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1.
Mol Genet Genomic Med ; 7(9): e914, 2019 Sep.
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.

3.
J Clin Invest ; 129(3): 1240-1256, 2019 Mar 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.

4.
Ann Neurol ; 85(3): 385-395, 2019 Mar.
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.

5.
Orphanet J Rare Dis ; 13(1): 45, 2018 Apr 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.

6.
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
7.
Metab Brain Dis ; 32(6): 2149-2154, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28868593

RESUMO

Sengers syndrome is a rare autosomal recessive metabolic disorder caused by lack of acylglycerol kinase due to mutations in the AGK gene. It is characterized by congenital cataract, hypertrophic cardiomyopathy, myopathy and lactic acidosis. Two clinical forms have been described: a severe neonatal form, and a more benign form displaying exercise intolerance. We describe two siblings with congenital cataract, cardiomyopathy, hypotonia, intellectual disability and lactic acidosis. Whole exome sequencing revealed a homozygous c.1035dup mutation in the two siblings, supporting a diagnosis of Sengers syndrome. Our patients presented an intermediate form with intellectual deficiency, an unusual feature in Sengers syndrome. This permitted a prenatal diagnosis for a following pregnancy.


Assuntos
Cardiomiopatias/genética , Catarata/genética , Deficiência Intelectual/genética , Mutação , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Criança , Pré-Escolar , Humanos , Masculino , Fenótipo , Irmãos
8.
Am J Hum Genet ; 100(2): 257-266, 2017 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-28132689

RESUMO

Phenylketonuria (PKU, phenylalanine hydroxylase deficiency), an inborn error of metabolism, can be detected through newborn screening for hyperphenylalaninemia (HPA). Most individuals with HPA harbor mutations in the gene encoding phenylalanine hydroxylase (PAH), and a small proportion (2%) exhibit tetrahydrobiopterin (BH4) deficiency with additional neurotransmitter (dopamine and serotonin) deficiency. Here we report six individuals from four unrelated families with HPA who exhibited progressive neurodevelopmental delay, dystonia, and a unique profile of neurotransmitter deficiencies without mutations in PAH or BH4 metabolism disorder-related genes. In these six affected individuals, whole-exome sequencing (WES) identified biallelic mutations in DNAJC12, which encodes a heat shock co-chaperone family member that interacts with phenylalanine, tyrosine, and tryptophan hydroxylases catalyzing the BH4-activated conversion of phenylalanine into tyrosine, tyrosine into L-dopa (the precursor of dopamine), and tryptophan into 5-hydroxytryptophan (the precursor of serotonin), respectively. DNAJC12 was undetectable in fibroblasts from the individuals with null mutations. PAH enzyme activity was reduced in the presence of DNAJC12 mutations. Early treatment with BH4 and/or neurotransmitter precursors had dramatic beneficial effects and resulted in the prevention of neurodevelopmental delay in the one individual treated before symptom onset. Thus, DNAJC12 deficiency is a preventable and treatable cause of intellectual disability that should be considered in the early differential diagnosis when screening results are positive for HPA. Sequencing of DNAJC12 may resolve any uncertainty and should be considered in all children with unresolved HPA.


Assuntos
Distonia/genética , Deficiência Intelectual/genética , Fenilcetonúrias/genética , Proteínas Repressoras/genética , Alelos , Sequência de Aminoácidos , Biopterina/análogos & derivados , Biopterina/metabolismo , Estudos de Casos e Controles , Dopamina/deficiência , Dopamina/metabolismo , Éxons , Feminino , Fibroblastos/metabolismo , Deleção de Genes , Estudo de Associação Genômica Ampla , Proteínas de Choque Térmico HSP70/genética , Humanos , Masculino , Linhagem , Fenilalanina/metabolismo , Fenilalanina Hidroxilase/genética , Serotonina/deficiência , Serotonina/metabolismo , Triptofano/metabolismo , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismo , Tirosina/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo
9.
Pediatr Neurol ; 66: 59-62, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27843092

