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ANKRD11 (ankyrin repeat domain 11) is a chromatin regulator and the only gene associated with KBG syndrome, a rare neurodevelopmental disorder. We have previously shown that Ankrd11 regulates murine embryonic cortical neurogenesis. Here, we show a novel olfactory bulb phenotype in a KBG syndrome mouse model and two diagnosed patients. Conditional knockout of Ankrd11 in murine embryonic neural stem cells leads to aberrant postnatal olfactory bulb development and reduced size due to reduction of the olfactory bulb granule cell layer. We further show that the rostral migratory stream has incomplete migration of neuroblasts, reduced cell proliferation as well as aberrant differentiation of neurons. This leads to reduced neuroblasts and neurons in the olfactory bulb granule cell layer. In vitro, Ankrd11-deficient neural stem cells from the postnatal subventricular zone display reduced migration, proliferation, and neurogenesis. Finally, we describe two clinically and molecularly confirmed KBG syndrome patients with anosmia and olfactory bulb and groove hypo-dysgenesis/agenesis. Our report provides evidence that Ankrd11 is a novel regulator of olfactory bulb development and neuroblast migration. Moreover, our study highlights a novel clinical sign of KBG syndrome linked to ANKRD11 perturbations in mice and humans.
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Anormalidades Múltiplas , Doenças do Desenvolvimento Ósseo , Deficiência Intelectual , Anormalidades Dentárias , Humanos , Animais , Camundongos , Fácies , Bulbo Olfatório , Modelos Animais de DoençasRESUMO
PACS2 pathogenic variants are associated with an autosomal dominant syndrome (OMIM DEE66), associating developmental and epileptic encephalopathy, facial dysmorphism, and cerebellar dysgenesis. However, no malformation of cortical development has been reported yet. We report here a seven-year-old child with a history of infantile epileptic spasm syndrome and a right insular polymicrogyria and pachygyria due to de novo PACS2 recurrent mutation c.625G>A (p.Glu209Lys). Our observation raises the question of the role of PACS2 in the cortical development. It also reminds the importance of cerebellar anomalies in the recognition of PACS-related DEE.
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Epilepsia Generalizada , Epilepsia , Polimicrogiria , Criança , Humanos , Epilepsia/genética , Síndrome , Fenótipo , Mutação , Proteínas de Transporte Vesicular/genéticaRESUMO
Introduction: Fetal alcohol spectrum disorders (FASD) range from fetal alcohol syndrome (FAS) to non-syndromic forms (NS-FASD). The neuroanatomical consequences of prenatal alcohol exposure are mainly the reduction in brain size, but also focal abnormalities such as those of the corpus callosum (CC). We previously showed a narrowing of the CC for brain size, using manual measurement and its usefulness to improve diagnostic certainty. Our aim was to automate these measurements of the CC and identify more recurrent abnormalities in FAS subjects, independently of brain size reduction. Methods: We developed a fast, automated, and normalization-free method based on spectral analysis to generate thicknesses of the CC continuously and at singular points (genu, body, isthmus, and splenium), and its length (LCC). We applied it on midsagittal section of the CC extracted from T1-anatomical brain MRI of 89 subjects with FASD (52 FAS, 37 NS-FASD) and 126 with typically development (6-20 y-o). After adjusting for batch effect, we compared the mean profiles and thicknesses of the singular points across the 3 groups. For each parameter, we established variations with age (growth charts) and brain size in the control group (scaling charts), then identified participants with abnormal measurements (<10th percentile). Results: We confirmed the slimming of the posterior half of the CC in both FASD groups, and of the genu section in the FAS group, compared to the control group. We found a significant group effect for the LCC, genu, median body, isthmus, and splenium thicknesses (p < 0.05). We described a body hump whose morphology did not differ between groups. According to the growth charts, there was an excess of FASD subjects with abnormal LCC and isthmus, and of FAS subjects with abnormal genu and splenium. According to the scaling charts, this excess remained only for LCC, isthmus and splenium, undersized for brain size. Conclusion: We characterized size-independent anomalies of the posterior part of the CC in FASD, with an automated method, confirming and extending our previous study. Our new tool brings the use of a neuroanatomical criterion including CC damage closer to clinical practice. Our results suggest that an FAS signature identified in NS-FASD, could improve diagnosis specificity.
