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2.
Acta Neuropathol Commun ; 8(1): 48, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32293553

RESUMO

Bi-allelic pathogenic variants in genes of the EIF2B family are responsible for Childhood Ataxia with Central nervous system Hypomyelination/Vanishing White Matter disease, a progressive neurodegenerative disorder of the central white matter. Only seven molecularly proven cases with antenatal onset have been reported so far. We report for the first time the neuropathological findings obtained from two foetuses harbouring deleterious variants in the EIF2B5 gene who presented in utero growth retardation and microcephaly with simplified gyral pattern that led to a medical termination of the pregnancy at 27 and 32 weeks of gestation. Neuropathological examination confirmed microcephaly with delayed gyration, periventricular pseudo-cysts and severe cerebellar hypoplasia. Histologically, the cerebellar cortex was immature, the dentate nuclei were fragmented and myelin stains revealed almost no myelination of the infratentorial structures. Bergmann glia was virtually absent associated to a drastic decreased number of mature astrocytes in the cerebellar white matter, multiple nestin-positive immature astrocytes as well as increased numbers of PDGRFα-positive oligodendrocyte precursors. Whole exome sequencing performed in the two foetuses and their parents allowed the identification of two EIF2B5 compound heterozygous variants in the two foetuses: c.468C > G p.Ile156Met and c.1165G > A p.Val389Met, the parents being heterozygous carriers. These variants are absent in the genome Aggregation Database (gnomAD r2.0.2). Contrary to the variant Ile156Met already described in a patient with CACH syndrome, the variant p.Val389Met is novel and predicted to be deleterious using several softwares. Neuropathological findings further expand the phenotypic spectrum of the disease that very likely occurs during early gestation and may manifest from the second half of pregnancy by a severe impairment of cerebral and cerebellar development.

4.
Hum Mutat ; 41(4): 837-849, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31898846

RESUMO

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31413903

RESUMO

Background: KIF1C (Kinesin Family Member 1C) variants have been associated with hereditary spastic paraplegia and spastic ataxia. Case report: We report fraternal twins presenting with cerebellar ataxia and dystonic tremor. Their brain MRI showed a hypomyelinating leukoencephalopathy. Whole exome sequencing identified a homozygous KIF1C variant in both patients. Discussion: KIF1C variants can manifest as a complex movement disorder with cerebellar ataxia and dystonic tremor. KIF1C variants may also cause a hypomyelinating leukoencephalopathy.


Assuntos
Ataxia Cerebelar/genética , Cinesina/genética , Mutação/genética , Tremor/genética , Adolescente , Ataxia Cerebelar/diagnóstico , Distonia/genética , Distúrbios Distônicos , Feminino , Humanos , Masculino , Paraplegia Espástica Hereditária/genética , Tremor/diagnóstico , Gêmeos Dizigóticos
6.
Mol Genet Genomic Med ; 7(9): e914, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31368241

RESUMO

INTRODUCTION: RNA polymerase III (Pol III)-related leukodystrophies are a group of autosomal recessive neurodegenerative disorders caused by mutations in POLR3A and POLR3B. Recently a recessive mutation in POLR1C causative of Pol III-related leukodystrophies was identified. METHODS: We report the case of a Tunisian girl of 14 years of age who was referred to our department for evaluation of progressive ataxia that began at the age of 5. Genetic diagnosis was performed by NGS and Sanger analysis. In silico predictions were performed using SIFT, PolyPhen-2, and Mutation Taster. RESULTS: Neurological examination showed cerebellar and tetrapyramidal syndrome, mixed movement disorders with generalized dystonia and severe myoclonus leading to death at 25 years. Brain MRI scans showed diffuse hypomyelination associated with cerebellar atrophy. It also showed bilateral T2 hypointensity of the ventrolateral thalamus, part of the posterior limb of the internal capsule, the substantia nigra and the subthalamic nucleus. Next generation sequencing leukodystrophy panel including POLR3A and POLR3B was negative. Sanger sequencing of the coding regions of POLR1C revealed a novel homozygous mutation. CONCLUSION: The clinical and imaging findings of patients with POLR1C hypomyelinating leukodystrophy are reviewed. Interestingly, severe myoclonic dystonia and T2 hypointensity of the substantia nigra and the subthalamic nucleus are not reported yet and could be helpful for the diagnosis of POLR1C hypomyelinating leukodystrophy.

