RESUMO
The varying clinical manifestations of Lyme borreliosis, transmitted by Ixodes ricinus and caused by Borrelia burgdorferi, frequently pose diagnostic problems. Diagnostic strategies vary between early and late disease manifestations and usually include serological methods. Erythema migrans is pathognomonic and does not require any further laboratory investigations. In contrast, the diagnosis of neuroborreliosis requires the assessment of serum and cerebrospinal fluid. Lyme arthritis is diagnosed in the presence of newly recognized arthritis and high-titer serum IgG antibodies against B. burgdorferi. The committee concludes the following recommendations: Borrelial serology should only be ordered in case of well-founded clinical suspicion for Lyme borreliosis, i.e., manifestations compatible with the diagnosis. Tests for borrelial genomic sequences in ticks or lymphocyte proliferation assays should not be ordered. When results of such tests or of serological investigations that were not indicated are available, they should not influence therapeutic decisions. Laboratories should be cautious when interpreting results of serological tests and abstain from giving therapeutic recommendations and from proposing retesting after some time without intimate knowledge of patient's history and disease manifestations.
Assuntos
Borrelia burgdorferi/isolamento & purificação , Doença de Lyme/diagnóstico , Adolescente , Animais , Antígenos de Bactérias/imunologia , Artrite Infecciosa/diagnóstico , Borrelia burgdorferi/imunologia , Criança , Eritema Migrans Crônico/diagnóstico , Humanos , Ixodes/microbiologia , Doença de Lyme/sangue , Doença de Lyme/líquido cefalorraquidiano , Neuroborreliose de Lyme/diagnósticoRESUMO
BACKGROUND: Heterozygous gain-of-function variants in SAMD9L are associated with ataxia-pancytopenia syndrome (ATXPC) and monosomy 7 myelodysplasia and leukemia syndrome-1 (M7MLS1). Association with peripheral neuropathy has rarely been described. METHODS: Whole-exome sequencing (WES) from DNA extracted from peripheral blood was performed in a 10-year-old female presenting with demyelinating neuropathy, her similarly affected mother and the unaffected maternal grandparents. In addition to evaluation of single nucleotide variants, thorough work-up of copy number and exome-wide variant allele frequency data was performed. RESULTS: Combined analysis of the mother's and daughter's duo-exome data and analysis of the mother's and her parents' trio-exome data initially failed to detect a disease-associated variant. More detailed analysis revealed a copy number neutral loss of heterozygosity of 7q in the mother and led to reanalysis of the exome data for respective sequence variants. Here, a previously reported likely pathogenic variant in the SAMD9L gene on chromosome 7q (NM_152703.5:c.2956C>T; p.(Arg986Cys)) was identified that was not detected with standard filter settings because of a low percentage in blood cells (13%). The variant also showed up in the daughter at 32%, a proportion well below the expected 50%, which in each case can be explained by clonal selection processes in the blood due to this SAMD9L variant. CONCLUSION: The report highlights the specific pitfalls of molecular genetic analysis of SAMD9L and, furthermore, shows that gain-of-function variants in this gene can lead to a clinical picture associated with the leading symptom of peripheral neuropathy. Due to clonal hematopoietic selection, displacement of the mutant allele occurred, making diagnosis difficult.
Assuntos
Síndromes Mielodisplásicas , Doenças do Sistema Nervoso Periférico , Criança , Feminino , Humanos , Alelos , Síndromes Mielodisplásicas/genética , Doenças do Sistema Nervoso Periférico/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
The aim of this study was to determine the body composition and resting metabolic rate (RMR) of girls with Rett syndrome (RS) (n=15) and to compare them with an equally handicapped group of girls with developmental disabilities (DD) (n=13). Body composition was measured by bioelectrical impedance analysis and RMR - the amount of energy expended while at rest - by indirect calorimetry. Weight, height, body mass index (BMI), BMI percentiles and food intake were all measured and calculated by standardized procedures. Feeding time, ambulatory status and ability to self-feed were also assessed. Due to the sampling, there were no significant differences in age, height, weight, BMI, BMI percentiles and ambulatory status. Significant differences between groups were found for lower percentage lean body mass (LBM) (64.2±14.6 vs. 84.4±24.6) and higher absolute and relative fat mass (FM) in RS. RMR values adjusted for LBM were significantly higher in the group of girls with RS (approximately 160 kcal/day), indicating that higher energy expenditure is a component of increased risk of severely low body weight.
