RESUMO
We report the outcomes of an adult and pediatric split liver transplant from an adult male donor who died due to an unrecognized UCD, OTC deficiency. Recognizing inborn errors of metabolism can be challenging, especially in adult centers where such disorders are rarely encountered. Shortage of donors for liver transplantation has led to procedures to maximize donor utilization, such as split and live donor grafts. The cause of death should be ascertained before accepting a cadaveric donor organ.
Assuntos
Transplante de Fígado , Doença da Deficiência de Ornitina Carbomoiltransferase/diagnóstico , Complicações Pós-Operatórias/diagnóstico , Adulto , Criança , Evolução Fatal , Feminino , Humanos , Transplante de Fígado/métodos , Masculino , Doença da Deficiência de Ornitina Carbomoiltransferase/etiologiaRESUMO
Individuals with two or more copies of the MECP2 gene, located at Xq28, share clinical features and a distinct facial phenotype known as MECP2 Duplication syndrome. We have examined perinatal characteristics, early childhood development and medical co-morbidities in this disorder. The International Rett Syndrome Phenotype Database (InterRett), which collects information from caregivers and clinicians on individuals with Rett syndrome and MECP2 associated disorders, was used as the data source. Data were available on 56 cases (49 males and 7 females) with MECP2 Duplication syndrome. Median age at ascertainment was 7.9 years (range: 1.2-37.6 years) and at diagnosis 3.0 years (range: 3 weeks-37 years). Less than a third (29%) learned to walk. Speech deterioration was reported in 34% and only 20% used word approximations or better at ascertainment. Over half (55%) had been hospitalised for respiratory infections in the first 2 years of life. Just under half (44%) had seizures, occurring daily in nearly half of this group. The majority (89%) had gastrointestinal problems and a third had a gastrostomy. Following the recent demonstration of phenotype reversal in a mouse model of MECP2 Duplication, a clear understanding of the natural history is crucial to the design and implementation of future therapeutic strategies.
Assuntos
Deficiência Intelectual/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Deficiência Intelectual Ligada ao Cromossomo X/fisiopatologia , Proteína 2 de Ligação a Metil-CpG/genética , Adolescente , Adulto , Animais , Criança , Pré-Escolar , Bases de Dados Genéticas , Feminino , Trato Gastrointestinal/fisiopatologia , Trato Gastrointestinal/cirurgia , Humanos , Lactente , Deficiência Intelectual/fisiopatologia , Estimativa de Kaplan-Meier , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/epidemiologia , Deficiência Intelectual Ligada ao Cromossomo X/terapia , Camundongos , Fenótipo , Síndrome de Rett/epidemiologia , Síndrome de Rett/genética , Síndrome de Rett/fisiopatologia , Adulto JovemRESUMO
OTC deficiency, a partially dominant X-linked trait, is the most frequent inborn error of the urea cycle. We describe a female patient with a contiguous gene deletion syndrome encompassing the OTC, DMD, RPGR, CYBB and XK genes, amongst others, only manifesting features of OTC deficiency. Molecular characterization was ascertained by MLPA and confirmed by CGH microarray, which revealed an 8.7 Mb deletion of the X-chromosome. Complete de novo deletion of the OTC gene led to a severe clinical phenotype in the proband. The application of high resolution molecular genetic techniques such as MLPA and array CGH, in mutation negative OTC cases allows the identification of chromosomal rearrangements, such as large deletions and provides information for accurate genetic counseling and prenatal diagnosis.
