RESUMO
We report on a patient with terminal deletion of the long arm of chromosome 14 displaying brain interhemispheric fusion limited to the midline anterior frontal cortex associated with hypoplastic corpus callosum and incomplete rotation of the left hippocampus in a clinical setting of motor and intellectual disability with poor language, and social behavior abnormalities with aggressiveness. Some possible correlations between clinical signs and symptoms and various aspects of the complex brain malformation are briefly discussed and compared with other known abnormalities of chromosome 14. The different neuropathology of the most common forms and the new forms of holoprosencephaly recently described is also discussed and leads us to suggest classifying the interhemispheric fusion of this case as a "minimal" form of holoprosencephaly. This appears to be the first description in a 14q deletion patient.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 14/genética , Holoprosencefalia/genética , Encéfalo/diagnóstico por imagem , Lobo Frontal/diagnóstico por imagem , Holoprosencefalia/classificação , Holoprosencefalia/diagnóstico por imagem , Humanos , Masculino , Neuroimagem , Adulto JovemRESUMO
Mowat-Wilson syndrome (MWS) is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene and is characterized by distinctive facial features, epilepsy, moderate to severe intellectual disability, corpus callosum abnormalities and other congenital malformations. Epilepsy is considered a main manifestation of the syndrome, with a prevalence of about 70-75%. In order to delineate the electroclinical phenotype of epilepsy in MWS, we investigated epilepsy onset and evolution, including seizure types, EEG features, and response to anti-epileptic therapies in 22 patients with genetically confirmed MWS. Onset of seizures occurred at a median age of 14.5 months (range: 1-108 months). The main seizure types were focal and atypical absence seizures. In all patients the first seizure was a focal seizure, often precipitated by fever. The semiology was variable, including hypomotor, versive, or focal clonic manifestations; frequency ranged from daily to sporadic. Focal seizures were more frequent during drowsiness and sleep. In 13 patients, atypical absence seizures appeared later in the course of the disease, usually after the age of 4 years. Epilepsy was usually quite difficult to treat: seizure freedom was achieved in nine out of the 20 treated patients. At epilepsy onset, the EEGs were normal or showed only mild slowing of background activity. During follow-up, irregular, diffuse frontally dominant and occasionally asymmetric spike and waves discharges were seen in most patients. Sleep markedly activated these abnormalities, resulting in continuous or near-to-continuous spike and wave activity during slow wave sleep. Slowing of background activity and poverty of physiological sleep features were seen in most patients. Our data suggest that a distinct electroclinical phenotype, characterized by focal and atypical absence seizures, often preceded by febrile seizures, and age-dependent EEG changes, can be recognized in most patients with MWS.
Assuntos
Doença de Hirschsprung/fisiopatologia , Deficiência Intelectual/fisiopatologia , Microcefalia/fisiopatologia , Convulsões/fisiopatologia , Adolescente , Anticonvulsivantes/uso terapêutico , Criança , Pré-Escolar , Análise Mutacional de DNA , Eletroencefalografia , Fácies , Feminino , Doença de Hirschsprung/tratamento farmacológico , Doença de Hirschsprung/genética , Proteínas de Homeodomínio/genética , Humanos , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/genética , Masculino , Microcefalia/tratamento farmacológico , Microcefalia/genética , Mutação , Fenótipo , Proteínas Repressoras/genética , Estudos Retrospectivos , Convulsões/tratamento farmacológico , Convulsões/genética , Ácido Valproico/uso terapêutico , Adulto Jovem , Homeobox 2 de Ligação a E-box com Dedos de ZincoRESUMO
PURPOSE: To characterize epileptic phenotype, electroencephalography (EEG) features, and epileptic evolution in patients with ring 14 r(14) syndrome. METHODS: Twenty-two patients with ring chromosome 14 were enrolled in the study. We examined age at onset, seizure semiology and frequency at onset and at follow-up, drug responsiveness/resistance, and interictal/ictal EEG data. The degree of severity of the epileptic phenotype negatively influences child cognitive development. KEY FINDINGS: The incidence of epilepsy in patients with r(14) syndrome is virtually 100%, characterized by early onset, polymorphic seizures, and drug-resistant seizures. In addition, we ascertained focal secondarily generalized epilepsy, seizure cluster tendency, frequent status epilepticus, and a rather typical epilepsy evolution. EEG abnormalities consisted of slow background activity with pseudoperiodic bursts of generalized slow waves in the early stage, focal frontotemporal or temporoposterior slow waves with multifocal spikes interposed, and unusual rhythmic fast recruiting posterior spikes followed by secondary generalization. The degree of severity of the epileptic phenotype negatively influences child cognitive development. SIGNIFICANCE: This study provides a more precise definition of seizure types, natural history, and drug responsiveness of r(14) syndrome, a highly epileptogenic chromosomal condition.