7.
Dev Med Child Neurol ; 61(12): 1439-1447, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31410843

RESUMO

The aim of the study was to redefine the phenotype of Allan-Herndon-Dudley syndrome (AHDS), which is caused by mutations in the SLC16A2 gene that encodes the brain transporter of thyroid hormones. Clinical phenotypes, brain imaging, thyroid hormone profiles, and genetic data were compared to the existing literature. Twenty-four males aged 11 months to 29 years had a mutation in SLC16A2, including 12 novel mutations and five previously described mutations. Sixteen patients presented with profound developmental delay, three had severe intellectual disability with poor language and walking with an aid, four had moderate intellectual disability with language and walking abilities, and one had mild intellectual disability with hypotonia. Overall, eight had learned to walk, all had hypotonia, 17 had spasticity, 18 had dystonia, 12 had choreoathetosis, 19 had hypomyelination, and 10 had brain atrophy. Kyphoscoliosis (n=12), seizures (n=7), and pneumopathies (n=5) were the most severe complications. This study extends the phenotypic spectrum of AHDS to a mild intellectual disability with hypotonia. Developmental delay, hypotonia, hypomyelination, and thyroid hormone profile help to diagnose patients. Clinical course depends on initial severity, with stable acquisition after infancy; this may be adversely affected by neuro-orthopaedic, pulmonary, and epileptic complications. WHAT THIS PAPER ADDS: Mild intellectual disability is associated with SLC16A2 mutations. A thyroid hormone profile with a free T3 /T4 ratio higher than 0.75 can help diagnose patients. Patients with SLC16A2 mutations present a broad spectrum of neurological phenotypes that are also observed in other hypomyelinating disorders. Axial hypotonia is a consistent feature of Allan-Herndon-Dudley syndrome and leads to specific complications.


Assuntos
Deficiência Intelectual , Retardo Mental Ligado ao Cromossomo X , Transportadores de Ácidos Monocarboxílicos/genética , Hipotonia Muscular , Atrofia Muscular , Simportadores/genética , Hormônios Tireóideos/sangue , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Deficiências do Desenvolvimento/sangue , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Humanos , Lactente , Deficiência Intelectual/sangue , Deficiência Intelectual/etiologia , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Transtornos do Desenvolvimento da Linguagem , Imagem por Ressonância Magnética , Masculino , Retardo Mental Ligado ao Cromossomo X/sangue , Retardo Mental Ligado ao Cromossomo X/complicações , Retardo Mental Ligado ao Cromossomo X/genética , Retardo Mental Ligado ao Cromossomo X/fisiopatologia , Hipotonia Muscular/sangue , Hipotonia Muscular/complicações , Hipotonia Muscular/etiologia , Hipotonia Muscular/genética , Hipotonia Muscular/fisiopatologia , Atrofia Muscular/sangue , Atrofia Muscular/complicações , Atrofia Muscular/genética , Atrofia Muscular/fisiopatologia , Fenótipo , Adulto Jovem
8.
Mol Genet Genomic Med ; 7(9): e839, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31393079

RESUMO

BACKGROUND: The most common inherited peripheral neuropathy is Charcot-Marie-Tooth disease (CMT), with a prevalence of 1/2500. Other symptoms can be associated to the condition, such as hearing loss. Currently, no global hearing impairment assessment has been determined, and the physiopathology is not well known. METHODS: The aim of the study was to analyze among a French series of 3,412 patients with inherited peripheral neuropathy (IPN), the ones who also suffer from hearing loss, to establish phenotype-genotype correlations. An NGS strategy for IPN one side and nonsyndromic hearing loss (NSHL) on the other side, were performed. RESULTS: Hearing loss (HL) was present in only 44 patients (1.30%). The clinical data of 27 patients were usable. Demyelinating neuropathy was diagnosed in 15 cases and axonal neuropathy in 12 cases. HL varied from mild to profound. Five cases of auditory neuropathy were noticed. Diagnosis was made for 60% of these patients. Seven novel pathogenic variants were discovered in five different genes: PRPS1; MPZ; SH3TC2; NEFL; and ABHD12. Two patients with PMP22 variant, had also an additional variant in COCH and MYH14 respectively. No pathogenic variant was found at the DFNB1 locus. Genotype-phenotype correlations do exist, especially with SH3TC2, PRPS1, ABHD12, NEFL, and TRPV4. CONCLUSION: Involvement of PMP22 is not enough to explain hearing loss in patients suffering from IPN. HL can be due to cochlear impairment and/or auditory nerve dysfunction. HL is certainly underdiagnosed, and should be evaluated in every patient suffering from IPN.

