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1.
Prenat Diagn ; 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31273809

RESUMO

OBJECTIVE: Uniparental disomy (UPD) testing is currently recommended during pregnancy in fetuses carrying a balanced Robertsonian translocation (ROB) involving chromosome 14 or 15, both chromosomes containing imprinted genes. The overall risk that such a fetus presents a UPD has been previously estimated to be around ~0.6-0.8%. However, because UPD are rare events and this estimate has been calculated from a number of studies of limited size, we have reevaluated the risk of UPD in fetuses for whom one of the parents was known to carry a nonhomologous ROB (NHROB). METHOD: We focused our multicentric study on NHROB involving chromosome 14 and/or 15. A total of 1747 UPD testing were performed in fetuses during pregnancy for the presence of UPD(14) and/or UPD(15). RESULT: All fetuses were negative except one with a UPD(14) associated with a maternally inherited rob(13;14). CONCLUSION: Considering these data, the risk of UPD following prenatal diagnosis of an inherited ROB involving chromosome 14 and/or 15 could be estimated to be around 0.06%, far less than the previous estimation. Importantly, the risk of miscarriage following an invasive prenatal sampling is higher than the risk of UPD. Therefore, we do not recommend prenatal testing for UPD for these pregnancies and parents should be reassured.

5.
Clin Genet ; 2018 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-30298622

RESUMO

Reunion Island is a French oversea department in the Indian Ocean with 1.6/1000, an estimated prevalence of deafness that is almost double as compared to the mainland France. Twelve children having isolated bilateral prelingual profound deafness along with motor delay attributed to vestibular areflexia were enrolled. Their mean walking age was 19 months. Electroretinography and temporal bone CT-scans were normal in all cases. A novel homozygous frameshift lipoma HMGIC fusion partner-like 5 (LHFPL5) variant c.185delT p.(Phe62Serfs*23) was identified using whole-exome sequencing. It was found in seven families. Four patients from two different families from both Reunion Island and mainland France, were compound heterozygous: c.185delT p.(Phe62Serfs*23) and c.472C > T p.(Arg158Trp). The phenotype observed in our patients completely mimics the hurry-scurry (hscy) murine Tmhs knock-out model. The recurrent occurrence of same LHFPL5 variant in Reunion Island is attributed to common ancestor couple born in 1693.

6.
Hum Mutat ; 39(7): 970-982, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29664219

RESUMO

Myotonic dystrophy type 1 (DM1) is a dominant multisystemic disorder associated with high variability of symptoms and anticipation. DM1 is caused by an unstable CTG repeat expansion that usually increases in successive generations and tissues. DM1 family pedigrees have shown that ∼90% and 10% of transmissions result in expansions and contractions of the CTG repeat, respectively. To date, the mechanisms of CTG repeat contraction remain poorly documented in DM1. In this report, we identified two new DM1 families with apparent contractions and no worsening of DM1 symptoms in two and three successive maternal transmissions. A new and unique CAG interruption was found in 5' of the CTG expansion in one family, whereas multiple 5' CCG interruptions were detected in the second family. We showed that these interruptions are associated with maternal intergenerational contractions and low somatic mosaicism in blood. By specific triplet-prime PCR, we observed that CTG repeat changes (contractions/expansions) occur preferentially in 3' of the interruptions for both families.

