RESUMEN
In African neurological practice, muscle disorders are either underdiagnosed or underrepresented. This may in part be due to the large burden of other more common neurological disorders. In this report we describe the first Tanzanian patient with genetically confirmed Becker muscular dystrophy. His phenotype and genotype were compatible with elsewhere in the world. Remarkably, this patient reported his progressive weakness of the legs with difficulty in walking only after a fall. We demonstrate that muscular dystrophies occur in sub-Saharan Africa. Neurologists must however be aware that patients are likely to delay seeking medical care for muscle disorders.
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Distrofia Muscular de Duchenne , Humanos , Masculino , Persona de Mediana Edad , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/fisiopatología , Linaje , TanzaníaRESUMEN
Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder with classical features, which can be also recognised in a low resource setting. It had been described in various populations across the globe, but very few cases have been reported from Africa. In a boy with features of a progressive central nervous system condition and adrenal failure, ABCD1 gene screening was performed based on a clinical history and basic radiological features which were compatible with ALD. A common ABCD1 mutation was identified in this patient, which is the first report of genetically confirmed ALD in Sub-Saharan Africa. ALD is likely under recognised in those areas where there is no neurologist. This genetic confirmation widens geographical distribution of ABCD1-associated disease, and illustrates recognisability of this disorder, even when encountered in a low-resource environment.
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We report a case of a male baby who has characteristic signs of Freeman-Sheldon syndrome, a rare but recognizable, severe autosomal dominant form of distal arthrogryposis. Diagnosis was based on the distinctive clinical characteristics of the syndrome and confirmed by genetic analysis that showed a de novo missense mutation c.2015G>A (p.Arg672His) of the MYH3 gene. We highlight the different features present in our patient and describe the etiology of the Freeman-Sheldon phenotype and how its clinical complications can be dealt with. To the best of our knowledge, this is the first molecularly confirmed case of Freeman-Sheldon syndrome in sub-Saharan Africa.
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The tenascin-X (TNX) deficient type Ehlers-Danlos syndrome (EDS) is similar to the classical type of EDS. Because of the limited awareness among geneticists and the challenge of the molecular analysis of the TNXB gene, the TNX-deficient type EDS is probably to be under diagnosed. We therefore performed an observational, cross-sectional study. History and physical examination were performed. Results of serum TNX measurements were collected and mutation analysis was performed by a combination of next-generation sequencing (NGS), Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Included were 17 patients of 11 families with autosomal recessive inheritance and childhood onset. All patients had hyperextensible skin without atrophic scarring. Hypermobility of the joints was observed in 16 of 17 patients. Deformities of the hands and feet were observed frequently. TNX serum level was tested and absent in 11 patients (seven families). Genetic testing was performed in all families; 12 different mutations were detected, most of which are suspected to lead to non-sense mRNA mediated decay. In short, patients with the TNX-deficient type EDS typically have generalized joint hypermobility, skin hyperextensibility and easy bruising. In contrast to the classical type, the inheritance pattern is autosomal recessive and atrophic scarring is absent. Molecular analysis of TNXB in a diagnostic setting is challenging.
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Síndrome de Ehlers-Danlos/genética , Inestabilidad de la Articulación/genética , Anomalías Cutáneas/genética , Tenascina/genética , Adolescente , Adulto , Anciano , Niño , Estudios Transversales , Diagnóstico Diferencial , Síndrome de Ehlers-Danlos/sangre , Síndrome de Ehlers-Danlos/fisiopatología , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inestabilidad de la Articulación/sangre , Inestabilidad de la Articulación/fisiopatología , Masculino , Persona de Mediana Edad , Mutación , Anomalías Cutáneas/sangre , Anomalías Cutáneas/fisiopatología , Tenascina/sangre , Adulto JovenRESUMEN
BACKGROUND: Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, genotype and phenotype--genotype correlation has been lacking. METHODS: We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8). RESULTS AND CONCLUSIONS: Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 3' end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones.
