[Show abstract][Hide abstract] ABSTRACT: Ciliopathies are a group of hereditary disorders associated with defects in cilia structure and function. The distal appendages (DAPs) of centrioles are involved in the docking and anchoring of the mother centriole to the cellular membrane during ciliogenesis. The molecular composition of DAPs was recently elucidated and mutations in two genes encoding DAPs components (CEP164/NPHP15, SCLT1) have been associated with human ciliopathies, namely nephronophthisis and orofaciodigital syndrome. To identify additional DAP components defective in ciliopathies, we independently performed targeted exon sequencing of 1,221 genes associated with cilia and 5 known DAP protein-encoding genes in 1,255 individuals with a nephronophthisis-related ciliopathy. We thereby detected biallelic mutations in a key component of DAP-encoding gene, CEP83, in seven families. All affected individuals had early-onset nephronophthisis and four out of eight displayed learning disability and/or hydrocephalus. Fibroblasts and tubular renal cells from affected individuals showed an altered DAP composition and ciliary defects. In summary, we have identified mutations in CEP83, another DAP-component-encoding gene, as a cause of infantile nephronophthisis associated with central nervous system abnormalities in half of the individuals.
The American Journal of Human Genetics 05/2014; · 11.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION: Patients with methylmalonic acidemia (MMA) may develop many complications despite medical treatment, in particular, severe central nervous system damage and chronic kidney disease (CKD). A kidney transplant may partially correct the metabolic dysfunctions. Liver, kidney and combined liver-kidney transplantations have been advocated but no guidelines are available to identify the most suitable organ to transplant. PATIENTS AND METHODS: Four patients with MMA (mut° phenotype) received a kidney graft because of repeated metabolic decompensations, with progression to CKD in 3 patients (end-stage kidney disease in two patients and CKD stage III in one patient with an estimated glomerular filtration rate [eGFR] of 40ml/min/1.73m(2)) but normal renal function in one (eGFR of 93ml/min/1.73m(2)) before transplantation. RESULTS: The medium age at transplantation was 7.9y (5-10.2) and the median follow-up was 2.8years (1.8-4.6). Renal transplantation improved the relevant metabolic parameters in 4/4 patients and renal function in the patients with CKD. Plasma and urinary MMA levels immediately decreased and remained normal or subnormal (mean values of plasma MMA before transplantation 1530μmol/L versus 240μmol/L after transplantation, and mean values of urine MMA before transplantation 4700mmol/mol creatinine versus 2300mmol/mol creatinine after transplantation). No further acute metabolic decompensation was observed and protein-intake was increased from 0.60 to 0.83g/Kg/day. One patient transplanted at age 9.7years developed a hepatoblastoma at age 11years with subsequent neurological complications and eventually died. The three other patients are alive. Two of them remained neurologically stable. The 3rd patient who displayed choreoathetosis transiently improved his neurological condition immediately after transplantation and then remained stable. CONCLUSION: Kidney transplantation represents an interesting alternative therapeutic option in methylmalonic aciduria, for renal complications but also as a "cellular therapy" that may significantly reduce metabolic decompensations and hospitalizations. However, further neurological impairment remains possible.
Molecular Genetics and Metabolism 05/2013; · 2.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: AIM: The aim of this study was to describe the magnetic resonance imaging (MRI) findings and the neurological and neuropsychological outcomes in paediatric, diarrhoea-associated haemolytic-uraemic syndrome (D+HUS) with central nervous system impairment treated with eculizumab, a monoclonal antibody. METHOD: The 14-month single-centre prospective study included seven children (three males, four females; age range 16mo-7y 8mo; median age 3y 7mo) with typical D+HUS and acute neurological impairment. In the acute phase of the disease, neurological assessment and brain magnetic resonance imaging (MRI), including measurement of the apparent diffusion coefficient (ADC), were performed, and neuropsychological evaluation and brain MRI were also carried out 6 months after disease onset. RESULTS: In the acute phase, basal ganglia and white matter abnormalities with ADC restriction were a common and reversible MRI finding. In all the surviving patients (5/7), follow-up MRI after 6 months was normal, indicating reversible lesions. Clinical and neuropsychological evaluations after 6 months were also normal. INTERPRETATION: This specific brain MRI pattern consisting of an ADC decrease in basal ganglia and white matter without major T2/fluid-attenuated inversion recovery (FLAIR) injury may be a key finding in the acute phase of the disease in favour of a vasculitis hypothesis. These reversible lesions were associated with a good neurological outcome. These results call for further evaluation of the potential role of eculizumab in the choice of treatment for severe D+HUS, particularly in the case of early neurological signs.
