[Show abstract][Hide abstract] ABSTRACT: The mitochondrial ribosomes are required for the synthesis of mitochondrial DNA-encoded subunits of the oxidative phosphorylation (OXPHOS) system. Here, we present a neonate with fatal lactic acidosis and combined OXPHOS deficiency caused by a homozygous mutation in MRPS22, a gene encoding a mitochondrial ribosomal small subunit protein. Brain imaging revealed several structural abnormalities, including agenesis of the corpus callosum, multiple periventricular cysts, and suspected intracerebral calcifications. Moreover, echocardiography demonstrated atrial and ventricular septal defects as well as a coronary artery fistula. Our report expands the clinical spectrum of this rare mitochondrial disorder and confirms the severe clinical phenotype associated with this defect.
[Show abstract][Hide abstract] ABSTRACT: We report a novel type of mutation in the death ligand FasL that was associated with a severe phenotype of the autoimmune lymphoproliferative syndrome in two patients. A frameshift mutation in the intracellular domain led to complete loss of FasL expression. Cell death signaling via its receptor and reverse signaling via its intracellular domain were completely abrogated. In vitro lymphocyte proliferation induced by weak T cell receptor stimulation could be blocked and cell death was induced by engagement of FasL in T cells derived from healthy individuals and a heterozygous carrier, but not in FasL-deficient patient derived cells. Expression of genes implicated in lymphocyte proliferation and activation (CCND1, NFATc1, NF-κB1) was increased in FasL-deficient T cells and could not be downregulated by FasL engagement as in healthy cells. Our data thus suggest, that deficiency in FasL reverse signaling may contribute to the clinical lymphoproliferative phenotype of ALPS.
[Show abstract][Hide abstract] ABSTRACT: Organ-specific dose reduction significantly reduces the radiation exposure of radiosensitive organs. The purpose of this study was to assess the impact of a novel organ-specific dose reduction algorithm on image quality of pediatric chest CT. We included 28 children (mean age 10.9 +/- 4.8 years, range 3-18 years) who had contrast-enhanced chest CT on a 128-row scanner. CT was performed at 100 kV using automated tube current modulation and a novel organ-specific dose-reduction algorithm (XCare (TM); Siemens, Forchheim, Germany). Seven children had a previous chest CT performed on a 64-row scanner at 100 kV without organ-specific dose reduction. Subjective image quality was assessed using a five-point scale (1-not diagnostic; 5-excellent). Contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR) were assessed in the descending aorta. Overall mean subjective image quality was 4.1 +/- 0.6. In the subgroup of the seven children examined both with and without organ-specific dose reduction, subjective image quality was comparable (score 4.4 +/- 0.5 with organ-specific dose reduction vs. 4.4 +/- 0.7 without it; P > 0.05). There was no significant difference in mean signal-to-noise ratio and contrast-to-noise ratio with organ-specific dose reduction (38.3 +/- 10.1 and 28.5 +/- 8.7, respectively) and without the reduction (35.5 +/- 8.5 and 26.5 +/- 7.8, respectively) (P > 0.05). Volume computed tomography dose index (CTDIvol) and size-specific dose estimates did not differ significantly between acquisitions with the organ-specific dose reduction (1.7 +/- 0.8 mGy) and without the reduction (1.7 +/- 0.8 mGy) (P > 0.05). Organ-specific dose reduction does not have an impact on image quality of pediatric chest CT and can therefore be used in clinical practice to reduce radiation dose of radiosensitive organs such as breast and thyroid gland.
[Show abstract][Hide abstract] ABSTRACT: Biotin-responsive basal ganglia disease (BBGD) is an autosomal recessive disorder, which is caused by mutations in the SLC19A3 gene. BBGD typically causes (sub)acute episodes with encephalopathy and subsequent neurological deterioration. If untreated, the clinical course may be fatal. Our report on a 6-year-old child with BBGD highlights that the disease is a crucial differential diagnosis of Leigh syndrome. Therefore, biotin and thiamine treatment is recommended for any patient with symmetrical basal ganglia lesions and neurological symptoms until BBGD is excluded. In addition, we exemplify that deformation-field-based morphometry of brain magnetic resonance images constitutes a novel quantitative tool, which might be very useful to monitor disease course and therapeutic effects in neurometabolic disorders.
[Show abstract][Hide abstract] ABSTRACT: Diagnostic assessment of osteoarthritis in children and adolescents is difficult. Here, we report the sixth family with a COL2A1 mutation R275C. The index patient, her mother and her three brothers had severe coxarthrosis, in some cases requiring surgery. Only the mother was hard of hearing, and only her children had brachydactyly of the fourth digit. The index patient suffered a femoral neck fracture after minor trauma at a time when osteoarthritis was not yet radiologically detectable. Hip fracture or osteoarthritis of unclear origin in childhood should prompt genetic work-up for the purposes of correct classification and genetic counseling.