Assuntos
Metabolismo Basal , Transtornos da Nutrição Infantil/metabolismo , Deficiências do Desenvolvimento/metabolismo , Síndrome de Rett/metabolismo , Composição Corporal , Índice de Massa Corporal , Peso Corporal , Calorimetria Indireta , Criança , Pré-Escolar , Ingestão de Alimentos , Ingestão de Energia , Metabolismo Energético , Feminino , HumanosRESUMO
Niemann-Pick disease type C (NP-C) is a devastating genetic disorder characterised by progressive neurological deterioration. However, data on the progression of neurological manifestations, particularly across different patient age-of-disease onsets, are limited. This is an observational retrospective cohort study designed to assess the progression of neurological disease in patients with NP-C. Physicians were asked to retrospectively complete a web-based questionnaire for each patient, at diagnosis and at up to three follow-up visits. An NP-C-specific disability scale was used to measure disease progression. The scale comprised four key parameters of neurological disease progression; ambulation, manipulation, language and swallowing. Disease progression was evaluated based on the annual rate of change in each parameter and the composite score using a linear mixed model analysis, and by classifying patients according to the number of worsened parameters during the observation period. Data were collected from 57 patients. The rate of deterioration was similar across the four individual parameters of the disability scale. The mean (95% CI) annual disease progression was +0.12 (0.09, 0.15) units. Among patients with a time interval of at least 1 year between diagnosis and last visit (n=49), 42 (86%) patients had progressed disease and 7 (14%) patients had stable disease. Disease progression was consistently more rapid in patients diagnosed in early childhood, compared with those diagnosed in late childhood, or with juvenile or adult presentation. In conclusion, our findings showed a progression in all four parameters of the disability scale, representing a continuous, unbroken progression of neurological manifestations.
Assuntos
Doença de Niemann-Pick Tipo C/diagnóstico , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Avaliação da Deficiência , Progressão da Doença , Feminino , Humanos , Masculino , Estudos RetrospectivosRESUMO
Miglustat has been shown to stabilize disease progression in children, juveniles and adults with Niemann-Pick disease type C (NP-C), a rare genetic disorder characterized by progressive neurological deterioration. We report findings from a retrospective observational cohort study assessing the effects of miglustat on neurological disease progression in patients treated in the clinical practice setting. Data from all NP-C patients prescribed miglustat at 25 expert centers were evaluated using a disease disability scale. The scale analyzed four key parameters of neurological disease progression in NP-C (ambulation, manipulation, language, swallowing). Mean individual parameter scores and a composite score were calculated at baseline (time of diagnosis) and up to 4 follow-up visits. Overall, 66 patients were included (mean [SD] age at diagnosis, 9.7 [7.6] years, and at treatment start, 12.8 [9.5] years). The median (range) miglustat exposure was 1.46 (0.05-4.51) years. Mean annual progression was +0.11 score units/year from diagnosis to treatment start, indicating disease progression prior to therapy, and decreasing to -0.01 score units/year from treatment start to last clinic visit, indicating stabilization. Stabilization of neurological disease on miglustat was observed in all age groups, but the magnitude of the effect was greater in patients diagnosed in late childhood and in juveniles and adults. Stabilization of neurological disease was also observed in a subset of 19 patients with extended pre-treatment information. Overall, these data support previous clinical trial findings indicating clinically relevant beneficial effects of miglustat on neurological disease progression in patients with NP-C.
