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1.
Eur J Hum Genet ; 27(10): 1611-1618, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31278393

RESUMO

The developmental and epileptic encephalopathies (DEE) are a heterogeneous group of chronic encephalopathies frequently associated with rare de novo nonsynonymous coding variants in neuronally expressed genes. Here, we describe eight probands with a DEE phenotype comprising intellectual disability, epilepsy, and hypotonia. Exome trio analysis showed de novo variants in TRPM3, encoding a brain-expressed transient receptor potential channel, in each. Seven probands were identically heterozygous for a recurrent substitution, p.(Val837Met), in TRPM3's S4-S5 linker region, a conserved domain proposed to undergo conformational change during gated channel opening. The eighth individual was heterozygous for a proline substitution, p.(Pro937Gln), at the boundary between TRPM3's flexible pore-forming loop and an adjacent alpha-helix. General-population truncating variants and microdeletions occur throughout TRPM3, suggesting a pathomechanism other than simple haploinsufficiency. We conclude that de novo variants in TRPM3 are a cause of intellectual disability and epilepsy.

2.
Genet Med ; 21(9): 2036-2042, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30739909

RESUMO

PURPOSE: To define the clinical characteristics of patients with variants in TCF20, we describe 27 patients, 26 of whom were identified via exome sequencing. We compare detailed clinical data with 17 previously reported patients. METHODS: Patients were ascertained through molecular testing laboratories performing exome sequencing (and other testing) with orthogonal confirmation; collaborating referring clinicians provided detailed clinical information. RESULTS: The cohort of 27 patients all had novel variants, and ranged in age from 2 to 68 years. All had developmental delay/intellectual disability. Autism spectrum disorders/autistic features were reported in 69%, attention disorders or hyperactivity in 67%, craniofacial features (no recognizable facial gestalt) in 67%, structural brain anomalies in 24%, and seizures in 12%. Additional features affecting various organ systems were described in 93%. In a majority of patients, we did not observe previously reported findings of postnatal overgrowth or craniosynostosis, in comparison with earlier reports. CONCLUSION: We provide valuable data regarding the prognosis and clinical manifestations of patients with variants in TCF20.

3.
Ann Neurol ; 84(5): 766-780, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30295347

RESUMO

OBJECTIVE: Several small case series identified KCTD7 mutations in patients with a rare autosomal recessive disorder designated progressive myoclonic epilepsy (EPM3) and neuronal ceroid lipofuscinosis (CLN14). Despite the name KCTD (potassium channel tetramerization domain), KCTD protein family members lack predicted channel domains. We sought to translate insight gained from yeast studies to uncover disease mechanisms associated with deficiencies in KCTD7 of unknown function. METHODS: Novel KCTD7 variants in new and published patients were assessed for disease causality using genetic analyses, cell-based functional assays of patient fibroblasts and knockout yeast, and electron microscopy of patient samples. RESULTS: Patients with KCTD7 mutations can exhibit movement disorders or developmental regression before seizure onset, and are distinguished from similar disorders by an earlier age of onset. Although most published KCTD7 patient variants were excluded from a genome sequence database of normal human variations, most newly identified patient variants are present in this database, potentially challenging disease causality. However, genetic analysis and impaired biochemical interactions with cullin 3 support a causal role for patient KCTD7 variants, suggesting deleterious alleles of KCTD7 and other rare disease variants may be underestimated. Both patient-derived fibroblasts and yeast lacking Whi2 with sequence similarity to KCTD7 have impaired autophagy consistent with brain pathology. INTERPRETATION: Biallelic KCTD7 mutations define a neurodegenerative disorder with lipofuscin and lipid droplet accumulation but without defining features of neuronal ceroid lipofuscinosis or lysosomal storage disorders. KCTD7 deficiency appears to cause an underlying autophagy-lysosome defect conserved in yeast, thereby assigning a biological role for KCTD7. Ann Neurol 2018;84:774-788.

4.
Am J Hum Genet ; 102(5): 985-994, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29656860

RESUMO

N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.