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Introduction: Fetal alcohol spectrum disorders (FASD) range from fetal alcohol syndrome (FAS) to non-syndromic non-specific forms (NS-FASD) that are still underdiagnosed and could benefit from new neuroanatomical markers. The main neuroanatomical manifestation of prenatal alcohol exposure on developmental toxicity is the reduction in brain size, but repeated imaging observations have long driven the attention on the corpus callosum (CC), without being all convergent. Our study proposed a new segmentation of the CC that relies on both a sulci-based cortical segmentation and the "hemispherotopic" organization of the transcallosal fibers. Methods: We collected a monocentric series of 37 subjects with FAS, 28 with NS-FASD, and 38 with typical development (6 to 25 years old) using brain MRI (1.5T). Associating T1- and diffusion-weighted imaging, we projected a sulci-based cortical segmentation of the hemispheres on the midsagittal section of the CC, resulting in seven homologous anterior-posterior parcels (frontopolar, anterior and posterior prefrontal, precentral, postcentral, parietal, and occipital). We measured the effect of FASD on the area of callosal and cortical parcels by considering age, sex, and brain size as linear covariates. The surface proportion of the corresponding cortical parcel was introduced as an additional covariate. We performed a normative analysis to identify subjects with an abnormally small parcel. Results: All callosal and cortical parcels were smaller in the FASD group compared with controls. When accounting for age, sex, and brain size, only the postcentral (η2 = 6.5%, pFDR = 0.032) callosal parcel and % of the cortical parcel (η2 = 8.9%, pFDR = 0.007) were still smaller. Adding the surface proportion (%) of the corresponding cortical parcel to the model, only the occipital parcel was persistently reduced in the FASD group (η2 = 5.7%, pFDR = 0.014). In the normative analysis, we found an excess of subjects with FASD with abnormally small precentral and postcentral (peri-isthmic) and posterior-splenial parcels (pFDR < 0.05). Conclusion: The objective sulcal and connectivity-based method of CC parcellation proved to be useful not only in confirming posterior-splenial damage in FASD but also in the narrowing of the peri-isthmic region strongly associated with a specific size reduction in the corresponding postcentral cortical region (postcentral gyrus). The normative analysis showed that this type of callosal segmentation could provide a clinically relevant neuroanatomical endophenotype, even in NS-FASD.
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In fetal alcohol spectrum disorders (FASD), brain growth deficiency is a hallmark of subjects both with fetal alcohol syndrome (FAS) and with non-syndromic FASD (NS-FASD, i.e., those without specific diagnostic features). However, although the cerebellum was suggested to be more severely undersized than the rest of the brain, it has not yet been given a specific place in the FASD diagnostic criteria where neuroanatomical features still count for little if anything in diagnostic specificity. We applied a combination of cerebellar segmentation tools on a 1.5 T 3DT1 brain MRI dataset from a monocentric population of 89 FASD (52 FAS, 37 NS-FASD) and 126 typically developing controls (6-20 years old), providing 8 volumes: cerebellum, vermis and 3 lobes (anterior, posterior, inferior), plus total brain volume. After adjustment of confounders, the allometric scaling relationship between these cerebellar volumes (Vi ) and the total brain or cerebellum volume (Vt ) was fitted (Vi = bVt a ), and the effect of group (FAS, control) on allometric scaling was evaluated. We then estimated for each cerebellar volume in the FAS population the deviation from the typical scaling (v DTS) learned in the controls. Lastly, we trained and tested two classifiers to discriminate FAS from controls, one based on the total cerebellum v DTS only, the other based on all the cerebellar v DTS, comparing their performance both in the FAS and the NS-FASD group. Allometric scaling was significantly different between FAS and control group for all the cerebellar volumes (p < .001). We confirmed the excess of total cerebellum volume deficit (v DTS = -10.6%) and revealed an antero-inferior-posterior gradient of volumetric undersizing in the hemispheres (-12.4%, 1.1%, 2.0%, respectively) and the vermis (-16.7%, -9.2%, -8.6%, repectively). The classifier based on the intracerebellar gradient of v DTS performed more efficiently than the one based on total cerebellum v DTS only (AUC = 92% vs. 82%, p = .001). Setting a high probability threshold for >95% specificity of the classifiers, the gradient-based classifier identified 35% of the NS-FASD to have a FAS cerebellar phenotype, compared to 11% with the cerebellum-only classifier (pFISHER = 0.027). In a large series of FASD, this study details the volumetric undersizing within the cerebellum at the lobar and vermian level using allometric scaling, revealing an anterior-inferior-posterior gradient of vulnerability to prenatal alcohol exposure. It also strongly suggests that this intracerebellar gradient of volumetric undersizing may be a reliable neuroanatomical signature of FAS that could be used to improve the specificity of the diagnosis of NS-FASD.
