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1.
Orphanet J Rare Dis ; 18(1): 11, 2023 01 14.
Article in English | MEDLINE | ID: mdl-36639812

ABSTRACT

BACKGROUND: Mutations in the GATOR1 complex genes, DEPDC5 and NPRL3, play a major role in the development of lesional and non-lesional focal epilepsy through increased mTORC1 signalling. We aimed to assess the effects of mTORC1 hyperactivation on GABAergic inhibitory circuits, in 3 and 5 individuals carrying DEPDC5 and NPRL3 mutations respectively using a multimodal approach including transcranial magnetic stimulation (TMS), magnetic resonance spectroscopy (MRS), and electroencephalography (EEG). RESULTS: Inhibitory functions probed by TMS and MRS showed no effect of mutations on cortical GABAergic receptor-mediated inhibition and GABA concentration, in both cortical and subcortical regions. However, stronger EEG theta oscillations and stronger and more synchronous gamma oscillations were observed in DEPDC5 and NPRL3 mutations carriers. CONCLUSIONS: These results suggest that DEPDC5 and NPRL3-related epileptic mTORopathies may not directly modulate GABAergic functions but are nonetheless characterized by a stronger neural entrainment that may be reflective of a cortical hyperexcitability mediated by increased mTORC1 signaling.


Subject(s)
Epilepsy , Humans , Epilepsy/genetics , GTPase-Activating Proteins/genetics , Signal Transduction , Mechanistic Target of Rapamycin Complex 1/genetics , Mutation
2.
Neurogenetics ; 23(2): 115-127, 2022 04.
Article in English | MEDLINE | ID: mdl-35106698

ABSTRACT

Peroxisome biogenesis disorders-Zellweger spectrum disorders (PBD-ZSD)-are primarily autosomal recessive disorders caused by mutations in any of 13 PEX genes involved in peroxisome assembly. Compared to other PEX-related disorders, some PEX16 defects are associated with an atypical phenotype consisting of spasticity, cerebellar dysfunction, preserved cognition, and prolonged survival. In this case series, medical records and brain MRIs from 7 patients with this PEX16 presentation were reviewed to further characterize this phenotype. Classic PBD features such as sensory deficits and amelogenesis imperfecta were absent in all 7 patients, while all patients had hypertonia. Five patients were noted to have dystonia and received a treatment trial of levodopa/carbidopa. Four treated patients had partial but significant improvements in their dystonia and tremors, and 1 patient had only minimal response. Brain MRI studies commonly showed T2/FLAIR hyperintensities in the brainstem, superior and middle cerebellar peduncles, corticospinal tracts, and splenium of the corpus callosum. Genetic analysis revealed novel biallelic variants in 3 probands (c.683C > T/372delG; c.692A > G homozygous; c.865C > G/451C > T) and 1 novel variant (c.956_958delCGC) in another proband. We demonstrated residual PEX16 protein amounts by immunoblotting in fibroblasts available from 5 patients with this atypical PEX16 disease (3 from this series, 2 previously reported), in contrast to the absence of PEX16 protein in fibroblasts from a patient with the severe ZSD presentation. This study further characterizes the phenotype of PEX16 defects by highlighting novel and distinctive clinical, neuroradiological, and molecular features of the disease and proposes a potential treatment for the dystonia. ClinicalTrials.gov Identifier: NCT01668186. Date of registration: January 2012.


Subject(s)
Dystonia , Zellweger Syndrome , Female , Humans , Male , Membrane Proteins/genetics , Mutation , Peroxisomal Disorders , Zellweger Syndrome/genetics , Zellweger Syndrome/metabolism
3.
Eur J Hum Genet ; 23(11): 1505-12, 2015 Nov.
Article in English | MEDLINE | ID: mdl-25735478

ABSTRACT

CACNA1A loss-of-function mutations classically present as episodic ataxia type 2 (EA2), with brief episodes of ataxia and nystagmus, or with progressive spinocerebellar ataxia (SCA6). A minority of patients carrying CACNA1A mutations develops epilepsy. Non-motor symptoms associated with these mutations are often overlooked. In this study, we report 16 affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual deficiency, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia. Sequencing revealed one CACNA1A gene deletion, two deleterious CACNA1A point mutations including one known stop-gain and one new frameshift variant and a new splice-site variant. This report illustrates the phenotypic heterogeneity of CACNA1A loss-of-function mutations and stresses the cognitive and epileptic manifestations caused by the loss of CaV2.1 channels function, presumably affecting cerebellar, cortical and limbic networks.