Assuntos
1-Desoxinojirimicina/análogos & derivados , Inibidores Enzimáticos/uso terapêutico , Doença de Niemann-Pick Tipo C/tratamento farmacológico , 1-Desoxinojirimicina/administração & dosagem , 1-Desoxinojirimicina/uso terapêutico , Adolescente , Criança , Estudos de Coortes , Inibidores Enzimáticos/administração & dosagem , Feminino , Humanos , Masculino , Doença de Niemann-Pick Tipo C/patologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Acute disseminated encephalomyelitis (ADEM) is an acute, inflammatory-demyelinating disorder of the CNS with a favourable outcome in the majority of cases. OBJECTIVE: The aim of this study was to examine the long-term outcome of children with an initially severe form of ADEM. METHODS: Children with ADEM according to the criteria of the International Pediatric MS Study Group (IPMSSG) referred to the rehabilitation centre Vogtareuth were included. Neurological impairment was evaluated with a standardized telephone-based interview assessing the EDSS score. Neuropsychological outcome was assessed with review of the medical records and a standardized parental questionnaire (KOPKIJ). RESULTS: Twelve children (1 year 9 months to 13 years of age) were included. All children had focal-neurological signs and changes in mental status at presentation and an MRI of the brain showing a range of white and gray matter lesions. 11/12 patients with a mean follow-up of 6.2 years (2-13.6 years) had a monophasic course of the disease. One child had a multiphasic ADEM. Two children had an EDSS score of 0, three an EDSS of 2, five an EDSS between 3 and 5 and two children had an EDSS score of 6 and 9. Results of a standardized parental questionnaire (KOPKIJ) revealed that 7 children had deficits in the categories alertness, memory, school performance, visual-spatial skills and/or impulse control. CONCLUSION: The results of our study indicate that children with an initially severe manifestation of ADEM continue to have in the majority of cases neurological and neuropsychological handicaps.
Assuntos
Transtornos Cognitivos/etiologia , Encefalomielite Aguda Disseminada/complicações , Encefalomielite Aguda Disseminada/diagnóstico , Adolescente , Encéfalo/patologia , Criança , Pré-Escolar , Transtornos Cognitivos/diagnóstico , Estudos de Coortes , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética/métodos , Masculino , Exame Neurológico/métodos , Testes Neuropsicológicos , Medula Espinal/patologiaRESUMO
Cardio-facio-cutaneous (CFC) and Costello syndrome (CS) are congenital disorders with a significant clinical overlap. The recent discovery of heterozygous mutations in genes encoding components of the RAS-RAF-MAPK pathway in both CFC and CS suggested a similar underlying pathogenesis of these two disorders. While CFC is heterogeneous with mutations in BRAF, MAP2K1, MAP2K2 and KRAS, HRAS alterations are almost exclusively associated with CS. We carried out a comprehensive mutation analysis in 51 CFC-affected patients and 31 individuals with CS. Twelve different BRAF alterations were found in twenty-four patients with CFC (47.0%), two MAP2K1 mutations in five (9.8%) and two MAP2K2 sequence variations in three CFC-affected individuals (5.9%), whereas three patients had a KRAS alteration (5.9%). We identified four different missense mutations of HRAS in twenty-eight cases with CS (90.3%), while KRAS mutations were detected in two infants with a phenotype meeting criteria for CS (6.5%). In 14 informative families, we traced the parental origin of HRAS alterations and demonstrated inheritance of the mutated allele exclusively from the father, further confirming a paternal bias in the parental origin of HRAS mutations in CS. Careful clinical evaluation of patients with BRAF and MAP2K1/2 alterations revealed the presence of slight phenotypic differences regarding craniofacial features in MAP2K1- and MAP2K2-mutation positive individuals, suggesting possible genotype-phenotype correlations.
Assuntos
Anormalidades Múltiplas/genética , Fácies , Cardiopatias Congênitas/genética , Mutação , Anormalidades da Pele/genética , Adulto , Criança , Análise Mutacional de DNA , Deficiências do Desenvolvimento , Humanos , Deficiência Intelectual , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 2/genética , Fenótipo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras) , Síndrome , Proteínas ras/genéticaRESUMO
OBJECTIVE: Mutations in the CDKL5 gene cause an early-onset epileptic encephalopathy. To date, little is known about effective antiepileptic treatment in this disorder. METHOD: Accordingly, the aim of this retrospective study was to explore the role of different antiepileptic drugs (AEDs) and the ketogenic diet (KD) in the treatment of this rare genetic disorder. We evaluated the efficacy in 39 patients with CDKL5 mutations at 3, 6 and 12 months after the introduction of each treatment. One patient was lost to follow-up after 6 and 12 months. RESULTS: The responder rate (>50% reduction in seizure frequency) to at least one AED or KD was 69% (27/39) after 3 months, 45% (17/38) after 6 months and 24% (9/38) after 12 months. The highest rate of seizure reduction after 3 months was reported for FBM (3/3), VGB (8/25), CLB (4/17), VPA (7/34), steroids (5/26), LTG (5/23) and ZNS (2/11). Twelve patients (31%) experienced a seizure aggravation to at least one AED. Most patients showed some but only initial response to various AEDs with different modes of actions. SIGNIFICANCE: Considering both age-related and spontaneous fluctuation in seizure frequency and the unknown impact of many AEDs or KD on cognition, our data may help defining realistic treatment goals and avoiding overtreatment in patients with CDKL5 mutations. There is a strong need to develop new treatment strategies for patients with this rare mutation.