Assuntos
Deleção Cromossômica , Deleção de Genes , Doença da Deficiência de Ornitina Carbomoiltransferase/genética , Ornitina Carbamoiltransferase/genética , Mapeamento Cromossômico , Cromossomos Humanos X/genética , Hibridização Genômica Comparativa , Saúde da Família , Feminino , Genes Ligados ao Cromossomo X , Humanos , Lactente , Técnicas de Amplificação de Ácido Nucleico , Doença da Deficiência de Ornitina Carbomoiltransferase/diagnóstico , SíndromeRESUMO
Glutaric aciduria type I (GA I), a cerebral organic acidaemia with the potential for severe neurological consequences, can now be detected by tandem mass spectrometry newborn screening. Early detection with implementation of careful management strategies appears to lessen the likelihood of neurological damage. We assessed the outcome in all 10 GA I patients detected in New South Wales during the last decade. Three patients were detected clinically and 7 by newborn screening. Diagnosis was confirmed by detection of significantly elevated urinary 3-hydroxybutyrate and glutarate in urine, isolated elevation of glutarylcarnitine in plasma, typical clinical and MRI findings in several, and mutation analysis or enzyme analysis on cultured skin fibroblasts in 4 cases. The birth frequency was 1:90,000. Following diagnosis, treatment was initiated in all children with oral carnitine (100 mg/kg per day) and a low-protein diet supplemented with a lysine-free, low-tryptophan amino acid formula. Disability was assessed in fields of motor, cognitive and speech development and scored according to Kyllerman. Clinically diagnosed patients were all symptomatic, with severity scores (out of 9) of 3, 5 and 9. Six of seven patients detected by newborn screening are asymptomatic, 4 being aged 2-6 years. One patient had a severe decompensation at 7 months, despite full management advice and treatment, and later died. Our data support previous findings that early diagnosis reduces neurological complications, but show that even with early diagnosis and careful management severe complications may ensue in some.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Glutaril-CoA Desidrogenase/deficiência , Triagem Neonatal , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Estudos de Coortes , Progressão da Doença , Feminino , Seguimentos , Humanos , Recém-Nascido , Masculino , Triagem Neonatal/métodos , Prognóstico , País de GalesRESUMO
The early progressive form of the X-linked disorder, Hunter syndrome or mucopolysaccharidosis type II (MPS II) (OMIM #309900), is characterized by cognitive decline, and pulmonary and cardiac complications that often cause death before 20 years of age. Deficiency of the lysosomal enzyme, iduronate-2-sulfatase (EC 3.1.6.13) results in deposition of the glycosaminoglycans, dermatan, and heparan sulfate in various tissues. In recent years, enzyme replacement therapy (ERT) has become the mainstay of treatment, but is expensive and ineffective in arresting cognitive decline. Hematopoietic stem cell transplantation (HSCT) also provides enzyme replacement, and may be effective in stabilizing neurocognitive function if initiated early, though data are limited. We present a case series of four patients who demonstrated neurocognitive stabilization with early HSCT. HSCT is a potentially underutilized treatment strategy for select groups of MPS II patients.
RESUMO
This paper describes the development of a video-based evaluation tool for use in Rett syndrome (RTT). Components include a parent-report checklist, and video filming and coding protocols that contain items on eating, drinking, communication, hand function and movements, personal care and mobility. Ninety-seven of the 169 families who initially agreed to participate returned a videotape within 8 months of the first request. Subjects whose videos were returned had a similar age profile to those who did not provide a video but were more likely to have classical than atypical RTT. Evidence of the content and social validity and inter-rater reliability on 11 videos is provided. Video may provide detailed, objective assessment of function and behaviour in RTT.
Assuntos
Síndrome de Rett/diagnóstico , Gravação de Videoteipe , Adolescente , Adulto , Criança , Diagnóstico Diferencial , Estudos de Viabilidade , Feminino , Humanos , Masculino , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/etiologia , Fenótipo , Síndrome de Rett/complicaçõesRESUMO
Rett syndrome (RS) is a severe neurodevelopmental disorder that contributes significantly to severe intellectual disability in females worldwide. It is caused by mutations in MECP2 in the majority of cases, but a proportion of atypical cases may result from mutations in CDKL5, particularly the early onset seizure variant. The relationship between MECP2 and CDKL5, and whether they cause RS through the same or different mechanisms is unknown, but is worthy of investigation. Mutations in MECP2 appear to give a growth disadvantage to both neuronal and lymphoblast cells, often resulting in skewing of X inactivation that may contribute to the large degree of phenotypic variation. MeCP2 was originally thought to be a global transcriptional repressor, but recent evidence suggests that it may have a role in regulating neuronal activity dependent expression of specific genes such as Hairy2a in Xenopus and Bdnf in mouse and rat.