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Transtornos do Espectro Alcoólico Fetal , Efeitos Tardios da Exposição Pré-Natal , Humanos , Gravidez , Feminino , Transtornos do Espectro Alcoólico Fetal/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Imageamento por Ressonância MagnéticaRESUMO
AIM: To identify easily accessible neuroanatomical abnormalities useful for diagnosing fetal alcohol spectrum disorders (FASD) in fetal alcohol syndrome (FAS) but more importantly for the probabilistic diagnosis of non-syndromic forms (NS-FASD). METHOD: We retrospectively collected monocentric data from 52 individuals with FAS, 37 with NS-FASD, and 94 paired typically developing individuals (6-20 years, 99 males, 84 females). On brain T1-weighted magnetic resonance imaging, we measured brain size, corpus callosum length and thicknesses, vermis height, then evaluated vermis foliation (Likert scale). For each parameter, we established variations with age and brain size in comparison individuals (growth and scaling charts), then identified participants with abnormal measurements (<10th centile). RESULTS: According to growth charts, there was an excess of FAS with abnormally small brain, isthmus, splenium, and vermis. According to scaling charts, this excess remained only for isthmus thickness and vermis height. The vermis foliation was pathological in 18% of those with FASD but in no comparison individual. Overall, 39% of those with FAS, 27% with NS-FASD, but only 2% of comparison individuals presented with two FAS-recurrent abnormalities, and 19% of those with FAS had all three. Considering the number of anomalies, there was a higher likelihood of a causal link with alcohol in 14% of those with NS-FASD. INTERPRETATION: Our results suggest that adding an explicit composite neuroanatomical-radiological criterion for FASD diagnosis may improve its specificity, especially in NS-FASD. WHAT THIS PAPER ADDS: Neuroanatomical anomalies independent of microcephaly can be measured with clinical-imaging tools. Small-for-age brain, small-for-brain-size callosal isthmus or vermian height, and disrupted vermis foliation are fetal alcohol syndrome (FAS)-recurrent anomalies. Associations of these anomalies are frequent in fetal alcohol spectrum disorder (FASD) even without FAS, while exceptional in typically developing individuals. These associations support higher likelihood of causal link with alcohol in some individuals with non-syndromic FASD. A new explicit and composite neuroanatomical-radiological criterion can improve the specificity of FASD diagnosis.
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Transtornos do Espectro Alcoólico Fetal , Feminino , Masculino , Gravidez , Humanos , Estudos Retrospectivos , Encéfalo , Corpo Caloso , EtanolRESUMO
AIM: To characterize the cortical structure, developmental, and cognitive profiles of patients with WD repeat domain 62 (WDR62)-related primary microcephaly. METHOD: In this observational study, we describe the developmental, neurological, cognitive, and brain imaging characteristics of 17 patients (six males, 11 females; mean age 12y 3mo standard deviation [SD] 5y 8mo, range 5y-24y 6mo) and identify 14 new variants of WDR62. We similarly analyse the phenotypes and genotypes of the 59 previously reported families. RESULTS: Brain malformations, including pachygyria, neuronal heterotopia, schizencephaly, and microlissencephaly, were present in 11 out of 15 patients. The mean full-scale IQ of the 11 assessed patients was 51.8 (standard deviation [SD] 12.6, range 40-70). Intellectual disability was severe in four patients, moderate in four, and mild in three. Scores on the Vineland Adaptive Behavior Scales obtained from 10 patients were low for communication and motor skills (mean 38.29, SD 7.74, and 37.71, SD 5.74 respectively). The socialization score was higher (mean 47.14, SD 12.39). We found a significant difference between scores for communication and daily living skills (mean 54.43, SD 11.6; p=0.001, one-way analysis of variance). One patient displayed progressive ataxia. INTERPRETATION: WDR62-related cognitive consequences may be less severe than expected because 3 out of 11 of the assessed patients had only mild intellectual disability and relatively preserved abilities of autonomy in daily life. We identified progressive ataxia in the second decade of life in one patient, which should encourage clinicians to follow up patients in the long term.
