RESUMEN
Background Familial hemiplegic migraine (FHM) is a rare monogenic migraine subtype characterised by attacks associated with transient motor weakness. Clinical information is mainly based on reports of small families with only short follow-up. Here, we document a prospective 15-year follow-up of an extended family with FHM type 2. Patients and methods After diagnosing FHM in a patient with severe attacks associated with coma and fever, we identified eight more family members with FHM and one with possible FHM. All family members were prospectively followed for 15 years. In total 13 clinically affected and 21 clinically non-affected family members were genetically tested and repeatedly investigated. Results A novel p.Arg348Pro ATP1A2 mutation was found in 14 family members: 12 with clinical FHM, one with psychomotor retardation and possible FHM, and one without FHM features. In 9/12 (75%) family members with genetically confirmed FHM, attacks were severe, long-lasting, and often associated with impaired consciousness and fever. Such attacks were frequently misdiagnosed and treated as viral meningitis or stroke. Epilepsy was reported in three family members with FHM and in the one with psychomotor retardation and possible FHM. Ataxia was not observed. Conclusion FHM should be considered in patients with recurrent coma and fever.
Asunto(s)
Migraña con Aura/genética , ATPasa Intercambiadora de Sodio-Potasio/genética , Coma/genética , Femenino , Fiebre/genética , Estudios de Seguimiento , Humanos , Masculino , Migraña con Aura/complicaciones , Mutación , Linaje , Estudios ProspectivosRESUMEN
Autosomal dominant polycystic kidney disease (ADPKD), due to a heterozygous mutation in PKD1 or PKD2, is usually an adult onset disease. Renal cystic disease is generally milder in PKD2 patients than in PKD1 patients. Recently, several PKD1 patients with a severe renal cystic phenotype due to a second modifying PKD1 allele, or carrying two incomplete penetrant PKD1 alleles, have been described. This study reports for the first time a patient with neonatal onset of PKD homozygous for an incomplete penetrant PKD2 missense variant due to uniparental disomy.
Asunto(s)
Homocigoto , Mutación Missense , Riñón Poliquístico Autosómico Dominante/diagnóstico por imagen , Riñón Poliquístico Autosómico Dominante/genética , Canales Catiónicos TRPP/genética , Disomía Uniparental , Secuencia de Aminoácidos , Secuencia de Bases , Análisis Mutacional de ADN , Humanos , Recién Nacido , Riñón/patología , Masculino , Datos de Secuencia Molecular , Linaje , Receptores de Superficie Celular/genética , UltrasonografíaRESUMEN
Studies to identify copy number variants (CNVs) on the X-chromosome have revealed novel genes important in the causation of X-linked mental retardation (XLMR). Still, for many CNVs it is unclear whether they are associated with disease or are benign variants. We describe six different CNVs on the X-chromosome in five male patients with mental retardation that were identified by conventional karyotyping and single nucleotide polymorphism array analysis. One deletion and five duplications ranging in size from 325 kb to 12.5 Mb were observed. Five CNVs were maternally inherited and one occurred de novo. We discuss the involvement of potential candidate genes and focus on the complexity of X-chromosomal duplications in males inherited from healthy mothers with different X-inactivation patterns. Based on size and/or the presence of XLMR genes we were able to classify CNVs as pathogenic in two patients. However, it remains difficult to decide if the CNVs in the other three patients are pathogenic or benign.
Asunto(s)
Duplicación Cromosómica , Cromosomas Humanos X , Discapacidad Intelectual Ligada al Cromosoma X , Inactivación del Cromosoma X/genética , Southern Blotting , Dosificación de Gen , Humanos , Cariotipificación , Masculino , Discapacidad Intelectual Ligada al Cromosoma X/genética , Discapacidad Intelectual Ligada al Cromosoma X/fisiopatología , Análisis de Secuencia por Matrices de Oligonucleótidos , Eliminación de SecuenciaRESUMEN
Pediatric myelodysplastic syndrome (MDS) is a heterogeneous disease covering a spectrum ranging from aplasia (RCC) to myeloproliferation (RAEB(t)). In adult-type MDS there is increasing evidence for abnormal function of the bone-marrow microenvironment. Here, we extensively studied the mesenchymal stromal cells (MSCs) derived from children with MDS. MSCs were expanded from the bone-marrow of 17 MDS patients (RCC: n=10 and advanced MDS: n=7) and pediatric controls (n=10). No differences were observed with respect to phenotype, differentiation capacity, immunomodulatory capacity or hematopoietic support. mRNA expression analysis by Deep-SAGE revealed increased IL-6 expression in RCC- and RAEB(t)-MDS. RCC-MDS MSC expressed increased levels of DKK3, a protein associated with decreased apoptosis. RAEB(t)-MDS revealed increased CRLF1 and decreased DAPK1 expressions. This pattern has been associated with transformation in hematopoietic malignancies. Genes reported to be differentially expressed in adult MDS-MSC did not differ between MSC of pediatric MDS and controls. An altered mRNA expression profile, associated with cell survival and malignant transformation, of MSC derived from children with MDS strengthens the hypothesis that the micro-environment is of importance in this disease. Our data support the understanding that pediatric and adult MDS are two different diseases. Further evaluation of the pathways involved might reveal additional therapy targets.