Assuntos
Anticonvulsivantes/uso terapêutico , Dieta Cetogênica , Epilepsia/dietoterapia , Epilepsia/tratamento farmacológico , Adulto , Epilepsia/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Serina-Treonina Quinases/genética , Estudos Retrospectivos , Convulsões/prevenção & controle , Resultado do Tratamento , Adulto JovemRESUMO
In the present study, we report sICAM-1 concentration in the cerebrospinal fluid (CSF) and serum of patients with neuroborreliosis (NB, n = 11), compared to the data from a control group of patients with corresponding blood/CSF barrier dysfunction but without inflammation in the central nervous system (disc prolaps, DP, n = 11). In NB, the sICAM-1 concentration in CSF was increased up to six-fold (ranges: 6.6-42.8 ng/ml and 2.2-9.8 ng/ml for NB and DP respectively) with no change in serum sICAM-1. The corresponding sICAM-1 CSF/serum concentration quotients (Q(ICAM)) were in the ranges: 22.5-171.3 X 10(-3), and 8.8-27.8 X 10(-3) for NB and DP respectively. This finding can be explained by increase of the brain-derived fraction of sICAM-1 in NB. In one case we observed increased Q(ICAM) on 6th day after admission to the hospital (171.3 X 10(-3) at the time of the first lumbar puncture slightly increasing to 243.6 x 10(-3) five days later), followed by normalization, in two remaining repunctured patients we observed decreasing QICAM with normalizing Q(Alb).
Assuntos
Molécula 1 de Adesão Intercelular/líquido cefalorraquidiano , Neuroborreliose de Lyme/líquido cefalorraquidiano , Adolescente , Adulto , Idoso , Criança , Feminino , Seguimentos , Humanos , Molécula 1 de Adesão Intercelular/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
X-linked adrenoleucodystrophy (ALD) has been shown to be one of the most frequent causes of Addison's disease in men. It is characterized by an impaired peroxisomal beta-oxidation of very long chain fatty acids and is associated with mutations of the ALD gene resulting in a defective peroxisomal membrane transport protein. There is a striking variability of endocrinological and neurological symptoms in patients with ALD, with no clearly evident correlation between mutations of the ALD gene and the different neurological phenotypes. No data on endocrinological symptoms and the ALD genotype have been published so far. We report endocrinological, clinical, laboratory and molecular genetic data from 55 patients with ALD from 34 families. Endocrinological symptoms of adrenal insufficiency were observed in 33 patients, 20 of whom showed additional neurological symptoms of cerebral ALD or adrenomyeloneuropathy. Isolated neurological symptoms were seen in 12 patients; in nine patients there were neither endocrinological nor neurological symptoms. Mutations of the ALD gene (n = 28) were detected in 50 patients (including nine sets of brothers) from 32 families. No correlation was found between the ALD gene mutation and endocrinological dysfunction. However, we found that all sets of brothers were concordant for the endocrinological phenotype (cortisol synthesis was reduced in two sets and normal in seven sets), whereas four sets showed a discordant neurological phenotype. As yet unknown hereditary factors other than mutations within the ALD gene may interfere with the endocrinological phenotype more strongly than with the neurological phenotype of ALD.