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Proteínas de Ciclo Celular , Deficiência Intelectual , Microcefalia , Proteínas do Tecido Nervoso , Adolescente , Ataxia , Proteínas de Ciclo Celular/genética , Criança , Pré-Escolar , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Masculino , Microcefalia/diagnóstico , Microcefalia/genética , Proteínas do Tecido Nervoso/genética , Adulto JovemAssuntos
COVID-19 , Leucoencefalopatias , Humanos , Imageamento por Ressonância Magnética , RecidivaRESUMO
PURPOSE: KCNQ2-epileptic encephalopathy (EE) is a neonatal epilepsy syndrome characterized by a typical clinical presentation and EEG recording, but without any brain or cortical abnormal development on MRI. Most of the patients have a severe developmental impairment. The epileptogenic mechanisms are thought to be the result of the changes of the M-current density causing a change of brain excitability. Although recent studies allow us to better understand the physiopathology of KCNQ2-EE, the neuropathology of this ion channel dysfunction has only been previously described in a single case report. METHODS: We report the neuropathology study of a case of KCNQ2-EE with a typical electro-phenotype due to a de novo heterozygous single nucleotide pathogenic variant in the exon 5 of the KCNQ2 gene (NM_172107.2:c.802C>T; p.Leu268Phe). RESULTS: At the macroscopic level, the brain had a normal structure with a normal neocortical gyral pattern. At the histological level, the cortex had a usual six-layer lamination in all lobes but blurred gray-white matter boundaries due to excessive heterotopic neurons in deep white matter were observed. This diffuse mild malformation of cortical development is suggestive of a neuronal migration disorder. CONCLUSION: In recent years, our understanding of the role of ion channel dysfunctions in early brain development has expanded from the occurrence of EE to brain malformation. Through this rare neuropathological report, we emphasize the role of KCNQ2 channels in the process of cortical development. As for other genetic neonatal onset epilepsies, more reports are needed to further delineate the range of neuropathological abnormalities for KCNQ2-EE.
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Encefalopatias , Epilepsia Generalizada , Epilepsia , Doenças do Recém-Nascido , Encefalopatias/genética , Epilepsia/genética , Epilepsia Generalizada/genética , Humanos , Recém-Nascido , Canal de Potássio KCNQ2/genética , Mutação/genética , FenótipoRESUMO
A wide spectrum of disorders involves the parotid glands, in infancy and childhood. Acute or chronic inflammatory/infectious diseases are predominant. The first branchial cleft anomalies are congenital lesions that typically manifest during childhood. Tumor lesions are more likely to be benign, with infantile hemangioma the most common in infancy and pleomorphic adenoma the most frequent in childhood. Malignant tumors are uncommon, with mucoepidermoid carcinoma the least rare. Infiltrative parotid diseases are rare and have some pediatric clinical specificities. These common and uncommon disorders of parotid glands during childhood and their imaging characteristics are reviewed.
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OBJECTIVES: The aims of this study were first to calculate the Positive Predictive Value (PPV) of DW-MRI to detect cholesteatoma and then to analyze false positives. METHODS: All temporal bone MRI with DWI sequences performed in our pediatric university hospital between 2005 and 2015 were included retrospectively. 46 patients with a cholesteatoma diagnosis on the MRI report and who underwent surgery were studied. RESULTS: The number of DW-MRI for identification of cholesteatoma has grown in ten years. We calculated an 89% Positive Predictive Value. DW-MRI sensitivities were 100.0% and 70.7% for respectively keratin and squamous epithelium. CONCLUSION: DW-MRI hypersignal is not synonymous of cholesteatoma diagnosis. Indeed, this diagnosis relies on the importance of a proper otoscopic examination, a suggestive medical history, CT scan data and analysis of other MRI sequences, including T1-weighted sequence, to rule out other etiologies of middle ear DW-MRI hypersignal.
