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1.
Hum Mol Genet ; 31(6): 958-974, 2022 03 21.
Artículo en Inglés | MEDLINE | ID: mdl-34635923

RESUMEN

Mutations in mitochondrial DNA encoded subunit of ATP synthase, MT-ATP6, are frequent causes of neurological mitochondrial diseases with a range of phenotypes from Leigh syndrome and NARP to ataxias and neuropathies. Here we investigated the functional consequences of an unusual heteroplasmic truncating mutation m.9154C>T in MT-ATP6, which caused peripheral neuropathy, ataxia and IgA nephropathy. ATP synthase not only generates cellular ATP, but its dimerization is required for mitochondrial cristae formation. Accordingly, the MT-ATP6 truncating mutation impaired the assembly of ATP synthase and disrupted cristae morphology, supporting our molecular dynamics simulations that predicted destabilized a/c subunit subcomplex. Next, we modeled the effects of the truncating mutation using patient-specific induced pluripotent stem cells. Unexpectedly, depending on mutation heteroplasmy level, the truncation showed multiple threshold effects in cellular reprogramming, neurogenesis and in metabolism of mature motor neurons (MN). Interestingly, MN differentiation beyond progenitor stage was impaired by Notch hyperactivation in the MT-ATP6 mutant, but not by rotenone-induced inhibition of mitochondrial respiration, suggesting that altered mitochondrial morphology contributed to Notch hyperactivation. Finally, we also identified a lower mutation threshold for a metabolic shift in mature MN, affecting lactate utilization, which may be relevant for understanding the mechanisms of mitochondrial involvement in peripheral motor neuropathies. These results establish a critical and disease-relevant role for ATP synthase in human cell fate decisions and neuronal metabolism.


Asunto(s)
Heteroplasmia , ATPasas de Translocación de Protón Mitocondriales , Adenosina Trifosfato , Ataxia/genética , ADN Mitocondrial/genética , Humanos , ATPasas de Translocación de Protón Mitocondriales/genética , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Neuronas Motoras/metabolismo , Mutación
2.
Neurogenetics ; 24(4): 291-301, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37606798

RESUMEN

Charcot-Marie-Tooth disease (CMT) is a heterogeneous set of hereditary neuropathies whose genetic causes are not fully understood. Here, we characterize three previously unknown variants in PMP22 and assess their effect on the recently described potential CMT biomarkers' growth differentiation factor 15 (GDF15) and neurofilament light (NFL): first, a heterozygous PMP22 c.178G > A (p.Glu60Lys) in one mother-son pair with adult-onset mild axonal neuropathy. The variant led to abnormal splicing, confirmed in fibroblasts by reverse transcription PCR. Second, a de novo PMP22 c.35A > C (p.His12Pro), and third, a heterozygous 3.2 kb deletion predicting loss of exon 4. The latter two had severe CMT and ultrasonography showing strong nerve enlargement similar to a previous case of exon 4 loss due to a larger deletion. We further studied patients with PMP22 duplication (CMT1A) finding slightly elevated plasma NFL, as measured by the single molecule array immunoassay (SIMOA). In addition, plasma GDF15, as measured by ELISA, correlated with symptom severity for CMT1A. However, in the severely affected individuals with PMP22 exon 4 deletion or p.His12Pro, these biomarkers were within the range of variability of CMT1A and controls, although they had more pronounced nerve hypertrophy. This study adds p.His12Pro and confirms PMP22 exon 4 deletion as causes of severe CMT, whereas the previously unknown splice variant p.Glu60Lys leads to mild axonal neuropathy. Our results suggest that GDF15 and NFL do not distinguish CMT1A from advanced hypertrophic neuropathy caused by rare PMP22 variants.


