RESUMO
A 25-month-old boy, born to consanguineous parents, had progressive spastic tetraplegia, and increased signal of the white matter on cerebral T2-weighted magnetic resonance imaging indicative of diffuse leukodystrophy. Elevated blood and cerebrospinal fluid lactate levels pointed to a respiratory chain defect. Cytochrome-c oxidase deficiency was demonstrated in cultured skin fibroblasts and skeletal muscle. This report extends the phenotype of COX deficiency in infancy. Systematic study of blood and CSF lactate should be carried out in every infant with leukodystrophy.
Assuntos
Deficiência de Citocromo-c Oxidase , Esclerose Cerebral Difusa de Schilder/enzimologia , Encéfalo/diagnóstico por imagem , Pré-Escolar , Esclerose Cerebral Difusa de Schilder/diagnóstico por imagem , Esclerose Cerebral Difusa de Schilder/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , RadiografiaRESUMO
Joint predisposition to malignant melanoma and nervous system tumors (NSTs) is a puzzle. Several melanoma susceptibility genes have been identified, including p16, a clustered tumor suppressor. However, the molecular bases of inherited proclivity to NSTs in the absence of a recognizable genetic syndrome are unknown. We analyzed two families with joint proneness to melanoma and NSTs in view of genetic linkage and identification of the causal molecular lesions. Highly informative linkage markers were used for segregation analyses of the predisposition alleles in the two pedigrees. Characterization of the molecular lesions required hemizygosity mapping based on microsatellite markers physically mapped to contigs of the 9p21 region and a Southern blot approach using several PCR-generated probes. Both families were found to be allelic and linked to p16 markers. In the family segregating the melanoma/NST syndrome, a large germ-line deletion ablated the whole p16, p19, and p15 gene cluster (or INK4 locus), whereas a more circumscribed molecular lesion disrupting p16 and p19 but leaving p15 unaltered segregated with the melanoma-astrocytoma syndrome (MIM 155755). Our results suggest that multiple cancer susceptibility in these two families ensues from contiguous tumor suppressor gene deletion. Indeed, known phenotypes associated with germ-line p16 mutations and an apparent correlation between the deletion span and tumor spectrum in the two families suggest a new model of cancer pathogenesis based on the inactivation of contiguous tumor suppressor genes, an alternative to the established pleiotropic effects of single-gene disruption.
Assuntos
Proteínas de Ciclo Celular , Inibidor p16 de Quinase Dependente de Ciclina , Deleção de Genes , Melanoma/genética , Segunda Neoplasia Primária/genética , Síndromes Neoplásicas Hereditárias/genética , Neoplasias do Sistema Nervoso/genética , Proteínas Supressoras de Tumor , Adulto , Idoso , Alelos , Proteínas de Transporte/genética , Cromossomos Humanos Par 9 , Inibidor de Quinase Dependente de Ciclina p15 , Inibidor de Quinase Dependente de Ciclina p19 , Feminino , Genes p16 , Predisposição Genética para Doença , Humanos , Masculino , Repetições de Microssatélites , Linhagem , Análise de Sequência de DNARESUMO
Classical congenital muscular dystrophy with merosin deficiency is caused by mutations in the laminin alpha2 chain gene (LAMA2). Extended sequencing of the introns flanking the 64 LAMA2 exons was carried out and, based on these sequences, oligonucleotide primers were designed to amplify the coding region of each exon separately. By PCR-SSCP analysis, we identified eight new mutations in nine families originating from various countries. All induced a premature truncation of the protein, either in the short arm or in the globular C-terminal domain. A 2 bp deletion in exon 13, 2098delAG, was found in three French non-consanguineous families and a nonsense mutation of exon 20, Cys967stop, in two other non-consanguineous families originating from Italy. Determination of rare intragenic polymorphisms permitted us to show evidence of founder effects for these two mutations suggesting a remote degree of consanguinity between the families. Other, more frequent polymorphisms, G to A 1905 (exon 12), A to G 2848 (exon 19), A to G 5551 (exon 37), and G to A 6286 (exon 42), were used as intragenic markers for prenatal diagnosis. This study provides valuable methods for determining the molecular defects in LAMA2 causing merosin deficient congenital muscular dystrophy.