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Encefalopatías Metabólicas Innatas/genética , Creatina/deficiencia , Creatina/metabolismo , Discapacidad Intelectual Ligada al Cromosoma X/genética , Proteínas del Tejido Nervioso/genética , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/deficiencia , Adulto , Niño , Creatina/genética , Genes Ligados a X , Pruebas Genéticas , Genotipo , Humanos , Masculino , Fenotipo , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/genética , Estudios RetrospectivosRESUMEN
Fragile X-associated disorders caused by the premutation of the FMR1 gene, includes the fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS affects more than 40% of premutation males over the age of 50 and 75% over the age of 80. FMR1 molecular analysis was done using PCR and confirmed by Southern Blot. Three premutation males were diagnosed FXTAS using quantification based on the standard neurological examination. Cognitive impairment was assessed using Raven and WAIS-R test. MRI was done to identify the middle cerebellar peduncle (MCP) sign, white matter disease and/or cerebral atrophy. Three cases of FXTAS are identified, of five individuals older than 50 years in one family tree two met criteria for definite FXTAS and the third with sub-clinical symptoms, although cognitive and radiological criteria are met. These cases are the first identified FXTAS cases in rural Indonesia. In addition with lack of routine medical follow-up, complications of FXTAS, such as hypertension may go unrecognized and untreated, which may further exacerbate the central nervous system (CNS) findings of FXTAS.
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Ataxia/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/genética , Temblor/genética , Anciano , Ataxia/complicaciones , Salud de la Familia , Femenino , Síndrome del Cromosoma X Frágil/complicaciones , Predisposición Genética a la Enfermedad/genética , Humanos , Indonesia , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Linaje , Síndrome , Temblor/complicaciones , Expansión de Repetición de Trinucleótido/genéticaRESUMEN
BACKGROUND: Angelman- and Rett-like syndromes share a range of clinical characteristics, including intellectual disability (ID) with or without regression, epilepsy, infantile encephalopathy, postnatal microcephaly, features of autism spectrum disorder, and variable other neurological symptoms. The phenotypic spectrum generally has been well studied in children; however, evolution of the phenotypic spectrum into adulthood has been documented less extensively. To obtain more insight into natural course and prognosis of these syndromes with respect to developmental, medical, and socio-behavioral outcomes, we studied the phenotypes of 9 adult patients who were recently diagnosed with 6 different Angelman- and Rett-like syndromes. METHODS: All these patients were ascertained during an ongoing cohort study involving a systematic clinical genetic diagnostic evaluation of over 250, mainly adult patients with ID of unknown etiology. RESULTS: We describe the evolution of the phenotype in adults with EHMT1, TCF4, MECP2, CDKL5, and SCN1A mutations and 22qter deletions and also provide an overview of previously published adult cases with similar diagnoses. CONCLUSION: These data are highly valuable in adequate management and follow-up of patients with Angelman- and Rett-like syndromes and accurate counseling of their family members. Furthermore, they will contribute to recognition of these syndromes in previously undiagnosed adult patients.
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We here report on a 20-year-old female patient with EDS due to a homozygous CHST14 single nucleotide deletion resulting in D4ST-1 deficiency, accompanied by muscle hypoplasia and muscle weakness. Findings of muscle ultrasound, electromyography, and muscle biopsy pointed to a myopathy, similarly as in other EDS types. This myopathy probably contributes to the gross motor developmental delay in this type of EDS.
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Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/patología , Debilidad Muscular/genética , Sulfotransferasas/genética , Femenino , Humanos , Polimorfismo de Nucleótido Simple , Eliminación de Secuencia , Sulfotransferasas/deficiencia , Adulto JovenRESUMEN
The ability to flexibly adapt to the changing demands of the environment is often reported as a core deficit in fragile X syndrome (FXS). However, the cognitive processes that determine this attentional set-shifting deficit remain elusive. The present study investigated attentional set-shifting ability in fragile X syndrome males with the well-validated intra/extra dimensional set-shifting paradigm (IED) which offers detailed assessment of rule learning, reversal learning, and attentional set-shifting ability within and between stimulus dimensions. A novel scoring method for IED stage errors was employed to interpret set-shifting failure in terms of repetitive decision-making, distraction to irrelevance, and set-maintenance failure. Performance of FXS males was compared to typically developing children matched on mental age, adults matched on chronological age, and individuals with Down syndrome matched on both mental and chronological age. Results revealed that a significant proportion of FXS males already failed prior to the intra-dimensional set-shift stage, whereas all control participants successfully completed the stages up to the crucial extra-dimensional set-shift. FXS males showed a specific weakness in reversal learning, which was characterized by repetitive decision-making during the reversal of newly acquired stimulus-response associations in the face of simple stimulus configurations. In contrast, when stimulus configurations became more complex, FXS males displayed increased distraction to irrelevant stimuli. These findings are interpreted in terms of the cognitive demands imposed by the stages of the IED in relation to the alleged neural deficits in FXS.
