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2.
Am J Hum Genet ; 99(1): 236-45, 2016 Jul 07.
Article in English | MEDLINE | ID: mdl-27392078

ABSTRACT

Crisponi syndrome (CS)/cold-induced sweating syndrome type 1 (CISS1) is a very rare autosomal-recessive disorder characterized by a complex phenotype with high neonatal lethality, associated with the following main clinical features: hyperthermia and feeding difficulties in the neonatal period, scoliosis, and paradoxical sweating induced by cold since early childhood. CS/CISS1 can be caused by mutations in cytokine receptor-like factor 1 (CRLF1). However, the physiopathological role of CRLF1 is still poorly understood. A subset of CS/CISS1 cases remain yet genetically unexplained after CRLF1 sequencing. In five of them, exome sequencing and targeted Sanger sequencing identified four homozygous disease-causing mutations in kelch-like family member 7 (KLHL7), affecting the Kelch domains of the protein. KLHL7 encodes a BTB-Kelch-related protein involved in the ubiquitination of target proteins for proteasome-mediated degradation. Mono-allelic substitutions in other domains of KLHL7 have been reported in three families affected by a late-onset form of autosomal-dominant retinitis pigmentosa. Retinitis pigmentosa was also present in two surviving children reported here carrying bi-allelic KLHL7 mutations. KLHL7 mutations are thus associated with a more severe phenotype in recessive than in dominant cases. Although these data further support the pathogenic role of KLHL7 mutations in a CS/CISS1-like phenotype, they do not explain all their clinical manifestations and highlight the high phenotypic heterogeneity associated with mutations in KLHL7.


Subject(s)
Alleles , Autoantigens/genetics , Hand Deformities, Congenital/complications , Hand Deformities, Congenital/genetics , Hyperhidrosis/complications , Hyperhidrosis/genetics , Mutation , Retinitis Pigmentosa/complications , Retinitis Pigmentosa/genetics , Trismus/congenital , Amino Acid Sequence , Autoantigens/chemistry , Child , Child, Preschool , Death, Sudden , Facies , Female , Humans , Infant , Male , Models, Molecular , Pedigree , Phenotype , Syndrome , Trismus/complications , Trismus/genetics
3.
J Child Adolesc Psychopharmacol ; 19(6): 699-707, 2009 Dec.
Article in English | MEDLINE | ID: mdl-20035588

ABSTRACT

OBJECTIVE: The effects of a promising pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD), atomoxetine, were studied on executive functions in both ADHD and reading disorder (RD) because earlier research demonstrated an overlap in executive functioning deficits in both disorders. In addition, the effects of atomoxetine were explored on lexical decision. METHODS: Sixteen children with ADHD, 20 children with ADHD + RD, 21 children with RD, and 26 normal controls were enrolled in a randomized placebo-controlled crossover study. Children were measured on visuospatial working memory, inhibition, and lexical decision on the day of randomization and following two 28-day medication periods. RESULTS: Children with ADHD + RD showed improved visuospatial working memory performance and, to a lesser extent, improved inhibition following atomoxetine treatment compared to placebo. No differential effects of atomoxetine were found for lexical decision in comparison to placebo. In addition, no effects of atomoxetine were demonstrated in the ADHD and RD groups. CONCLUSION: Atomoxetine improved visuospatial working memory and to a lesser degree inhibition in children with ADHD + RD, which suggests differential developmental pathways for co-morbid ADHD + RD as compared to ADHD and RD alone. CLINICAL TRIAL REGISTRY: B4Z-MC-LYCK, NCT00191906; http://clinicaltrials.gov/ct2/show/NCT00191906.


Subject(s)
Adrenergic Uptake Inhibitors/therapeutic use , Attention Deficit Disorder with Hyperactivity/drug therapy , Decision Making/drug effects , Dyslexia/drug therapy , Executive Function/drug effects , Propylamines/therapeutic use , Atomoxetine Hydrochloride , Attention Deficit Disorder with Hyperactivity/complications , Attention Deficit Disorder with Hyperactivity/psychology , Child , Cross-Over Studies , Dose-Response Relationship, Drug , Dyslexia/complications , Dyslexia/psychology , Humans , Inhibition, Psychological , Memory/drug effects , Neuropsychological Tests , Reading , Treatment Outcome
4.
Brain ; 130(Pt 9): 2258-66, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17690130