Assuntos
Efeito Fundador , Laminina/genética , Distrofias Musculares/genética , Diagnóstico Pré-Natal , Criança , Análise Mutacional de DNA , Primers do DNA , Éxons , Feminino , Haplótipos , Humanos , Íntrons , Masculino , Repetições de Microssatélites , Distrofias Musculares/congênito , Distrofias Musculares/diagnóstico , Mutação , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo Genético , Polimorfismo Conformacional de Fita Simples , Análise de Sequência de DNARESUMO
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most commonly recognized defect of mitochondrial beta-oxidation. It is potentially fatal, but shows a wide clinical spectrum. The aim of the present study was to investigate whether any correlation exists between MCAD genotype and disease phenotype. We determined the prevalence of the 14 known and seven previously unknown non-G985 mutations in 52 families with MCAD deficiency not caused by homozygosity for the prevalent G985 mutation. This showed that none of the non-G985 mutations are prevalent, and led to the identification of both disease-causing mutations in 14 families in whom both mutations had not previously been reported. We then evaluated the severity of the mutations identified in these 14 families. Using expression of mutant MCAD in Escherichia coli with or without co-overexpression of the molecular chaperonins GroESL we showed that five of the missense mutations affect the folding and/or stability of the protein, and that the residual enzyme activity of some of them could be modulated to a different extent depending on the amounts of available chaperonins. Thus, some of the missense mutations may result in relatively high levels of residual enzyme activity, whereas the mutations leading to premature stop codons will result in no residual enzyme activity. By correlating the observed types of mutations identified to the clinical/biochemical data in the 14 patients in whom we identified both disease-causing mutations, we show that a genotype/phenotype correlation in MCAD deficiency is not straightforward. Different mutations may contribute with different susceptibilities for disease precipitation, when the patient is subjected to metabolic stress, but other genetic and environmental factors may play an equally important role.
Assuntos
Acil-CoA Desidrogenases/deficiência , Acil-CoA Desidrogenases/genética , Heterozigoto , Mutação , Acil-CoA Desidrogenase , Acil-CoA Desidrogenases/metabolismo , Adolescente , Alelos , Western Blotting , Chaperonina 10/genética , Chaperonina 10/metabolismo , Chaperonina 60/genética , Chaperonina 60/metabolismo , Criança , Pré-Escolar , Ativação Enzimática , Escherichia coli/genética , Éxons , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Fenótipo , Reação em Cadeia da Polimerase , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Mapeamento por Restrição , Análise de Sequência de DNA , Deleção de Sequência , TemperaturaRESUMO
A five-generation family is here reported in which several members developed malignant melanoma, dysplastic naevi, astrocytoma in all grades, benign or malignant schwannoma, neurofibroma, or meningioma in a single instance. Significant cosegregation of skin and nervous tumours, preclusion of allelism to type 1 neurofibromatosis and phenotypic departure from known syndromes of hereditary proneness to cancer make one suggest an original familial predisposition to both malignant melanoma and central/peripheral nervous tumours.
Assuntos
Síndrome do Nevo Displásico/genética , Melanoma/genética , Neoplasias do Sistema Nervoso/genética , Neoplasias Cutâneas/genética , Adulto , Criança , Feminino , Predisposição Genética para Doença , Humanos , Cariotipagem , Masculino , Linhagem , Polimorfismo Genético , SíndromeRESUMO
BACKGROUND: Acute bilateral striatal necrosis complicating the course of a post-infectious encephalitis is rare. CASE REPORT: A previously healthy 5-year-old boy presented with an atypical pneumonia; he rapidly developed, encephalitis revealed by a generalized status epilepticus. After transient improvement, he became confused and mutic, with dystonic postures of his limbs. Painful stimulation resulted in prolonged facial grimacing and doleful cry. CT scan and MRI showed abnormal signals in the whole basal ganglia, typical of bilateral striatal necrosis. Serologic tests for Mycoplasma pneumoniae were positive. The child recovered almost completely. CONCLUSION: A parainfectious process is probably responsible for the transient bilateral striatal necrosis seen in this patient who had Mycoplasma pneumoniae infection several days before the onset of neurologic symptoms. MRI seemed more reliable than CT-scan for the diagnosis of this condition.
Assuntos
Gânglios da Base/patologia , Encefalite/complicações , Mycoplasma pneumoniae , Pneumonia por Mycoplasma/complicações , Doença Aguda , Pré-Escolar , Humanos , Masculino , NecroseRESUMO
A male fetus presenting with prenatal hydrocephalus is reported. The fetus died during labor. Pathological examination disclosed four accessory spleens without any abnormalities of the situs. Hydrocephalus was secondary to aqueductal stenosis. Histological features of the aqueduct were consistent with a developmental defect. The association of such malformations has already been reported and could be explained by common regulatory mechanisms which control the splenic and neural tube development.