6.
J Pediatr Genet ; 6(2): 77-83, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28496994

RESUMO

Patients with unclear patterns of developmental and cognitive delay may go years without a definitive diagnosis despite extensive testing due to overlapping phenotypes of many genetic disorders. In this study, we identified causative variants in DYRK1A, KARS, or KAT6A in four individuals with global developmental delay and various findings including microcephaly and sensorineural hearing loss using whole exome sequencing. We present the cognitive, neurologic, and physical findings of four individuals to expand the clinical knowledge of possible features of the phenotypes of three rare genetic disorders. Through this process, we provide support for the use of whole exome sequencing in the setting of severe, intellectual disability or in those in whom a genetic disorder is suspected despite initial negative testing.

7.
Am J Hum Genet ; 98(4): 782-8, 2016 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-27040691

RESUMO

Through an international multi-center collaboration, 13 individuals from nine unrelated families and affected by likely pathogenic biallelic variants in TBC1-domain-containing kinase (TBCK) were identified through whole-exome sequencing. All affected individuals were found to share a core phenotype of intellectual disability and hypotonia, and many had seizures and showed brain atrophy and white-matter changes on neuroimaging. Minor non-specific facial dysmorphism was also noted in some individuals, including multiple older children who developed coarse features similar to those of storage disorders. TBCK has been shown to regulate the mammalian target of rapamycin (mTOR) signaling pathway, which is also stimulated by exogenous leucine supplementation. TBCK was absent in cells from affected individuals, and decreased phosphorylation of phospho-ribosomal protein S6 was also observed, a finding suggestive of downregulation of mTOR signaling. Lastly, we demonstrated that activation of the mTOR pathway in response to L-leucine supplementation was retained, suggesting a possible avenue for directed therapies for this condition.


Assuntos
Deficiência Intelectual/genética , Hipotonia Muscular/genética , Mutação , Proteínas Serina-Treonina Quinases/genética , Alelos , Criança , Pré-Escolar , Grupos de Populações Continentais/genética , Feminino , Variação Genética , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Hipotonia Muscular/diagnóstico , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
8.
Genet Med ; 18(11): 1143-1150, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26986877

RESUMO

PURPOSE: Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is an autosomal-dominant disorder characterized by optic atrophy and intellectual disability caused by loss-of-function mutations in NR2F1. We report 20 new individuals with BBSOAS, exploring the spectrum of clinical phenotypes and assessing potential genotype-phenotype correlations. METHODS: Clinical features of individuals with pathogenic NR2F1 variants were evaluated by review of medical records. The functional relevance of coding nonsynonymous NR2F1 variants was assessed with a luciferase assay measuring the impact on transcriptional activity. The effects of two start codon variants on protein expression were evaluated by western blot analysis. RESULTS: We recruited 20 individuals with novel pathogenic NR2F1 variants (seven missense variants, five translation initiation variants, two frameshifting insertions/deletions, one nonframeshifting insertion/deletion, and five whole-gene deletions). All the missense variants were found to impair transcriptional activity. In addition to visual and cognitive deficits, individuals with BBSOAS manifested hypotonia (75%), seizures (40%), autism spectrum disorder (35%), oromotor dysfunction (60%), thinning of the corpus callosum (53%), and hearing defects (20%). CONCLUSION: BBSOAS encompasses a broad range of clinical phenotypes. Functional studies help determine the severity of novel NR2F1 variants. Some genotype-phenotype correlations seem to exist, with missense mutations in the DNA-binding domain causing the most severe phenotypes.Genet Med 18 11, 1143-1150.


