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1.
Am J Hum Genet ; 108(1): 186-193, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33417887

RESUMO

POLR3B encodes the second-largest catalytic subunit of RNA polymerase III, an enzyme involved in transcription. Bi-allelic pathogenic variants in POLR3B are a well-established cause of hypomyelinating leukodystrophy. We describe six unrelated individuals with de novo missense variants in POLR3B and a clinical presentation substantially different from POLR3-related leukodystrophy. These individuals had afferent ataxia, spasticity, variable intellectual disability and epilepsy, and predominantly demyelinating sensory motor peripheral neuropathy. Protein modeling and proteomic analysis revealed a distinct mechanism of pathogenicity; the de novo POLR3B variants caused aberrant association of individual enzyme subunits rather than affecting overall enzyme assembly or stability. We expand the spectrum of disorders associated with pathogenic variants in POLR3B to include a de novo heterozygous POLR3B-related disorder.


Assuntos
Ataxia/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , RNA Polimerase III/genética , Adolescente , Adulto , Ataxia Cerebelar/genética , Criança , Pré-Escolar , Feminino , Genes Recessivos/genética , Heterozigoto , Humanos , Masculino , Mutação de Sentido Incorreto/genética , Proteômica/métodos , Adulto Jovem
2.
PLoS One ; 15(8): e0236808, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32750061

RESUMO

BACKGROUND: Ataxia with oculomotor apraxia type 1 (AOA1) is a rare autosomal recessive cerebellar ataxia, caused by mutations in the APTX gene. The disease is characterized by early-onset cerebellar ataxia, oculomotor apraxia and severe axonal polyneuropathy. The aim of this study was to detect the disease-causing variants in two unrelated consanguineous Jordanian families with cerebellar ataxia using whole exome sequencing (WES), and to correlate the identified mutation(s) with the clinical and cellular phenotypes. METHODS: WES was performed in three affected individuals and segregation analysis of p.W279* APTX candidate variant was performed. Expression levels of APTX were measured in patients' skin fibroblasts and peripheral blood mononuclear cells, followed by western blot analysis in skin fibroblasts. Genotoxicity assay was performed to detect the sensitivity of APTX mutated cells to H2O2, MMC, MMS and etoposide. RESULTS: A recurrent homozygous nonsense variant in APTX gene (c.837G>A, p.W279*) was revealed in all affected individuals. qRT-PCR showed normal APTX levels in peripheral blood and lower levels in fibroblast cells. However, western blot showed the absence of APTX protein in patients' skin fibroblasts. Significant hypersensitivity to H2O2, MMC and etoposide and lack of sensitivity to MMS were noted. CONCLUSIONS: This is the first study to report the identification of a nonsense variant in the APTX gene (c.837G>A; p.W279*) in AOA1 patients within the Jordanian population. This study confirmed the need of WES to assist in the diagnosis of cerebellar ataxia and it emphasizes the importance of studying the pathophysiology of the APTX gene.


Assuntos
Ataxia Cerebelar/genética , Códon sem Sentido , Dano ao DNA , Proteínas de Ligação a DNA/genética , Proteínas Nucleares/genética , Criança , Pré-Escolar , Consanguinidade , DNA/efeitos dos fármacos , Feminino , Humanos , Masculino , Mutagênicos/farmacologia , Sequenciamento Completo do Exoma
3.
BMC Neurol ; 20(1): 291, 2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32746785