Assuntos
Anormalidades Múltiplas/genética , Aqueduto do Mesencéfalo/anormalidades , Hidrocefalia/genética , Baço/anormalidades , Anormalidades Múltiplas/patologia , Adulto , Encéfalo/patologia , Aqueduto do Mesencéfalo/patologia , Doenças em Gêmeos/genética , Distocia/patologia , Evolução Fatal , Feminino , Humanos , Hidrocefalia/patologia , Recém-Nascido , Masculino , Gravidez , Baço/patologiaRESUMO
BACKGROUND: The acute form of Werdnig-Hoffman disease, infantile spinal muscular atrophy type I (SMA I), is characterized by severe paralytic hypotonia with neurogenic electromyographic (EMG) pattern and specific histologic features. PATIENTS: Four cases of very severe SMA I suffering from generalized muscle weakness at birth were included in the study. RESULTS: The neurogenic EMG pattern was observed at the first exam performed between D2 and D46. The muscular biopsy performed between D18 and D45 showed only a mild decrease of the muscle fiber size without grouping of fiber types. CONCLUSION: In those forms of SMA I with a neonatal clinical onset, the diagnosis is assessed by clinical and EMG findings while early muscular biopsy can be misleading. EMG is the relevant diagnostic test which confirms the anterior horn cell disease and can justify the DNA study.
Assuntos
Atrofias Musculares Espinais da Infância/diagnóstico , Biópsia , Eletromiografia , Feminino , Humanos , Recém-Nascido , Masculino , Músculo Esquelético/patologia , Atrofias Musculares Espinais da Infância/patologia , Atrofias Musculares Espinais da Infância/fisiopatologiaRESUMO
A selective deficiency of a specific laminin isovariant, merosin made of M, B1 and B2 chains, was found in a series of 17 patients affected with congenital muscular dystrophy (CMD). The merosin deficiency was complete in 15 cases, and almost complete in two cases. An overexpression of the laminin A chain was seen in these biopsies, while B1 and B2 chains were normally expressed. Comparison of the clinical data with a series of 18 "merosin-non deficient" cases showed that the "merosin-deficient" cases were forming a more homogenous group than the "non-deficient" one. Hypotonia, contractures, motor development delay were generally more severe in the "merosin-deficient" series of cases. Moreover, white matter alterations were seen in most cases explored by MRI or scan imaging. A genetic linkage with a 6q2 locus, corresponding to the M chain gene localization, was found in a panel of informative families from French and Turkish origin with "merosin deficient" CMD. "Merosin non-deficient" families did not map on this locus. So, the "merosin-deficient" CMD can be considered as a peculiar entity within the group of Congenital Muscular Dystrophies.
Assuntos
Laminina/deficiência , Músculos/patologia , Distrofias Musculares/congênito , Biópsia , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Recém-Nascido , Laminina/química , Laminina/genética , Masculino , Distrofias Musculares/genética , Distrofias Musculares/patologiaRESUMO
We report a case of acute bilateral striatal necrosis in an infant. CT and MRI findings are described.
Assuntos
Corpo Estriado/patologia , Dominância Cerebral/fisiologia , Imageamento por Ressonância Magnética , Tomografia Computadorizada por Raios X , Doença Aguda , Núcleo Caudado/patologia , Pré-Escolar , Seguimentos , Humanos , Masculino , Necrose , Putamen/patologia , Remissão EspontâneaRESUMO
Biochemical results concerning 64 patients suspected of mitochondrial myopathies are presented. Four clinical groups were studied including 21 encephalomyopathies, 42 ocular myopathies, 8 isolated myopathies and 3 cardiomyopathies. In 26 cases, the coexistence of a normal mitochondrial DNA and a mutated mitochondrial DNA (heteroplasmy) was found (19 simple deletions, 4 multiple deletions and 3 punctual mutations) and all cases presented with ocular disorders (excepted 2 cases with MERRF). Furthermore, 1 complex I deficiency (1 ocular myopathy), 1 complex IV deficiency (1 adult encephalomyopathy type Leigh), 3 complexes I + IV deficiencies (2 cases with a cardiomyopathy and 1 familial MELAS) and 2 pyruvate (1 adult from of Leigh's encephalomyopathy) dehydrogenase deficiencies (clinically and genetically different) did not show evidence of mitochondrial DNA mutation.
Assuntos
DNA Mitocondrial/genética , Mitocôndrias Musculares/fisiologia , Doenças Musculares/fisiopatologia , Western Blotting , Humanos , Doenças Musculares/genética , Polarografia , EspectrofotometriaRESUMO
A 6 week-old boy whose mother and sister present with hereditary hemorrhagic telangiectasia (HHT) presented suddenly with listlessness, hypotonia, and acute anemia. Cerebrospinal fluid was grossly hemorrhagic. Brain CT scan was compatible with subarachnoid and intracerebral hemorrhage. Operative investigation diagnosed a ruptured aneurysm of one branch of the right middle cerebral artery. A large clot was removed from the right frontal lobe. The ruptured artery was clipped. Further cerebral and abdominal angiographies did not show other aneurysms. The infant died 18 days later, with bilateral subdural hematoma. The family history and review of the literature suggest that the rupture of a cerebral aneurysm in this infant may have been an early manifestation of HHT. Brain CT scan study seems mandatory in every infant born to a mother with HHT.