Asunto(s)
Enfermedad de Charcot-Marie-Tooth , Neuropatía Hereditaria Motora y Sensorial , Adulto , Humanos , Factor 15 de Diferenciación de Crecimiento/genética , Filamentos Intermedios , Proteínas de la Mielina/genética , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/diagnóstico , Biomarcadores
3.
Brain ; 145(11): 3985-3998, 2022 11 21.
Artículo en Inglés | MEDLINE | ID: mdl-34957489

RESUMEN

Rhabdomyolysis is the acute breakdown of skeletal myofibres in response to an initiating factor, most commonly toxins and over exertion. A variety of genetic disorders predispose to rhabdomyolysis through different pathogenic mechanisms, particularly in patients with recurrent episodes. However, most cases remain without a genetic diagnosis. Here we present six patients who presented with severe and recurrent rhabdomyolysis, usually with onset in the teenage years; other features included a history of myalgia and muscle cramps. We identified 10 bi-allelic loss-of-function variants in the gene encoding obscurin (OBSCN) predisposing individuals to recurrent rhabdomyolysis. We show reduced expression of OBSCN and loss of obscurin protein in patient muscle. Obscurin is proposed to be involved in sarcoplasmic reticulum function and Ca2+ handling. Patient cultured myoblasts appear more susceptible to starvation as evidenced by a greater decreased in sarcoplasmic reticulum Ca2+ content compared to control myoblasts. This likely reflects a lower efficiency when pumping Ca2+ back into the sarcoplasmic reticulum and/or a decrease in Ca2+ sarcoplasmic reticulum storage ability when metabolism is diminished. OSBCN variants have previously been associated with cardiomyopathies. None of the patients presented with a cardiomyopathy and cardiac examinations were normal in all cases in which cardiac function was assessed. There was also no history of cardiomyopathy in first degree relatives, in particular in any of the carrier parents. This cohort is relatively young, thus follow-up studies and the identification of additional cases with bi-allelic null OBSCN variants will further delineate OBSCN-related disease and the clinical course of disease.


Asunto(s)
Calcio , Rabdomiólisis , Adolescente , Humanos , Rabdomiólisis/genética , Rabdomiólisis/diagnóstico , Rabdomiólisis/patología , Mialgia/genética , Retículo Sarcoplasmático/metabolismo , Pérdida de Heterocigocidad , Proteínas Serina-Treonina Quinasas , Factores de Intercambio de Guanina Nucleótido Rho/genética
4.
Hum Mol Genet ; 29(9): 1426-1439, 2020 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-32202298

RESUMEN

Defects in the mRNA export scaffold protein GANP, encoded by the MCM3AP gene, cause autosomal recessive early-onset peripheral neuropathy with or without intellectual disability. We extend here the phenotypic range associated with MCM3AP variants, by describing a severely hypotonic child and a sibling pair with a progressive encephalopathic syndrome. In addition, our analysis of skin fibroblasts from affected individuals from seven unrelated families indicates that disease variants result in depletion of GANP except when they alter critical residues in the Sac3 mRNA binding domain. GANP depletion was associated with more severe phenotypes compared with the Sac3 variants. Patient fibroblasts showed transcriptome alterations that suggested intron content-dependent regulation of gene expression. For example, all differentially expressed intronless genes were downregulated, including ATXN7L3B, which couples mRNA export to transcription activation by association with the TREX-2 and SAGA complexes. Our results provide insight into the molecular basis behind genotype-phenotype correlations in MCM3AP-associated disease and suggest mechanisms by which GANP defects might alter RNA metabolism.


Asunto(s)
Acetiltransferasas/genética , Flavoproteínas/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Enfermedades del Sistema Nervioso/genética , Proteínas Nucleares/genética , Monoéster Fosfórico Hidrolasas/genética , Factores de Transcripción/genética , Acetiltransferasas/química , Acetiltransferasas/ultraestructura , Edad de Inicio , Antígenos de Superficie/genética , Núcleo Celular/genética , Niño , Preescolar , Exodesoxirribonucleasas/genética , Femenino , Regulación de la Expresión Génica/genética , Glicoproteínas/genética , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Péptidos y Proteínas de Señalización Intracelular/química , Intrones/genética , Masculino , Enfermedades del Sistema Nervioso/patología , Proteínas Nucleares/ultraestructura , Enfermedades del Sistema Nervioso Periférico/genética , Enfermedades del Sistema Nervioso Periférico/patología , Fenotipo , Fosfoproteínas/genética , Conformación Proteica , Transporte de ARN/genética , ARN Mensajero/genética
5.
Acta Neurol Scand ; 145(1): 63-72, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34418069