RESUMO

BACKGROUND: Stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS) is an autosomal recessive disorder caused by defects in the ADP-Ribosylhydrolase Like 2 (ADPRHL2; OMIM: 618170) gene. This gene encodes the ADP-ribosylhydrolase enzyme (ARH3) that eliminates the addition of poly-ADP ribose (PAR) in the cellular stress onto proteins in the ADP-ribosylation process in which adding one or more ADP-ribose moieties onto the target proteins in the post-translational modification have occurred. In this study, we report a new case of CONDSIAS in the Iranian population. A literature review of CONDSIAS is also included. CASE PRESENTATION: A four-year-old female patient, born to a consanguineous Iranian family, was referred with various clinical symptoms including impaired speech, variable ataxia, infrequent seizures, and gradual onset of truncal hypotonia. Over time, she developed complete motor and speech regression, bilateral sensorineural hearing loss, infrequent seizures, abdominal distension and gastrointestinal (GI) intolerance, and loss of consciousness. To better molecularly diagnose, trio-whole-exome sequencing (WES) was performed on the proband and her parents. Sanger sequencing was also applied to investigate co-segregation analysis. Using in silico predictive tools, the possible impacts of the variant on the structure and function of ADPRHL2 protein were predicted. All basic metabolic tests were normal, while serial coronal magnetic resonance imaging (MRI) showed progressive cerebral and cerebellar atrophy in addition to cerebral white matter signal changes as a novel neuroimaging finding. GI intolerance was another novelty of clinical scenarios in the patient. An auditory brainstem response test showed a severe bilateral sensorineural hearing loss. An electroencephalogram also confirmed focal seizures. From the molecular perspective, a novel homozygous frameshift variant in the ADPRHL2 gene (NM_017825.2; c.636_639del, p.(Leu212fs)) was identified by WES. CONCLUSIONS: CONDSIAS is an ultra-rare neurodegenerative disorder. In the present study, we introduced extra-neurological and neuroimaging findings of this disorder in a female child caused by a novel frameshift variation in the ADPRHL2 gene.


Assuntos
Ataxia Cerebelar/genética , Glicosídeo Hidrolases/genética , Doenças Neurodegenerativas/genética , Convulsões/genética , Doenças Cerebelares , Pré-Escolar , Feminino , Mutação da Fase de Leitura , Homozigoto , Humanos , Irã (Geográfico) , Hipotonia Muscular/genética , Fenótipo
5.
Nervenarzt ; 91(6): 537-540, 2020 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-32367146

RESUMO

This article presents the case of a 74-year-old female patient who first developed a progressive disease with sensory neuropathy, cerebellar ataxia and bilateral vestibulopathy at the age of 60 years. The family history was unremarkable. Magnetic resonance imaging (MRI) showed atrophy of the cerebellum predominantly in the vermis and atrophy of the spinal cord. The patient was given the syndromic diagnosis of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). In 2019 the underlying genetic cause of CANVAS was discovered to be an intronic repeat expansion in the RFC1 gene with autosomal recessive inheritance. The patient exhibited the full clinical picture of CANVAS and was tested positive for this repeat expansion on both alleles. The CANVAS is a relatively frequent cause of late-onset hereditary ataxia (estimated prevalence 5­13/100,000). In contrast to the present patient, the full clinical picture is not always present. Therefore, testing for the RFC1 gene expansion is recommended in the work-up of patients with otherwise unexplained late-onset sporadic ataxia. As intronic repeat expansions cannot be identified by next generation sequencing methods, specific testing is necessary.


Assuntos
Vestibulopatia Bilateral , Ataxia Cerebelar , Doenças do Sistema Nervoso Periférico , Idoso , Ataxia , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/genética , Feminino , Humanos , Síndrome
6.
BMC Med Genet ; 21(1): 68, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32234020

RESUMO

BACKGROUND: The TWNK gene encodes the twinkle protein, which is a mitochondrial helicase for DNA replication. The dominant TWNK variants cause progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, while the recessive variants cause mitochondrial DNA depletion syndrome 7 and Perrault syndrome 5. Perrault syndrome is characterized by sensorineural hearing loss in both males and females and gonadal dysfunction in females. Patients with Perrault syndrome may present early-onset cerebellar ataxia, whereas middle-age-onset cerebellar ataxia caused by TWNK variants is rare. CASE PRESENTATION: A Japanese female born to consanguineous parents presented hearing loss at age 48, a staggering gait at age 53, and numbness in her distal extremities at age 57. Neurological examination revealed sensorineural hearing loss, cerebellar ataxia, decreased deep tendon reflexes, and sensory disturbance in the distal extremities. Laboratory tests showed no abnormal findings other than a moderate elevation of pyruvate concentration levels. Brain magnetic resonance imaging revealed mild cerebellar atrophy. Using exome sequencing, we identified a homozygous TWNK variant (NM_021830: c.1358G>A, p.R453Q). CONCLUSIONS: TWNK variants could cause middle-age-onset cerebellar ataxia. Screening for TWNK variants should be considered in cases of cerebellar ataxia associated with deafness and/or peripheral neuropathy, even if the onset is not early.