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Colesteatoma da Orelha Média , Imagem de Difusão por Ressonância Magnética , Criança , Colesteatoma da Orelha Média/diagnóstico por imagem , Colesteatoma da Orelha Média/cirurgia , Humanos , Imageamento por Ressonância Magnética , Valor Preditivo dos Testes , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
PURPOSE: TNR, encoding Tenascin-R, is an extracellular matrix glycoprotein involved in neurite outgrowth and neural cell adhesion, proliferation and migration, axonal guidance, myelination, and synaptic plasticity. Tenascin-R is exclusively expressed in the central nervous system with highest expression after birth. The protein is crucial in the formation of perineuronal nets that ensheath interneurons. However, the role of Tenascin-R in human pathology is largely unknown. We aimed to establish TNR as a human disease gene and unravel the associated clinical spectrum. METHODS: Exome sequencing and an online matchmaking tool were used to identify patients with biallelic variants in TNR. RESULTS: We identified 13 individuals from 8 unrelated families with biallelic variants in TNR sharing a phenotype consisting of spastic para- or tetraparesis, axial muscular hypotonia, developmental delay, and transient opisthotonus. Four homozygous loss-of-function and four different missense variants were identified. CONCLUSION: We establish TNR as a disease gene for an autosomal recessive nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus and highlight the role of central nervous system extracellular matrix proteins in the pathogenicity of spastic disorders.
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Espasticidade Muscular , Transtornos do Neurodesenvolvimento , Sistema Nervoso Central , Matriz Extracelular , Homozigoto , Humanos , Espasticidade Muscular/genética , Transtornos do Neurodesenvolvimento/genéticaRESUMO
BACKGROUND: Primary hereditary microcephaly (MCPH) comprises a large group of autosomal recessive disorders mainly affecting cortical development and resulting in a congenital impairment of brain growth. Despite the identification of >25 causal genes so far, it remains a challenge to distinguish between different MCPH forms at the clinical level. METHODS: 7 patients with newly identified mutations in CDK5RAP2 (MCPH3) were investigated by performing prospective, extensive and systematic clinical, MRI, psychomotor, neurosensory and cognitive examinations under similar conditions. RESULTS: All patients displayed neurosensory defects in addition to microcephaly. Small cochlea with incomplete partition type II was found in all cases and was associated with progressive deafness in 4 of them. Furthermore, the CDK5RAP2 protein was specifically identified in the developing cochlea from human fetal tissues. Microphthalmia was also present in all patients along with retinal pigmentation changes and lipofuscin deposits. Finally, hypothalamic anomalies consisting of interhypothalamic adhesions, a congenital midline defect usually associated with holoprosencephaly, was detected in 5 cases. CONCLUSION: This is the first report indicating that CDK5RAP2 not only governs brain size but also plays a role in ocular and cochlear development and is necessary for hypothalamic nuclear separation at the midline. Our data indicate that CDK5RAP2 should be considered as a potential gene associated with deafness and forme fruste of holoprosencephaly. These children should be given neurosensory follow-up to prevent additional comorbidities and allow them reaching their full educational potential. TRIAL REGISTRATION NUMBER: NCT01565005.
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Proteínas de Ciclo Celular/genética , Doenças Cocleares/genética , Microcefalia/genética , Proteínas do Tecido Nervoso/genética , Criança , Pré-Escolar , Cóclea/diagnóstico por imagem , Cóclea/metabolismo , Cóclea/patologia , Doenças Cocleares/diagnóstico por imagem , Doenças Cocleares/patologia , Anemia de Fanconi/genética , Anemia de Fanconi/patologia , Feminino , Humanos , Hipotálamo/diagnóstico por imagem , Hipotálamo/patologia , Lactente , Imageamento por Ressonância Magnética , Masculino , Microcefalia/diagnóstico por imagem , Microcefalia/patologia , Mutação , Neurogênese/genética , Linhagem , Retina/diagnóstico por imagem , Retina/patologiaRESUMO
Neuronal ceroid lipofuscinoses (NCLs) are rare, progressive disorders. Through this series of 20 patients with NCL, we illustrate differences between subtypes in their presenting symptoms and clinical, imaging, and electrophysiological results to raise awareness of symptom diversity. Data were available on presenting symptoms, genetics, magnetic resonance imaging (MRI), electroencephalography (including with low-frequency intermittent photic stimulation), visual responses, and electron microscopy. Causal mutations were identified in 10 patients. Eleven patients had neuronal ceroid lipofuscinosis type 2 (CLN2) disease and their most common presenting symptom was seizures, although motor and language defects were also reported. Five patients with CLN2 disease showed abnormalities at initial MRI, but only three showed a photic response with low-frequency stimulation. Seizures were not as common a presenting symptom in other NCL subtypes. Patients with NCLs present with diverse symptoms, which may not be characteristic in early disease stages. These signs and symptoms should lead to rapid diagnostic confirmatory testing for NCLs. WHAT THIS PAPER ADDS: Disease presentation is not uniform for neuronal ceroid lipofuscinoses. Characteristic clinical test results may not be identified in early disease stages.