RESUMEN

OBJECTIVES: Clinical diagnostics in adults with hereditary neurological diseases is complicated by clinical and genetic heterogeneity, as well as lifestyle effects. Here, we evaluate the effectiveness of exome sequencing and clinical costs in our difficult-to-diagnose adult patient cohort. Additionally, we expand the phenotypic and genetic spectrum of hereditary neurological disorders in Finland. METHODS: We performed clinical exome sequencing (CES) to 100 adult patients from Finland with neurological symptoms of suspected genetic cause. The patients were classified as myopathy (n = 57), peripheral neuropathy (n = 16), ataxia (n = 15), spastic paraplegia (n = 4), Parkinsonism (n = 3), and mixed (n = 5). In addition, we gathered the costs of prior diagnostic work-up to retrospectively assess the cost-effectiveness of CES as a first-line diagnostic tool. RESULTS: The overall diagnostic yield of CES was 27%. Pathogenic variants were found for 14 patients (in genes ANO5, CHCHD10, CLCN1, DES, DOK7, FKBP14, POLG, PYROXD1, SCN4A, TUBB3, and TTN) and likely pathogenic previously undescribed variants for 13 patients (in genes ABCD1, AFG3L2, ATL1, CACNA1A, COL6A1, DYSF, IRF2BPL, KCNA1, MT-ATP6, SAMD9L, SGCB, and TPM2). Age of onset below 40 years increased the probability of finding a genetic cause. Our cost evaluation of prior diagnostic work-up suggested that early CES would be cost-effective in this patient group, in which diagnostic costs increase linearly with prolonged investigations. CONCLUSIONS: Based on our results, CES is a cost-effective, powerful first-line diagnostic tool in establishing the molecular diagnosis in adult neurological patients with variable symptoms. Importantly, CES can markedly shorten the diagnostic odysseys of about one third of patients.


Asunto(s)
Enfermedades del Sistema Nervioso , Trastornos Parkinsonianos , Proteasas ATP-Dependientes , ATPasas Asociadas con Actividades Celulares Diversas , Adulto , Anoctaminas , Proteínas Portadoras , Estudios de Cohortes , Exoma/genética , Humanos , Mutación , Canal de Sodio Activado por Voltaje NAV1.4 , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/genética , Proteínas Nucleares , Isomerasa de Peptidilprolil , Estudios Retrospectivos
6.
Neurobiol Dis ; 141: 104940, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32437855

RESUMEN

Mitochondrial intermembrane space proteins CHCHD2 and CHCHD10 have roles in motor neuron diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy and axonal neuropathy and in Parkinson's disease. They form a complex of unknown function. Here we address the importance of these two proteins in human motor neurons. We show that gene edited human induced pluripotent stem cells (iPSC) lacking either CHCHD2 or CHCHD10 are viable and can be differentiated into functional motor neurons that fire spontaneous and evoked action potentials. Mitochondria in knockout iPSC and motor neurons sustain ultrastructure but show increased proton leakage and respiration, and reciprocal compensatory increases in CHCHD2 or CHCHD10. Knockout motor neurons have largely overlapping transcriptome profiles compared to isogenic control line, in particular for synaptic gene expression. Our results show that the absence of either CHCHD2 or CHCHD10 alters mitochondrial respiration in human motor neurons, inducing similar compensatory responses. Thus, pathogenic mechanisms may involve loss of synaptic function resulting from defective energy metabolism.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Proteínas de Unión al ADN/metabolismo , Proteínas Mitocondriales/metabolismo , Neuronas Motoras/metabolismo , Enfermedad de Parkinson/genética , Sinapsis/metabolismo , Factores de Transcripción/metabolismo , Transcriptoma , Esclerosis Amiotrófica Lateral/metabolismo , Diferenciación Celular , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Potenciales de la Membrana , Mitocondrias/metabolismo , Enfermedad de Parkinson/metabolismo
7.
Hum Mol Genet ; 26(8): 1432-1443, 2017 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-28158749