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Atención/fisiología , Síndrome del Cromosoma X Frágil/psicología , Aprendizaje Inverso/fisiología , Disposición en Psicología , Adulto , Cognición/fisiología , Toma de Decisiones/fisiología , Femenino , Humanos , Discapacidad Intelectual/psicología , Masculino , Pruebas NeuropsicológicasRESUMEN
OBJECTIVE: This study examined whether attention deficits in fragile X syndrome (FXS) can be traced back to abnormalities in basic information processing. METHOD: Sixteen males with FXS and 22 age-matched control participants (mean age 29 years) performed a standard oddball task to examine selective attention in both auditory and visual modalities. Five FXS males were excluded from analysis because they performed below chance level on the auditory task. ERPs were recorded to investigate the N1, P2, N2b, and P3b components. RESULTS: N1 and N2b components were significantly enhanced in FXS males to both auditory and visual stimuli. Interestingly, in FXS males, the P3b to auditory stimuli was significantly reduced relative to visual stimuli. These modality differences in information processing corresponded to behavioral results, showing more errors on the auditory than on the visual task. CONCLUSIONS: The current findings suggest that attentional impairments in FXS at the behavioral level can be traced back to abnormalities in event-related cortical activity. These information processing abnormalities in FXS may hinder the allocation of attentional resources needed for optimal processing at higher-levels. SIGNIFICANCE: These findings demonstrate that auditory information processing in FXS males is critically impaired relative to visual information processing.
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Atención/fisiología , Corteza Auditiva/fisiopatología , Síndrome del Cromosoma X Frágil/fisiopatología , Síndrome del Cromosoma X Frágil/psicología , Corteza Visual/fisiopatología , Estimulación Acústica , Adolescente , Adulto , Envejecimiento/fisiología , Percepción Auditiva/fisiología , Electroencefalografía , Potenciales Evocados/fisiología , Potenciales Evocados Auditivos/fisiología , Potenciales Evocados Visuales/fisiología , Síndrome del Cromosoma X Frágil/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Estimulación Luminosa , Desempeño Psicomotor/fisiología , Tiempo de Reacción/fisiología , Análisis de Regresión , Trastornos de la Sensación/etiología , Trastornos de la Sensación/fisiopatología , Trastornos de la Sensación/psicología , Percepción Visual/fisiología , Adulto JovenRESUMEN
OBJECTIVE: The present study investigated involuntary change detection in a two-tone pre-attentive auditory discrimination paradigm in order to better understand the information processing mechanisms underlying attention deficits in fragile X syndrome (FXS) males. METHODS: Sixteen males with the FXS full mutation and 20 age-matched control participants (mean age 29 years) were presented with series of auditory stimuli consisting of standard and deviant tones while watching a silent movie. RESULTS: Brain potentials recorded to the tones showed that N1 and P2, sensory evoked potentials, were significantly enhanced in FXS compared to age-matched control participants. In contrast to controls, the N1 to standard tones failed to show long-term habituation to stimulus repetition in FXS. Additionally, both mismatch negativity and P3a generation, reflecting automatic change detection and the involuntary switch of attention, respectively, were significantly attenuated in FXS males. CONCLUSIONS: The current study demonstrates that auditory stimulus discrimination in the FXS brain is already compromised during the pre-attentive stages of information processing. Furthermore, the apparent pre-attentive information processing deficiencies in FXS coincide with a weakness in the involuntary engagement of attentional resources. SIGNIFICANCE: The stimulus-driven information processing deficiencies in FXS might compromise information processing in several domains and, thus, present a key-deficit in FXS neurocognition.
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Umbral Auditivo/fisiología , Encéfalo/fisiopatología , Electroencefalografía , Potenciales Evocados Auditivos/fisiología , Síndrome del Cromosoma X Frágil/fisiopatología , Estimulación Acústica , Adolescente , Adulto , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Mapeo Encefálico , Estudios de Casos y Controles , Humanos , Masculino , Persona de Mediana Edad , Discriminación de la Altura Tonal/fisiología , Tiempo de Reacción/fisiología , Adulto JovenRESUMEN
BACKGROUND: Congenital atrichia is a rare autosomal recessive form of isolated alopecia which is caused by mutations in the human hairless (HR) gene. Patients are born with normal hair that is shed almost completely and irreversibly during the first weeks of life. OBJECTIVES: To investigate the molecular genetic basis of congenital atrichia in two patients, and to analyse the functional consequences of one newly identified and all seven previously identified HR splice site mutations using a minigene assay. METHODS: Molecular analysis of the HR gene was performed by direct DNA sequencing. To analyse the functional consequences of the splice site mutations, the respective sequences were cloned into a vector which allows directed splicing. After transfection of COS7 cells, isolation of RNA and cDNA synthesis, sequencing was performed to analyse the products. RESULTS: Two novel mutations were identified: an insertion in exon 2 (c.485insT; p.C162LfsX17), and a splice site mutation (c.2847-1G>A). In vitro analysis revealed aberrant splicing for all eight of the investigated HR splice site mutations. Comparison with the results of two biocomputational programs (neural network splice server and CRYP-SKIP) and calculation of consensus values revealed that the predictions of these two programs were consistent in only five and two of the eight mutations, respectively. CONCLUSIONS: This is the first report to analyse the consequences of HR splice site mutations using a cell-based in vitro assay. The results highlight the importance of performing splicing experiments to clarify the consequences of putative splice site mutations.