Subject(s)
Autistic Disorder/genetics , Brain Diseases/genetics , Calcium Channels/genetics , Cerebellar Diseases/genetics , Cognition Disorders/genetics , Adult , Ataxia/genetics , Ataxia/physiopathology , Autistic Disorder/physiopathology , Brain Diseases/physiopathology , Cerebellar Diseases/physiopathology , Child , Child, Preschool , Cognition Disorders/physiopathology , Haploinsufficiency , Humans , Infant , Nystagmus, Pathologic/genetics , Nystagmus, Pathologic/physiopathology , Point Mutation
4.
Neuropediatrics ; 45(6): 406-10, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25343331

ABSTRACT

Aicardi-Goutières syndrome (AGS) is a rare genetic disorder with inflammatory immune-mediated pathogenesis. Disease onset is most commonly marked by recurrent fevers, irritability, and developmental regression in the 1st year of life. A stable phase characterized by severe spastic quadriparesis and cognitive deficit follows. Brain calcifications, leukoencephalopathy, and cerebral atrophy are the radiological hallmarks of AGS and often show progression over time. We present an atypical patient with late-onset AGS characterized by spastic paraparesis and a leukoencephalopathy that markedly improved during follow-up, demonstrating a nonprogressive disease course and the exceptional amelioration of the white matter abnormalities.


Subject(s)
Autoimmune Diseases of the Nervous System/pathology , Leukoencephalopathies/diagnosis , Nervous System Malformations/pathology , Paraparesis, Spastic/diagnosis , Age Factors , Autoimmune Diseases of the Nervous System/complications , Autoimmune Diseases of the Nervous System/genetics , Child , Female , Humans , Leukoencephalopathies/complications , Mutation , Nervous System Malformations/complications , Nervous System Malformations/genetics , Paraparesis, Spastic/complications , Remission, Spontaneous , Ribonuclease H/genetics
5.
Am J Med Genet A ; 164A(11): 2834-42, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25258112

ABSTRACT

Fragile X syndrome (FXS) results from dynamic mutations leading ultimately to the absence of expression of the Fragile X Mental Retardation Protein (FMRP). It is characterized by synaptic upregulated protein synthesis and immature dendritic spines associated with altered brain plasticity and cognitive functions. Recent work in Fmr1 knockout mice has shown that lovastatin, an inhibitor of Ras-ERK1/2, normalized hippocampus protein synthesis. We hypothesize that lovastatin, as a disease-modifying drug, would counterweigh the absence of FMRP and improve behavior. Here we report a phase I study to assess the safety and efficacy of lovastatin in individuals with FXS. A total of 15 patients (13 males, 6-31 years old) were treated with escalating doses of lovastatin (up to 40 mg) for three months. Their behavior were assessed before and after treatment using the Aberrant Behavioral Checklist--Community (ABC-C) total score (primary outcome), as well as domains of the FXS validated version of the ABC-C (secondary outcomes). The treatment was well tolerated and minimal side effects were reported. Significant improvement in the primary outcome (P<0.005), as well as in secondary outcomes, were observed in the majority of the subjects (12/15). We think that long-term sustained treatment with diseased-modifying drugs would be necessary in order to improve behavior and ultimately learning. Lovastatin, well known for its long-term security profile, would be a good candidate for that purposes. Our study showing reassuring safety data along with potential functional benefit emphasizes the need of a placebo-controlled trial to ascertain lovastatin efficacy in FXS individuals.