Assuntos
Ataxia Cerebelar/genética , DNA Helicases/genética , Proteínas Mitocondriais/genética , Ataxia Cerebelar/complicações , Ataxia Cerebelar/diagnóstico , Consanguinidade , Feminino , Marcha Atáxica/complicações , Marcha Atáxica/diagnóstico , Marcha Atáxica/genética , Disgenesia Gonadal 46 XX/diagnóstico , Disgenesia Gonadal 46 XX/genética , Perda Auditiva/complicações , Perda Auditiva/diagnóstico , Perda Auditiva/genética , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Homozigoto , Humanos , Japão , Transtornos de Início Tardio/diagnóstico , Transtornos de Início Tardio/genética , Pessoa de Meia-Idade , Mutação , Linhagem
7.
Nucleic Acids Res ; 48(7): 3678-3691, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32123907

RESUMO

Genomic instability resulting from defective DNA damage responses or repair causes several abnormalities, including progressive cerebellar ataxia, for which the molecular mechanisms are not well understood. Here, we report a new murine model of cerebellar ataxia resulting from concomitant inactivation of POLB and ATM. POLB is one of key enzymes for the repair of damaged or chemically modified bases, including methylated cytosine, but selective inactivation of Polb during neurogenesis affects only a subpopulation of cortical interneurons despite the accumulation of DNA damage throughout the brain. However, dual inactivation of Polb and Atm resulted in ataxia without significant neuropathological defects in the cerebellum. ATM is a protein kinase that responds to DNA strand breaks, and mutations in ATM are responsible for Ataxia Telangiectasia, which is characterized by progressive cerebellar ataxia. In the cerebella of mice deficient for both Polb and Atm, the most downregulated gene was Itpr1, likely because of misregulated DNA methylation cycle. ITPR1 is known to mediate calcium homeostasis, and ITPR1 mutations result in genetic diseases with cerebellar ataxia. Our data suggest that dysregulation of ITPR1 in the cerebellum could be one of contributing factors to progressive ataxia observed in human genomic instability syndromes.


Assuntos
Ataxia Cerebelar/genética , Cerebelo/metabolismo , Metilação de DNA , DNA Polimerase beta/genética , Receptores de Inositol 1,4,5-Trifosfato/genética , Animais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Encéfalo/embriologia , Encéfalo/patologia , Cerebelo/anormalidades , Cerebelo/patologia , Citosina/metabolismo , Dano ao DNA , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Camundongos , Camundongos Knockout , Neurogênese/genética
8.
PLoS One ; 15(3): e0230566, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32208444