RESUMO

BACKGROUND: Leukoencephalopathy with temporal lobe cysts may be associated with monogenetic conditions such as Aicardi-Goutières syndrome or RNASET2 mutations and with congenital infections such as cytomegalovirus. In view of the fact that congenital cytomegalovirus is difficult to confirm outside the neonatal period, excluding a Mendelian disorder is extremely relevant, changing family planning and medical management in affected families. We performed diagnostic testing in individuals with leukoencephalopathy with temporal lobe cysts without a definitive diagnosis of congenital cytomegalovirus infection. METHODS: We reviewed a large-scale biorepository of patients with unsolved leukodystrophies and identified two individuals with required for meiotic nuclear division 1 (RMND1) mutations and similar magnetic resonance imaging (MRI) features, including temporal lobe cysts. Ten additional subjects with confirmed RMND1 mutations were identified as part of a separate disease specific cohort. Brain MRIs from all 12 individuals were reviewed for common neuroradiological features. RESULTS: MRI features in RMND1 mutations included temporal lobe swelling, with rarefaction and cystic evolution, enlarged tips of the temporal lobes, and multifocal subcortical white matter changes with confluent periatrial T2 signal hyperintensity. A combination of these features was present in ten of the 12 individuals reviewed. CONCLUSIONS: Despite the small number of reported individuals with RMND1 mutations, a clinically recognizable phenotype of leukoencephalopathy with temporal lobe swelling, rarefaction, and cystic changes has emerged in a subset of individuals. Careful clinical phenotyping, including for lactic acidosis, deafness, and severe muscle involvement seen in RMND1 mutation positive individuals, and MRI pattern recognition will be important in differentiating these patients from children with congenital infections like cytomegalovirus.


Assuntos
Neoplasias Encefálicas/genética , Proteínas de Ciclo Celular/genética , Infecções por Citomegalovirus/congênito , Surdez/genética , Leucoencefalopatias/genética , Neoplasias Encefálicas/diagnóstico por imagem , Criança , Pré-Escolar , Estudos de Coortes , Cistos/diagnóstico por imagem , Infecções por Citomegalovirus/diagnóstico por imagem , Infecções por Citomegalovirus/genética , Surdez/diagnóstico por imagem , Diagnóstico Diferencial , Humanos , Lactente , Leucoencefalopatias/diagnóstico por imagem , Mutação , Fenótipo , Lobo Temporal/diagnóstico por imagem
10.
Elife ; 52016 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-27623147

RESUMO

Previously, we identified QIL1 as a subunit of mitochondrial contact site (MICOS) complex and demonstrated a role for QIL1 in MICOS assembly, mitochondrial respiration, and cristae formation critical for mitochondrial architecture (Guarani et al., 2015). Here, we identify QIL1 null alleles in two siblings displaying multiple clinical symptoms of early-onset fatal mitochondrial encephalopathy with liver disease, including defects in respiratory chain function in patient muscle. QIL1 absence in patients' fibroblasts was associated with MICOS disassembly, abnormal cristae, mild cytochrome c oxidase defect, and sensitivity to glucose withdrawal. QIL1 expression rescued cristae defects, and promoted re-accumulation of MICOS subunits to facilitate MICOS assembly. MICOS assembly and cristae morphology were not efficiently rescued by over-expression of other MICOS subunits in patient fibroblasts. Taken together, these data provide the first evidence of altered MICOS assembly linked with a human mitochondrial disease and confirm a central role for QIL1 in stable MICOS complex formation.


Assuntos
Hepatopatias/genética , Hepatopatias/patologia , Proteínas de Membrana/deficiência , Encefalomiopatias Mitocondriais/genética , Encefalomiopatias Mitocondriais/patologia , Proteínas Mitocondriais/deficiência , Mutação , Feminino , Humanos , Recém-Nascido , Masculino , Testes de Sensibilidade Microbiana , Irmãos
11.
Mol Genet Metab Rep ; 7: 8-10, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27331002

RESUMO

BACKGROUND: MEGDEL (3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome) syndrome is a mitochondrial disorder associated with recessive mutations in SERAC1. OBJECTIVES: To report transient neonatal renal findings in MEGDEL syndrome. RESULTS: This 7 year-old girl was the first child of consanguineous Turkish parents. She exhibited an acute neonatal deterioration with severe lactic acidosis and liver failure. Initial evaluation revealed massive polyuria and renal failure with 3-methylglutaconic aciduria. Symptoms and biological findings progressively improved with symptomatic treatment but lactic acidosis and high lactate to pyruvate ratio along with 3-methylglutaconic aciduria persisted. At 8 months of age, a subacute neurological degradation occurred with severe hypotonia, dystonia with extrapyramidal movements and failure to thrive. Brain MRI revealed basal ganglia lesions suggestive of Leigh syndrome. At 3 years of age, sensorineural deafness was documented. MEGDEL syndrome was further confirmed by the identification of an already reported homozygous mutation in SERAC1. CONCLUSION: Transient neonatal polyuria and renal failure have not been reported to date in SERAC1 defective patients. Such neonatal kidney findings expand the clinical spectrum of MEGDEL syndrome.