Assuntos
Transtorno do Espectro Autista/genética , Fator I de Transcrição COUP/genética , Estudos de Associação Genética , Atrofia Óptica/genética , Adolescente , Adulto , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/fisiopatologia , Criança , Pré-Escolar , Feminino , Deleção de Genes , Humanos , Masculino , Mutação de Sentido Incorreto , Atrofia Óptica/complicações , Atrofia Óptica/fisiopatologia , Linhagem
9.
J AAPOS ; 19(5): 482-4, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26486039

RESUMO

Orbeli syndrome, or 13q deletion syndrome, is a rare condition caused by a distal deletion in the long arm of chromosome 13. The syndrome is characterized by severe physical malformations and developmental delays and has been associated with numerous ocular manifestations. We report the case of a 10-year-old boy with 13q deletion syndrome, who was evaluated for impaired vision and found to have bilateral retinal pigmentary changes resembling those seen in retinitis pigmentosa. There has only been one other case of retinal pigment variation in association with 13q deletion syndrome; however, this represents the first case of bilateral symmetric retinal pigmentary changes with corresponding rod and cone dysfunction on electroretinography.


Assuntos
Transtornos Cromossômicos/genética , Cromossomos Humanos Par 13/genética , Retinite Pigmentosa/genética , Criança , Deleção Cromossômica , Eletrorretinografia , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Células Fotorreceptoras de Vertebrados/fisiologia , Retinite Pigmentosa/fisiopatologia
10.
Ann Pediatr Cardiol ; 8(2): 153-6, 2015 May-Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26085771

RESUMO

Mutations in PRKAG2 gene that regulates the γ2 subunit of the adenosine monophosphate (AMP) dependent protein kinase have been associated with the development of atrioventricular (AV) accessory pathways, cardiac hypertrophy, and conduction system abnormalities. These patients can potentially be misdiagnosed as hypertrophic cardiomyopathy (HOCM) and/or Wolf-Parkinson White (WPW) syndrome due to similar clinical phenotype. Early recognition of this disease entity is very important as ablation of suspected accessory pathways is not effective and the natural history of the disease is very different from HOCM and WPW syndrome.

11.
Am J Med Genet A ; 158A(11): 2935-40, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22987394

RESUMO

We report on a 16-year-old female originally diagnosed with Marden-Walker syndrome due to features such as facial dysmorphism, several musculoskeletal anomalies, and atrial septal defect in addition to hypoplasia of the inferior vermis with normal-sized cerebellum and absence of the septum pellucidum. However, an SNP array performed at age 15 years detected a total of 142 Mb of long runs of homozygosity (ROH), and put the diagnosis in doubt. Using the Genomic Oligoarray and SNP array evaluation tool (http://www.ccs.miami.edu/ROH), CHST14 provided a "hit" as a gene mapping to the largest ROH region associated with a phenotype matching our patient's (if mutated). At that time, she was a cognitively intact, thin female with growth parameters below the 3rd percentile. Craniofacial features included microcephaly, midface hypoplasia, blepharophimosis, entropion, myopia, microretrognathia, and dental malocclusion. Musculoskeletal features included kyphoscoliosis, arachnodactyly, camptodactyly, and rocker-bottom feet with interphalangeal contractures. Her skin displayed large ecchymoses and poorly healed atrophic scars. Sequencing of CHST14 revealed a complex homozygous frameshift mutation involving a 7-bp deletion and an 11-bp insertion predicted to produce a truncated protein. This mutation was not seen in 100 controls of various ethnicities. Thus, our patient represents not only a novel (homozygous) mutation in CHST14, but is also the first patient with dermatan 4-O-sulfotransferase 1-deficient Ehlers-Danlos syndrome (adducted thumb-clubfoot syndrome) (DD-EDS ATCS) documented in the Western Hemisphere. Furthermore, our patient's central nervous system anomalies have not before been described in DD-EDS (ATCS).