RESUMO

A phenomenon of genetic compensation is commonly observed when an organism with a disease-bearing mutation shows incomplete penetrance of the disease phenotype. Such incomplete phenotypic penetrance, or genetic compensation, is more commonly found in stable knockout models, rather than transient knockdown models. As such, these incidents present a challenge for the disease modeling field, although a deeper understanding of genetic compensation may also hold the key for novel therapeutic interventions. In our study we created a knockout model of slc25a46 gene, which is a recently discovered important player in mitochondrial dynamics, and deleterious mutations in which are known to cause peripheral neuropathy, optic atrophy and cerebellar ataxia. We report a case of genetic compensation in a stable slc25a46 homozygous zebrafish mutant (hereafter referred as "mutant"), in contrast to a penetrant disease phenotype in the first generation (F0) slc25a46 mosaic mutant (hereafter referred as "crispant"), generated with CRISPR/Cas-9 technology. We show that the crispant phenotype is specific and rescuable. By performing mRNA sequencing, we define significant changes in slc25a46 mutant's gene expression profile, which are largely absent in crispants. We find that among the most significantly altered mRNAs, anxa6 gene stands out as a functionally relevant player in mitochondrial dynamics. We also find that our genetic compensation case does not arise from mechanisms driven by mutant mRNA decay. Our study contributes to the growing evidence of the genetic compensation phenomenon and presents novel insights about Slc25a46 function. Furthermore, our study provides the evidence for the efficiency of F0 CRISPR screens for disease candidate genes, which may be used to advance the field of functional genetics.


Assuntos
Sistemas CRISPR-Cas , Proteínas de Transporte da Membrana Mitocondrial/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Animais , Ataxia Cerebelar/genética , Modelos Animais de Doenças , Feminino , Marcação de Genes , Masculino , Mutagênese , Mutação , Atrofia Óptica/genética , Doenças do Sistema Nervoso Periférico/genética
10.
Sci Rep ; 10(1): 2168, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034189

RESUMO

Unipolar brush cells (UBCs) are excitatory granular layer interneurons in the vestibulocerebellum. Here we assessed motor coordination and balance to investigate if deletion of acid-sensing ion channel 5 (Asic5), which is richly expressed in type II UBCs, is sufficient to cause ataxia. The possible cellular mechanism underpinning ataxia in this global Asic5 knockout model was elaborated using brain slice electrophysiology. Asic5 deletion impaired motor performance and decreased intrinsic UBC excitability, reducing spontaneous action potential firing by slowing maximum depolarization rate. Reduced intrinsic excitability in UBCs was partially compensated by suppression of the magnitude and duration of delayed hyperpolarizing K+ currents triggered by glutamate. Glutamate typically stimulates burst firing subsequent to this hyperpolarization in normal type II UBCs. Burst firing frequency was elevated in knockout type II UBCs because it was initiated from a more depolarized potential compared to normal cells. Findings indicate that Asic5 is important for type II UBC activity and that loss of Asic5 contributes to impaired movement, likely, at least in part, due to altered temporal processing of vestibular input.


Assuntos
Canais Iônicos Sensíveis a Ácido/genética , Potenciais de Ação , Ataxia Cerebelar/metabolismo , Neurônios/metabolismo , Animais , Ataxia Cerebelar/genética , Ataxia Cerebelar/patologia , Ácido Glutâmico/metabolismo , Masculino , Camundongos , Neurônios/fisiologia , Potássio/metabolismo
11.
J Clin Neurosci ; 72: 31-38, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31959558

RESUMO

ATP1A3 related disease is a clinically heterogeneous condition currently classified as alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss. Recently, it has become apparent that a remarkably large subgroup is suffering from often difficult-to-treat epilepsy. The aim of the present study was to assess the prevalence and efficacy of commonly used anti-epileptic-drugs (AEDs) in patients with ATP1A3 related seizures. Therefore, we performed a retrospective study of patients in combination with a systematic literature-based review. Inclusion criteria were: verified ATP1A3 mutation, seizures and information about AED treatment. The literature review yielded records for 188 epileptic ATP1A3 patients. For 14/188 cases, information about anti-epileptic treatment was available. Combined with seven unpublished records of ATP1A3 patients, a sample size of 21 patients was reached. Most used AED were levetiracetam (n = 9), phenobarbital (n = 8), valproic acid (n = 7), and topiramate (n = 5). Seizure reduction was reported for 57% of patients (n = 12). No individual AEDs used (either alone or combined) had a success rate over 50%. There was no significant difference in the response rate between various AEDs. Ketogenic diet was effective in 2/4 patients. 43% of patients (n = 9) did not show any seizure relief. Even though Epilepsy is a significant clinical issue in ATP1A3 patients, only a minority of publications provide any information about patients' anti-epileptic treatment. The findings of treatment effectiveness in only 57% (or lower) of patients, and the non-existence of a clear first-line AED in ATP1A3 related epilepsy stresses the need for further research.