ABSTRACT

Four unrelated children are described with an identical brainstem and cerebellar malformation on MRI. The key findings are: vermal hypoplasia, subtotal absence of middle cerebellar peduncles, flattened ventral pons, vaulted pontine tegmentum, molar tooth aspect of the pontomesencephalic junction and absent inferior olivary prominence. Peripheral hearing impairment is present in all. Variable findings are: horizontal gaze palsy (1/4), impaired swallowing (2/4), facial palsy (3/4), bilateral sensory trigeminal nerve involvement (1/4), ataxia (2/4). Bony vertebral anomalies are found in 3/4. Additional MR studies in one patient using diffusion tensor imaging (DTI) with colour coding and fibre tracking revealed an ectopic transverse fibre bundle at the site of the pontine tegmentum and complete absence of transverse fibres in the ventral pons. The combined findings indicate an embryonic defect in axonal growth and guidance. Phenotypic analogy to mice with homozygous inactivation of Ntn1 encoding the secreted axonal guidance protein netrin1, or Dcc encoding its receptor Deleted in Colorectal Cancer led us to perform sequence analysis of NTN1 and DCC in all the patients. No pathogenic mutations were found. For the purpose of description the name 'pontine tegmental cap dysplasia' (PTCD) is proposed for the present malformation, referring to its most distinguishing feature on routine MRI.


Subject(s)
Axons/pathology , Cerebellum/abnormalities , Pons/abnormalities , Brain/pathology , Cerebellum/pathology , Child, Preschool , DNA Mutational Analysis , Female , Genes, DCC/genetics , Humans , Infant , Magnetic Resonance Imaging , Male , Nerve Growth Factors/genetics , Netrin-1 , Pons/pathology , Syndrome , Tumor Suppressor Proteins/genetics
5.
Ann Neurol ; 59(3): 504-11, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16374828

ABSTRACT

OBJECTIVE: The objective of this study was to describe leukoencephalopathy, lacunar infarcts, microbleeds and macrobleeds in the context of a collagen IV A1 mutation. METHODS: We examined a family with autosomal dominant porencephaly, in whom a defect in collagen IV A1 was detected recently. The patients underwent neurological, ophthalmological, and cardiological examinations and magnetic resonance imaging of the brain. Electron microscopy of a skin biopsy was performed. Extensive laboratory screening was performed for thrombophilia and increased bleeding tendency. RESULTS: The porencephaly was symptomatic in the infantile period in two patients, whereas it led to only minor neurological dysfunction in their affected mother. However, she experienced development of recurrent strokes in her 40s. In addition to the porencephaly, all patients had a leukoencephalopathy, which was most severe in the mother. Her magnetic resonance imaging results also showed lacunar infarcts, macrobleeds and a multitude of microbleeds. No other risk factors for recurrent stroke were found. Electron microscopy showed interruptions of the basement membrane of skin capillaries and inhomogeneous thickening of the basement membrane with pools of basement membrane fragments. INTERPRETATION: Leukoencephalopathy, ischemic infarcts, microbleeds, and macrobleeds are indicative of an underlying microangiopathy, of which the best-known causes are hypertension, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, and cerebral amyloid angiopathy. Mutations in collagen IV A1, a major component of the vascular basement membrane, appear to be another risk factor.


Subject(s)
Brain Diseases/genetics , Collagen Type IV/genetics , Mutation , Stroke/genetics , Adult , Brain Diseases/diagnosis , Brain Diseases/pathology , CADASIL/pathology , Cerebral Cortex/abnormalities , Cerebral Cortex/pathology , Cerebral Infarction/pathology , Disease Progression , Family Health , Female , Humans , Infant, Newborn , Longitudinal Studies , Magnetic Resonance Imaging/methods , Male , Microscopy, Electron, Transmission/methods , Middle Aged , Neurologic Examination , Ophthalmology/methods , Skin/pathology , Skin/ultrastructure , Stroke/diagnosis , Stroke/pathology
6.
Ann Neurol ; 57(3): 327-38, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15732098

ABSTRACT

The purpose of this study was to describe unusual variants of Alexander's disease. We studied 10 patients who did not meet previously established magnetic resonance imaging (MRI) criteria for Alexander's disease, but for whom this diagnosis was considered because of Rosenthal fibers at histological examination or presence of some MRI features suggestive of Alexander's disease. Sequence analysis of the GFAP gene was performed. In eight patients, MRI results showed predominantly posterior fossa lesions, especially multiple tumor-like brainstem lesions. One patient had asymmetrical frontal white matter abnormalities and basal ganglia abnormalities. One patient (Patient 10) developed degeneration of the frontal white matter. In nine patients, a mutation was found that was concluded to be pathogenic, because the mutation was de novo (five patients), a known mutation was found (two patients), or assembly of the glial fibrillary acidic protein was abnormal in cultured cells (two patients). In Patient 10, a DNA variation was found that was also present in the patient's clinically unaffected father and was concluded to be a polymorphism. In conclusion, DNA diagnostics is warranted in patients who display MRI features suggestive of Alexander's disease, even if they do not meet the full set of previously established MRI criteria.