Assuntos
Adrenoleucodistrofia/complicações , Adrenoleucodistrofia/genética , Doenças do Sistema Endócrino/etiologia , Ligação Genética , Cromossomo X , Doença de Addison/etiologia , Adolescente , Insuficiência Adrenal/etiologia , Hormônio Adrenocorticotrópico/sangue , Adrenoleucodistrofia/fisiopatologia , Adulto , Aldosterona/sangue , Androgênios/biossíntese , Encefalopatias/etiologia , Criança , Pré-Escolar , Humanos , Hidrocortisona/sangue , Masculino , Pessoa de Meia-Idade , Mutação , Renina/sangueRESUMO
Combined alteration of the pyruvate dehydrogenase complex and respiratory chain function is described in a 21 year-old male patient with overlapping MELAS (mitochondrial encephalomyopathy, lactic acidosis, and 'stroke-like' episodes) and Kearns-Sayre syndrome. Progressive external ophthalmoplegia, pigmentary retinopathy and right bundle branch block were present when he experienced the first 'stroke-like' episode at 18 years old. The A>G tRNALeu(UUR) point mutation at nucleotide 3243 of the mitochondrial DNA was predominant in muscle tissue (79%) and present, but at lower levels in fibroblasts (49%) and blood cells (37%). Biochemical analysis revealed diminished activities of pyruvate dehydrogenase (23%) and respiratory chain complexes I and IV (57%, respectively) in muscle, but normal activities in the fibroblasts. Immunochemical studies of the muscular pyruvate dehydrogenase components showed normal content of E1alpha, E1beta and E2 protein. Molecular screening of the E1alpha gene did not indicate a nuclear mutation. These observations suggest that mitochondrial DNA defects may be associated with altered nuclear encoded enzymes which are actively imported into mitochondria and constitute components of the mitochondrial matrix. Biochemical workup of mitochondrial disorders should not be restricted to the respiratory chain even if mitochondrial DNA mutations are present.
Assuntos
DNA Mitocondrial/genética , Síndrome de Kearns-Sayre/diagnóstico , Síndrome MELAS/diagnóstico , Mutação Puntual/genética , Doença da Deficiência do Complexo de Piruvato Desidrogenase/diagnóstico , Adulto , Humanos , Síndrome de Kearns-Sayre/enzimologia , Síndrome de Kearns-Sayre/genética , Síndrome MELAS/enzimologia , Síndrome MELAS/genética , Masculino , Doença da Deficiência do Complexo de Piruvato Desidrogenase/genéticaRESUMO
Aromatic L-amino acid decarboxylase (AADC) deficiency results in an impaired synthesis of catecholamines and serotonin, and has been reported only in two middle eastern families. We report on a European family with an affected child. The child showed the characteristic clinical picture of an extrapyramidal movement disorder, oculogyric crises and vegetative symptoms seen in the three patients described previously. Treatment with a combination of the AADC cofactor pyridoxine, the monoamine oxidase B inhibitor selegiline and bromocriptine was started during the fifth year of life and showed only a moderate clinical improvement in contrast to patients who have been treated since the first year of life.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Descarboxilases de Aminoácido-L-Aromático/deficiência , Doenças dos Gânglios da Base/genética , Doenças em Gêmeos/genética , Transtornos da Motilidade Ocular/genética , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Descarboxilases de Aminoácido-L-Aromático/genética , Doenças dos Gânglios da Base/diagnóstico , Pré-Escolar , Diagnóstico Diferencial , Feminino , Seguimentos , Humanos , Exame Neurológico , Transtornos da Motilidade Ocular/diagnósticoRESUMO
Cerebrospinal fluid data on 25 patients suffering from various phenotypes of X-linked adrenoleukodystrophy have been evaluated neurochemically including cerebrospinal fluid/serum quotient diagrams. Intrathecal IgA production in 13 of 14 patients with cerebral adrenoleukodystrophy was the most sensitive parameter in cerebrospinal fluid and was not seen in any of the neurologically asymptomatic patients or in the patients with adrenomyeloneuropathy. A blood-cerebrospinal fluid barrier dysfunction was found in 9 of these 14 patients. Additional intrathecal IgG or IgM synthesis was observed in 3 patients each. In 1 patient with lumbar punctures before and after onset of neurologic symptoms intrathecal IgA synthesis was seen only after the appearance of neurologic symptoms. Repetition of lumbar punctures in 5 neurologically symptomatic patients with cerebral adrenoleukodystrophy revealed a similar pattern of intrathecal IgA synthesis with a tendency of decreasing IgA concentration. The pathophysiologic aspects of intrathecal IgA synthesis are discussed in relation to other demyelinating and inflammatory neurologic diseases.