RESUMEN

De novo mutations in ATAD3A (ATPase family AAA-domain containing protein 3A) were recently found to cause a neurological syndrome with developmental delay, hypotonia, spasticity, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. Using whole-exome sequencing, we identified a dominantly inherited heterozygous variant c.1064G > A (p.G355D) in ATAD3A in a mother presenting with hereditary spastic paraplegia (HSP) and axonal neuropathy and her son with dyskinetic cerebral palsy, both with disease onset in childhood. HSP is a clinically and genetically heterogeneous disorder of the upper motor neurons. Symptoms beginning in early childhood may resemble spastic cerebral palsy. The function of ATAD3A, a mitochondrial inner membrane AAA ATPase, is yet undefined. AAA ATPases form hexameric rings, which are catalytically dependent on the co-operation of the subunits. The dominant-negative patient mutation affects the Walker A motif, which is responsible for ATP binding in the AAA module of ATAD3A, and we show that the recombinant mutant ATAD3A protein has a markedly reduced ATPase activity. We further show that overexpression of the mutant ATAD3A fragments the mitochondrial network and induces lysosome mass. Similarly, we observed altered dynamics of the mitochondrial network and increased lysosomes in patient fibroblasts and neurons derived through differentiation of patient-specific induced pluripotent stem cells. These alterations were verified in patient fibroblasts to associate with upregulated basal autophagy through mTOR inactivation, resembling starvation. Mutations in ATAD3A can thus be dominantly inherited and underlie variable neurological phenotypes, including HSP, with intrafamiliar variability. This finding extends the group of mitochondrial inner membrane AAA proteins associated with spasticity.


Asunto(s)
Adenosina Trifosfatasas/genética , Parálisis Cerebral/genética , Proteínas de la Membrana/genética , Proteínas Mitocondriales/genética , Paraplejía Espástica Hereditaria/genética , ATPasas Asociadas con Actividades Celulares Diversas , Adenosina Trifosfatasas/biosíntesis , Adolescente , Adulto , Axones/metabolismo , Axones/patología , Parálisis Cerebral/patología , Preescolar , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , Proteínas de la Membrana/biosíntesis , Mitocondrias/metabolismo , Mitocondrias/patología , Dinámicas Mitocondriales/genética , Membranas Mitocondriales/metabolismo , Membranas Mitocondriales/patología , Proteínas Mitocondriales/biosíntesis , Mutación , Paraplejía Espástica Hereditaria/patología , Serina-Treonina Quinasas TOR/genética
8.
Muscle Nerve ; 59(3): 354-357, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30246259

RESUMEN

INTRODUCTION: In this study we assessed the value of genetic screening for Fabry disease (FD) and hereditary ATTR amyloidosis in patients with idiopathic small-fiber neuropathy (SFN) or mixed neuropathy in a clinical setting. METHODS: This was a Nordic multicenter study with 9 participating centers. Patients with idiopathic SFN or mixed neuropathy were included. Genetic sequencing of the TTR and GLA genes was performed. RESULTS: There were 172 patients enrolled in the study. Genetic screening was performed in 155 patients. No pathogenic mutations in the TTR gene were found. A single patient had a possible pathogenic variant, R118C, in the GLA gene, but clinical investigation showed no firm signs of FD. DISCUSSION: Screening for hereditary ATTR amyloidosis and FD in patients with idiopathic SFN or mixed neuropathy without any additional disease-specific symptoms or clinical characteristics in a Nordic population appears to be of little value in a clinical setting. Muscle Nerve 59:354-357, 2019.