7.
J Med Genet ; 55(6): 359-371, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29618507

RESUMO

The Xq28 duplication involving the MECP2 gene (MECP2 duplication) has been mainly described in male patients with severe developmental delay (DD) associated with spasticity, stereotypic movements and recurrent infections. Nevertheless, only a few series have been published. We aimed to better describe the phenotype of this condition, with a focus on morphological and neurological features. Through a national collaborative study, we report a large French series of 59 affected males with interstitial MECP2 duplication. Most of the patients (93%) shared similar facial features, which evolved with age (midface hypoplasia, narrow and prominent nasal bridge, thick lower lip, large prominent ears), thick hair, livedo of the limbs, tapered fingers, small feet and vasomotor troubles. Early hypotonia and global DD were constant, with 21% of patients unable to walk. In patients able to stand, lower limbs weakness and spasticity led to a singular standing habitus: flexion of the knees, broad-based stance with pseudo-ataxic gait. Scoliosis was frequent (53%), such as divergent strabismus (76%) and hypermetropia (54%), stereotypic movements (89%), without obvious social withdrawal and decreased pain sensitivity (78%). Most of the patients did not develop expressive language, 35% saying few words. Epilepsy was frequent (59%), with a mean onset around 7.4 years of age, and often (62%) drug-resistant. Other medical issues were frequent: constipation (78%), and recurrent infections (89%), mainly lung. We delineate the clinical phenotype of MECP2 duplication syndrome in a large series of 59 males. Pulmonary hypertension appeared as a cause of early death in these patients, advocating its screening early in life.

8.
Eur J Med Genet ; 2018 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-29530802

RESUMO

Freidreich ataxia (FRDA) is the most common hereditary ataxia, nearly 98% of patients harbouring homozygous GAA expansions in intron 1 of the FXN gene (NM_000144.4). The remaining patients are compound heterozygous for an expansion and a point mutation or an exonic deletion. Molecular screening for FXN expansion is therefore focused on (GAA)n expansion analysis, commonly performed by triplet repeat primed PCR (PT-PCR). We report on an initial pitfall in the molecular characterization of a 15 year-old girl with Freidreich ataxia (FRDA) who carried a rare deletion in intron 1 of the FXN gene. Due to this deletion TP-PCR failed to amplify the GAA expansion. This exceptional configuration induced misinterpretation of the molecular defect in this patient, who was first reported as having no FXN expansion. NGS analysis of a panel of 212 genes involved in nuclear mitochondrial disorders further revealed an intragenic deletion encompassing exons 4-5 of the FXN gene. Modified TP-PCR analysis confirmed the presence of a classical (GAA)n expansion located in trans. This case points out the possible pitfalls in molecular diagnosis of FRDA in affected patients and their relatives: detection of the FXN expansion may be impaired by several non-pathological or pathological variants around the FXN (GAA)n repeat. We propose a new molecular strategy to accurately detect expansion by TP-PCR in FRDA patients.

10.
J Med Genet ; 55(6): 378-383, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29358270

RESUMO

BACKGROUND: Because the mitochondrial respiratory chain (RC) is ubiquitous, its deficiency can theoretically give rise to any symptom in any organ or tissue at any age with any mode of inheritance, owing to the twofold genetic origin of respiratory enzyme machinery, that is, nuclear and mitochondrial. Not all respiratory enzyme deficiencies are primary and secondary or artefactual deficiency is frequently observed, leading to a number of misleading conclusions and inappropriate investigations in clinical practice. This study is aimed at investigating the potential role of brain MRI in distinguishing primary RC deficiency from phenocopies and other aetiologies. METHODS: Starting from a large series of 189 patients (median age: 3.5 years (8 days-56 years), 58% males) showing signs of RC enzyme deficiency, for whom both brain MRIs and disease-causing mutations were available, we retrospectively studied the positive predictive value (PPV) and the positive likelihood ratio (LR+) of brain MRI imaging and its ability to discriminate between two groups: primary deficiency of the mitochondrial RC machinery and phenocopies. RESULTS: Detection of (1) brainstem hyperintensity with basal ganglia involvement (P≤0.001) and (2) lactate peak with either brainstem or basal ganglia hyperintensity was highly suggestive of primary RC deficiency (P≤0.01). Fourteen items had a PPV>95% and LR+ was greater than 9 for seven signs. Biallelic SLC19A3 mutations represented the main differential diagnosis. Non-significant differences between the two groups were found for cortical/subcortical atrophy, leucoencephalopathy and involvement of caudate nuclei, spinothalamic tract and corpus callosum. CONCLUSION: Based on these results and owing to invasiveness of skeletal muscle biopsies and cost of high-throughput DNA sequencing, we suggest giving consideration to brain MRI imaging as a diagnostic marker and an informative investigation to be performed in patients showing signs of RC enzyme deficiency.