9.
NPJ Genom Med ; 4: 17, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31341639

RESUMO

Neuro-ichthyotic syndromes are a group of rare genetic diseases mainly associated with perturbations in lipid metabolism, intracellular vesicle trafficking, or glycoprotein synthesis. Here, we report a patient with a neuro-ichthyotic syndrome associated with deleterious mutations in the ALDH1L2 (aldehyde dehydrogenase 1 family member L2) gene encoding for mitochondrial 10-formyltetrahydrofolate dehydrogenase. Using fibroblast culture established from the ALDH1L2-deficient patient, we demonstrated that the enzyme loss impaired mitochondrial function affecting both mitochondrial morphology and the pool of metabolites relevant to ß-oxidation of fatty acids. Cells lacking the enzyme had distorted mitochondria, accumulated acylcarnitine derivatives and Krebs cycle intermediates, and had lower ATP and increased ADP/AMP indicative of a low energy index. Re-expression of functional ALDH1L2 enzyme in deficient cells restored the mitochondrial morphology and the metabolic profile of fibroblasts from healthy individuals. Our study underscores the role of ALDH1L2 in the maintenance of mitochondrial integrity and energy balance of the cell, and suggests the loss of the enzyme as the cause of neuro-cutaneous disease.

11.
Ann Neurol ; 85(3): 385-395, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30635937

RESUMO

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.


Assuntos
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 , Imagem por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Mutação de Sentido Incorreto , Linhagem , Infecções Respiratórias , Ácido Succínico/metabolismo , Simportadores/metabolismo , Tonsilite , Sequenciamento Completo do Exoma
12.
J Clin Invest ; 129(3): 1240-1256, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30620337

RESUMO

Sphingolipid imbalance is the culprit in a variety of neurological diseases, some affecting the myelin sheath. We have used whole-exome sequencing in patients with undetermined leukoencephalopathies to uncover the endoplasmic reticulum lipid desaturase DEGS1 as the causative gene in 19 patients from 13 unrelated families. Shared features among the cases include severe motor arrest, early nystagmus, dystonia, spasticity, and profound failure to thrive. MRI showed hypomyelination, thinning of the corpus callosum, and progressive thalamic and cerebellar atrophy, suggesting a critical role of DEGS1 in myelin development and maintenance. This enzyme converts dihydroceramide (DhCer) into ceramide (Cer) in the final step of the de novo biosynthesis pathway. We detected a marked increase of the substrate DhCer and DhCer/Cer ratios in patients' fibroblasts and muscle. Further, we used a knockdown approach for disease modeling in Danio rerio, followed by a preclinical test with the first-line treatment for multiple sclerosis, fingolimod (FTY720, Gilenya). The enzymatic inhibition of Cer synthase by fingolimod, 1 step prior to DEGS1 in the pathway, reduced the critical DhCer/Cer imbalance and the severe locomotor disability, increasing the number of myelinating oligodendrocytes in a zebrafish model. These proof-of-concept results pave the way to clinical translation.


Assuntos
Animais Geneticamente Modificados , Encéfalo , Cloridrato de Fingolimode/farmacologia , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central , Proteínas de Peixe-Zebra , Peixe-Zebra , Animais , Animais Geneticamente Modificados/genética , Animais Geneticamente Modificados/metabolismo , Encéfalo/enzimologia , Encéfalo/patologia , Modelos Animais de Doenças , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/metabolismo , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/tratamento farmacológico , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/enzimologia , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Humanos , Locomoção/efeitos dos fármacos , Oligodendroglia/enzimologia , Oligodendroglia/patologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética
13.
Neurol Genet ; 4(6): e289, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30584594

RESUMO

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.