Assuntos
Encéfalo/fisiopatologia , Epilepsia/genética , Idade de Início , Pré-Escolar , Cromossomos Humanos Par 14/fisiologia , Eletroencefalografia , Epilepsia/fisiopatologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Cromossomos em AnelRESUMO
Epilepsy is the most common and serious neurological symptom in ring chromosome 14 syndrome, also characterised by mild dysmorphisms, acquired microcephaly, cognitive impairment, hypotonia and ocular abnormalities. Typically, early-onset, polymorphous and drug-resistant seizures are reported. Status epilepticus has not been previously reported. We describe a nine-year-old Caucasian boy with ring 14 syndrome who presented a severe early-onset and drug-resistant focal epilepsy with secondary generalised seizures and repetitive episodes of convulsive and non-convulsive status epilepticus. The electro-clinical evaluation of prolonged seizures and their long-term consequences is important for the practical management of these patients and for a better comprehension of the syndrome.
Assuntos
Cromossomos Humanos Par 14/genética , Epilepsias Parciais/fisiopatologia , Cromossomos em Anel , Convulsões/fisiopatologia , Estado Epiléptico/fisiopatologia , Criança , Eletroencefalografia , Epilepsias Parciais/complicações , Humanos , Lactente , Masculino , Convulsões/complicações , Sono/fisiologia , Estado Epiléptico/genética , Vigília/fisiologiaRESUMO
Autosomal recessive spastic paraplegia with thinning of corpus callosum (ARHSP-TCC) is a complex form of HSP initially described in Japan but subsequently reported to have a worldwide distribution with a particular high frequency in multiple families from the Mediterranean basin. We recently showed that ARHSP-TCC is commonly associated with mutations in SPG11/KIAA1840 on chromosome 15q. We have now screened a collection of new patients mainly originating from Italy and Brazil, in order to further ascertain the spectrum of mutations in SPG11, enlarge the ethnic origin of SPG11 patients, determine the relative frequency at the level of single Countries (i.e., Italy), and establish whether there is one or more common mutation. In 25 index cases we identified 32 mutations; 22 are novel, including 9 nonsense, 3 small deletions, 4 insertions, 1 in/del, 1 small duplication, 1 missense, 2 splice-site, and for the first time a large genomic rearrangement. This brings the total number of SPG11 mutated patients in the SPATAX collection to 111 cases in 44 families and in 17 isolated cases, from 16 Countries, all assessed using homogeneous clinical criteria. While expanding the spectrum of mutations in SPG11, this larger series also corroborated the notion that even within apparently homogeneous population a molecular diagnosis cannot be achieved without full gene sequencing.