[Show abstract][Hide abstract] ABSTRACT: At age 8 months, an infant girl displayed rapid developmental regression. Family history, birth, and initial development were unremarkable. After hospital admission, cerebral MRI showed bilateral cystic lesions in the centrum semiovale. Follow-up imaging after 3 months demonstrated a dramatic progression in these alterations with demyelination of the supratentorial white matter (figure). Biochemical and genetic analyses confirmed isolated mitochondrial complex I deficiency due to an NDUFS1 mutation (encoding NADH-dehydrogenase-ubiquinone Fe-S protein 1; see also reference (1), patient 1). Of note, leukoencephalopathy is uncommon in mitochondrial complex I mutations but may be a feature of NDUFS1 defects.(2.)
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Although the survival of children and adolescents with malignant germ-cell tumours has improved greatly in recent years, the outcome remains poor for those with refractory or recurrent malignant germ-cell tumours. We aimed to determine whether objective tumour response could be achieved in patients with refractory or recurrent malignant germ-cell tumours with PEI-regional deep hyperthermia as salvage treatment.
METHODS: Patients with refractory or recurrent non-testicular malignant germ-cell tumours after standard cisplatin-based chemotherapy were treated prospectively with PEI chemotherapy (cisplatin 40 mg/m2, delivered intravenously on days 1 and 4; etoposide 100 mg/m2, intravenously on days 1-4; and ifosfamide 1800 mg/m2, intravenously on days 1-4) plus simultaneous 1-h regional deep hyperthermia (41-43°C) on days 1 and 4. Patients received three to four treatment courses at 21-day intervals until residual tumour resection was possible; they subsequently received one or two additional courses of PEI-regional deep hyperthermia. Local radiotherapy was given for incompletely resected tumours. Chemotherapy and hyperthermia toxic effects were assessed using WHO grading. The primary endpoint was the proportion of patients who had an objective response as assessed with Response Evaluation Criteria in Solid Tumors version 1.0 guidelines. Secondary endpoints were the event-free survival and overall survival after 5 years. This ongoing PEI-regional deep hyperthermia study (Hyper-PEI protocol) is registered at the German Cancer Society, number 50-2732.
FINDINGS: 44 patients aged 7 months to 21 years (median 2 years 7 months) with refractory or recurrent malignant germ-cell tumours (nine patients with poor response, 23 patients with first relapse, 12 patients with multiple relapses) were included in this study. We identified 34 yolk sac tumours, eight embryonal carcinomas, one choriocarcinoma, and one dysgerminoma by histology analysis. Of the 35 patients who had sufficient clinical and radiographical data available for response assessment, 30 (86%) had an objective response to treatment (16 patients had complete remission and 14 had partial remission). 5-year event-free survival was 62% (95% CI 45-75), and 5-year overall survival was 72% (95% CI 55-83). The median follow-up of surviving patients was 82 months (range 9-195). WHO grade 3-4 neutropenia and thrombocytopenia occurred in all 181 chemotherapy cycles. Granulocytopenic fever, which required intercurrent hospital admission, was noted in 29 (66%) of 44 patients after 53 (29%) of 181 courses. Five patients experienced treatment-related grade-3 acute renal toxic effects.
INTERPRETATION: A multimodal strategy integrating PEI-regional deep hyperthermia and tumour resection with or without radiation can successfully treat children and adolescents with refractory or recurrent malignant non-testicular germ-cell tumours. The long-term prognosis of patients with poor response or after first relapse was almost similar to those receiving first-line treatment. This strategy merits further investigation.
FUNDING: Deutsche Krebshilfe eV, Bonn, Elterninitiative Kinderkrebsklinik Düsseldorf eV, the Barbara and Hubertus-Trettnerstiftung, and the Marie Quendt Fund.
The Lancet Oncology 06/2013; DOI:10.1016/S1470-2045(13)70271-7 · 24.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Leigh syndrome is a devastating neurodegenerative disease, typically manifesting in infancy or early childhood. However, also late-onset cases have been reported. Since its first description by Denis Archibald Leigh in 1951, it has evolved from a postmortem diagnosis, strictly defined by histopathological observations, to a clinical entity with indicative laboratory and radiological findings. Hallmarks of the disease are symmetrical lesions in the basal ganglia or brain stem on MRI, and a clinical course with rapid deterioration of cognitive and motor functions. Examinations of fresh muscle tissue or cultured fibroblasts are important tools to establish a biochemical and genetic diagnosis. Numerous causative mutations in mitochondrial and nuclear genes, encoding components of the oxidative phosphorylation system have been described in the past years. Moreover, dysfunctions in pyruvate dehydrogenase complex or coenzyme Q10 metabolism may be associated with Leigh syndrome. To date, there is no cure for affected patients, and treatment options are mostly unsatisfactory. Here, we review the most important clinical aspects of Leigh syndrome, and discuss diagnostic steps as well as treatment options.
Journal of neurology, neurosurgery, and psychiatry 06/2013; 85(3). DOI:10.1136/jnnp-2012-304426 · 6.81 Impact Factor