14.
Dev Neurosci ; 40(4): 301-311, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30261498

RESUMO

AIMS: We performed quantitative diffusion tensor imaging and brain tractography to distinguish clinical severity in a series of 35 patients with hypomyelinating PLP1-related disorders classified using the Motor Developmental Score according to the best motor function acquired before the age of 5 years and the gross motor function measure (GMFM) at the time of magnetic resonance imaging acquisition. METHODS: We calculated fractional anisotropy and diffusivity values in 26 regions of interest and the numbers of fibers and volumes of hemisphere tractograms. Fiber bundles on tractograms were characterized according to 3 criteria: size, direction of main-stream fibers, and connectivity of bundles (extratelencephalic projections, commissural fibers, and intrahemispheric connections). RESULTS: Age-adjusted multivariate analysis in 3 severity groups revealed increased isotropic diffusion in the superior cerebellar peduncle and grey matter in the most severe group, and larger tractogram volumes and increased numbers of fibers in the least severely affected group. Tractogram patterns showed preserved extratelencephalic projections and a main anterior-posterior aspect of intrahemispheric fibers in most patients, whereas interhemispheric connectivity was variable. The most severely affected and intermediate patients had less intrahemispheric connectivity, with a frequent predominant anterior-posterior direction of main-stream fibers. INTERPRETATION: Diffusion tensor imaging and tractographic parameters can operate as biomarkers to distinguish clinical severity in PLP1-related disorders and could improve our understanding of hypomyelinating leukodystrophies.


Assuntos
Encéfalo/metabolismo , Imagem de Tensor de Difusão , Proteína Proteolipídica de Mielina/metabolismo , Adolescente , Adulto , Anisotropia , Encéfalo/patologia , Criança , Pré-Escolar , Imagem de Tensor de Difusão/métodos , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética/métodos , Masculino , Adulto Jovem
15.
Blood ; 132(12): 1318-1331, 2018 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-29914977

RESUMO

Congenital neutropenias (CNs) are rare heterogeneous genetic disorders, with about 25% of patients without known genetic defects. Using whole-exome sequencing, we identified a heterozygous mutation in the SRP54 gene, encoding the signal recognition particle (SRP) 54 GTPase protein, in 3 sporadic cases and 1 autosomal dominant family. We subsequently sequenced the SRP54 gene in 66 probands from the French CN registry. In total, we identified 23 mutated cases (16 sporadic, 7 familial) with 7 distinct germ line SRP54 mutations including a recurrent in-frame deletion (Thr117del) in 14 cases. In nearly all patients, neutropenia was chronic and profound with promyelocytic maturation arrest, occurring within the first months of life, and required long-term granulocyte colony-stimulating factor therapy with a poor response. Neutropenia was sometimes associated with a severe neurodevelopmental delay (n = 5) and/or an exocrine pancreatic insufficiency requiring enzyme supplementation (n = 3). The SRP54 protein is a key component of the ribonucleoprotein complex that mediates the co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). We showed that SRP54 was specifically upregulated during the in vitro granulocytic differentiation, and that SRP54 mutations or knockdown led to a drastically reduced proliferation of granulocytic cells associated with an enhanced P53-dependent apoptosis. Bone marrow examination of SRP54-mutated patients revealed a major dysgranulopoiesis and features of cellular ER stress and autophagy that were confirmed using SRP54-mutated primary cells and SRP54 knockdown cells. In conclusion, we characterized a pathological pathway, which represents the second most common cause of CN with maturation arrest in the French CN registry.


Assuntos
Doenças da Medula Óssea/genética , Estresse do Retículo Endoplasmático , Insuficiência Pancreática Exócrina/genética , Lipomatose/genética , Mutação , Neutropenia/congênito , Partícula de Reconhecimento de Sinal/genética , Adolescente , Adulto , Apoptose , Autofagia , Doenças da Medula Óssea/metabolismo , Doenças da Medula Óssea/patologia , Criança , Pré-Escolar , Síndrome Congênita de Insuficiência da Medula Óssea , Insuficiência Pancreática Exócrina/metabolismo , Insuficiência Pancreática Exócrina/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Lipomatose/metabolismo , Lipomatose/patologia , Masculino , Pessoa de Meia-Idade , Neutropenia/genética , Neutropenia/metabolismo , Neutropenia/patologia , Síndrome de Shwachman-Diamond , Regulação para Cima , Adulto Jovem
16.
Clin Neurophysiol ; 129(6): 1121-1129, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29625343

RESUMO

OBJECTIVES: In patients with Friedreich ataxia (FRDA), mitochondrial failure leads to impaired cellular energetics. Since many FRDA patients have impaired hearing in noise, we investigated the objective consequences on standard auditory brainstem-evoked responses (ABRs). METHODS: In 37 FRDA patients, among whom 34 with abnormal standard ABRs, hearing sensitivity, speech-in-noise intelligibility and otoacoustic emissions were controlled. ABR recordings were split into four consecutive segments of the total time frame used for data collection, thus allowing the dynamics of ABR averaging to be observed. RESULTS: Most ears showed features of an auditory neuropathy spectrum disorder with flattened ABRs and impaired speech-in-noise intelligibility contrasting with near-normal hearing sensitivity and normal preneural responses. Yet split-ABRs revealed short-lived wave patterns in 26 out of 68 ears with flattened standard ABRs (38%). While averaging went on, the pattern of waves shifted so that interwave latencies increased by 35% on average. CONCLUSIONS: In FRDA, the assumption of stationarity used for extracting standard ABRs is invalid. The preservation of early split-ABRs indicates no short-term dyssynchrony of action potentials. A large decrease in conduction velocity along auditory neurons occurs within seconds, attributed to fast energetic failure. SIGNIFICANCE: This model of metabolic sensory neuropathy warns against exposure of metabolically-impaired patients to sustained auditory stimulation.