Assuntos
Adrenoleucodistrofia/líquido cefalorraquidiano , Imunoglobulina A/líquido cefalorraquidiano , Adolescente , Adrenoleucodistrofia/classificação , Adrenoleucodistrofia/imunologia , Adulto , Criança , Pré-Escolar , Estudos Transversais , Análise Discriminante , Progressão da Doença , Ligação Genética , Humanos , Imunoglobulina A/biossíntese , Imunoglobulina G/biossíntese , Imunoglobulina G/líquido cefalorraquidiano , Imunoglobulina M/biossíntese , Imunoglobulina M/líquido cefalorraquidiano , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fenótipo , Cromossomo XRESUMO
We report three unrelated boys with X-linked adrenoleukodystrophy with onset of typical neurological symptoms of cerebral adrenoleukodystrophy between the age of 7 and 11 years. In contrast to the expected rapid progression, these patients showed an apparent arrest of initial neurological deterioration for subsequent periods of 5-12 years. Repeated neuroimaging revealed no progression of demyelination. Despite regional variability of demyelination, proton magnetic resonance spectroscopy revealed a specific metabolic pattern in all patients, with only moderate reduction of N-acetylaspartate, normal or reduced choline-containing compounds, normal or enhanced myo-inositol and no detectable lactate, which differs from findings in progressive cerebral adrenoleukodystrophy which usually exhibits a severe reduction of N-acetylaspartate and marked increases of choline-containing compounds, myo-inositol, and lactate. The ability to identify this newly described subgroup of patients with cerebral adrenoleukodystrophy is important for medical advice and planning of therapy.
Assuntos
Encefalopatias Metabólicas/genética , Espectroscopia de Ressonância Magnética , Transtornos Peroxissômicos/genética , Aberrações dos Cromossomos Sexuais/genética , Cromossomo X , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Encéfalo/patologia , Encefalopatias Metabólicas/diagnóstico , Criança , Colina/metabolismo , Doenças Desmielinizantes/diagnóstico , Doenças Desmielinizantes/genética , Feminino , Humanos , Inositol/metabolismo , Ácido Láctico/metabolismo , Masculino , Transtornos Peroxissômicos/diagnósticoRESUMO
Activity assay and isoelectric focusing analysis of human biopsy and autopsy liver specimens showed the existence of two major aldehyde dehydrogenases (ALDH I, ALDH II). Subcellular distribution of these isozymes was determined in autopsy livers from alcoholics and nonalcoholics. Nearly 70% of the total ALDH activity was recovered in the cytosol which contained both the major isozymes. Densitometric evaluation of isozyme bands showed that about 65% of the cytosolic enzyme activity was due to ALDH II and the rest due to ALDH I isozyme. Only about 5% of the total ALDH activity was found in the mitochondrial fraction (70% ALDH I and 30% ALDH II). Significantly reduced total and specific ALDH activities were noted in all the subcellular fractions from cirrhotic liver specimens. Apparently, ALDH I isozyme from cytosol and mitochondria is primarily responsible for the oxidation of small amounts of acetaldehyde normally found in the blood of nonalcoholics after drinking moderate amounts of alcohol. However, in alcoholics who exhibit higher blood acetaldehyde concentrations after drinking alcohol, ALDH II isozyme may be of greater physiological significance.
Assuntos
Álcool Desidrogenase/análise , Alcoolismo/enzimologia , Isoenzimas/análise , Fígado/enzimologia , Frações Subcelulares/enzimologia , Citosol/enzimologia , Humanos , Focalização Isoelétrica , Cirrose Hepática Alcoólica/enzimologia , Mitocôndrias Hepáticas/enzimologiaRESUMO
BACKGROUND: Symptoms of Vitamin B (12) deficiency in infancy include growth retardation, regression of psychomotor development, muscular hypotonia and brain atrophy. Besides an inappropriate vegetarian diet of the infants, a vegan diet or a pernicious anaemia of the mother may lead to an insufficient vitamin B (12) supply of the child. PATIENTS AND METHODS: We report here the neurological symptoms of 4 fully breast-fed infants from mothers on vegan diet or with pernicious anaemia. DISCUSSION AND CONCLUSION: Vitamin B (12) deficiency can easily be diagnosed by detection of methylmalonic acid when measuring the organic acids in urine. Vitamin B (12) deficiency should be avoided or diagnosed as early as possible since a supplementation of mother and child can prevent neurological symptoms of the baby. Furthermore, the neurological symptoms of the infant with manifest vitamin B (12) deficiency are (partially) reversible.