Assuntos
Agenesia do Corpo Caloso , Deleção de Genes , Mutação , Proteínas/genética , Paraplegia Espástica Hereditária/genética , Adolescente , Adulto , Argélia , Sequência de Bases , Brasil , Análise Mutacional de DNA , Saúde da Família , Feminino , Frequência do Gene , Genes Recessivos , Testes Genéticos , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Marrocos , Linhagem , Portugal , Paraplegia Espástica Hereditária/diagnóstico , Paraplegia Espástica Hereditária/etnologia , Adulto JovemRESUMO
The ring 14 (r14) syndrome is a rare condition, whose precise clinical and genetic characterization is still lacking. We analyzed a total of 20 patients with r14 and another 9 patients with a linear 14q deletion. The ring was complete, with no apparent loss of chromosome material, in 6 cases; a terminal 14q deletion, varying in size from 0.65 to 5 Mb, was detected in the remaining 14 cases. Deleted ring chromosomes were 70% paternal and 30% maternal. UPD (14) was never detected. With respect to the linear 14q deletions, three were proximal, varying in size from 4 to 7.2 Mb, and six distal, varying in size from 4.8 to 20 Mb. The majority of the linear deletions were also of paternal origin, and UPD (14) was excluded in all cases. Clinically, the r14 syndrome was characterized by a recognizable phenotype, consisting of shortness of stature, a distinctive facial appearance, microcephaly, scoliosis, and ocular abnormalities, which included abnormal retinal pigmentation, strabismus, glaucoma, and abnormal macula. All patients except one had mental retardation. Drug-resistant epilepsy was another highly consistent finding. Aggressive and hyperactive behavior was noted in about half of the patients. Based on genotype-phenotype correlations, we could deduce that retinal abnormalities, epilepsy, microcephaly, and mental retardation map within the proximal 14q11.2-q12 region. Likewise, behavior disorders and scoliosis could be assigned to the 14q32 region.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 14 , Cromossomos em Anel , Adolescente , Adulto , Criança , Pré-Escolar , Análise Citogenética , Epilepsia/genética , Fácies , Feminino , Marcadores Genéticos , Humanos , Hibridização in Situ Fluorescente , Lactente , Deficiência Intelectual/genética , Masculino , Repetições de Microssatélites , Hibridização de Ácido Nucleico , Análise de Sequência com Séries de Oligonucleotídeos , Mapeamento Físico do Cromossomo , Síndrome , Adulto JovemRESUMO
Complex tics have been widely reported in literature, especially in children with Tourette syndrome. We describe the case of a fracture line of both peroneal bones in a 13-year-old child with Tourette syndrome and obsessive-compulsive disorder. He was admitted to our hospital because of pain in his legs. Radiography showed fractures of both peroneal bones, more marked on the left side. The clinical history was strongly suggestive of obsessive-compulsive disorder and Tourette syndrome with associated simple and complex motor tics. Radiographic follow-up showed spontaneous resolution of the fractures.
Assuntos
Fraturas de Estresse/etiologia , Transtornos de Tique/complicações , Adolescente , Seguimentos , Fraturas de Estresse/diagnóstico por imagem , Humanos , Masculino , Transtorno Obsessivo-Compulsivo/complicações , Radiografia , Síndrome de Tourette/complicaçõesRESUMO
OBJECTIVE: To determine if laminin-alpha2 deficiency is due to mutations in the LAMA2 gene or secondary to mutations in other congenital muscular dystrophy genes. METHODS: We performed molecular analysis of LAMA2, by single-strand conformation polymorphism and sequencing, in 15 patients with undetectable or greatly reduced laminin-alpha2 expression. We also performed 4 prenatal diagnoses and investigated a founder effect. RESULTS: We found 1 known and 9 previously undescribed LAMA2 mutations spanning all protein domains. These were nonsense or frameshifts causing laminin-alpha2 absence or, in 1 case, a homozygous missense mutation producing partial protein expression and milder phenotype. LAMA2 mutations were undetected in 5 patients, in 2 of whom FKRP mutations explained the phenotype. In 3 prenatal cases, the fetus was heterozygous for the mutation of interest and pregnancy continued; in 1 case, the fetus was affected and aborted. In 2 patients, the Cys967Stop mutation and identical haplotypes flanking the LAMA2 gene indicated a founder effect. CONCLUSIONS: The clinical phenotype was severe in most patients with LAMA2 mutations and associated with undetectable protein expression. One case with no protein and another with partial expression had milder phenotypes. Typical white matter alterations on magnetic resonance imaging were found in all patients with LAMA2 mutations, supporting the utility of magnetic resonance imaging in differential diagnosis. The founder mutation (Cys967Stop) probably originated in Albania. Genetic characterization of affected families is mainly of use for prenatal diagnosis.