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Encéfalo/diagnóstico por imagem , Lipofuscinoses Ceroides Neuronais/diagnóstico , Encéfalo/fisiopatologia , Pré-Escolar , Eletroencefalografia , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Lipofuscinoses Ceroides Neuronais/diagnóstico por imagem , Lipofuscinoses Ceroides Neuronais/fisiopatologia , Estudos Retrospectivos , Tripeptidil-Peptidase 1RESUMO
OBJECTIVE: SLC13A3 encodes the plasma membrane Na+ /dicarboxylate cotransporter 3, which imports inside the cell 4 to 6 carbon dicarboxylates as well as N-acetylaspartate (NAA). SLC13A3 is mainly expressed in kidney, in astrocytes, and in the choroid plexus. We describe two unrelated patients presenting with acute, reversible (and recurrent in one) neurological deterioration during a febrile illness. Both patients exhibited a reversible leukoencephalopathy and a urinary excretion of α-ketoglutarate (αKG) that was markedly increased and persisted over time. In one patient, increased concentrations of cerebrospinal fluid NAA and dicarboxylates (including αKG) were observed. Extensive workup was unsuccessful, and a genetic cause was suspected. METHODS: Whole exome sequencing (WES) was performed. Our teams were connected through GeneMatcher. RESULTS: WES analysis revealed variants in SLC13A3. A homozygous missense mutation (p.Ala254Asp) was found in the first patient. The second patient was heterozygous for another missense mutation (p.Gly548Ser) and an intronic mutation affecting splicing as demonstrated by reverse transcriptase polymerase chain reaction performed in muscle tissue (c.1016 + 3A > G). Mutations and segregation were confirmed by Sanger sequencing. Functional studies performed on HEK293T cells transiently transfected with wild-type and mutant SLC13A3 indicated that the missense mutations caused a marked reduction in the capacity to transport αKG, succinate, and NAA. INTERPRETATION: SLC13A3 deficiency causes acute and reversible leukoencephalopathy with marked accumulation of αKG. Urine organic acids (especially αKG and NAA) and SLC13A3 mutations should be screened in patients presenting with unexplained reversible leukoencephalopathy, for which SLC13A3 deficiency is a novel differential diagnosis. ANN NEUROL 2019;85:385-395.