Assuntos
Proteína 2 de Ligação a Metil-CpG/genética , Proteínas Serina-Treonina Quinases/genética , Síndrome de Rett/genética , Animais , Modelos Animais de Doenças , Humanos , Mutação , Neurônios/fisiologiaRESUMO
Hand radiographs of 100 girls representing 73% of the known Australian population of girls with Rett syndrome, age 20 years or less, were available for this study. Control radiographs were matched for age, sex, and laterality. Bone age was assessed against standard radiographs in Greulich and Pyle [1959: Radiographic Atlas of Skeletal Development of the Hands and Wrist, 2nd ed.]. A metacarpophalangeal pattern (MCPP) profile comparing the relative lengths of the hand bones with mean population norms by age was produced by converting the length of each of the 19 metacarpal and phalangeal bones into a Z score. In girls less than 15 years old, bone age was more advanced in Rett syndrome than in age-matched control girls (left hand P = 0.03, right hand 0.004), but was most advanced in the younger group and normalized with age. In Rett syndrome, the mean Z score for the 19 metacarpal and phalangeal bones was 1.0 in children under 5 years, -0.27 in those aged 5-11 years, and -1.7 in those aged 12 years and over. This variation between age groups was much greater than in the controls. The dips in the MCPP profile occurred at MC2 and D1, and the peaks at M5, P5, and M4. An MCPP profile may provide an additional aid to diagnosis in cases of Rett syndrome where all the criteria are not met, but in children under age 5 years, advanced bone age may be more helpful as a marker.
Assuntos
Determinação da Idade pelo Esqueleto , Ossos da Extremidade Superior/diagnóstico por imagem , Mãos/diagnóstico por imagem , Síndrome de Rett/diagnóstico por imagem , Adolescente , Adulto , Ossos da Extremidade Superior/anormalidades , Criança , Pré-Escolar , Feminino , Humanos , Análise por Pareamento , Metacarpo/anormalidades , Metacarpo/diagnóstico por imagemRESUMO
Rett syndrome and Angelman syndrome are neurodevelopmental disorders characterized by severe intellectual disability, microcephaly, speech disturbance, movement disorders with gait and/or truncal ataxia, and occasionally a similar facial appearance. Both conditions can be difficult to diagnose in girls early in their clinical course and can be difficult to distinguish from each other. Genomic imprinting is a known association in Angelman syndrome and previously has been suggested in Rett syndrome. Our aim was to evaluate the methylation status in a cohort of classical patients with Rett syndrome, using a methylation system for chromosome 15q11-13. Methylation analysis of chromosome 15 has not been previously reported in Rett syndrome. Furthermore, we document the clinical features of 31 girls with classical Rett syndrome and confirm the phenotypic similarities between Rett syndrome and Angelman syndrome. The methylation studies in these girls with Rett syndrome were normal. This excludes an imprinting error of the Angelman syndrome critical region on chromosome 15 (15q11-13) as an association with Rett syndrome, and indicates that methylation studies may be useful in distinguishing Rett syndrome from Angelman syndrome in young patients with an overlapping clinical phenotype. A normal methylation pattern, however, does not exclude the diagnosis of Angelman syndrome and clear distinction between the two syndromes will evolve over time.
