of the upper aerodigestive tract. In those situations, tracheostomy may be necessary for mechanical ventilation weaning and the initiation of oral feeding.


Subject(s)
Bronchogenic Cyst/diagnosis , Respiratory Distress Syndrome, Newborn/etiology , Bronchogenic Cyst/complications , Diagnosis, Differential , Female , Humans , Infant, Newborn , Magnetic Resonance Imaging , Respiratory Distress Syndrome, Newborn/diagnosis
15.
Eur J Paediatr Neurol ; 49: 120-128, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38492551

ABSTRACT

OBJECTIVES: To observe hyperechoic nodular or punctate white matter lesions (HNPL) in a population of preterm infants using routine cranial ultrasound (cUS), to describe the characteristics of HNPL, and to compare them with punctate white matter lesions (PWML) detected in magnetic resonance imaging (MRI). DESIGN: Retrospective observational single-center cohort study. SETTING: Level 2B neonatal unit in France. PATIENTS: 307 infants born <33 weeks gestation undergoing routine cUS with a total of 961 cUS performed. MAIN OUTCOME MEASURES: Description of lesions (HNPL/PWML): presence or absence, number, size, location, and structural distribution. RESULTS: Among the 307 included infants, 63 (20.5%) had at least one cerebral lesion, with 453 HNPL for 63 infants. HNPL were numerous (more than three in 66.6% of cases), primarily grouped in clusters (76.2%), located near the lateral ventricles (96.8%), and measuring more than 2 mm (79%). HNPL were diagnosed on day 29 on average and persisted until term. Overall, 43 MRI were performed in 307 infants, on average 18.9 days after last cUS, in 21 of those the indication was presence of HPNL on cUS. Of these 21 MRI, 14/21 presented 118 PWML compared to 173 HNPL on cUS. In the remaining MRI (7/21), no PWML were detected compared to 47 HNPL on cUS. CONCLUSIONS: In our population of 307 preterm infants, cUS allowed the diagnosis of HNPL, with a large similarity to PWML in MRI and a better sensitivity. But in the absence of data on inter-observer variability, we cannot exclude overdiagnosis of HNPL.


Subject(s)
Infant, Premature , Magnetic Resonance Imaging , White Matter , Humans , Infant, Newborn , Female , Male , Magnetic Resonance Imaging/methods , White Matter/diagnostic imaging , White Matter/pathology , Retrospective Studies , Leukoencephalopathies/diagnostic imaging , Ultrasonography/methods , Cohort Studies , Brain/diagnostic imaging , Brain/pathology
16.
Ann Clin Transl Neurol ; 10(10): 1937-1943, 2023 10.
Article in English | MEDLINE | ID: mdl-37491839

ABSTRACT

We present the phenotype of an infant with the largest ATN1 CAG expansion reported to date (98 repeats). He presented at 4 months with developmental delay, poor eye contact, acquired microcephaly, failure to thrive. He progressively developed dystonia-parkinsonism with paroxysmal oromandibular and limbs dyskinesia and fatal outcome at 17 months. Cerebral MRI disclosed globus pallidus T2-WI hyperintensities and brain atrophy. Molecular analysis was performed post-mortem following the diagnosis of dentatorubral-pallidoluysian atrophy (DRPLA) in his symptomatic father. Polyglutamine expansion defects should be considered when neurodegenerative genetic disease is suspected even in infancy and parkinsonism can be a presentation of infantile-onset DRPLA.