Subject(s)
Behavior/drug effects , Fragile X Syndrome/drug therapy , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Lovastatin/pharmacology , Lovastatin/therapeutic use , Adolescent , Adult , Child , Female , Fragile X Mental Retardation Protein/genetics , Fragile X Syndrome/genetics , Fragile X Syndrome/psychology , Humans , Male , Mutation , Treatment Outcome , Young Adult
6.
Dev Med Child Neurol ; 51(8): 600-6, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19627332

ABSTRACT

Global developmental delay (GDD) is defined as evidence of significant delays in two or more developmental domains. Our study determined the cognitive skills of a cohort of young children with GDD. A retrospective chart review of all children diagnosed with GDD within a single developmental clinic was carried out. Scores on fine motor (Peabody Developmental Motor Scale 2), expressive language (Expressive One Word Picture Vocabulary Test) and receptive language (Reynell Developmental Language Scales or Clinical Evaluation of Language Fundamentals - Preschool 2) testing, and cognitive performance (Wechsler Preschool and Primary Scale of Intelligence, Third Edition) were obtained. A multiple regression analysis was performed and correlations obtained. Results from a total of 93 patients (86 males, seven females) were retained for analysis. Mean age was 3 years 8 months (SD 10mo, range 2.5-4.75y). Cognitive scores were widely distributed, with 73% of participants displaying a global IQ score of 70 or more, despite concurrent global delay. Significant correlation was present for fine motor and expressive language scores, when isolated and compared with cognitive performance (p values of 0.04 and 0.05 respectively). The conclusion was made that an initial diagnosis of GDD is not necessarily associated with objective cognitive impairment.


Subject(s)
Cognition/physiology , Developmental Disabilities/psychology , Child, Preschool , Cohort Studies , Developmental Disabilities/complications , Developmental Disabilities/physiopathology , Female , Humans , Infant , Intelligence/physiology , Language Development , Male , Motor Skills/physiology , Neuropsychological Tests , Retrospective Studies
7.
Pediatr Neurol ; 39(5): 307-16, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18940553

ABSTRACT

Reports of acute combined central and peripheral nervous system acquired inflammatory demyelination are rare in children. This study aimed to (1) define the clinical features and prognoses of patients with this entity; and (2) compare these patients with children presenting isolated acute central or peripheral nervous system demyelination. A retrospective chart review of 523 children with central or peripheral nervous system demyelination hospitalized between 1993-2006 was undertaken. Among these, 93 fulfilled criteria (clinical features and positive magnetic resonance imaging or electromyography/nerve conduction studies) for either acute central (n = 37; 39.8%) or peripheral (n = 43; 46%) nervous system demyelination, or a combination of the two (n = 13; 14%). Significant differences between groups were evident for age (median, 10 versus 7 versus 11 years, respectively; P = 0.047), admission to pediatric intensive care unit (8% versus 30% versus 58%, respectively; P = 0.001), length of hospital stay (median, 8 versus 9 versus 29 days, respectively; P < 0.001), treatment with steroids (52% versus 7% versus 75%, respectively; P < 0.001) and immunoglobulins (11% versus 81% versus 75%, respectively; P < 0.001), and poor evolution (3% versus 12% versus 54%, respectively; P = 0.002). This entity in children is not rare, and has a poorer outcome than isolated central or peripheral nervous system demyelination. Assessment is needed for a better understanding of risk factors, etiologies, management, and prognosis.


Subject(s)
Central Nervous System Diseases/epidemiology , Demyelinating Diseases/epidemiology , Peripheral Nervous System Diseases/epidemiology , Acute Disease , Adolescent , Central Nervous System Diseases/pathology , Child , Child, Preschool , Demyelinating Diseases/pathology , Female , Humans , Infant , Magnetic Resonance Imaging , Male , Peripheral Nervous System Diseases/pathology , Retrospective Studies , Risk Factors
8.
J Child Neurol ; 23(7): 752-7, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18354151