Assuntos
Anormalidades Múltiplas/diagnóstico , Aracnodactilia/diagnóstico , Blefarofimose/diagnóstico , Doenças do Tecido Conjuntivo/diagnóstico , Contratura/diagnóstico , Síndrome de Ehlers-Danlos/diagnóstico , Sulfotransferases/deficiência , Adolescente , Sequência de Bases , Encéfalo/patologia , Hibridização Genômica Comparativa , Diagnóstico Diferencial , Síndrome de Ehlers-Danlos/genética , Facies , Feminino , Genótipo , Humanos , Dados de Sequência Molecular , Mutação , Fenótipo , Coluna Vertebral/patologia , Sulfotransferases/genética , Tomografia Computadorizada por Raios X
13.
Eur J Hum Genet ; 19(1): 102-7, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20736978

RESUMO

Genome-wide high-resolution array analysis is rapidly becoming a reliable method of diagnostic investigation in individuals with mental retardation and congenital anomalies, leading to the identification of several novel microdeletion and microduplication syndromes. We have identified seven individuals with duplication on chromosome 14q11.2q13.1, who exhibited idiopathic developmental delay and cognitive impairment, severe speech delay, and developmental epilepsy. Among these cases, the minimal common duplicated region on chromosome 14q11.2q13.1 includes only three genes, FOXG1, C14orf23, and PRKD1. We propose that increased dosage of Forkhead Box G1 (FOXG1) is the best candidate to explain the abnormal neurodevelopmental phenotypes observed in our patients. Deletions and inactivating mutations of FOXG1 have been associated with a Rett-like syndrome characterized by hypotonia, irritability, developmental delay, hand stereotypies, and deceleration of head growth. FOXG1, encoding a brain-specific transcription factor, has an important role in the developing brain. In fact, in vivo studies in chicken brain demonstrated that overexpression of FOXG1 results in thickening of the neuroepithelium and outgrowth of the telencephalon and mesencephalum, secondary to a reduction in neuroepithelial cell apoptosis.


Assuntos
Cromossomos Humanos Par 14/genética , Deficiências do Desenvolvimento/genética , Epilepsia/genética , Fatores de Transcrição Forkhead/genética , Duplicação Gênica , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Proteínas do Tecido Nervoso/genética , Adulto , Pré-Escolar , Hibridização Genômica Comparativa , Feminino , Humanos , Lactente , Masculino , Análise de Sequência com Séries de Oligonucleotídeos
15.
Ann Neurol ; 67(6): 834-7, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20517947

RESUMO

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an autosomal recessive disease characterized by early infantile macrocephaly and delayed motor and cognitive deterioration. Magnetic resonance imaging (MRI) shows diffusely abnormal and swollen cerebral white matter and subcortical cysts. On follow-up, atrophy ensues. Approximately 80% of MLC patients have mutations in MLC1. We report 16 MLC patients without MLC1 mutations. Eight retained the classical clinical and MRI phenotype. The other 8 showed major MRI improvement. They lacked motor decline. Five had normal intelligence; 3 displayed cognitive deficiency. In conclusion, 2 phenotypes can be distinguished among the non-MLC1 mutated MLC patients: a classical and a benign phenotype.


Assuntos
Cistos/genética , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Proteínas de Membrana/genética , Mutação/genética , Adolescente , Adulto , Encefalopatias/complicações , Encefalopatias/patologia , Criança , Cistos/complicações , Análise Mutacional de DNA , Feminino , Seguimentos , Humanos , Leucoencefalopatias/complicações , Imagem por Ressonância Magnética/métodos , Masculino , Estudos Retrospectivos , Adulto Jovem
16.
Arch Neurol ; 67(2): 239-44, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20142534

RESUMO

OBJECTIVE: To describe a novel POLG missense mutation (c.3218C>T; p.P1073L) that, in association with 2 previously described mutations, caused an Alpers-like hepatocerebral syndrome in 4 children. DESIGN: Genotype-phenotype correlation. SETTING: Tertiary care universities. PATIENTS: Four children, 2 related and 2 unrelated, with the novel p.P1073L mutation (all patients) and either the p.A467T (2 patients), p.G848S (1 patient), or p.W748S (1 patient) mutation presented with psychomotor delay, encephalopathy, and liver failure. INTERVENTIONS: Detailed clinical and laboratory examinations including brain magnetic resonance imaging, muscle biopsy, measurement of mitochondrial DNA, and sequencing of the POLG gene. MAIN OUTCOME MEASURES: Definition of clinical variability. RESULTS: All 4 patients had psychomotor delay, seizures, and liver disease. Three patients had severe gastrointestinal dysmotility, which may be associated with the new p.P1073L mutation. CONCLUSIONS: The heterozygous presence of the novel p.P1073L mutation in trans with another recessive POLG mutation causes a hepatocerebral disorder identical or very similar to Alpers syndrome. This adds to the already striking clinical heterogeneity of POLG mutations. In the Belgian patients, the familial occurrence without consanguinity is related to the high frequency of the recessive p.A467T and p.W748S mutations in northwestern Europe and reveals a pitfall for diagnosis and genetic counseling.