Subject(s)
Alexander Disease/genetics , Genetic Variation , Glial Fibrillary Acidic Protein/genetics , Adolescent , Adult , Alexander Disease/pathology , Brain Stem/pathology , Child , Child, Preschool , DNA Mutational Analysis/methods , Female , Glial Fibrillary Acidic Protein/metabolism , Humans , Magnetic Resonance Imaging/methods , Male
7.
Biol Psychiatry ; 54(7): 763-8, 2003 Oct 01.
Article in English | MEDLINE | ID: mdl-14512218

ABSTRACT

We report two adult patients with succinic semialdehyde dehydrogenase deficiency, manifesting as gamma-hydroxybutyric aciduria. For both, the clinical presentation included significant behavioral disturbances and psychosis (hallucinations, disabling anxiety, aggressive behavior, and sleep disorder), leading to multiple therapeutic attempts. Intervention with benzodiazepines appeared most efficacious, resulting in decreased aggression and agitation and improvement in anxiety. A review of 56 published and unpublished studies of SSADH-deficient patients revealed that 42% manifested behavioral disturbances, whereas 13% (predominantly adults) displayed psychotic symptomatology. To explore the potential biochemical basis of these behavioral abnormalities, we studied cerebrospinal fluid derived from 13 patients, which revealed significantly elevated GHB (65- to 230-fold), high free and total GABA (up to threefold), and low glutamine. Although within the control range, homovanillic and 5-hydroxyindoleacetic acids (end products of dopamine and serotonin metabolism, respectively) showed a significant linear correlation with increasing GHB concentration, suggesting enhanced dopamine and serotonin turnover. We conclude that elevated GABA combined with low glutamine suggest disruption of the glial-neuronal glutamine/GABA/glutamate shuttle necessary for replenishment of neuronal neurotransmitters, whereas altered dopamine and serotonin metabolism may be causally linked to the hyperkinetic movement disorders and behavioral disturbances seen in SSADH-deficient patients.


Subject(s)
Aldehyde Oxidoreductases/deficiency , Metabolism, Inborn Errors/psychology , Sodium Oxybate/urine , Adult , Aldehyde Oxidoreductases/cerebrospinal fluid , Atrophy/pathology , Cerebellum/anatomy & histology , Chromatography, High Pressure Liquid , Chromatography, Ion Exchange , Female , Globus Pallidus/anatomy & histology , Glutamic Acid/metabolism , Hallucinations , Homovanillic Acid/cerebrospinal fluid , Humans , Hydroxyindoleacetic Acid/cerebrospinal fluid , Intellectual Disability , Magnetic Resonance Imaging/instrumentation , Magnetic Resonance Imaging/methods , Male , Metabolism, Inborn Errors/cerebrospinal fluid , Metabolism, Inborn Errors/physiopathology , Statistics as Topic , Succinate-Semialdehyde Dehydrogenase , gamma-Aminobutyric Acid/metabolism
8.
Eur J Pediatr ; 161(5): 259-61, 2002 May.
Article in English | MEDLINE | ID: mdl-12012220

ABSTRACT

UNLABELLED: Neuroleptic malignant syndrome (NMS) is a rare but serious disorder caused by antipsychotic medication including phenothiazines. For sedative purposes, increasing doses of alimemazine were administered to a 4-year-old multiple handicapped girl, with cerebral damage of the basal ganglia. She developed extra-pyramidal motor disturbances, an autonomic disorder, lowered consciousness and hyperthermia, characterising NMS. Alimemazine was stopped and dantrolene and supportive measures, including ventilation under sedation and paralysis with midazolam and vecuronium, were started. As clinical symptoms remained unabated, increasing doses of bromocriptine were administered. Two days after maximal bromocriptine dosage, her clinical condition improved and paralysis and ventilation were stopped. Midazolam and bromocriptine could be gradually decreased and suspended during the following months. A few days after bromocriptine cessation NMS recurred and was complicated by a fatal cardiorespiratory arrest. CONCLUSION: caution must be exercised when prescribing alimemazine, especially to children with basal ganglia damage and in the case of inexplicable fever and restlessness, neuroleptic malignant syndrome should be considered. Long-term therapy with bromocriptine combined with dantrolene and midazolam may be a successful medical treatment.


Subject(s)
Neuroleptic Malignant Syndrome/etiology , Trimeprazine/adverse effects , Basal Ganglia/drug effects , Basal Ganglia/pathology , Child, Preschool , Female , Humans
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