11.
J Med Genet ; 55(4): 278-284, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29358272

RESUMO

BACKGROUND: Stüve-Wiedemann syndrome (SWS) is characterised by bowing of the lower limbs, respiratory distress and hyperthermia that are often responsible for early death. Survivors develop progressive scoliosis and spontaneous fractures. We previously identified LIFR mutations in most SWS cases, but absence of LIFR pathogenic changes in five patients led us to perform exome sequencing and to identify homozygosity for a FAM46A mutation in one case [p.Ser205Tyrfs*13]. The follow-up of this case supported a final diagnosis of osteogenesis imperfecta (OI), based on vertebral collapses and blue sclerae. METHODS AND RESULTS: This prompted us to screen FAM46A in 25 OI patients with no known mutations.We identified a homozygous deleterious variant in FAM46A in two affected sibs with typical OI [p.His127Arg]. Another homozygous variant, [p.Asp231Gly], also classed as deleterious, was detected in a patient with type III OI of consanguineous parents using homozygosity mapping and exome sequencing.FAM46A is a member of the superfamily of nucleotidyltransferase fold proteins but its exact function is presently unknown. Nevertheless, there are lines of evidence pointing to a relevant role of FAM46A in bone development. By RT-PCR analysis, we detected specific expression of FAM46A in human osteoblasts andinterestingly, a nonsense mutation in Fam46a has been recently identified in an ENU-derived (N-ethyl-N-nitrosourea) mouse model characterised by decreased body length, limb, rib, pelvis, and skull deformities and reduced cortical thickness in long bones. CONCLUSION: We conclude that FAM46A mutations are responsible for a severe form of OI with congenital bowing of the lower limbs and suggest screening this gene in unexplained OI forms.

12.
J Med Genet ; 55(2): 131-136, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28754700

RESUMO

BACKGROUND: Mitochondrial DNA (mtDNA) disorders have a high clinical variability, mainly explained by variation of the mutant load across tissues. The high recurrence risk of these serious diseases commonly results in requests from at-risk couples for prenatal diagnosis (PND), based on determination of the mutant load on a chorionic villous sample (CVS). Such procedures are hampered by the lack of data regarding mtDNA segregation in the placenta.The objectives of this report were to determine whether mutant loads (1) are homogeneously distributed across the whole placentas, (2) correlate with those in amniocytes and cord blood cells and (3) correlate with the mtDNA copy number. METHODS: We collected 11 whole placentas carrying various mtDNA mutations (m.3243A>G, m.8344A>G, m.8993T>G, m.9185T>C and m.10197G>A) and, when possible, corresponding amniotic fluid samples (AFSs) and cord blood samples. We measured mutant loads in multiple samples from each placenta (n= 6-37), amniocytes and cord blood cells, as well as total mtDNA content in placenta samples. RESULTS: Load distribution was homogeneous at the sample level when average mutant load was low (<20%) or high (>80%) at the whole placenta level. By contrast, a marked heterogeneity was observed (up to 43%) in the intermediate range (20%-80%), the closer it was to 40%-50% the mutant load, the wider the distribution. Mutant loads were found to be similar in amniocytes and cord blood cells, at variance with placenta samples. mtDNA content correlated to mutant load in m.3243A>G placentas only. CONCLUSION: These data indicate that (1) mutant load determined from CVS has to be interpreted with caution for PND of some mtDNA disorders and should be associated with/substituted by a mutant load measurement on amniocytes; (2) the m.3243A>G mutation behaves differently from other mtDNA mutations with respect to the impact on mtDNA copy number, as previously shown in human preimplantation embryogenesis.