Developmental Medicine & Child Neurology 05/2013; · 2.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Intraflagellar transport (IFT) depends on two evolutionarily conserved modules, subcomplexes A (IFT-A) and B (IFT-B), to drive ciliary assembly and maintenance. All six IFT-A components and their motor protein, DYNC2H1, have been linked to human skeletal ciliopa-thies, including asphyxiating thoracic dystrophy (ATD; also known as Jeune syndrome), Sensenbrenner syndrome, and Mainzer-Saldino syndrome (MZSDS). Conversely, the 14 subunits in the IFT-B module, with the exception of IFT80, have unknown roles in human disease. To identify additional IFT-B components defective in ciliopathies, we independently performed different mutation analyses: candidate-based sequencing of all IFT-B-encoding genes in 1,467 individuals with a nephronophthisis-related ciliopathy or whole-exome resequencing in 63 individuals with ATD. We thereby detected biallelic mutations in the IFT-B-encoding gene IFT172 in 12 fam-ilies. All affected individuals displayed abnormalities of the thorax and/or long bones, as well as renal, hepatic, or retinal involvement, consistent with the diagnosis of ATD or MZSDS. Additionally, cerebellar aplasia or hypoplasia characteristic of Joubert syndrome was present in 2 out of 12 families. Fibroblasts from affected individuals showed disturbed ciliary composition, suggesting alteration of ciliary transport and signaling. Knockdown of ift172 in zebrafish recapitulated the human phenotype and demonstrated a genetic interaction between ift172 and ift80. In summary, we have identified defects in IFT172 as a cause of complex ATD and MZSDS. Our findings link the group of skeletal ciliopathies to an additional IFT-B component, IFT172, similar to what has been shown for IFT-A. Cilia are hair-like structures that project from the surface of most mammalian cells and are involved in diverse signaling pathways. Mutations in genes encoding ciliary
The American Journal of Human Genetics 01/2013; · 11.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Renal manifestations are rare in Kawasaki disease (KD). Acute renal failure with tubular necrosis, tubulointerstitial nephritis and renovascular hypertension have been reported in KD, but only one case of a patient with KD associated with nephrotic syndrome (NS) has been reported to date, with the patient improving on steroid therapy but dying from coronary aneurysm.
We report the cases of three children, aged 4, 4.5 and 8 years, respectively, who presented with typical KD symptoms (high fever, diffuse maculopapular rash, conjunctivitis, peripheral oedema, cervical adenopathies and high C reactive protein levels) and developed NS.
Patient 1 had a haemodynamic shock due to cardiac dysfunction and transient renal failure. Ten days later, he developed a NS which spontaneously disappeared 1 week later. Patient 2 had a NS on admission with normal plasma creatinine and no haematuria. Proteinuria disappeared within 10 days. Patient 3 developed NS 5 days after onset with a moderate increase in plasma creatinine. Proteinuria disappeared within 2 weeks. All three patients were treated with intravenous immunoglobulins, antibiotic therapy and aspirin, but none of them received steroid therapy. To date, all three patients have maintained long-term remission.
In conclusion, proteinuria with NS may develop during the acute phase of KD with persistent remission occurring without steroid therapy.
[Show abstract][Hide abstract] ABSTRACT: Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by branchial, ear, and renal anomalies. Over 80 mutations in EYA1 have been reported in BOR. Mutations in SIX1, a DNA binding protein that associates with EYA1, have been reported less frequently. One group has recently described four missense mutations in SIX5 in five unrelated patients with BOR. Here, we report a screening of these three genes in a cohort of 140 patients from 124 families with BOR. We identified 36 EYA1 mutations in 42 unrelated patients, 2 mutations, and 1 change of unknown significance in SIX1 in 3 unrelated patients, but no mutation in SIX5. We did not find correlation between genotype and phenotype, and observed a high phenotypic variability between and within BOR families. We show the difficulty in establishing a molecular diagnosis strategy in BOR syndrome: the screening focusing on patients with typical BOR would detect a mutation rate of 76%, but would also miss mutations in 9% of patients with atypical BOR. We detected a deletion removing three EYA1 exons in a patient who was previously reported to carry the SIX5 Thr552Met mutation. This led us to reconsider the role of SIX5 in the development of BOR.
Human Mutation 02/2011; 32(2):183-90. · 5.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To compare the clinical data at diagnosis, treatment and neurological outcome in 34 children with opsoclonus-myoclonus syndrome (OMS) associated with a detected neuroblastoma or not.
This is a multicentric retrospective study of 34 children presenting with OMS from four pediatric centers diagnosed between 1988 and 2008.
Twenty-two patients had OMS associated with a neuroblastoma. These patients all had neuroblastomas with favourable prognostic features; all underwent surgery, six received chemotherapy. Twelve children had OMS without a detected neuroblastoma. For OMS, the main treatment in all children was corticotherapy (n=33), but immunoglobulins (n=13), cyclophosphamide (n=4) and rituximab (n=4) were also given. In the 27 OMS patients with or without neuroblastoma whose follow up was greater than two years, the neurological outcome was evaluated: 59.3% had neurological sequelae, including motor, praxic and/or language sequelae (n=9), persistent ataxia (n=6) and moderate motor deficit (n=3). No significant difference in neurological outcome was noted between the two patient groups.
Our retrospective study provides further evidence that OMS with or without a detected neuroblastoma is the same disease, whose major challenges are the neurological sequelae. An international collaboration is required to improve the knowledge about OMS, the treatment and the outcome in this rare disorder.
European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society 09/2010; 14(5):400-9. · 2.01 Impact Factor