Assuntos
DNA Polimerase Dirigida por DNA/genética , Esclerose Cerebral Difusa de Schilder/genética , Predisposição Genética para Doença , Mutação/genética , Adolescente , Criança , Pré-Escolar , Polimerase do DNA Mitocondrial , DNA Mitocondrial/genética , Saúde da Família , Feminino , Gastroenteropatias/etiologia , Gastroenteropatias/genética , Estudos de Associação Genética/métodos , Genótipo , Humanos , Lactente , Fígado/patologia , Imagem por Ressonância Magnética/métodos , Masculino , Músculo Esquelético/patologia , Fenótipo
17.
Brain ; 132(Pt 11): 3165-74, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19720722

RESUMO

Childhood-onset mitochondrial encephalomyopathies are usually severe, relentlessly progressive conditions that have a fatal outcome. However, a puzzling infantile disorder, long known as 'benign cytochrome c oxidase deficiency myopathy' is an exception because it shows spontaneous recovery if infants survive the first months of life. Current investigations cannot distinguish those with a good prognosis from those with terminal disease, making it very difficult to decide when to continue intensive supportive care. Here we define the principal molecular basis of the disorder by identifying a maternally inherited, homoplasmic m.14674T>C mt-tRNA(Glu) mutation in 17 patients from 12 families. Our results provide functional evidence for the pathogenicity of the mutation and show that tissue-specific mechanisms downstream of tRNA(Glu) may explain the spontaneous recovery. This study provides the rationale for a simple genetic test to identify infants with mitochondrial myopathy and good prognosis.


Assuntos
Deficiência de Citocromo-c Oxidase , Encefalomiopatias Mitocondriais , Mutação Puntual , Sequência de Bases , Deficiência de Citocromo-c Oxidase/genética , Deficiência de Citocromo-c Oxidase/patologia , Deficiência de Citocromo-c Oxidase/fisiopatologia , Diagnóstico Diferencial , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Mitocôndrias/metabolismo , Encefalomiopatias Mitocondriais/genética , Encefalomiopatias Mitocondriais/patologia , Encefalomiopatias Mitocondriais/fisiopatologia , Biologia Molecular , Dados de Sequência Molecular , Músculo Esquelético/patologia , Conformação de Ácido Nucleico , Linhagem , Fenótipo , Prognóstico
18.
Hum Genet ; 126(3): 411-23, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19449031

RESUMO

Mutations in the dystrophin gene (DMD) cause Duchenne and Becker muscular dystrophies and the majority of cases are due to DMD gene rearrangements. Despite the high incidence of these aberrations, little is known about their causative molecular mechanism(s). We examined 792 DMD/BMD clinical samples by oligonucleotide array-CGH and report on the junction sequence analysis of 15 unique deletion cases and three complex intragenic rearrangements to elucidate potential underlying mechanism(s). Furthermore, we present three cases with intergenic rearrangements involving DMD and neighboring loci. The cases with intragenic rearrangements include an inversion with flanking deleted sequences; a duplicated segment inserted in direct orientation into a deleted region; and a splicing mutation adjacent to a deletion. Bioinformatic analysis demonstrated that 7 of 12 breakpoints combined among 3 complex cases aligned with repetitive sequences, as compared to 4 of 30 breakpoints for the 15 deletion cases. Moreover, the inversion/deletion case may involve a stem-loop structure that has contributed to the initiation of this rearrangement. For the duplication/deletion and splicing mutation/deletion cases, the presence of the first mutation, either a duplication or point mutation, may have elicited the deletion events in an attempt to correct preexisting mutations. While NHEJ is one potential mechanism for these complex rearrangements, the highly complex junction sequence of the inversion/deletion case suggests the involvement of a replication-based mechanism. Our results support the notion that regional genomic instability, aided by the presence of repetitive elements, a stem-loop structure, and possibly preexisting mutations, may elicit complex rearrangements of the DMD gene.