13.
J Inherit Metab Dis ; 41(4): 623-629, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28856627

RESUMO

Propionic acidemia is the result of a deficiency in propionyl-CoA carboxylase activity. Chronic neurologic and cognitive complications frequently occur, but the psychiatric evolution of the disorder is not well documented. We conducted a pedopsychiatric evaluation of 19 children, adolescents and young adults, aged between 2 and 25 years, using ADI-R, CARS-T, as well as ADOS when autism spectrum disorder was suspected. Previous psychometric examinations were also taken into consideration. Thirteen patients had an IQ < 80. Two patients presented with autism and two additional patients with other autism spectrum disorders. Five patients did not fulfill diagnostic criteria for autism spectrum disorder but showed difficulties indicative of a broader autism phenotype (BAP). Four other patients had severe anxiety manifestations related to their disease. Two patients presented with acute psychotic episodes. The number of decompensations in the first 3 years of life was lower in patients with autism spectrum disorder or related symptoms. These patients were also older when they were assessed (median age of 15 years old versus 11 years old). There was no significant correlation between 3-hydroxypropionate levels during the first 6 years of life and autism spectrum disorder diagnosis. In conclusion, autism spectrum disorder is frequent in patients with propionic acidemia. These patients should undergo in-depth psychiatric evaluation and be screened for autism spectrum disorder. Further studies are needed to understand the underlying mechanisms.

14.
Med Sci (Paris) ; 33(6-7): 642-645, 2017 Jun-Jul.
Artigo em Francês | MEDLINE | ID: mdl-28990567

RESUMO

The recent birth from a mitochondrial DNA mutation carrier of a child, conceived after transfer in a donor oocyte of the meiotic spindle, taken from the maternal oocyte, revived the debate on the safety of these procedures. The doubts concern mainly the possibility of genetic reversion, the uncertainties about potential disturbances of the dialogue between nuclear and mitochondrial genomes and the side effects of a heteroplasmic state induced by these techniques. The possibility to expand nuclear transfer applications to patients experiencing in vitro fertilization failure, urges us to answer these questions rapidly.


Assuntos
Doenças Mitocondriais/prevenção & controle , Técnicas de Transferência Nuclear , Técnicas de Reprodução Assistida , Animais , Clonagem de Organismos/métodos , DNA Mitocondrial/efeitos adversos , DNA Mitocondrial/genética , Fertilização In Vitro/métodos , Humanos , Doenças Mitocondriais/genética
15.
J Hepatol ; 2017 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-28939132

RESUMO

Inborn urea cycle disorders are under-recognised metabolic causes of hyperammonemia in adults. A 28-year-old primigravida, seven weeks pregnant, affected by hyperemesis gravidarum developed acute liver injury (ALI) and then acute liver failure (ALF) in less than 48 h. Because the patient developed atypical features, especially mildly elevated aminotransferases contrasting with very high blood ammonia levels (281 µmol/L), concomitant with normal serum creatinine, an inborn error of metabolism was suspected. We performed emergency metabolic analyses, stopped all protein intake and started with intravenous (i.v.) high caloric intake, nitrogen scavenger drugs and haemodialysis. The neurological and hepatic status of the patient quickly improved together with normalisation of her ammonemia levels. High plasma glutamine and urinary orotic acid, alongside low plasma arginine, citrulline and ornithine were suggestive of an ornithine transcarbamylase deficiency, later confirmed by molecular analyses. Foetal sex was female, as determined by foetal DNA analysis in maternal blood, and foetal development was unremarkable throughout the pregnancy. Delivery was induced at 39 weeks with a close monitoring of ammonemia levels and i.v. perfusion of carbohydrates and lipids during labour and immediately post-partum to avoid hypercatabolism. Delivery was uneventful and the patient delivered a healthy female baby. Urea cycle disorders should be contemplated in non-jaundiced patients with ALI or ALF, severe hyperammonemia and normal serum creatinine regardless of serum aminotransferase levels. The prompt recognition of this rare condition and the rapid initiation of adequate metabolic therapy are mandatory to prevent irreversible neurological sequelae and to avoid liver transplantation.