Assuntos
Efeito Fundador , Laminina/genética , Distrofias Musculares/genética , Mutação/genética , Diagnóstico Pré-Natal , Adolescente , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Humanos , Imuno-Histoquímica , Lactente , Laminina/deficiência , Masculino , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , GravidezRESUMO
AIMS: To determine efficacy and safety of corticosteroid treatment in patients with severe Sydenham's chorea paralytic form. METHODS: This is a 4 years observational study on ten patient with severe paralytic form of Sydenham's chorea unresponsive to neuroleptics and antiepileptics agents, treated with intravenous methylprednisolone followed by oral deflazacort therapy. Chorea paralytica patients were bedridden, unable to take independent steps, showed severe generalized hypotonia and were hospitalized for 3-4 weeks. Additional clinical evaluations were undertaken at 1, 3 and 6 months and 1, 2 and 4 years from onset of chorea. Severity chorea at the onset and during follow up was rated according to Universidade Federal de Minas Gerais (UFMG) Sydenham's Chorea Rating Scale (USCRS). In all children video-recording was performing at onset and during clinical follow-up. RESULTS: We reported a significant improvement in swallowing and chewing with partial recovery of language 2-3 days after starting intravenous methylprednisolone treatment and complete disappearance of movement disorders after 3-4 weeks of treatment. All our patients were followed for 4 years from onset and none experienced relapse of chorea, other movement disorders or psychiatric disturbances. The treatment with deflazacort was well-tolerated in all children with no significant side effects reported. CONCLUSION: Our data showed that high dose of methylprednisolone intravenously followed by deflazacort therapy may be effective and well-tolerated in children with severe paralytic form of Sydenham's chorea.
Assuntos
Corticosteroides/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Coreia/tratamento farmacológico , Idade de Início , Anticonvulsivantes/uso terapêutico , Antipsicóticos/uso terapêutico , Antiestreptolisina/metabolismo , Criança , Coreia/psicologia , Deglutição , Feminino , Humanos , Masculino , Mastigação , Metilprednisolona/uso terapêutico , Transtornos dos Movimentos/tratamento farmacológico , Transtornos dos Movimentos/etiologia , Miocardite/complicações , Exame Neurológico , Paralisia/tratamento farmacológico , Paralisia/etiologia , Pregnenodionas/uso terapêutico , Febre Reumática/complicaçõesRESUMO
Spastic paraplegia 3A is the second most common form of hereditary autosomal dominant spastic paraplegia. This form is mainly associated with an early age of onset and pure phenotype, although recently complicated forms were reported. We describe a patient carrying a new C>T P344S>CT mutation in exon 10 of the spastic paraplegia 3A gene with unusual, complicated, and extremely severe phenotype. At the last neurologic examination performed at 17 years of life, the patient disclosed spastic tetraparesis, sensorimotor axonal neuropathy, cognitive and cranial nerve impairment, mild pes cavus, and distal amyotrophy.
Assuntos
Proteínas de Ligação ao GTP/genética , Proteínas de Membrana/genética , Mutação/genética , Paraplegia Espástica Hereditária/genética , Paraplegia Espástica Hereditária/fisiopatologia , Adolescente , Eletrofisiologia/métodos , Feminino , Humanos , Neurorradiografia/métodos , Fenótipo , Paraplegia Espástica Hereditária/diagnósticoRESUMO
We report the first case of a child with recessive hereditary methemoglobinemia type II with demonstrated cerebellar atrophy. This very rare blood disorder results in mild cyanosis, profound mental and motor impairment, and movement disorders in infancy and childhood. We suggest that children with unexplained severe encephalopathy and cerebellar atrophy should also be tested for hereditary methemoglobinemia type II.
Assuntos
Atrofia/genética , Atrofia/patologia , Cerebelo/patologia , Metemoglobinemia/genética , Encéfalo/patologia , Pré-Escolar , Genes Recessivos , Humanos , Imageamento por Ressonância Magnética , MasculinoRESUMO
OBJECTIVE: To determine if a significant proportion of patients with myoclonic-astatic epilepsy (MAE) have glucose transporter 1 (GLUT1) deficiency. DESIGN: Genetic analysis. SETTING: Ambulatory and hospitalized care. PATIENTS: Eighty-four unrelated probands with MAE were phenotyped and SLC2A1 was sequenced and analyzed by multiplex ligation-dependent probe amplification. Any identified mutations were then screened in controls. MAIN OUTCOME MEASURE: Any SLC2A1 mutations. RESULTS: Four of 84 probands with MAE had a mutation of SLC2A1 on sequencing. Multiplex ligation-dependent probe amplification analysis did not reveal any genomic rearrangements in 75 of the remaining cases; 5 could not be tested. Two patients with MAE with SLC2A1 mutations also developed paroxysmal exertional dyskinesia in childhood. CONCLUSIONS: Five percent of our patients with MAE had SLC2A1 mutations, suggesting that patients with MAE should be tested for GLUT1 deficiency. Diagnosis of GLUT1 deficiency is a strong indication for early use of the ketogenic diet, which may substantially improve outcome of this severe disorder.