Assuntos
Aneurisma Intracraniano/etiologia , Telangiectasia Hemorrágica Hereditária/complicações , Hemorragia Cerebral/etiologia , Humanos , Lactente , Masculino , Ruptura Espontânea/etiologia , Telangiectasia Hemorrágica Hereditária/genéticaRESUMO
A breast-fed boy, born to first-cousin parents, had been vomiting since birth; his general condition remained good until age 6 weeks when vomiting became more frequent, and his status suddenly worsened, with polypnea, shock, hypothermia, jaundice, presence of blood in urine, gastric juice, stool, and bleeding tendency during veno-punctures. There was an huge hepatomegaly and a splenomegaly. Hypoglycaemia, metabolic acidosis, severe blood coagulation disturbances, elevated liver enzymes, hypoalbuminemia, pointed to an acute liver failure. He was resuscitated with current supportive measures, and was given a wide spectrum antibiotherapy. Because serologic tests for syphilis were positive in the child and his mother, including the presence of specific IgM the infant was then given Penicillin G therapy only, which resulted in a complete recovery. One month later, a needle liver biopsy showed residual signs of hepatitis. Other possible infectious or metabolic causes of acute liver failure occurring early in life had been excluded.
Assuntos
Hepatopatias/congênito , Sífilis Congênita/complicações , Doença Aguda , Amicacina/uso terapêutico , Transtornos da Coagulação Sanguínea/etiologia , Cefotaxima/uso terapêutico , Consanguinidade , Feminino , Hepatomegalia , Humanos , Recém-Nascido , Hepatopatias/terapia , Masculino , Penicilina G/uso terapêutico , Gravidez , Sorodiagnóstico da Sífilis , Sífilis Congênita/terapia , Vômito/etiologiaRESUMO
Evidence that inherited disorders of mitochondrial fatty acid beta-oxidation can cause sudden infant death syndrome (SIDS) comes from case reports, systematic autopsy studies, and family studies. Family studies are important when no pediatric autopsy has been done, which is still frequent. After reviewing the fatty acid beta-oxidation, and its pathophysiology, we present the results of our metabolic study on 189 siblings of SIDS victims, and on 84 'near-miss' infants. We have found evidence for a disorder of fat oxidation in 28 (15%) infants in the first group, and in 14 (17%) infants in the second group. Diagnosing and treating such disorders early in infancy may prevent some cases of SIDS to occur.
Assuntos
Ácidos Graxos/metabolismo , Erros Inatos do Metabolismo Lipídico/complicações , Morte Súbita do Lactente/etiologia , Adipatos/urina , Adolescente , Carnitina/sangue , Carnitina/deficiência , Carnitina/urina , Criança , Pré-Escolar , Ácidos Graxos Dessaturases/deficiência , Ácidos Graxos/sangue , Humanos , Lactente , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/tratamento farmacológico , Erros Inatos do Metabolismo Lipídico/fisiopatologia , Malonatos/urina , Oxirredução , Morte Súbita do Lactente/prevenção & controleRESUMO
Forty-two pregnancies in 39 myasthenic mothers were studied between 1978 and 1987. In 4 cases myasthenia gravis began during pregnancy and for 20 patients the clinical condition exacerbated in 15 cases, usually during the first 3 months, or during the postpartum. Except for 1 case, clinical exacerbation was controlled by anticholinesterase drug adjustment. Obstetrical problems were uncommon: abortion in 1 case and premature delivery in 4 cases. In 2 babies with severe fetal involvement polyhydramnios was present. Twenty-one babies had neonatal myasthenia gravis (NMG). In 17 cases, transient symptoms were present at delivery or shortly afterwards and full recovery occurred from a few days to 4 months. In 4 babies the clinical presentation was atypical: 1 showed a long evolution (15 months) and residual facial bilateral weakness, and three others presented fetal involvement (arthrogryposis). In these latter cases, presentation was severe with polyhydramnios, respiratory failure and long standing evolution in 2 cases (4 months and 1 year). Antiacetylcholine receptor antibodies (anti-AChR Ab) were found in all myasthenic babies and in 19 out of 20 asymptomatic babies. Maternal antibody titers were usually slightly higher than umbilical cord titers. There was a good correlation between maternal titer and onset or severity of disorder in baby. Among the 15 high titer mothers (greater than 60 nM), 13 had a myasthenic baby, 6 of them with serious disease. Conversely all low titer mothers (less than 10 nM) had a symptom-free baby. Therefore, anti-AChR Ab titration in the mother is predictive for NMG onset. Mother's myasthenia gravis severity and treatment were not correlated to the clinical condition of the newborns.