Asunto(s)
Neuropatías Amiloides Familiares/diagnóstico , Amiloidosis Familiar/diagnóstico , Amiloidosis Familiar/genética , Enfermedad de Fabry/diagnóstico , Enfermedad de Fabry/genética , Adulto , Anciano , Anciano de 80 o más Años , Proteínas de Unión al Calcio/genética , Proteínas de la Matriz Extracelular/genética , Femenino , Pruebas Genéticas , Genotipo , Humanos , Masculino , Tamizaje Masivo/métodos , Persona de Mediana Edad , Mutación/genética , Resultados Negativos , Prealbúmina/genética , Estudios Prospectivos , Estudios Retrospectivos , Países Escandinavos y Nórdicos , Adulto Joven , Proteína Gla de la Matriz
9.
Neurobiol Dis ; 119: 159-171, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30092269

RESUMEN

Following the involvement of CHCHD10 in FrontoTemporal-Dementia-Amyotrophic Lateral Sclerosis (FTD-ALS) clinical spectrum, a founder mutation (p.Gly66Val) in the same gene was identified in Finnish families with late-onset spinal motor neuronopathy (SMAJ). SMAJ is a slowly progressive form of spinal muscular atrophy with a life expectancy within normal range. In order to understand why the p.Ser59Leu mutation, responsible for severe FTD-ALS, and the p.Gly66Val mutation could lead to different levels of severity, we compared their effects in patient cells. Unlike affected individuals bearing the p.Ser59Leu mutation, patients presenting with SMAJ phenotype have neither mitochondrial myopathy nor mtDNA instability. The expression of CHCHD10S59L mutant allele leads to disassembly of mitochondrial contact site and cristae organizing system (MICOS) with mitochondrial dysfunction and loss of cristae in patient fibroblasts. We also show that G66V fibroblasts do not display the loss of MICOS complex integrity and mitochondrial damage found in S59L cells. However, S59L and G66V fibroblasts show comparable accumulation of phosphorylated mitochondrial TDP-43 suggesting that the severity of phenotype and mitochondrial damage do not depend on mitochondrial TDP-43 localization. The expression of the CHCHD10G66V allele is responsible for mitochondrial network fragmentation and decreased sensitivity towards apoptotic stimuli, but with a less severe effect than that found in cells expressing the CHCHD10S59L allele. Taken together, our data show that cellular phenotypes associated with p.Ser59Leu and p.Gly66Val mutations in CHCHD10 are different; loss of MICOS complex integrity and mitochondrial dysfunction, but not TDP-43 mitochondrial localization, being likely essential to develop a severe motor neuron disease.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Proteínas de Unión al ADN/genética , Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Mitocondrias/genética , Mitocondrias/patología , Proteínas Mitocondriales/genética , Adulto , Proteínas de Unión al ADN/análisis , Femenino , Células HEK293 , Células HeLa , Humanos , Masculino , Proteínas de la Membrana/análisis , Proteínas de la Membrana/genética , Persona de Mediana Edad , Mitocondrias/ultraestructura , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/patología , Proteínas Mitocondriales/análisis , Mutación/genética , Proteínas de Saccharomyces cerevisiae/análisis , Proteínas de Saccharomyces cerevisiae/genética , Índice de Severidad de la Enfermedad
10.
Brain ; 140(8): 2093-2103, 2017 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-28633435

RESUMEN

Defects in mRNA export from the nucleus have been linked to various neurodegenerative disorders. We report mutations in the gene MCM3AP, encoding the germinal center associated nuclear protein (GANP), in nine affected individuals from five unrelated families. The variants were associated with severe childhood onset primarily axonal (four families) or demyelinating (one family) Charcot-Marie-Tooth neuropathy. Mild to moderate intellectual disability was present in seven of nine affected individuals. The affected individuals were either compound heterozygous or homozygous for different MCM3AP variants, which were predicted to cause depletion of GANP or affect conserved amino acids with likely importance for its function. Accordingly, fibroblasts of affected individuals from one family demonstrated severe depletion of GANP. GANP has been described to function as an mRNA export factor, and to suppress TDP-43-mediated motor neuron degeneration in flies. Thus our results suggest defective mRNA export from nucleus as a potential pathogenic mechanism of axonal degeneration in these patients. The identification of MCM3AP variants in affected individuals from multiple centres establishes it as a disease gene for childhood-onset recessively inherited Charcot-Marie-Tooth neuropathy with intellectual disability.