Assuntos
Síndrome de Angelman/genética , Cromossomos Humanos Par 15/genética , Metilação de DNA , Síndrome de Rett/genética , Adolescente , Adulto , Síndrome de Angelman/diagnóstico , Criança , Pré-Escolar , Aberrações Cromossômicas , Transtornos Cromossômicos , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Fenótipo , Síndrome de Rett/diagnósticoRESUMO
Rett syndrome is a severe neurodevelopmental disorder of unknown etiology, occurring almost exclusively in female patients. The etiology and functional significance of plasma carnitine deficiency seen in some patients with Rett syndrome is unknown. To investigate whether L-carnitine might be of benefit in Rett syndrome, a randomized, placebo-controlled, double-blind crossover trial of L-carnitine has been completed in 35 subjects. Eight-week treatment phases were completed for both a placebo and L-carnitine. Outcome was measured by parents/caregivers and at medical follow-up using three established tools: the Rett Syndrome Motor Behavioral Assessment, the Hand Apraxia Scale, and the Patient Well-Being Index. Analysis comparing change between baseline and week 8 of treatment for L-carnitine and the placebo showed that both parents/caregivers and medical follow-up detected improvements in the subjects' well-being. In addition, medical review showed an improvement on the Hand Apraxia Scale for a higher proportion of girls on L-carnitine. Identification of predictors of clinical improvement has been limited by the power of the study. These findings suggest that L-carnitine is of benefit in some patients with Rett syndrome. While L-carnitine did not lead to major functional changes in ability, the type of changes reported could still have a substantial impact on the girls and their families. Information is still needed, however, to determine if only subgroups of girls with the disorder are responsive to L-carnitine and the appropriate duration of therapy.
Assuntos
Carnitina/uso terapêutico , Síndrome de Rett/tratamento farmacológico , Adolescente , Adulto , Carnitina/sangue , Criança , Pré-Escolar , Constipação Intestinal/tratamento farmacológico , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Testes Neuropsicológicos , Pais , Placebos , Qualidade de Vida , Inquéritos e QuestionáriosRESUMO
The neurologic disorder Rett syndrome was originally described exclusively in girls. We present two boys with clinical features of Rett syndrome. Other than head circumference deceleration, no longer considered mandatory, patient 1 meets all of the criteria. Using fluorescent in situ hybridization analysis, 97.6% of cells were found to be karyotypically normal (46,XY). No mutation was detected on screening of the coding region of the MECP2 gene. The second patient also has classic features of Rett syndrome. However, cytogenetic analysis of peripheral blood revealed a karyotype 47,XXY[23]/46,XY[7] confirming mosaicism for Klinefelter's syndrome. A T158M missense mutation in the methylcytosine-binding domain of the MECP2 gene was identified. A diagnostic bias against the clinical identification of Rett syndrome in boys may exist. This presentation of the male phenotype could be more common than it would appear, although boys with MECP2 mutations might also manifest in other ways. Rett syndrome remains a clinical diagnosis that should not be dismissed in boys, and thorough evaluation including karyotype and mutation testing is warranted.
Assuntos
Proteínas Cromossômicas não Histona , Proteínas Repressoras , Síndrome de Rett/epidemiologia , Encéfalo/patologia , Criança , Pré-Escolar , Proteínas de Ligação a DNA/genética , Eletroencefalografia , Humanos , Incidência , Imageamento por Ressonância Magnética , Masculino , Proteína 2 de Ligação a Metil-CpG , Mutação Puntual/genética , Reação em Cadeia da Polimerase , Síndrome de Rett/diagnóstico , Síndrome de Rett/genéticaRESUMO
The sleep patterns of a cohort of 83 Rett syndrome females were characterized using a sleep diary for 7 consecutive days and nights and compared with normative sleep data. The mean total sleep time of the cohort was 10.75 h, daytime sleep 0.77 h, sleep efficiency 89.7%, and sleep latency 0.52 h. When subjects were categorized according to age and Rett syndrome classification, there was no significant difference in their sleep characteristics. There was a significant difference in the percentage predicted total sleep time (P<0.001) and Z scores for total sleep time (P<0.001), when subjects were categorized according to age and compared with normal children. The Rett syndrome subjects in this study did not show the age related decrease in total and daytime sleep time seen in normal children. The immature sleep pattern demonstrated in this cohort, may be a consequence of arrested brain development.