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Alopecia/genética , Mutación/genética , Factores de Transcripción/genética , Alopecia/congénito , Niño , ADN Complementario/genética , Exones/genética , Femenino , Humanos , Lactante , Sitios de Empalme de ARNRESUMEN
We present a patient with iron overload, who was initially diagnosed with hereditary haemochromatosis. Family analysis, however, established that the iron overload was secondary to congenital sideroblastic anaemia. The patient died of a hepatocellular carcinoma, likely a complication of iron overload, despite phlebotomies. Increased awareness, as well as development of evidence-based clinical guidelines, is required for timely diagnosis and adequate treatment.
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Anemia Sideroblástica/diagnóstico , Necesidades y Demandas de Servicios de Salud , Anciano , Anemia Sideroblástica/complicaciones , Anemia Sideroblástica/congénito , Anemia Sideroblástica/terapia , Carcinoma Hepatocelular/etiología , Diagnóstico Diferencial , Diagnóstico Precoz , Familia , Resultado Fatal , Hemocromatosis , Humanos , Sobrecarga de Hierro/complicaciones , Sobrecarga de Hierro/etiología , Masculino , LinajeRESUMEN
Stüve-Wiedemann syndrome (SWS, OMIM 601559) is a severe autosomal recessive condition caused by mutations in the leukemia inhibitory receptor (LIFR) gene. The main characteristic features are bowing of the long bones, neonatal respiratory distress, swallowing/sucking difficulties and dysautonomia symptoms including temperature instability often leading to death in the first years of life. We report here four patients with SWS who have survived beyond 36 months of age with no LIFR mutation. These patients have been compared with six unreported SWS survivors carrying null LIFR mutations. We provide evidence of clinical homogeneity of the syndrome in spite of the genetic heterogeneity.
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Anomalías Múltiples/genética , Heterogeneidad Genética , Osteocondrodisplasias/genética , Anomalías Múltiples/fisiopatología , Femenino , Estudios de Seguimiento , Genes Recesivos , Humanos , Subunidad alfa del Receptor del Factor Inhibidor de Leucemia/genética , Masculino , Osteocondrodisplasias/fisiopatología , SíndromeRESUMEN
We report on a boy with partial trisomies for chromosomes 8 and 22 caused by the presence of a small supernumerary marker chromosome (sSMC), a der(22)t(8;22)(p22;q11.21), inherited from a t(8;22)(p22;q11.21) translocation carrier mother. He has mild mental retardation, unability to speak distinct words and several minor anomalies i.e. high forehead and hairline, telecanthus, upslanting palpebral fissures, depressed nasal bridge, nail hypoplasia, toe position anomaly and 5th finger clinodactyly. He has two maternal uncles and one maternal aunt with mental retardation. G-banding technique showed 47,XY,+mar whilst his mother's karyotype showed a balanced reciprocal translocation between the chromosomes 8 and 22. Fluorescence In Situ Hybridization (FISH) technique with probes for centromere 22 and 8pter were used to detect the origin of marker chromosome and confirmed the marker chromosome in the proband showing to be extra chromosomal material originated from chromosome 8 and 22. Additional genome wide microarray analysis, using the Affymetrix Nspl 250K SNP array platform was performed to further characterize the marker chromosome and resulted in a der(22)t(8;22)(p22;q11.21). Furthermore, cytogenetic analysis of three affected family members showed the same unbalanced translocation, due to 3:1 meiotic segregation. This indicated the viability of this unbalanced pattern and combined with the recurrent miscarriages by the proband's mother, the mechanism of transmitting extrachromosomal material is probably not a random process. Since, there is no similar translocation (8p;22q) reported and the chromosomal translocation largely exists of additional 8p22-8pter we compare the clinical outcomes with reported cases of 8p22-8pter triplication, although there is a part of genetic material derived from chromosome 22 present. This unique familial chromosome translocation case from Indonesia will give insight in the underlying mechanism of this recurrent chromosomal abnormality and clinical features of the patients will be compared to previously published cases.