Asunto(s)
Acetiltransferasas/genética , Enfermedad de Charcot-Marie-Tooth/genética , Predisposición Genética a la Enfermedad/genética , Discapacidad Intelectual/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Acetiltransferasas/metabolismo , Adolescente , Adulto , Células Cultivadas , Enfermedad de Charcot-Marie-Tooth/complicaciones , Niño , Preescolar , Femenino , Fibroblastos/metabolismo , Humanos , Discapacidad Intelectual/complicaciones , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Mutación , Linaje , Adulto Joven
11.
Duodecim ; 133(7): 683-7, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29243459

RESUMEN

We present a Finnish family in which adrenomyeloneuropathy (AMN) caused by the mutation in the ABCD1 gene was revealed as the cause of spastic paraparesis. . Two patients had hypoadrenalism, which is in some cases some associated with the disease . AMN is a hereditary disease manifested both in men and women. but owing to the location of the gene in the X chromosome the symptoms are usually more severe in male patients. . Diagnoses was trucked down with gene-panel sequencing and confirmed through detection of an elevated level of very long-chain fatty acids in the serum of the patients. Specific molecular genetic diagnosis is beneficial, because it enables precise genetic counseling as well as recognition and treatment of associated symptoms, such as severe cortisol deficiency.


Asunto(s)
Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP/genética , Adrenoleucodistrofia/genética , Paraparesia Espástica/genética , Adulto , Anciano , Femenino , Finlandia , Humanos , Masculino , Mutación , Linaje , Fenotipo , Análisis de Secuencia de ADN
13.
Hum Mol Genet ; 22(15): 2975-83, 2013 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-23562820

RESUMEN

Inherited peripheral neuropathies are a heterogeneous group of disorders that can affect patients of all ages. Children with inherited neuropathy often develop severe disability, but the genetic causes of recessive early-onset axonal neuropathies are not fully known. We have taken a whole-exome sequencing approach to identify causative disease mutations in single patients with early-onset axonal neuropathy. Here, we report compound heterozygous mutations in the tripartite motif containing 2 (TRIM2) gene in a patient with childhood-onset axonal neuropathy, low weight and small muscle mass. We show that the patient fibroblasts are practically devoid of TRIM2, through mRNA and protein instability caused by the mutations. TRIM2 is an E3 ubiquitin ligase that ubiquitinates neurofilament light chain, a component of the intermediate filament in axons. Resembling the findings in our patient's sural nerve biopsy, Trim2-gene trap mice showed axonopathy with accumulations of neurofilaments inside axons. Our results suggest that loss-of-function mutations in TRIM2 are a cause of axonal neuropathy, which we propose to develop as a consequence of axonal accumulation of neurofilaments, secondary to lack of its ubiquitination by TRIM2.


Asunto(s)
Axones/metabolismo , Enfermedad de Charcot-Marie-Tooth/genética , Proteínas Nucleares/deficiencia , Adolescente , Axones/patología , Biopsia , Enfermedad de Charcot-Marie-Tooth/diagnóstico , Exoma , Femenino , Fibroblastos/metabolismo , Humanos , Mutación , Proteínas de Neurofilamentos/metabolismo , Estabilidad del ARN , Análisis de Secuencia de ADN , Nervio Sural/metabolismo , Nervio Sural/patología
15.
Duodecim ; 130(6): 589-93, 2014.
Artículo en Fi | MEDLINE | ID: mdl-24724458

RESUMEN

Syphilis is an infectious disease caused by Treponema pallidum. We describe two patients with chronic syphilis causing neurosyphilis. The first had had several brain infarctions due to the presence of meningovascular syphilis. Second patient suffered from motor and psychiatric symptoms caused by syphilis. The symptoms of our patients were alleviated by antibiotic therapy. Recognition of the multifaceted symptom picture of syphilis is increasingly important, because the occurrence of the disease has increased in our country over the last few decades. An early enough treatment can prevent permanent disability of the patient.