16.
J Allergy Clin Immunol ; 140(6): 1671-1682.e2, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28249776

RESUMO

BACKGROUND: Incontinentia pigmenti (IP; MIM308300) is a severe, male-lethal, X-linked, dominant genodermatosis resulting from loss-of-function mutations in the IKBKG gene encoding nuclear factor κB (NF-κB) essential modulator (NEMO; the regulatory subunit of the IκB kinase [IKK] complex). In 80% of cases of IP, the deletion of exons 4 to 10 leads to the absence of NEMO and total inhibition of NF-κB signaling. Here we describe a new IKBKG mutation responsible for IP resulting in an inactive truncated form of NEMO. OBJECTIVES: We sought to identify the mechanism or mechanisms by which the truncated NEMO protein inhibits the NF-κB signaling pathway. METHODS: We sequenced the IKBKG gene in patients with IP and performed complementation and transactivation assays in NEMO-deficient cells. We also used immunoprecipitation assays, immunoblotting, and an in situ proximity ligation assay to characterize the truncated NEMO protein interactions with IKK-α, IKK-ß, TNF receptor-associated factor 6, TNF receptor-associated factor 2, receptor-interacting protein 1, Hemo-oxidized iron regulatory protein 2 ligase 1 (HOIL-1), HOIL-1-interacting protein, and SHANK-associated RH domain-interacting protein. Lastly, we assessed NEMO linear ubiquitination using immunoblotting and investigated the formation of NEMO-containing structures (using immunostaining and confocal microscopy) after cell stimulation with IL-1ß. RESULTS: We identified a novel splice mutation in IKBKG (c.518+2T>G, resulting in an in-frame deletion: p.DelQ134_R256). The mutant NEMO lacked part of the CC1 coiled-coil and HLX2 helical domain. The p.DelQ134_R256 mutation caused inhibition of NF-κB signaling, although the truncated NEMO protein interacted with proteins involved in activation of NF-κB signaling. The IL-1ß-induced formation of NEMO-containing structures was impaired in fibroblasts from patients with IP carrying the truncated NEMO form (as also observed in HOIL-1-/- cells). The truncated NEMO interaction with SHANK-associated RH domain-interacting protein was impaired in a male fetus with IP, leading to defective linear ubiquitination. CONCLUSION: We identified a hitherto unreported disease mechanism (defective linear ubiquitination) in patients with IP.


Assuntos
Fibroblastos/fisiologia , Quinase I-kappa B/metabolismo , Incontinência Pigmentar/metabolismo , Pele/patologia , Ubiquitinas/metabolismo , Clonagem Molecular , Feminino , Células HEK293 , Humanos , Quinase I-kappa B/genética , Incontinência Pigmentar/genética , Masculino , Mutação/genética , NF-kappa B/metabolismo , Linhagem , Ligação Proteica , Transdução de Sinais , Ativação Transcricional , Ubiquitinação
17.
J Med Genet ; 54(5): 324-329, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28069933

RESUMO

BACKGROUND: While mitochondrial DNA (mtDNA) copy number is strictly regulated during differentiation and according to cell type, very little is known regarding the mechanism which accurately controls mtDNA copy number in human. Exon 2 of the human POLG gene, encoding the catalytic subunit of the mitochondrial-specific DNA polymerase gamma, contains a CpG island, highly conserved in mice and human. Changes of DNA methylation at the POLG locus have been shown to modulate mtDNA copy number during cell differentiation in both mouse and human. METHODS: We have investigated the epigenetic modification of the POLG gene, by assessing the methylation level of its exon 2 using deep-Next Generation Sequencing analysis of bisulfite-treated DNA. Analysis were performed on various tissues at either postnatal or prenatal stages, on samples from carriers of mtDNA mutations, patients carrying two loss-of-function POLG mutations and controls. RESULTS: Very high methylation levels at POLG exon 2 were found (94±3%) and no variation was observed according to either developmental stage or tissue of origin, except for sperm samples for which lower methylation levels were found (80%). This high level of methylation was neither correlated with the presence of mtDNA mutations (94±1% of methylated alleles), nor with biallelic POLG mutations (93%±2%), even in tissues where a mtDNA depletion had been observed. CONCLUSIONS: This study suggests that, at variance with mouse and un/de-differentiated human cells, differentiated human cells control mtDNA levels irrespective of POLG methylation. The factors which actually control the mtDNA levels in such cell types remain to be identified.