Assuntos
Síndrome de Rett/fisiopatologia , Transtornos do Sono-Vigília/fisiopatologia , Sono/fisiologia , Adolescente , Fatores Etários , Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Epilepsia/etiologia , Epilepsia/fisiopatologia , Feminino , Humanos , Transtornos dos Movimentos/etiologia , Transtornos dos Movimentos/fisiopatologia , Transtornos do Sono-Vigília/etiologiaRESUMO
Treatment strategies in Rett syndrome so far have been essentially symptomatic and supportive. In order to establish the medium-term effects of L-carnitine, an open label trial was performed in a cohort of 21 Rett syndrome females, with a control group of 62 Rett syndrome females of a similar age, for a 6-month period. Compared with the Rett syndrome controls, treatment with L-carnitine led to significant improvements in sleep efficiency (P=0.027), especially in the subjects with a baseline sleep efficiency less than 90%, energy level (P<0.005) and communication skills (P=0.004). There was no significant difference in the subject's level of physical activity, hand function or in the quality of life of the subject's parents. In addition, before and after comparisons of the treatment group showed improvements in expressive speech (P=0.011). Treatment with L-carnitine seems to be of significant benefit in a subgroup of girls with Rett syndrome. In these girls, small but discernible improvements may be of considerable importance to their parents and carers.
Assuntos
Carnitina/uso terapêutico , Recuperação de Função Fisiológica/efeitos dos fármacos , Síndrome de Rett/tratamento farmacológico , Adolescente , Adulto , Apraxias/tratamento farmacológico , Apraxias/etiologia , Apraxias/fisiopatologia , Carnitina/sangue , Criança , Feminino , Inquéritos Epidemiológicos , Humanos , Recuperação de Função Fisiológica/fisiologia , Transtornos Respiratórios/tratamento farmacológico , Transtornos Respiratórios/etiologia , Transtornos Respiratórios/fisiopatologia , Síndrome de Rett/fisiopatologia , Transtornos do Sono-Vigília/tratamento farmacológico , Transtornos do Sono-Vigília/etiologia , Transtornos do Sono-Vigília/fisiopatologia , Distúrbios da Fala/tratamento farmacológico , Distúrbios da Fala/etiologia , Distúrbios da Fala/fisiopatologia , Inquéritos e Questionários , Resultado do TratamentoRESUMO
An international group recommends that papers relating phenotypes to genotypes involving mutations in the X chromosome gene MECP2 should provide a minimum data set reporting the range of disturbances frequently encountered in Rett Syndrome. A simple scoring system is suggested which will facilitate comparison among the various clinical profiles. Features are described which should prompt screening for MECP2 mutations.
Assuntos
Proteínas Cromossômicas não Histona , Proteínas de Ligação a DNA/genética , Mecanismo Genético de Compensação de Dose , Mutação/genética , Proteínas Repressoras , Síndrome de Rett/genética , Feminino , Humanos , Masculino , Proteína 2 de Ligação a Metil-CpG , Fenótipo , Síndrome de Rett/diagnósticoRESUMO
PURPOSE: Rett syndrome is a neurodevelopmental disorder that occurs almost exclusively in females. In recent years there has been increased knowledge concerning the multidisciplinary management of individuals with Rett syndrome. The aim of this paper is to provide an update of the clinical phenotype, natural history and current genetic understanding of the disorder. RESULTS/CONCLUSION: Rett syndrome is thought to be the second most common cause of severe mental retardation in females after Down syndrome. it now appears that females with RS present with a much broader phenotype than originally described. Recently, mutations in the MECP2 gene encoding X-linked methyl-CpG-binding-protein 2 have been identified in some females with Rett syndrome.