12.
Eur J Paediatr Neurol ; 20(4): 604-10, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27091087

RESUMO

BACKGROUND: Cystic leukoencephalopathy without megalencephaly is a disorder related in some cases to RNASET2 mutations and characterized by bilateral anterior temporal subcortical cysts and multifocal lobar white matter lesions with sparing of central white matter structures. This phenotype significantly overlaps with the sequelae of in utero cytomegalovirus (CMV) infection, including the presence of intracranial calcification in some cases. Aicardi-Goutières syndrome (AGS) is another inherited leukodystrophy with cerebral calcification mimicking congenital infection. Clinical, radiological and biochemical criteria for the diagnosis of AGS have been established, although the breadth of phenotype associated with mutations in the AGS-related genes is much greater than previously envisaged. PATIENTS AND METHODS: We describe the clinical, biochemical and radiological findings of five patients demonstrating a phenotype reminiscent of AGS. RESULTS: All patients were found to carry biallelic mutations of RNASET2. CONCLUSIONS: Our patients illustrate the clinical and radiological overlap that can be seen between RNASET2-related leukodystrophy and AGS in some cases. Our data highlight the need to include both disorders in the same differential diagnosis, and hint at possible shared pathomechanisms related to auto-inflammation which are worthy of further investigation.


Assuntos
Doenças Autoimunes do Sistema Nervoso/fisiopatologia , Encéfalo/fisiopatologia , Cistos/fisiopatologia , Leucoencefalopatias/fisiopatologia , Malformações do Sistema Nervoso/fisiopatologia , Adolescente , Doenças Autoimunes do Sistema Nervoso/diagnóstico por imagem , Doenças Autoimunes do Sistema Nervoso/genética , Encéfalo/diagnóstico por imagem , Calcinose/diagnóstico por imagem , Criança , Pré-Escolar , Cistos/diagnóstico por imagem , Cistos/genética , Infecções por Citomegalovirus/congênito , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Imagem por Ressonância Magnética , Masculino , Mutação , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/genética , Fenótipo , Ribonucleases/genética , Tomografia Computadorizada por Raios X , Proteínas Supressoras de Tumor/genética , Adulto Jovem
13.
Neurol Sci ; 37(3): 403-9, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26577183

RESUMO

Arylsulfatase A (ASA) is a lysosomal enzyme involved in the catabolism of cerebroside sulfate. ASA deficiency is associated with metachromatic leukodystrophy (MLD). Low ASA activities have also been reported in a more common condition with no apparent clinical consequences termed ASA pseudo-deficiency (ASA-PD) which is associated with two linked mutations in the ASA gene (c.1049A>G and c.*96A>G). This study aimed to investigate the frequency of the two ASA-PD variants and their linkage disequilibrium (LD) among Tunisians. ASA-PD variants were detected in 129 healthy Tunisians and their frequencies were compared to those described worldwide. The frequency of the PD allele was estimated at 17.4% for the overall sample, with c.1049A>G and c.*96A>G frequencies of 25.6 and 17.4%, respectively. This study also revealed a high LD between the two ASA-PD variants (r(2) = 0.61). Inter-population analysis revealed similarities in the ASA-PD genetic structure between Tunisians and populations from Middle East with c.*96A>G frequencies being the highest in the world. A significant North vs. South genetic differentiation in the ASA-PD frequency was also observed in Tunisian population who seems genetically intermediate between Africans, Middle-Easterners and Europeans. This is the first report on the allele frequency of the ASA-PD in North Africa, revealing a relatively high frequency of the PD allele among Tunisians. This study gives also evidence on the importance of discriminating ASA-PD allele from pathological mutations causing MLD and supporting enzymatic activity testing with both sulfatiduria determination and genetic testing in the differential diagnosis of MLD in the Tunisian population.


Assuntos
Cerebrosídeo Sulfatase/deficiência , Cerebrosídeo Sulfatase/genética , Frequência do Gene , Adulto , Grupo com Ancestrais do Continente Africano/genética , Alelos , Grupo com Ancestrais do Continente Europeu/genética , Técnicas de Genotipagem , Haplótipos , Humanos , Desequilíbrio de Ligação , Mutação , Polimorfismo Genético , Prevalência , Análise de Componente Principal , Tunísia/epidemiologia
14.
Eur J Paediatr Neurol ; 20(2): 323-330, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26643067