Assuntos
Diferenciação Celular/genética , Ilhas de CpG/genética , Metilação de DNA/genética , Polimerase do DNA Mitocondrial/genética , DNA Mitocondrial/genética , Éxons/genética , Mutação/genética , Adolescente , Adulto , Animais , Sequência de Bases , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Camundongos , Pessoa de Meia-Idade , Gravidez , Adulto Jovem
18.
Hum Pathol ; 62: 160-169, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28087478

RESUMO

Lysinuric protein intolerance (LPI) is a rare autosomal recessive disease caused by mutations in the SLC7A7 gene encoding the light subunit of a cationic amino acid transporter. Symptoms mimic primary urea cycle defects but dysimmune symptoms are also described. Renal involvement in LPI was first described in the 1980s. In 2007, it appeared that it could concern as much as 75% of LPI patients and could lead to end-stage renal disease. The most common feature is proximal tubular dysfunction and nephrocalcinosis but glomerular lesions are also reported. However, very little is known regarding histological lesions associated with LPI. We gathered every kidney biopsy of LPI-proven patients in our highly specialized pediatric and adult institution. Clinical, biological, and histological information was analyzed. Five LPI patients underwent kidney biopsy in our institution between 1986 and 2015. Clinically, 4/5 presented with proximal tubular dysfunction and 3/5 with nephrotic range proteinuria. Histology showed unspecific tubulointerstitial lesions and nephrocalcinosis in 3/5 biopsies and marked peritubular capillaritis in one child. Glomerular lesions were heterogeneous: lupus-like-full house membranoproliferative glomerulonephritis (MPGN) in one child evolved towards monotypic IgG1κ MPGN sensitive to immunomodulators. One patient presented with glomerular non-AA non-AL amyloidosis. Renal biopsy is particularly relevant in LPI presenting with glomerular symptoms for which variable histological lesions can be responsible, implying specific treatment and follow-up.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/patologia , Rim/patologia , Adolescente , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Amiloidose/etiologia , Amiloidose/patologia , Biópsia , Criança , Progressão da Doença , Feminino , Imunofluorescência , Cadeias Leves da Proteína-1 Reguladora de Fusão/genética , Predisposição Genética para Doença , Glomerulonefrite Membranoproliferativa/etiologia , Glomerulonefrite Membranoproliferativa/patologia , Humanos , Lactente , Masculino , Mutação , Nefrocalcinose/etiologia , Nefrocalcinose/patologia , Síndrome Nefrótica/etiologia , Síndrome Nefrótica/patologia , Paris , Fenótipo , Proteinúria/etiologia , Proteinúria/patologia , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/patologia , Fatores de Tempo
19.
Orphanet J Rare Dis ; 12(1): 3, 2017 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-28057010

