RESUMEN
Mitochondrial diseases are a group of inherited diseases with highly varied and complex clinical presentations. Here, we report four individuals, including two siblings, affected by a progressive mitochondrial encephalopathy with biallelic variants in the cardiolipin biosynthesis gene CRLS1. Three affected individuals had a similar infantile presentation comprising progressive encephalopathy, bull's eye maculopathy, auditory neuropathy, diabetes insipidus, autonomic instability, cardiac defects and early death. The fourth affected individual presented with chronic encephalopathy with neurodevelopmental regression, congenital nystagmus with decreased vision, sensorineural hearing loss, failure to thrive and acquired microcephaly. Using patient-derived fibroblasts, we characterized cardiolipin synthase 1 (CRLS1) dysfunction that impaired mitochondrial morphology and biogenesis, providing functional evidence that the CRLS1 variants cause mitochondrial disease. Lipid profiling in fibroblasts from two patients further confirmed the functional defect demonstrating reduced cardiolipin levels, altered acyl-chain composition and significantly increased levels of phosphatidylglycerol, the substrate of CRLS1. Proteomic profiling of patient cells and mouse Crls1 knockout cell lines identified both endoplasmic reticular and mitochondrial stress responses, and key features that distinguish between varying degrees of cardiolipin insufficiency. These findings support that deleterious variants in CRLS1 cause an autosomal recessive mitochondrial disease, presenting as a severe encephalopathy with multi-systemic involvement. Furthermore, we identify key signatures in cardiolipin and proteome profiles across various degrees of cardiolipin loss, facilitating the use of omics technologies to guide future diagnosis of mitochondrial diseases.
Asunto(s)
Encefalopatías , Enfermedades Mitocondriales , Animales , Ratones , Encefalopatías/genética , Encefalopatías/metabolismo , Cardiolipinas/genética , Cardiolipinas/metabolismo , Mitocondrias/genética , Mitocondrias/metabolismo , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , ProteómicaRESUMEN
BACKGROUND: Kikuchi-Fujimoto disease (KFD) or necrotizing histiocytic lymphadenitis, was described separately by both Kikuchi and Fujimoto in Japan in the early 1970's. Despite its rarity in the pediatric population, it is an important differential in persistent lymphadenopathy. Familial cases of KFD in the literature are rare. Here we describe the first reported case of KFD in non-identical twin sisters. CASE PRESENTATION: Twin 1 presented with a 3-week history of worsening right-sided cervical lymphadenopathy, daily fevers, significant lethargy, weight loss and arthralgia of her knees and ankles at the age of 12 years in 2015. She had had an unremarkable medical history. A biopsy of her lymph nodes showed histiocytic necrosis consistent with KFD. Twin 2 presented with a three-week history of lethargy, fatigue, weight loss and left-sided posterior cervical chain lymphadenopathy at 16 years of age in 2018. She had a history of frequently relapsing nephrotic syndrome and celiac disease. A biopsy of her lymph nodes was undertaken and showed histiocytic necrosis consistent with KFD. CONCLUSIONS: KFD is a rare but self-limiting pathological process of necrotizing histiocytic lymphadenitis. Although further research is needed, there is an increasing amount of evidence which suggests a multifactorial pathological basis of disease. The two cases we document here are the first reported cases of familial KFD in dizygotic HLA-identical twins which reinforces the likely HLA-linkage in the etiology of KFD.
Asunto(s)
Biopsia/métodos , Enfermedad Celíaca , Antígenos HLA/análisis , Linfadenitis Necrotizante Histiocítica , Ganglios Linfáticos/patología , Síndrome Nefrótico , Adolescente , Causalidad , Enfermedad Celíaca/complicaciones , Enfermedad Celíaca/diagnóstico , Niño , Femenino , Linfadenitis Necrotizante Histiocítica/sangre , Linfadenitis Necrotizante Histiocítica/complicaciones , Linfadenitis Necrotizante Histiocítica/diagnóstico , Linfadenitis Necrotizante Histiocítica/fisiopatología , Humanos , Pruebas Inmunológicas/métodos , Linfadenopatía/etiología , Linfadenopatía/patología , Anamnesis , Síndrome Nefrótico/complicaciones , Síndrome Nefrótico/diagnóstico , Gemelos DicigóticosRESUMEN
PURPOSE: Potentially pathogenic autoantibodies are found increasingly in adults with seizure disorders, including focal seizures and those of unknown cause. In this study, we investigated a cohort of children with new-onset seizures to see whether there were autoantibodies and the relationship to any specific seizure or epilepsy type. METHODS: We prospectively recruited 114 children (2 months to 16 years) with new-onset seizures presenting between September 2009 and November 2011, as well as 65 controls. Patients were clinically assessed and classified according to the new International League Against Epilepsy (ILAE) organization of seizures and epilepsies classification system. Sera were tested for autoantibodies to a range of antigens, blind to the clinical and classification details. KEY FINDINGS: Eleven (9.7%) of 114 patients were positive for one or more autoantibodies compared to 3 of 65 controls (4.6%, p = ns). Patients had antibodies to the voltage-gated potassium channel (VGKC) complex (n = 4), contactin-associated protein-like 2 (CASPR2) (n = 3), N-methyl-d-aspartate receptors (NMDARs) (n = 2), or VGKC-complex and NMDAR (n = 2). None had antibodies to glutamic acid decarboxylase, contactin-2, or to glycine, 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl) propionic acid (AMPA), or γ-aminobutyric acid B receptors. Ten of these 11 patients were classified as having epilepsy according to the new ILAE organization of seizures and epilepsy. Although, there were no significant differences in the demographic and clinical features between antibody-positive and antibody-negative patients, the classification of "unknown cause" was higher in the antibody positive (7/10; 70%) compared with the antibody negative subjects (23/86; 26.7%; p = 0.0095, Fisher's exact test). Furthermore, four of these seven patients with epilepsy (57.1%) were classified as having predominantly focal seizures compared with 12 of the 86 antibody-negative patients (13.9%; p = 0.015). SIGNIFICANCE: Because autoantibodies were more frequent in pediatric patients with new-onset epilepsy of "unknown cause," often with focal epilepsy features, this group of children may benefit most from autoantibody screening and consideration of immune therapy.