Assuntos
Proteínas Cromossômicas não Histona , Proteínas Repressoras , Síndrome de Rett/diagnóstico , Síndrome de Rett/genética , Idade de Início , Proteínas de Ligação a DNA/genética , Diagnóstico Diferencial , Progressão da Doença , Ligação Genética/genética , Humanos , Proteína 2 de Ligação a Metil-CpG , Biologia Molecular , Mutação/genética , Neuroquímica , Equipe de Assistência ao Paciente , Fenótipo , Síndrome de Rett/classificação , Síndrome de Rett/epidemiologia , Distribuição por Sexo , Cromossomo X/genéticaRESUMO
Rett syndrome (RTT) is a severe neurodevelopmental disorder. Apparently normal at birth, girls with RTT undergo developmental regression and acquire a neurological and behavioural phenotype that has been used to define clinical diagnostic criteria for the disorder. Recently mutations in the methyl-CpG binding protein 2 gene (MECP2), located on Xq28 have been identified in females with RTT. We report a girl whose clinical course was complicated by congenital abnormalities of the respiratory tract and gastrointestinal system. In addition neurological abnormalities were evident in the newborn period. By the age of 3 years she had developed a phenotype very suggestive of RTT, but had not demonstrated deceleration of head growth and the development of expressive language was prevented by the presence of the tracheostomy. The clinical impression of RTT was confirmed by the recent finding of a mutation in the MECP2 gene. This case report highlights the importance of considering the clinical diagnosis of RTT even in the presence of other conditions and emphasises that girls with RTT may not be normal from birth.
Assuntos
Anormalidades Múltiplas/genética , Proteínas Cromossômicas não Histona , Proteínas de Ligação a DNA/genética , Proteínas Repressoras , Síndrome de Rett/genética , Cromossomo X , Anormalidades Múltiplas/diagnóstico , Criança , Feminino , Testes Genéticos , Humanos , Proteína 2 de Ligação a Metil-CpG , Síndrome de Rett/complicações , Síndrome de Rett/diagnósticoRESUMO
Bezoar formation is a rare but well-recognised complication of previous gastric surgery and persimmon ingestion. We present a case of bezoar formation in the duodenum of a child with a grossly dilated, dysmotile duodenum following surgery for jejunal atresia. The presenting symptoms were vomiting, diarrhoea, and growth failure, with evidence of malabsorption secondary to bacterial overgrowth in the bezoar. Plication of the duodenum to reduce its size and improve its motility may reduce the likelihood of future bezoar formation.
RESUMO
Mucopolysaccharidosis type VI, Maroteaux-Lamy syndrome is a lysosomal storage disorder with progressive, multisystem involvement caused by deficiency of the lysosomal enzyme N-acetylgalactosamine-4-sulfatase leading to accumulation of the glycosaminoglycan, keratan sulfate. Enzyme replacement therapy (ERT) has been shown to clinically benefit affected individuals. A combined treatment regime of ERT and hemopoietic stem cell transplantation (HSCT) has led to reduced morbidity and mortality in patients with MPS I. We have demonstrated that a treatment regime of ERT combined with HSCT in a 3-year-old girl with MPS VI provided similar benefit. This treatment regimen should be considered in the management of selected patients with MPS VI. Neither HSCT nor ERT can correct or completely prevent progression of the musculoskeletal complications. Long-term follow-up and regular assessments for these complications is necessary.
Assuntos
Síndrome de Cockayne/líquido cefalorraquidiano , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Adolescente , Síndrome de Cockayne/diagnóstico , Síndrome de Cockayne/metabolismo , Diagnóstico Diferencial , Humanos , Imageamento por Ressonância Magnética , Masculino , Fenótipo , Tomografia Computadorizada por Raios XRESUMO
MECP2 mutations mainly occur in females with Rett syndrome. Mutations have been described in 11 boys with progressive encephalopathy: seven of nine with affected sisters and two de novo. The authors report four de novo occurrences: three pathogenic and one potentially pathogenic. Common features include failure to thrive, respiratory insufficiency, microcephaly, and abnormal motor control. MECP2 mutations should be assessed in boys with progressive encephalopathy and one or more of respiratory insufficiency, abnormal movements or tone, and intractable seizures.