ABSTRACT

Few cases of simultaneous acute demyelination of the peripheral and central nervous systems are reported. Four patients diagnosed as having Guillain-Barré syndrome and acute disseminated encephalomyelitis during the same hospitalization are described herein. Two patients manifest an atypical form of Guillain-Barré syndrome, with magnetic resonance imaging of the head showing acute disseminated encephalomyelitis. A third patient has acute disseminated encephalomyelitis and develops Guillain-Barré syndrome during his hospitalization. A fourth patient demonstrates transverse myelitis that evolves into Guillain-Barré syndrome, with demyelination seen on brain magnetic resonance imaging. All patients are treated with intravenous immunoglobulins or corticosteroids. Three patients have a favorable outcome; 1 patient has a chronic inflammatory demyelinating polyradiculoneuropathy. Guillain-Barré syndrome and acute disseminated encephalomyelitis can occur simultaneously in the pediatric population. This may be explained by a shared epitope between peripheral and central nervous system myelin. Further research is necessary to better describe this entity and its prognosis.


Subject(s)
Encephalomyelitis, Acute Disseminated/complications , Guillain-Barre Syndrome/complications , Immunoglobulins, Intravenous/therapeutic use , Adolescent , Child , Child, Preschool , Electromyography , Encephalomyelitis, Acute Disseminated/drug therapy , Female , Glucocorticoids/therapeutic use , Guillain-Barre Syndrome/drug therapy , Humans , Magnetic Resonance Imaging , Male , Prednisone/analogs & derivatives , Prednisone/therapeutic use
9.
Pediatr Neurol ; 38(1): 1-9, 2008 Jan.
Article in English | MEDLINE | ID: mdl-18054685

ABSTRACT

With the advent of magnetic resonance imaging as a rapid and accurate way to diagnose arterial ischemic stroke, cerebrospinal fluid assessment is rarely performed, unless infectious or inflammatory processes are obvious. Recent advances in the understanding of the pathophysiology of childhood stroke have implicated a growing list of discrete or occult infectious and inflammatory conditions which may involve intracranial arteries and neighboring structures. Cerebrospinal-fluid assessment may allow the detection of markers identifying processes (including infectious, inflammatory, metabolic, and traumatic) potentially involved in cerebral vasculopathy and stroke. The analysis of cerebrospinal fluid in arterial ischemic strokes, including apparently idiopathic strokes, may yield essential information on pathophysiology, allowing for optimal therapeutic decisions and prognostic considerations.


Subject(s)
Brain Ischemia/cerebrospinal fluid , Brain Ischemia/diagnosis , Cerebral Arteries/physiopathology , Cerebrospinal Fluid/chemistry , Stroke/cerebrospinal fluid , Stroke/diagnosis , Biomarkers/cerebrospinal fluid , Brain Ischemia/therapy , Central Nervous System Infections/cerebrospinal fluid , Central Nervous System Infections/complications , Central Nervous System Infections/diagnosis , Cerebral Arteries/pathology , Child , Diagnosis, Differential , Encephalitis/cerebrospinal fluid , Encephalitis/complications , Encephalitis/diagnosis , Humans , Stroke/therapy , Vasculitis, Central Nervous System/cerebrospinal fluid , Vasculitis, Central Nervous System/complications , Vasculitis, Central Nervous System/diagnosis
10.
Curr Opin Pediatr ; 16(6): 617-22, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15548922

ABSTRACT

PURPOSE OF REVIEW: To facilitate and standardize the diagnosis of cerebrovascular conditions in childhood, particularly in the field of arterial ischemic diseases. RECENT FINDINGS: Progress in diagnostic techniques in the past decade have led to newly established etiologies for childhood stroke, most of which represent some form of vascular pathology. These advances must be integrated into a modern nomenclature system with revised definitions of stroke and arterial wall diseases-arteriopathies-in childhood. SUMMARY: This nomenclature system is intended to facilitate and enhance clinical research in childhood stroke, particularly multicenter collaborative studies.


Subject(s)
Cerebrovascular Disorders/classification , Adolescent , Cerebrovascular Disorders/diagnosis , Child , Humans , Multicenter Studies as Topic/standards , Stroke/classification , Stroke/diagnosis , Terminology as Topic
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