Assuntos
Epilepsia/genética , Hemiplegia/genética , ATPase Trocadora de Sódio-Potássio , Adulto , Anticonvulsivantes/uso terapêutico , Ataxia Cerebelar/genética , Criança , Distúrbios Distônicos , Epilepsia/dietoterapia , Epilepsia/tratamento farmacológico , Feminino , Perda Auditiva Neurossensorial , Hemiplegia/dietoterapia , Hemiplegia/tratamento farmacológico , Humanos , Levetiracetam , Masculino , Mutação , Atrofia Óptica/genética , Reflexo Anormal , Estudos Retrospectivos , Convulsões/genética , Topiramato , Ácido Valproico/uso terapêutico
12.
PLoS Genet ; 16(1): e1008527, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31999692

RESUMO

A form of hereditary cerebellar ataxia has recently been described in the Norwegian Buhund dog breed. This study aimed to identify the genetic cause of the disease. Whole-genome sequencing of two Norwegian Buhund siblings diagnosed with progressive cerebellar ataxia was carried out, and sequences compared with 405 whole genome sequences of dogs of other breeds to filter benign common variants. Nine variants predicted to be deleterious segregated among the genomes in concordance with an autosomal recessive mode of inheritance, only one of which segregated within the breed when genotyped in additional Norwegian Buhunds. In total this variant was assessed in 802 whole genome sequences, and genotyped in an additional 505 unaffected dogs (including 146 Buhunds), and only four affected Norwegian Buhunds were homozygous for the variant. The variant identified, a T to C single nucleotide polymorphism (SNP) (NC_006585.3:g.88890674T>C), is predicted to cause a tryptophan to arginine substitution in a highly conserved region of the potassium voltage-gated channel interacting protein KCNIP4. This gene has not been implicated previously in hereditary ataxia in any species. Evaluation of KCNIP4 protein expression through western blot and immunohistochemical analysis using cerebellum tissue of affected and control dogs demonstrated that the mutation causes a dramatic reduction of KCNIP4 protein expression. The expression of alternative KCNIP4 transcripts within the canine cerebellum, and regional differences in KCNIP4 protein expression, were characterised through RT-PCR and immunohistochemistry respectively. The voltage-gated potassium channel protein KCND3 has previously been implicated in spinocerebellar ataxia, and our findings suggest that the Kv4 channel complex KCNIP accessory subunits also have an essential role in voltage-gated potassium channel function in the cerebellum and should be investigated as potential candidate genes for cerebellar ataxia in future studies in other species.


Assuntos
Ataxia Cerebelar/genética , Doenças do Cão/genética , Proteínas Interatuantes com Canais de Kv/genética , Polimorfismo de Nucleotídeo Único , Animais , Ataxia Cerebelar/veterinária , Cerebelo/metabolismo , Cães , Proteínas Interatuantes com Canais de Kv/metabolismo , Mutação , Sequenciamento Completo do Genoma/veterinária
13.
Eur J Med Genet ; 63(1): 103623, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30684668

RESUMO

Human MSTO1 is involved in the regulation of mitochondrial distribution and morphology and its unregulated expression leads to mitochondrial disorder. Despite its significance for mitochondrial functions, human MSTO1 gene is rarely studied before 2017. As of late, MSTO1 mutations have been reported to cause clinical manifestations such as myopathy, cerebellar atrophy and ataxia, motor developmental delay, and pigmentary retinopathy. Here we have performed a whole-exome sequencing in a family which includes two brothers showing cerebellar atrophy and ataxia, intellectual disability, and myopathy. As a result, two mutations were identified. One of these mutations has been identified as a missense mutation, c.836G > A; p. (Arg279His) and a novel frameshift variant, c.1259delG; p. (Gly420ValfsTer2). So, the two brothers both had compound heterozygous mutations with a combination of protein-truncation mutation and missense mutation. These findings suggested an association of MSTO1 mutations with the early onset of symptoms and revealed the genotype-phenotype correlation between different mutation cases. In this case, the two brothers both have pes planus which is not reported in other cases. This might suggest that the novel mutation is responsible for dysmorphia. Thus, the recessive and novel MSTO1 mutations enriches genetic information on the pathogenicity of MSTO1 in humans.