Assuntos
Percepção Auditiva/fisiologia , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Ataxia de Friedreich/fisiopatologia , Audição/fisiologia , Condução Nervosa/fisiologia , Adolescente , Adulto , Audiometria de Tons Puros , Limiar Auditivo/fisiologia , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inteligibilidade da Fala/fisiologia , Percepção da Fala/fisiologia , Adulto Jovem
17.
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.


Assuntos
Exotropia/genética , Hipertensão Pulmonar/genética , Deficiência Intelectual/genética , Retardo Mental Ligado ao Cromossomo X/genética , Proteína 2 de Ligação a Metil-CpG/genética , Adolescente , Adulto , Criança , Pré-Escolar , Cromossomos Humanos X/genética , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Epilepsia/complicações , Epilepsia/genética , Epilepsia/fisiopatologia , Exotropia/complicações , Exotropia/fisiopatologia , França/epidemiologia , Humanos , Hiperopia/complicações , Hiperopia/genética , Hiperopia/fisiopatologia , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/fisiopatologia , Lactente , Deficiência Intelectual/complicações , Deficiência Intelectual/fisiopatologia , Masculino , Retardo Mental Ligado ao Cromossomo X/complicações , Retardo Mental Ligado ao Cromossomo X/fisiopatologia , Linhagem , Fenótipo , Distúrbios Somatossensoriais/genética , Distúrbios Somatossensoriais/fisiopatologia , Transtorno de Movimento Estereotipado/complicações , Transtorno de Movimento Estereotipado/genética , Transtorno de Movimento Estereotipado/fisiopatologia , Adulto Jovem
18.
Orphanet J Rare Dis ; 13(1): 45, 2018 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-29615062

RESUMO

BACKGROUND: KARS encodes lysyl- transfer ribonucleic acid (tRNA) synthetase, which catalyzes the aminoacylation of tRNA-Lys in the cytoplasm and mitochondria. Eleven families/sporadic patients and 16 different mutations in KARS have been reported to date. The associated clinical phenotype is heterogeneous ranging from early onset encephalopathy to isolated peripheral neuropathy or nonsyndromic hearing impairment. Recently additional presentations including leukoencephalopathy as predominant cerebral involvement or cardiomyopathy, isolated or associated with muscular and cerebral involvement, have been reported. A progressive Leukoencephalopathy with brainstem and spinal cord calcifications was previously described in a singleton patient and in two siblings, without the identification of the genetic cause. We reported here about a new severe phenotype associated with biallelic KARS mutations and sharing some common points with the other already reported phenotypes, but with a distinct clinical and neuroimaging picture. Review of KARS mutant patients published to date will be also discussed. RESULTS: Herein, we report the clinical, biochemical and molecular findings of 2 unreported Italian patients affected by developmental delay, acquired microcephaly, spastic tetraparesis, epilepsy, sensory-neural hypoacusia, visual impairment, microcytic hypochromic anaemia and signs of hepatic dysfunction. MRI pattern in our patients was characterized by progressive diffuse leukoencephalopathy and calcifications extending in cerebral, brainstem and cerebellar white matter, with spinal cord involvement. Genetic analysis performed on these 2 patients and in one subject previously described with similar MRI pattern revealed the presence of biallelic mutations in KARS in all 3 subjects. CONCLUSIONS: With our report we define the molecular basis of the previously described Leukoencephalopathy with Brainstem and Spinal cord Calcification widening the spectrum of KARS related disorders, particularly in childhood onset disease suggestive for mitochondrial impairment. The review of previous cases does not suggest a strict and univocal genotype/phenotype correlation for this highly heterogeneous entity. Moreover, our cases confirm the usefulness of search for common brain and spine MR imaging pattern and of broad genetic screening, in syndromes clinically resembling mitochondrial disorders in spite of normal biochemical assay.