Subject(s)
Brain Diseases , Dyskinesias , Parkinsonian Disorders , Male , Infant , Humans , Brain Diseases/genetics , Peptides , Parkinsonian Disorders/diagnosis , Parkinsonian Disorders/genetics
17.
Eur J Med Genet ; 66(5): 104733, 2023 May.
Article in English | MEDLINE | ID: mdl-36842471

ABSTRACT

Autosomal recessive primary microcephaly type 3 (MCPH3) caused by pathogenic variations in CDK5RAP2, is characterized by sensorineural hearing loss, abnormality of skin pigmentation, ocular defects and severe microcephaly associated with neurodevelopmental delay. In this study, we expand the phenotype of MCPH3 as we describe a 10-year-old girl with a biallelic exonic frameshift variant in CDK5RAP2 displaying previously unreported features usually associated with Meier-Gorlin and microcephalic osteodysplastic primordial dwarfism type II (MOPDII). We further describe the clinical phenotype of this form of centrosomal-based primary microcephaly and emphasize the importance of skeletal defect screening in affected individuals.


Subject(s)
Dwarfism , Microcephaly , Osteochondrodysplasias , Female , Humans , Microcephaly/pathology , Dwarfism/genetics , Dwarfism/diagnosis , Osteochondrodysplasias/genetics , Osteochondrodysplasias/diagnosis , Fetal Growth Retardation/genetics , Fetal Growth Retardation/diagnosis , Nerve Tissue Proteins , Cell Cycle Proteins/genetics
18.
Mov Disord Clin Pract ; 10(5): 811-818, 2023 May.
Article in English | MEDLINE | ID: mdl-37205256

ABSTRACT

Background: Aromatic l-amino acid decarboxylase deficiency (AADCD) is a rare, early-onset, dyskinetic encephalopathy mostly reflecting a defective synthesis of brain dopamine and serotonin. Intracerebral gene delivery (GD) provided a significant improvement among AADCD patients (mean age, ≤6 years). Objective: We describe the clinical, biological, and imaging evolution of two AADCD patients ages >10 years after GD. Methods: Eladocagene exuparvovec, a recombinant adeno-associated virus containing the human complimentary DNA encoding the AADC enzyme, was administered into bilateral putamen by stereotactic surgery. Results: Eighteen months after GD, patients showed improvement in motor, cognitive and behavioral function, and in quality of life. Cerebral l-6-[18F] fluoro-3, 4-dihydroxyphenylalanine uptake was increased at 1 month, persisting at 1 year compared to baseline. Conclusion: Two patients with a severe form of AADCD had an objective motor and non-motor benefit from eladocagene exuparvovec injection even when treated after the age of 10 years, as in the seminal study.

19.
JCI Insight ; 8(21)2023 Nov 08.
Article in English | MEDLINE | ID: mdl-37768732

ABSTRACT

Retinitis pigmentosa (RP) is the most common inherited retinal disease (IRD) and is characterized by photoreceptor degeneration and progressive vision loss. We report 4 patients presenting with RP from 3 unrelated families with variants in TBC1D32, which to date has never been associated with an IRD. To validate TBC1D32 as a putative RP causative gene, we combined Xenopus in vivo approaches and human induced pluripotent stem cell-derived (iPSC-derived) retinal models. Our data showed that TBC1D32 was expressed during retinal development and that it played an important role in retinal pigment epithelium (RPE) differentiation. Furthermore, we identified a role for TBC1D32 in ciliogenesis of the RPE. We demonstrated elongated ciliary defects that resulted in disrupted apical tight junctions, loss of functionality (delayed retinoid cycling and altered secretion balance), and the onset of an epithelial-mesenchymal transition-like phenotype. Last, our results suggested photoreceptor differentiation defects, including connecting cilium anomalies, that resulted in impaired trafficking to the outer segment in cones and rods in TBC1D32 iPSC-derived retinal organoids. Overall, our data highlight a critical role for TBC1D32 in the retina and demonstrate that TBC1D32 mutations lead to RP. We thus identify TBC1D32 as an IRD-causative gene.


Subject(s)
Induced Pluripotent Stem Cells , Retinal Degeneration , Retinitis Pigmentosa , Humans , Retina , Retinitis Pigmentosa/genetics , Retinal Degeneration/genetics , Retinal Pigment Epithelium , Adaptor Proteins, Signal Transducing
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