Assuntos
Proteínas de Ciclo Celular/genética , Ataxia Cerebelar/genética , Proteínas do Citoesqueleto/genética , Deficiência Intelectual/genética , Doenças Musculares/genética , Adolescente , Ataxia Cerebelar/diagnóstico por imagem , Ataxia Cerebelar/patologia , Criança , Estudos de Associação Genética , Heterozigoto , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/patologia , Masculino , Doenças Musculares/diagnóstico por imagem , Doenças Musculares/patologia , Mutação , Mutação de Sentido Incorreto/genética , Linhagem , Fenótipo , Sequenciamento Completo do Exoma
14.
Pract Neurol ; 20(1): 55-58, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31467149

RESUMO

Friedreich's ataxia is classically considered a disease with onset in the first or second decade. However, late-onset (age of onset 25-39 years) and very-late-onset (age of onset >40 years) forms do occur rarely. Misdiagnosis is common, particularly because the later onset forms of Friedreich's ataxia commonly do not show characteristic features of the disorder (areflexia, dysarthria, sensory neuropathy, extensor plantars, amyotrophy, cardiac involvement, diabetes mellitus, scoliosis). Also, there may be atypical features such as spasticity, brisk reflexes and laryngeal dystonia. We present the clinical, imaging and genetic findings of a kindred with very-late-onset Friedreich's ataxia and discuss the pitfalls and risk of misdiagnosis.


Assuntos
Ataxia Cerebelar/diagnóstico por imagem , Ataxia Cerebelar/genética , Ataxia de Friedreich/diagnóstico por imagem , Ataxia de Friedreich/genética , Fatores Etários , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem
15.
Brain Dev ; 42(1): 6-18, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31493945

RESUMO

BACKGROUND: The purpose of this prospective study was to identify the characteristics of pediatric recessive ataxias and the mutations leading to them. METHODS: Eighty-four pediatric patients aged 0-18 years presenting to our clinic, evaluated by means of imaging, metabolic or pathological investigation, or single-gene test, in whom Friedreich's ataxia was excluded, and predicted to carry the progressive autosomal recessive ataxia gene were included in the study. Patients' demographic, clinical, laboratory, and radiological characteristics were recorded. DNA and panel sequencing directed toward ataxia-related genes was performed using the next-generation sequencing method. RESULTS: A molecular diagnosis was established in 21 (25%) of the 84 patients. Genetically, infantile neuroaxonal dystrophy (7/21), ataxia with oculomotor apraxia type 1 (5/21), neuronal ceroid lipofuscinosis type 5 (2/21), ataxia with oculomotor apraxia type 2 (1/21), Lafora disease (1/21), tremor ataxia syndrome accompanying central hypomyelination (1/21), Charlevoix-Saguenay ataxia (1/21), Marinesco-Sjögren syndrome (1/21), VLDRL-associated cerebellar hypoplasia (1/21), and TSEN54-related pontocerebellar hypoplasia (1/21) mutations were detected. CONCLUSIONS: Approximately 25% of our patients were diagnosed. Novel mutations in the known genes were identified and are important in terms of phenotype-genotype correlation.