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Ácido Aspártico/análogos & derivados , Ácidos Cetoglutáricos/metabolismo , Leucoencefalopatias/genética , Simportadores/genética , Adolescente , Ácido Aspártico/líquido cefalorraquidiano , Ácido Aspártico/metabolismo , Pré-Escolar , Feminino , Células HEK293 , Humanos , Ácidos Cetoglutáricos/líquido cefalorraquidiano , Ácidos Cetoglutáricos/urina , Leucoencefalopatias/metabolismo , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Mutação de Sentido Incorreto , Linhagem , Infecções Respiratórias , Ácido Succínico/metabolismo , Simportadores/metabolismo , Tonsilite , Sequenciamento do ExomaRESUMO
Importance: In children with sickle cell anemia (SCA), high transcranial Doppler (TCD) velocities are associated with stroke risk, which is reduced by chronic transfusion. Whether matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) can reduce velocities in patients with SCA is unknown. Objective: To determine the association of MSD-HSCT with TCD velocities as a surrogate for the occurrence of ischemic stroke in children with SCA. Design, Setting, and Participants: Nonrandomized controlled intervention study conducted at 9 French centers. Patients with SCA were enrolled between December 2010 and June 2013, with 3-year follow-up ending in January 2017. Children with SCA were eligible if younger than 15 years, required chronic transfusions for persistently elevated TCD velocities, and had at least 1 sibling without SCA from the same 2 parents. Families agreed to HLA antigen typing and transplantation if a matched sibling donor was identified or to standard care in the absence of a matched sibling donor. Exposures: MSD-HSCT (n = 32), compared with standard care (n = 35) (transfusions for ≥1 year with potential switch to hydroxyurea thereafter), using propensity score matching. Main Outcomes and Measures: The primary outcome was the highest time-averaged mean of maximum velocities in 8 cerebral arteries, measured by TCD (TCD velocity) at 1 year. Twenty-five of 29 secondary outcomes were analyzed, including the highest TCD velocity at 3 years and normalization of velocities (<170 cm/s) and ferritin levels at 1 and 3 years. Results: Sixty-seven children with SCA (median age, 7.6 years; 35 girls [52%]) were enrolled (7 with stroke history). In the matched sample, highest TCD velocities at 1 year were significantly lower on average in the transplantation group (129.6 cm/s) vs the standard care group (170.4 cm/s; difference, -40.8 cm/s [95% CI, -62.9 to -18.6]; P < .001). Of the 25 analyzed secondary end points, 4 showed significant differences, including the highest TCD velocity at 3 years (112.4 cm/s in the transplantation group vs 156.7 cm/s in the standard care group; difference, -44.3 [95% CI, -71.9 to -21.1]; P = .001); normalization rate at 1 year (80.0% in the transplantation group vs 48.0% in the standard care group; difference, 32.0% [95% CI, 0.2% to 58.6%]; P = .045); and ferritin levels at 1 year (905 ng/mL in the transplantation group vs 2529 ng/mL in the standard care group; difference, -1624 [95% CI, -2370 to -879]; P < .001) and 3 years (382 ng/mL in the transplantation group vs 2170 ng/mL in the standard care group; difference, -1788 [95% CI, -2570 to -1006]; P < .001). Conclusions and Relevance: Among children with SCA requiring chronic transfusion because of persistently elevated TCD velocities, MSD-HSCT was significantly associated with lower TCD velocities at 1 year compared with standard care. Further research is warranted to assess the effects of MSD-HSCT on clinical outcomes and over longer follow-up. Trial Registration: ClinicalTrials.gov Identifier: NCT01340404.
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Anemia Falciforme/terapia , Circulação Cerebrovascular/fisiologia , Transplante de Células-Tronco Hematopoéticas , Irmãos , Ultrassonografia Doppler Transcraniana , Aloenxertos , Anemia Falciforme/diagnóstico por imagem , Anemia Falciforme/fisiopatologia , Velocidade do Fluxo Sanguíneo , Criança , Feminino , Ferritinas/sangue , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pontuação de Propensão , Qualidade de Vida , Condicionamento Pré-TransplanteRESUMO
OBJECTIVE: To identify the genetic cause of hypomyelinating leukodystrophy in 2 consanguineous families. METHODS: Homozygosity mapping combined with whole-exome sequencing of consanguineous families was performed. Mutation consequences were determined by studying the structural change of the protein and by the RNA analysis of patients' fibroblasts. RESULTS: We identified a biallelic mutation in a gene coding for a Pol III-specific subunit, POLR3K (c.121C>T/p.Arg41Trp), that cosegregates with the disease in 2 unrelated patients. Patients expressed neurologic and extraneurologic signs found in POLR3A- and POLR3B-related leukodystrophies with a peculiar severe digestive dysfunction. The mutation impaired the POLR3K-POLR3B interactions resulting in zebrafish in abnormal gut development. Functional studies in the 2 patients' fibroblasts revealed a severe decrease (60%-80%) in the expression of 5S and 7S ribosomal RNAs in comparison with control. CONCLUSIONS: These analyses underlined the key role of ribosomal RNA regulation in the development and maintenance of the white matter and the cerebellum as already reported for diseases related to genes involved in transfer RNA or translation initiation factors.