Asunto(s)
Antibacterianos/uso terapéutico , Neurosífilis/complicaciones , Neurosífilis/tratamiento farmacológico , Humanos , Neurosífilis/diagnóstico
16.
Neuromuscul Disord ; 35: 29-32, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38219297

RESUMEN

Patients with myopathies caused by pathogenic variants in tropomyosin genes TPM2 and TPM3 usually have muscle hypotonia and weakness, their muscle biopsies often showing fibre size disproportion and nemaline bodies. Here, we describe a series of patients with hypercontractile molecular phenotypes, high muscle tone, and mostly non-specific myopathic biopsy findings without nemaline bodies. Three of the patients had trismus, whilst in one patient, the distal joints of her fingers flexed on extension of the wrists. In one biopsy from a patient with a rare TPM3 pathogenic variant, cores and minicores were observed, an unusual finding in TPM3-caused myopathy. The variants alter conserved contact sites between tropomyosin and actin.


Asunto(s)
Enfermedades Musculares , Miopatías Nemalínicas , Humanos , Femenino , Músculo Esquelético/patología , Tropomiosina/genética , Enfermedades Musculares/patología , Hipertonía Muscular/patología , Fenotipo , Miopatías Nemalínicas/genética , Miopatías Nemalínicas/patología , Mutación
17.
Neurogenetics ; 14(2): 123-32, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23456260

RESUMEN

We describe a founder mutation in the gene encoding ganglioside-induced differentiation associated-protein 1 (GDAP1), leading to amino acid change p.H123R, as a common cause of autosomal dominant axonal Charcot-Marie-Tooth (CMT2) neuropathy in Finland. The mutation explains up to 14 % of CMT2 in Finland, where most patients with axonal neuropathy have remained without molecular diagnosis. Only three families out of 28 were found to carry putative disease mutations in the MFN2 gene encoding mitofusin 2. In addition, the MFN2 variant p.V705I was commonly found in our patients, but we provide evidence that this previously described mutation is a common polymorphism and not pathogenic. GDAP1-associated polyneuropathy caused predominantly a mild and slowly progressive phenotype. Besides distal leg muscle weakness, most patients showed mild proximal weakness, often with asymmetry and pes cavus. Our findings broaden the understanding of GDAP1 mutations in CMT2 phenotypes and provide support for the use of whole-exome sequencing in CMT gene diagnostics.


Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Adolescente , Adulto , Axones/metabolismo , Enfermedad de Charcot-Marie-Tooth/patología , Niño , Finlandia , GTP Fosfohidrolasas/genética , Predisposición Genética a la Enfermedad , Humanos , Persona de Mediana Edad , Proteínas Mitocondriales/genética , Linaje , Fenotipo , Polineuropatías/etiología , Polineuropatías/genética , Adulto Joven
18.
Front Neurol ; 14: 1277944, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38020590

RESUMEN

Introduction: Spinal muscular atrophy, Jokela type (SMAJ) is a rare autosomal dominantly hereditary form of spinal muscular atrophy caused by a point mutation c.197G>T in CHCHD10. CHCHD10 is known to be involved in the regulation of mitochondrial function even though patients with SMAJ do not present with multiorgan symptoms of mitochondrial disease. We aimed to characterize the cardiopulmonary oxidative capacity of subjects with SMAJ compared to healthy controls and patients with mitochondrial myopathy. Methods: Eleven patients with genetically verified SMAJ, 26 subjects with mitochondrial myopathy (MM), and 28 healthy volunteers underwent a cardiopulmonary exercise test with lactate and ammonia sampling. The effect of the diagnosis group on the test results was analysed using a linear model. Results: Adjusted for sex, age, and BMI, the SMAJ group had lower power output (p < 0.001), maximal oxygen consumption (VO2 max) (p < 0.001), and mechanical efficiency (p < 0.001) compared to the healthy controls but like that in MM. In the SMAJ group and healthy controls, plasma lactate was lower than in MM measured at rest, light exercise, and 30 min after exercise (p ≤ 0.001-0.030) and otherwise lactate in SMAJ was lower than controls and MM, in longitudinal analysis p = 0.018. In MM, the ventilatory equivalent for oxygen was higher (p = 0.040), and the fraction of end-tidal CO2 lower in maximal exercise compared to healthy controls (p = 0.023) and subjects with SMAJ. Conclusion: In cardiopulmonary exercise test, subjects with SMAJ showed a similar decrease in power output and oxidative capacity as subjects with mitochondrial myopathy but did not exhibit findings typical of mitochondrial disease.