Assuntos
Ataxia Cerebelar/genética , Adolescente , Criança , Pré-Escolar , Feminino , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Fenótipo , Estudos Prospectivos
16.
J Neurol ; 267(1): 203-213, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31612321

RESUMO

ATP8A2-related disorders are autosomal recessive conditions that associate encephalopathy with or without hypotonia, psychomotor delay, abnormal movements, chorea, tremor, optic atrophy and cerebellar atrophy (CARMQ4). Through a multi-centric collaboration, we identified six point mutations (one splice site and five missense mutations) involving ATP8A2 in six individuals from five families. Two patients from one family with the homozygous p.Gly585Val mutation had a milder presentation without encephalopathy. Expression and functional studies of the missense mutations demonstrated that protein levels of four of the five missense variants were very low and lacked phosphatidylserine-activated ATPase activity. One variant p.Ile215Leu, however, expressed at normal levels and displayed phospholipid-activated ATPase activity similar to the non-mutated protein. We therefore expand for the first time the phenotype related to ATP8A2 mutations to less severe forms characterized by cerebellar ataxia without encephalopathy and suggest that ATP8A2 should be analyzed for all cases of syndromic or non-syndromic recessive or sporadic ataxia.


Assuntos
Adenosina Trifosfatases/genética , Ataxia Cerebelar/genética , Ataxia Cerebelar/patologia , Ataxia Cerebelar/fisiopatologia , Proteínas de Transferência de Fosfolipídeos/genética , Adulto , Criança , Pré-Escolar , Consanguinidade , Feminino , Genes Recessivos , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Mutação Puntual
17.
Brain ; 143(1): 303-319, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31855245

RESUMO

Homozygous mutations in the progranulin gene (GRN) are associated with neuronal ceroid lipofuscinosis 11 (CLN11), a rare lysosomal-storage disorder characterized by cerebellar ataxia, seizures, retinitis pigmentosa, and cognitive disorders, usually beginning between 13 and 25 years of age. This is a rare condition, previously reported in only four families. In contrast, heterozygous GRN mutations are a major cause of frontotemporal dementia associated with neuronal cytoplasmic TDP-43 inclusions. We identified homozygous GRN mutations in six new patients. The phenotypic spectrum is much broader than previously reported, with two remarkably distinct presentations, depending on the age of onset. A childhood/juvenile form is characterized by classical CLN11 symptoms at an early age at onset. Unexpectedly, other homozygous patients presented a distinct delayed phenotype of frontotemporal dementia and parkinsonism after 50 years; none had epilepsy or cerebellar ataxia. Another major finding of this study is that all GRN mutations may not have the same impact on progranulin protein synthesis. A hypomorphic effect of some mutations is supported by the presence of residual levels of plasma progranulin and low levels of normal transcript detected in one case with a homozygous splice-site mutation and late onset frontotemporal dementia. This is a new critical finding that must be considered in therapeutic trials based on replacement strategies. The first neuropathological study in a homozygous carrier provides new insights into the pathological mechanisms of the disease. Hallmarks of neuronal ceroid lipofuscinosis were present. The absence of TDP-43 cytoplasmic inclusions markedly differs from observations of heterozygous mutations, suggesting a pathological shift between lysosomal and TDP-43 pathologies depending on the mono or bi-allelic status. An intriguing observation was the loss of normal TDP-43 staining in the nucleus of some neurons, which could be the first stage of the TDP-43 pathological process preceding the formation of typical cytoplasmic inclusions. Finally, this study has important implications for genetic counselling and molecular diagnosis. Semi-dominant inheritance of GRN mutations implies that specific genetic counselling should be delivered to children and parents of CLN11 patients, as they are heterozygous carriers with a high risk of developing dementia. More broadly, this study illustrates the fact that genetic variants can lead to different phenotypes according to their mono- or bi-allelic state, which is a challenge for genetic diagnosis.