RESUMO

BACKGROUND: Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) was first described in 2002. After the recent identification of TUBB4A mutation as the genetic basis of the disease, the clinical and neuroimaging phenotype related to TUBB4A mutations expanded, ranging from primary dystonia type 4 with normal MRI to severe H-ABC cases. PATIENTS AND METHODS: The study included patients referred to us for an unclassified hypomyelinating leukodystrophy. We selected patients with deleterious heterozygous TUBB4A mutations. Molecular analysis of TUBB4A was performed on genomic DNA extracted from peripheral blood. RESULTS: The series included 12 patients (5 females and 7 males). Five patients carried the common mutation c.745G > A (p.Asp249Asn), while the remaining harbored different mutations. Three new mutations were found in 5 patients. Clinical and neuroimaging observations are described. A clear correlation between the clinical presentation and the genotype seems to be absent in our group of 12 patients. CONCLUSIONS: TUBB4A-mutated patients manifest a comparable clinical and neuroimaging picture but they can differ from each other in terms of rate of disease progression. Extrapyramidal signs can be absent in the first stages of the disease, and a careful evaluation of MRI is fundamental to obtain the final diagnosis. From a therapeutic perspective a trial with l-dopa should be considered in all patients presenting extrapyramidal symptoms.


Assuntos
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Tubulina (Proteína)/genética , Adulto , Progressão da Doença , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , Neuroimagem , Fenótipo
15.
BMC Neurol ; 15: 244, 2015 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-26607867

RESUMO

BACKGROUND: X-linked adrenoleukodystrophy (X-ALD; OMIM: 300100) is the most common peroxisomal disease caused by mutations in the ATP-binding cassette, sub-family D member 1 gene or ABCD1 (geneID: 215), the coding gene for the adrenoleukodystrophy protein (ALDP), which is an ATP-binding transport protein associated to an active transport of very long chain fatty acids (VLCFAs). Dysfunction of ALDP induces an accumulation of VLCFAs in all tissues leading to a neurodegenerative disorder that involves the nervous system white matter. CASE PRESENTATION: In our case report, magnetic resonance imaging (MRI) as well as the high levels of VLCFAs prompted the diagnosis the X-ALD. Molecular analysis of ABCD1 gene have shown a pathogenic homozygous nonsense mutation (c.1677C > G; p.(Tyr559*)) in exon 7. CONCLUSION: Thus, we identified here a novel mutation in the ABCD1 gene in a Moroccan patient causing X-linked adrenoleukodystrophy.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Adrenoleucodistrofia/genética , Códon sem Sentido , Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP , Criança , Éxons , Homozigoto , Humanos , Masculino , Marrocos
16.
BMC Med Genet ; 16: 77, 2015 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-26329556

RESUMO

BACKGROUND: Pelizaeus-Merzbacher disease (PMD) is an X-linked dysmyelinating disorder characterized by nystagmus, hypotonia, ataxia, progressive spasticity, and cognitive decline. PMD classically results from a duplication of a genomic segment encompassing the entire PLP1 gene. Since the PLP1 gene is located in Xq22, PMD affects mostly boys. METHODS AND RESULTS: Here we report the case of a girl with typical PMD. Copy number analysis of the PLP1 locus revealed a duplication of the entire gene and FISH analysis showed that the extra copy of the PLP1 gene was actually inserted in chromosome 1p36. This insertion of an additional copy of PLP1 in an autosome led to a functional duplication irrespective of the X-inactivation pattern. Subsequent overexpression of PLP1 was the cause of the PMD phenotype observed in this girl. Further sequencing of the breakpoint junction revealed a microhomology and thus suggested a replication based mechanism (such as FoSTeS or MMBIR). CONCLUSION: This case emphasizes the susceptibility of the PLP1 locus to complex rearrangement likely driven by the Xq22 local genomic architecture. In addition, careful consideration should be given to girls with classical PMD clinical features since they usually experience complex PLP1 genomic alteration with a distinct risk of inheritance.


Assuntos
Cromossomos Humanos Par 1/genética , Duplicação Gênica/genética , Mutagênese Insercional/genética , Proteína Proteolipídica de Mielina/genética , Doença de Pelizaeus-Merzbacher/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Imagem por Ressonância Magnética , Análise em Microsséries , Doença de Pelizaeus-Merzbacher/patologia , Inativação do Cromossomo X/genética
17.
Eur J Med Genet ; 58(9): 466-70, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26208460