RESUMO

BACKGROUND: Lysinuric protein intolerance (LPI) is a rare metabolic disease resulting from recessive-inherited mutations in the SLC7A7 gene encoding the cationic amino-acids transporter subunit y+LAT1. The disease is characterised by protein-rich food intolerance with secondary urea cycle disorder, but symptoms are heterogeneous ranging from infiltrative lung disease, kidney failure to auto-immune complications. This retrospective study of all cases treated at Necker Hospital (Paris, France) since 1977 describes LPI in both children and adults in order to improve therapeutic management. RESULTS: Sixteen patients diagnosed with LPI (12 males, 4 females, from 9 families) were followed for a mean of 11.4 years (min-max: 0.4-37.0 years). Presenting signs were failure to thrive (n = 9), gastrointestinal disorders (n = 2), cytopenia (n = 6), hyperammonemia (n = 10) with acute encephalopathy (n = 4) or developmental disability (n = 3), and proteinuria (n = 1). During follow-up, 5 patients presented with acute hyperammonemia, and 8 presented with developmental disability. Kidney disease was observed in all patients: tubulopathy (11/11), proteinuria (4/16) and kidney failure (7/16), which was more common in older patients (mean age of onset 17.7 years, standard deviation 5.33 years), with heterogeneous patterns including a lupus nephritis. We noticed a case of myocardial infarction in a 34-year-old adult. Failure to thrive and signs of haemophagocytic-lymphohistiocytosis were almost constant. Recurrent acute pancreatitis occurred in 2 patients. Ten patients developed an early lung disease. Six died at the mean age of 4 years from pulmonary alveolar proteinosis. This pulmonary involvement was significantly associated with death. Age-adjusted plasma lysine concentrations at diagnosis showed a trend toward increased values in patients with a severe disease course and premature death (Wilcoxon p = 0.08; logrank, p = 0.17). Age at diagnosis was a borderline predictor of overall survival (logrank, p = 0.16). CONCLUSIONS: As expected, early pulmonary involvement with alveolar proteinosis is frequent and severe, being associated with an increased risk of death. Kidney disease frequently occurs in older patients. Cardiovascular and pancreatic involvement has expanded the scope of complications. A borderline association between increased levels of plasma lysine and poorer outome is suggested. Greater efforts at prevention are warranted to optimise the long-term management in these patients.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/sangue , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Adolescente , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Criança , Pré-Escolar , Humanos , Lactente , Nefropatias/sangue , Nefropatias/metabolismo , Nefropatias/patologia , Nefrite Lúpica/sangue , Nefrite Lúpica/metabolismo , Nefrite Lúpica/patologia , Lisina/sangue , Múltiplas Afecções Crônicas , Mutação , Infarto do Miocárdio/sangue , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Pancreatite/sangue , Pancreatite/metabolismo , Pancreatite/patologia , Proteinose Alveolar Pulmonar/sangue , Proteinose Alveolar Pulmonar/metabolismo , Proteinose Alveolar Pulmonar/patologia , Estudos Retrospectivos , Distúrbios Congênitos do Ciclo da Ureia/sangue , Distúrbios Congênitos do Ciclo da Ureia/metabolismo , Distúrbios Congênitos do Ciclo da Ureia/patologia , Adulto Jovem
20.
Hum Mutat ; 37(12): 1354-1362, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27650058

RESUMO

Perrault syndrome (PS) is a rare autosomal recessive condition characterized by deafness and gonadic dysgenesis. Recently, mutations in five genes have been identified: C10orf2, CLPP, HARS2, HSD17B4, and LARS2. Probands included are presented with sensorineural deafness associated with gonadic dysgenesis. DNA was sequenced using next-generation sequencing (NGS) with a panel of 35 deafness genes including the five Perrault genes. Exonic variations known as pathogenic mutations or detected with <1% frequency in public databases were extracted and subjected to segregation analysis within each family. Both mutations and low coverage regions were analyzed by Sanger sequencing. Fourteen female index patients were included. The screening in four cases has been extended to four family members presenting with PS phenotype. For four unrelated patients (28.6%), causative mutations were identified: three homozygous mutations in C10orf2, CLPP, and HARS2, and one compound heterozygous mutation in LARS2. Three additional heterozygous mutations in LARS2 and HSD17B4 were found in three independent familial cases. All these missense mutations were verified by Sanger sequencing. Familial segregation analyses confirmed the molecular diagnosis in all cases carrying biallelic mutations. Because of NGS, molecular analysis confirmed the clinical diagnosis of PS in 28.6% of our cohort and four novel mutations were found in four Perrault genes. For the unsolved cases, exome sequencing should be performed to search for a sixth unknown PS gene.


Assuntos
Disgenesia Gonadal 46 XX/genética , Perda Auditiva Neurossensorial/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação de Sentido Incorreto , Análise de Sequência de DNA/métodos , Adolescente , Aminoacil-tRNA Sintetases/genética , Criança , Pré-Escolar , DNA Helicases/genética , Endopeptidase Clp/genética , Exoma , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Proteínas Mitocondriais/genética , Linhagem , Proteína Multifuncional do Peroxissomo-2/genética
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