Assuntos
Tronco Encefálico/patologia , Calcinose/genética , Calcinose/patologia , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Lisina-tRNA Ligase/genética , Medula Espinal/patologia , Predisposição Genética para Doença , Humanos
19.
Brain Pathol ; 28(5): 611-630, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29027761

RESUMO

Pelizaeus-Merzbacher disease (PMD) is a fatal hypomyelinating disorder characterized by early impairment of motor development, nystagmus, choreoathetotic movements, ataxia and progressive spasticity. PMD is caused by variations in the proteolipid protein gene PLP1, which encodes the two major myelin proteins of the central nervous system, PLP and its spliced isoform DM20, in oligodendrocytes. Large duplications including the entire PLP1 gene are the most frequent causative mutation leading to the classical form of PMD. The Plp1 overexpressing mouse model (PLP-tg66/66 ) develops a phenotype very similar to human PMD, with early and severe motor dysfunction and a dramatic decrease in lifespan. The sequence of cellular events that cause neurodegeneration and ultimately death is poorly understood. In this work, we analyzed patient-derived fibroblasts and spinal cords of the PLP-tg66/66 mouse model, and identified redox imbalance, with altered antioxidant defense and oxidative damage to several enzymes involved in ATP production, such as glycolytic enzymes, creatine kinase and mitochondrial proteins from the Krebs cycle and oxidative phosphorylation. We also evidenced malfunction of the mitochondria compartment with increased ROS production and depolarization in PMD patient's fibroblasts, which was prevented by the antioxidant N-acetyl-cysteine. Finally, we uncovered an impairment of mitochondrial dynamics in patient's fibroblasts which may help explain the ultrastructural abnormalities of mitochondria morphology detected in spinal cords from PLP-tg66/66 mice. Altogether, these results underscore the link between redox and metabolic homeostasis in myelin diseases, provide insight into the pathophysiology of PMD, and may bear implications for tailored pharmacological intervention.


Assuntos
Dinâmica Mitocondrial , Estresse Oxidativo , Doença de Pelizaeus-Merzbacher/metabolismo , Animais , Células Cultivadas , Criança , Pré-Escolar , DNA Mitocondrial , Fibroblastos/metabolismo , Fibroblastos/patologia , Ácido Glutâmico/metabolismo , Humanos , Lactente , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteínas Mitocondriais/metabolismo , Proteína Proteolipídica de Mielina/genética , Proteína Proteolipídica de Mielina/metabolismo , Doença de Pelizaeus-Merzbacher/patologia , RNA Mensageiro/metabolismo , Medula Espinal/metabolismo , Medula Espinal/patologia
20.
Brain ; 140(10): 2550-2556, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28969374

RESUMO

Hypomyelinating leukodystrophies are genetically heterogeneous disorders with overlapping clinical and neuroimaging features reflecting variable abnormalities in myelin formation. We report on the identification of biallelic inactivating mutations in NKX6-2, a gene encoding a transcription factor regulating multiple developmental processes with a main role in oligodendrocyte differentiation and regulation of myelin-specific gene expression, as the cause underlying a previously unrecognized severe variant of hypomyelinating leukodystrophy. Five affected subjects (three unrelated families) were documented to share biallelic inactivating mutations affecting the NKX6-2 homeobox domain. A trio-based whole exome sequencing analysis in the first family detected a homozygous frameshift change [c.606delinsTA; p.(Lys202Asnfs*?)]. In the second family, homozygosity mapping coupled to whole exome sequencing identified a homozygous nucleotide substitution (c.565G>T) introducing a premature stop codon (p.Glu189*). In the third family, whole exome sequencing established compound heterozygosity for a non-conservative missense change affecting a key residue participating in DNA binding (c.599G>A; p.Arg200Gln) and a nonsense substitution (c.589C>T; p.Gln197*), in both affected siblings. The clinical presentation was homogeneous, with four subjects having severe motor delays, nystagmus and absent head control, and one individual showing gross motor delay at the age of 6 months. All exhibited neuroimaging that was consistent with hypomyelination. These findings define a novel, severe form of leukodystrophy caused by impaired NKX6-2 function.


Assuntos
Genes Homeobox/genética , Proteínas de Homeodomínio/genética , Leucoencefalopatias/genética , Mutação/genética , Adolescente , Criança , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Potenciais Evocados Auditivos do Tronco Encefálico , Saúde da Família , Feminino , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/patologia , Leucoencefalopatias/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Modelos Moleculares
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