RESUMO

Alexander disease (AxD), a fatal degenerative leukoencephalopathy, is caused by de novo heterozygous missense mutations in the Glial Fibrillary Acidic Protein (GFAP) gene. The pathological hallmark of the disease is the presence of Rosenthal fibers, cytoplasmic inclusions in astrocytes, composed mainly of GFAP, αB-crystallin and HSP27. To date, several patients with a typical presentation of the disease or displaying characteristic Rosenthal fibers in brain material have been reported with no GFAP mutation. Recently, several studies have demonstrated a correlation between Rosenthal fiber formation and wild-type GFAP overexpression, despite the absence of mutations. We tested the hypothesis that a GFAP gene rearrangement could modulate AxD severity or promote GFAP overexpression and aggregation, resulting in leukoencephalopathy. A QMPSF assay was validated for 11 exonic fragments: 3 in control genes (CFTR, DSCR1, F9) and 8 corresponding to GFAP exons. A total of 97 patients suspected of AxD were analyzed: 28 with a GFAP mutation; 69 with clinical and magnetic resonance imaging criteria compatible with the disease. Neither duplications nor deletions of GFAP were found, suggesting that GFAP coding-region rearrangements may not be involved in AxD or Alexander-related leukoencephalopathies. In addition, 80 patients with undetermined leukodystrophies, and negative for PLP1, GJA12, Sox10 and MCT8 mutations and PLP1 and Lamin B1 rearrangements, were tested. These patients were also negative for GFAP rearrangements. Other hypotheses should be investigated for a molecular diagnosis in patients with undetermined leukoencephalopathy: mutations in GFAP isoforms, splicing sites or regulatory regions, or defaults in genes encoding molecular partners of GFAP.


Assuntos
Doença de Alexander/genética , Rearranjo Gênico , Proteína Glial Fibrilar Ácida/genética , Leucoencefalopatias/genética , Doença de Alexander/diagnóstico , Estudos de Casos e Controles , Variações do Número de Cópias de DNA , Éxons , Feminino , Deleção de Genes , Duplicação Gênica , Regulação da Expressão Gênica , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Leucoencefalopatias/diagnóstico , Masculino , Mutação de Sentido Incorreto , Reprodutibilidade dos Testes
18.
Clin Biochem ; 48(18): 1317-23, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26162493

RESUMO

OBJECTIVES: The aim of this study was to develop a reliable, rapid and cost-effective molecular diagnostic assay allowing widespread routine investigation of eIF2B-related disorders (CACH/VWM syndrome). This heterogeneous disease is caused by autosomal recessive mutations in the genes encoding the five subunits of the translation-initiation factor eIF2B. Such a diagnostic method would be particularly adapted to the apparently acute presentation of the disease. DESIGN AND METHODS: We developed a multiplex PCR amplification method for 7 genomic regions of the eIF2B genes in a single run. This method targeted the 8 most frequent mutations representing 61.4% of all mutations identified to date in our laboratory. These mutations affected eIF2B2 exon 5, eIF2B3 exon 2, eIF2B4 exons 8 and 11 and eIF2B5 exons 5, 7 and 8. PCR products were then pooled and subjected to a primer-extension assay validated using previously genotyped samples. RESULTS: The results were compared to screening and/or direct sequencing methods: 100% agreement between methods confirmed equivalent sensitivity and specificity. The new assay was highly superior in terms of cost, time to results and robustness despite sample heterogeneity. CONCLUSIONS: This genotyping strategy allows the detection of all eIF2B mutations targeted. A second multiplex primer-extension assay is in development to detect the 11 next-most frequent mutations, thus raising the global detection rate to 76.8%. Our approach is widely applicable as it involves standard techniques and equipment. Moreover, it can easily be further adapted to the clinical and genetic heterogeneity of eIF2B-related disorders by including or excluding mutations.


Assuntos
Fator de Iniciação 2B em Eucariotos/genética , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/genética , Reação em Cadeia da Polimerase Multiplex/métodos , Mutação , Alelos , Biomarcadores/metabolismo , Primers do DNA/síntese química , Fator de Iniciação 2B em Eucariotos/metabolismo , Éxons , Expressão Gênica , Genótipo , Heterozigoto , Homozigoto , Humanos , Leucoencefalopatias/patologia , Reação em Cadeia da Polimerase Multiplex/normas , Subunidades Proteicas
20.
Orphanet J Rare Dis ; 10: 13, 2015 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-25758857

RESUMO

Recently an early onset lethal encephalopathy has been described in relation to mutations of NFU1, one of the genes involved in iron-sulfur cluster metabolism. We report a new NFU1 mutated patient presenting with a milder phenotype characterized by a later onset, a slowly progressive spastic paraparesis with relapsing-remitting episodes, mild cognitive impairment and a long survival. The early white matter abnormalities observed on MRI was combined with a mixed sensory-motor neuropathy in the third decade. Our case clearly suggests the importance of considering NFU1 mutation in slowly evolving leukoencephalopathy with high glycine concentration.


Assuntos
Proteínas de Transporte/metabolismo , Paraparesia Espástica/metabolismo , Adulto , Proteínas de Transporte/genética , Humanos , Masculino , Paraparesia Espástica/genética , Paraparesia Espástica/patologia
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