Assuntos
Demência Frontotemporal/genética , Lipofuscinoses Ceroides Neuronais/genética , Transtornos Parkinsonianos/genética , Progranulinas/genética , Adolescente , Adulto , Idade de Início , Ataxia Cerebelar/genética , Criança , Disfunção Cognitiva/genética , Epilepsia/genética , Feminino , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/fisiopatologia , Heterozigoto , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Lipofuscinoses Ceroides Neuronais/diagnóstico por imagem , Lipofuscinoses Ceroides Neuronais/fisiopatologia , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/fisiopatologia , Progranulinas/metabolismo , Processamento de RNA/genética , Doenças Raras , Retinite Pigmentosa/genética , Proteinopatias TDP-43/diagnóstico por imagem , Proteinopatias TDP-43/genética , Proteinopatias TDP-43/fisiopatologia , Adulto Jovem
18.
Orphanet J Rare Dis ; 14(1): 282, 2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31796091

RESUMO

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare inborn lipid-storage disease caused by mutations in the sterol 27-hydroxylase (CYP27A1) gene with an autosomal recessive pattern of inheritance. To date, only 19 CTX patients from 16 families have been reported in the Chinese population. RESULTS: Three novel likely pathogenic mutations (c.368_374delCCAGTAC, c.389 T > A and c.571C > T) and 7 previously reported pathogenic mutations (c.379C > T, c.435G > T, c.1016C > T, c.1214G > A, c.1263 + 1G > A, c.1420C > T and c.1435C > T) were identified. In addition, we summarized the genotypes and phenotypes of reported Chinese CTX patients. The most predominant mutations in CYP27A1 were c.410G > A and c.379C > T, and the most common clinical manifestations were pyramidal signs, xanthomatosis, cerebellar ataxia, and cognitive impairment. CONCLUSION: Our study broadens the genetic and clinical spectrum of CTX and provides insightful information to help better diagnose and understand the disease.


Assuntos
Colestanotriol 26-Mono-Oxigenase/genética , Xantomatose Cerebrotendinosa/genética , Xantomatose Cerebrotendinosa/patologia , Adulto , Grupo com Ancestrais do Continente Asiático , Ataxia Cerebelar/genética , Ataxia Cerebelar/patologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Xantomatose/genética , Xantomatose/patologia
19.
Neuroimage Clin ; 24: 102043, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31678909

RESUMO

Genetically determined cerebellar ataxias (CA) are a heterogeneous group of disorders with progressive decline of cerebellar functions. The cerebellum influences internal forward models that play a role in cognitive control, but whether these processes are dysfunctional in CA is unclear. Here, we examined sensory predictive coding processes and response adaptation in CA and healthy controls (HC) using behavioral tests with concomitant EEG recordings. N = 23 patients and N = 29 age- and sex-matched HC were studied. Sensory prediction coding was tested with an auditory distraction paradigm and error-related behavioral adaptation with a visual flanker task. As neurophysiological markers we studied different event-related potentials: the P3a for orientation of attention; the N2 and the error-related negativity (ERN) for cognitive adaptation processes/consequences of response errors; error-related positivity (Pe) for error-awareness; the mismatch negativity (MMN) for sensory predictive coding; and reorientation negativity (RON) for reorientation after unexpected events. Overall reaction times were slower in patients compared to HC, but error rates did not differ. Both in patients and HC, P3a amplitudes were larger in distraction trials, but the P3a amplitude was smaller in patients compared to HC. The MMN as well as behavioral and EEG-correlates of response adaptation (ERN/N2) did not differ between groups, while the Pe was attenuated in patients. During sensory predictive coding, RON amplitudes were significantly larger in HC compared to patients. In HC, but not in patients, RON amplitudes were also larger in deviant compared to frequent trials. Processes generating internal forward models are largely intact in genetically determined CA, whereas updating of mental models and error awareness are disturbed in these patients.


Assuntos
Adaptação Psicológica/fisiologia , Encéfalo/fisiopatologia , Ataxia Cerebelar/fisiopatologia , Potenciais Evocados/fisiologia , Adulto , Idoso , Atenção/fisiologia , Ataxia Cerebelar/genética , Eletroencefalografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Reação/fisiologia , Adulto Jovem
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