Assuntos
Aleitamento Materno/efeitos adversos , Dieta Vegetariana/efeitos adversos , Mães , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/etiologia , Deficiência de Vitamina B 12/complicações , Adolescente , Criança , Feminino , Humanos , Troca Materno-Fetal , Gravidez , Deficiência de Vitamina B 12/diagnósticoRESUMO
BACKGROUND: Lissencephaly is a neuronal migration disorder leading to absent or reduced gyration and a broadened but poorly organized cortex. The most common form of lissencephaly is isolated, referred as classic or type 1 lissencephaly. Type 1 lissencephaly is mostly associated with a heterozygous deletion of the entire LIS1 gene, whereas intragenic heterozygous LIS1 mutations or hemizygous DCX mutations in males are less common. METHODS: Eighteen unrelated patients with type 1 lissencephaly were clinically and genetically assessed. In addition, patients with subcortical band heterotopia (n = 1) or lissencephaly with cerebellar hypoplasia (n = 2) were included. RESULTS: Fourteen new and seven previously described LIS1 mutations were identified. We observed nine truncating mutations (nonsense, n = 2; frameshift, n = 7), six splice site mutations, five missense mutations, and one in-frame deletion. Somatic mosaicism was assumed in three patients with partial subcortical band heterotopia in the occipital-parietal lobes or mild pachygyria. We report three mutations in exon 11, including a frameshift which extends the LIS1 protein, leading to type 1 lissencephaly and illustrating the functional importance of the WD domains at the C terminus. Furthermore, we present two patients with novel LIS1 mutations in exon 10 associated with lissencephaly with cerebellar hypoplasia type a. CONCLUSION: In contrast to previous reports, our data suggest that neither type nor position of intragenic mutations in the LIS1 gene allows an unambiguous prediction of the phenotypic severity. Furthermore, patients presenting with mild cerebral malformations such as subcortical band heterotopia or cerebellar hypoplasia should be considered for genetic analysis of the LIS1 gene.
Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Córtex Cerebral/anormalidades , Predisposição Genética para Doença/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação/genética , Malformações do Sistema Nervoso/genética , Adolescente , Adulto , Movimento Celular/genética , Cerebelo/anormalidades , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiopatologia , Criança , Pré-Escolar , Coristoma/genética , Coristoma/metabolismo , Análise Mutacional de DNA , Feminino , Marcadores Genéticos/genética , Testes Genéticos , Genótipo , Humanos , Lactente , Masculino , Malformações do Sistema Nervoso/metabolismo , Malformações do Sistema Nervoso/fisiopatologia , Penetrância , FenótipoRESUMO
Pyridoxine-dependent epilepsy, although described some decades ago, may still be an underdiagnosed disorder. We have recently described isolated pipecolic acid elevations in the plasma and/or CSF of three patients with pyridoxine-dependent epilepsy with an intriguing inverse correlation to the oral intake of pyridoxine. We have now confirmed these findings in a further 6 unrelated patients with pyridoxine-dependent epilepsy. Pipecolic acid in plasma was 4.3- to 15.3 fold elevated compared to the upper normal range before pyridoxine and remained in the mildly elevated range while on pyridoxine. Pipecolic acid was even more markedly elevated in CSF. The extent of pipecolic acid elevation in CSF exceeded that of plasma by a factor of 2.2 to 4.8. This clearly discriminates pyridoxine-dependent epilepsy from other possible defects with elevated pipecolic acid. Determination of pipecolic acid in plasma and/or CSF should be included in the diagnostic work-up of patients with therapy-resistant seizures. It will in addition prevent patients with pyridoxine-dependent epilepsy from experiencing potentially dangerous pyridoxine-withdrawal, which until now has been necessary to prove the diagnosis.
Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Ácidos Pipecólicos/metabolismo , Piridoxina/uso terapêutico , Biomarcadores/metabolismo , Encéfalo/patologia , Epilepsia/diagnóstico , Humanos , Lactente , Recém-Nascido , Resultado do Tratamento , Suspensão de TratamentoRESUMO
Creatine monohydrate given orally led to a long-lasting improvement of muscular weakness and ataxia in a girl with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.