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Anomalías Múltiples/genética , Cromosomas Humanos Par 22/genética , Cromosomas Humanos Par 8/genética , Salud de la Familia , Translocación Genética , Trisomía , Niño , Huesos Faciales/anomalías , Humanos , Discapacidad Intelectual/genética , Masculino , Linaje , Cráneo/anomalíasRESUMEN
Background/Methods. Marfan syndrome (MFS) is a heritable connective tissue disorder usually caused by a mutation in the fibrillin 1 (FBN1) gene. Typical characteristics of MFS that have been described include dolichostenomelia, ectopia lentis and aortic root dilatation. However, there is great clinical variability in the expression of the syndrome's manifestations, both between and within families. Here we discuss the clinical variability of MFS by describing a large fourgeneration Dutch family with MFS.Results. Nineteen individuals of one family with a single missense FBN1 mutation (c.7916A>G) were identified. The same mutation was found in one unrelated person. Clinical variability was extensive and not all mutation carriers fulfilled the diagnostic criteria for MFS. Some patients only expressed mild skeletal abnormalities, whereas aortic root dilation was present in eight patients, an acute type A aortic dissection was recorded in two other patients, and a mitral valve prolapse was present in eight patients. In some patients cardiac features were not present on initial screening, but did however develop over time.Conclusion. MFS is a clinically highly variable syndrome, which means a meticulous evaluation of suspected cases is crucial. Mutation carriers should be re-evaluated regularly as cardiovascular symptoms may develop over time. (Neth Heart J 2010;18:85-9.).
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Mutations in the UPF3B gene, which encodes a protein involved in nonsense-mediated mRNA decay, have recently been described in four families with specific (Lujan-Fryns and FG syndromes), nonspecific X-linked mental retardation (XLMR) and autism. To further elucidate the contribution of UPF3B to mental retardation (MR), we screened its coding sequence in 397 families collected by the EuroMRX consortium. We identified one nonsense mutation, c.1081C>T/p.Arg361(*), in a family with nonspecific MR (MRX62) and two amino-acid substitutions in two other, unrelated families with MR and/or autism (c.1136G>A/p.Arg379His and c.1103G>A/p.Arg368Gln). Functional studies using lymphoblastoid cell lines from affected patients revealed that c.1081C>T mutation resulted in UPF3B mRNA degradation and consequent absence of the UPF3B protein. We also studied the subcellular localization of the wild-type and mutated UPF3B proteins in mouse primary hippocampal neurons. We did not detect any obvious difference in the localization between the wild-type UPF3B and the proteins carrying the two missense changes identified. However, we show that UPF3B is widely expressed in neurons and also presents in dendritic spines, which are essential structures for proper neurotransmission and thus learning and memory processes. Our results demonstrate that in addition to Lujan-Fryns and FG syndromes, UPF3B protein truncation mutations can cause also nonspecific XLMR. We also identify comorbidity of MR and autism in another family with UPF3B mutation. The neuronal localization pattern of the UPF3B protein and its function in mRNA surveillance suggests a potential function in the regulation of the expression and degradation of various mRNAs present at the synapse.
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Trastorno Autístico/genética , Codón sin Sentido/genética , Discapacidad Intelectual/genética , Neuronas/metabolismo , Proteínas de Unión al ARN/genética , Adulto , Sustitución de Aminoácidos/genética , Animales , Trastorno Autístico/complicaciones , Línea Celular , Espinas Dendríticas/metabolismo , Regulación hacia Abajo , Femenino , Hipocampo/metabolismo , Humanos , Discapacidad Intelectual/complicaciones , Masculino , Ratones , Persona de Mediana Edad , Linaje , Estabilidad del ARN , Proteínas de Unión al ARN/metabolismoRESUMEN
Jeune syndrome (asphyxiating thoracic dystrophy, ATD) is a rare autosomal recessive skeletal dysplasia characterized by a small, narrow chest and variable limb shortness with a considerable neonatal mortality as a result of respiratory distress. Renal, hepatic, pancreatic and ocular complications may occur later in life. We describe 13 cases with ages ranging from 9 months to 22 years. Most patients experienced respiratory problems in the first years of their life, three died, one experienced renal complications, and one had hepatic problems. With age, the thoracic malformation tends to become less pronounced and the respiratory problems decrease. The prognosis of ATD seems better than described in literature and in our opinion this justifies long term intensive treatment in the first years. We also propose a follow-up protocol for patients with ATD.