19.
Cell Calcium ; 114: 102782, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37481871

RESUMEN

Inositol 1,4,5-trisphosphate receptors (IP3Rs) are ER Ca2+-release channels that control a broad set of cellular processes. Animal models lacking IP3Rs in different combinations display severe developmental phenotypes. Given the importance of IP3Rs in human diseases, we investigated their role in human induced pluripotent stem cells (hiPSC) by developing single IP3R and triple IP3R knockouts (TKO). Genome edited TKO-hiPSC lacking all three IP3R isoforms, IP3R1, IP3R2, IP3R3, failed to generate Ca2+ signals in response to agonists activating GPCRs, but retained stemness and pluripotency. Steady state metabolite profiling and flux analysis of TKO-hiPSC indicated distinct alterations in tricarboxylic acid cycle metabolites consistent with a deficiency in their pyruvate utilization via pyruvate dehydrogenase, shifting towards pyruvate carboxylase pathway. These results demonstrate that IP3Rs are not essential for hiPSC identity and pluripotency but regulate mitochondrial metabolism. This set of knockout hiPSC is a valuable resource for investigating IP3Rs in human cell types of interest.

20.
Hum Mol Genet ; 19(13): 2695-705, 2010 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-20413656

RESUMEN

Mitochondrial DNA (mtDNA) is an essential multicopy genome, compacted into protein-DNA clusters called nucleoids. Maintaining an adequate mtDNA copy number is crucial for cellular viability. Loss of mtDNA results in severe human syndromes, whereas increased mtDNA copy number has been suggested to improve survival from myocardial infarction in mice and to be a promising therapeutic strategy for mitochondrial disease. The mechanisms that regulate mtDNA amount and organization are, however, not fully understood. Of the proteins required for mtDNA existence, only the mitochondrial helicase Twinkle and mitochondrial transcription factor A (TFAM) have been shown to increase mtDNA copy number in vivo, when expressed in physiological levels. Here we studied how Twinkle and TFAM affect mtDNA synthesis and nucleoid structure in mice. Using in vivo BrdU labeling, we show that Twinkle specifically regulates de novo mtDNA synthesis. Remarkably, high mtDNA copy number in mice is accompanied by nucleoid enlargement, which in turn correlates with defective transcription, age-related accumulation of mtDNA deletions and respiratory chain (RC) deficiency. Simultaneous overexpression of Twinkle and TFAM in bitransgenic mice has an additive effect on mtDNA copy number, increasing it up to 6-fold in skeletal muscle. Bitransgenic mice also exhibit further enlargement of nucleoids and aggravation of the RC defect. In conclusion, we show that Twinkle acts as a regulator of mtDNA replication initiation, and provide evidence that high mtDNA copy number and alteration of nucleoid architecture may be detrimental to mitochondrial function.


Asunto(s)
Variaciones en el Número de Copia de ADN , ADN Helicasas/metabolismo , Replicación del ADN , ADN Mitocondrial/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas del Grupo de Alta Movilidad/metabolismo , Proteínas Mitocondriales/metabolismo , Animales , Animales Modificados Genéticamente , Variaciones en el Número de Copia de ADN/fisiología , ADN Mitocondrial/genética , Transporte de Electrón , Humanos , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/metabolismo , Músculo Esquelético/patología
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