Assuntos
Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/genética , Transportador de Glucose Tipo 1/deficiência , Transportador de Glucose Tipo 1/genética , Mutação/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Dieta Cetogênica/métodos , Epilepsias Mioclônicas/dietoterapia , Humanos , Masculino , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Methylmalonic aciduria and homocystinuria, cblC type, is the most common inborn error of vitamin B(12) (cobalamin) metabolism. The recent cloning of the disease gene, MMACHC, has permitted genotype-phenotype correlation. In a 1-year-old girl, compound heterozygous c.271dupA and c.616C>T mutations in MMACHC were identified as causing an early onset methylmalonic aciduria and homocystinuria, cblC type, which was complicated by sensorimotor peripheral demyelinating neuropathy.
Assuntos
Doenças Desmielinizantes/urina , Homocistinúria/urina , Ácido Metilmalônico/urina , Doenças do Sistema Nervoso Periférico/urina , Doenças Desmielinizantes/complicações , Feminino , Estudos de Associação Genética , Homocistinúria/complicações , Humanos , Lactente , Condução Nervosa/fisiologia , Doenças do Sistema Nervoso Periférico/complicaçõesRESUMO
A case of acute and reversible bilateral basal ganglia with thalami involvement associated with serological evidence of Mycoplasma pneumoniae infection is reported. Increased titers of immunoglobulin M antibodies against GM1 ganglioside components were found during an acute phase of neurological illness. Brain magnetic resonance imaging (MRI) showed bilateral involvement of the basal ganglia and thalamus, which disappeared 1 month later. The child recovered fully after corticosteroid and immunoglobulin therapy, and antiganglioside antibodies returned to within the normal range. The authors speculate on the diagnostic hypothesis regarding selective basal ganglia and thalamic involvement and the relationship with anti-GM1 ganglioside immunoglobulin M antibodies.
Assuntos
Autoanticorpos/sangue , Encefalite/imunologia , Encefalite/patologia , Pneumonia por Mycoplasma/complicações , Tálamo/patologia , Antibacterianos/uso terapêutico , Autoanticorpos/biossíntese , Pré-Escolar , Corpo Estriado/patologia , Corpo Estriado/fisiopatologia , Progressão da Doença , Encefalite/fisiopatologia , Gangliosídeos/imunologia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Imageamento por Ressonância Magnética/métodos , Masculino , Pneumonia por Mycoplasma/imunologia , Pneumonia por Mycoplasma/patologia , Esteroides/uso terapêutico , Tálamo/fisiopatologia , Resultado do TratamentoRESUMO
A 14-year-old boy with an episode of acute weakness resembling acute demyelinating encephalomyelitis and polyradiculoneuritis after a febrile illness is described. Molecular analysis showed a mutation at codon 164 of the connexin 32 gene. Neuroradiological and neurophysiological follow-up is reported during acute and chronic phases of disease, suggesting that during metabolic stress connexin 32 mutations lead to a loss of normal cellular communication and reversible cell dysfunction in oligodendrocytes and in Schwann cells. These data confirm that altered gating properties of connexin 32 could give rise to acute, transient central and peripheral nervous system symptoms in situations of metabolic stress.
Assuntos
Encéfalo/fisiopatologia , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/fisiopatologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Sistema Nervoso Periférico/fisiopatologia , Adolescente , Doença de Charcot-Marie-Tooth/diagnóstico , Conexinas/genética , Eletrodiagnóstico , Junções Comunicantes/genética , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Mutação/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína beta-1 de Junções ComunicantesRESUMO
We report an atypical neurophysiologic pattern of isolated vitamin E deficiency in a 13-year-old boy. Electroneurography- electromyography, somatosensory evoked potentials, serum vitamin E concentration and genetic analysis of the alpha-tocopherol transfer protein gene were performed. Nerve conduction study failed to show peripheral neuropathy whereas needle electromyography of distal muscles demonstrated chronic neurogenic motor unit potentials. Both clinical and neurophysiologic data fulfilled the criteria of distal hereditary motor neuropathy. Later on, somatosensory-evoked potential displayed absence of spinal and central response. The serum vitamin E level was low, and the patient was found to be homozygous for a 513insTT mutation in exon 3 of the alpha-tocopherol transfer protein gene. To our knowledge this is the first case of isolated deficiency of vitamin E that presents the classic neurophysiologic and clinical features of distal hereditary motor neuropathy.