Assuntos
Distrofina/genética , Rearranjo Gênico , Mutação , Processamento Alternativo , Hibridização Genômica Comparativa , Biologia Computacional/métodos , Feminino , Deleção de Genes , Humanos , Recém-Nascido , Masculino , Hibridização de Ácido Nucleico , Análise de Sequência com Séries de Oligonucleotídeos , Gravidez , Reação em Cadeia da Polimerase Via Transcriptase Reversa
19.
Genet Med ; 11(3): 169-75, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19367190

RESUMO

PURPOSE: The implementation of the expanded newborn screening panel of 29 disorders recommended by the American College of Medical Genetics in Puerto Rico and United States Virgin Islands is still in development or in early stages. Efforts in the territories are complicated by educational and resource barriers that generate a wide gap between the islands and the US mainland. METHODS: To meet immediate educational needs, we conducted in-services for local newborn screening professionals. The efficacy of the educational intervention was measured by pre and posttest scores and a seminar evaluation. An assessment was obtained to document local newborn screening needs and barriers, with focus on human resources, intervention, language, social issues, education, and communication. RESULTS: Statistical significance was found (P value < or =0.05) between pre and posttest scores of the educational intervention. Needs and barriers associated with expanded newborn screening were also documented. CONCLUSION: Puerto Rico and United States Virgin Islands face different challenges in their implementation of expanded newborn screening. The data obtained in the present study serves as foundation for the development of public policy and long-term educational programs.


Assuntos
Educação em Saúde/métodos , Triagem Neonatal/métodos , Atitude Frente a Saúde , Feminino , Pessoal de Saúde/psicologia , Humanos , Recém-Nascido , Masculino , Determinação de Necessidades de Cuidados de Saúde , Triagem Neonatal/psicologia , Desenvolvimento de Programas/métodos , Porto Rico , Ilhas Virgens Americanas
20.
Neuromuscul Disord ; 18(6): 453-9, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18504129

RESUMO

Mitochondrial DNA depletion syndrome (MDS) is characterized by a reduction in mtDNA copy number and has been associated with mutations in eight nuclear genes, including enzymes involved in mitochondrial nucleotide metabolism (POLG, TK2, DGUOK, SUCLA2, SUCLG1, PEO1) and MPV17. Recently, mutations in the RRM2B gene, encoding the p53-controlled ribonucleotide reductase subunit, have been described in seven infants from four families, who presented with various combinations of hypotonia, tubulopathy, seizures, respiratory distress, diarrhea, and lactic acidosis. All children died before 4 months of age. We sequenced the RRM2B gene in three unrelated cases with unexplained severe mtDNA depletion. The first patient developed intractable diarrhea, profound weakness, respiratory distress, and died at 3 months. The other two unrelated patients had a much milder phenotype and are still alive at ages 27 and 36 months. All three patients had lactic acidosis and severe depletion of mtDNA in muscle. Muscle histochemistry showed RRF and COX deficiency. Sequencing the RRM2B gene revealed three missense mutations and two single nucleotide deletions in exons 6, 8, and 9, confirming that RRM2B mutations are important causes of MDS and that the clinical phenotype is heterogeneous and not invariably fatal in infancy.


Assuntos
Proteínas de Ciclo Celular/genética , DNA Mitocondrial/genética , Deleção de Genes , Doenças Mitocondriais/etiologia , Mutação , Ribonucleotídeo Redutases/genética , Animais , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Doenças Mitocondriais/genética , Modelos Moleculares , Músculo Esquelético/patologia
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