RESUMEN
POLR3A encodes the largest subunit of the DNA-dependent RNA polymerase III. Pathogenic variants in this gene are associated with dysregulation of tRNA production and other non-coding RNAs. POLR3A-related disorders include variable phenotypes. The genotype-phenotype correlation is still unclear. Phenotypic analysis and exome sequencing were performed in four affected siblings diagnosed clinically with hereditary spastic ataxia, two healthy siblings and their unaffected mother. All four affected siblings (ages 46-55) had similar clinical features of early childhood-onset hypodontia and adolescent-onset progressive spastic ataxia. None had progeria, gonadal dysfunction or dysmorphism. All affected individuals had biallelic POLR3A pathogenic variants composed by two cis-acting intronic splicing-altering variants, c.1909 + 22G > A and c.3337-11 T > C. The two healthy siblings had wild-type alleles. The mother and another unaffected sibling were heterozygous for the allele containing both variants. This is the first report addressing the clinical consequence associated with homozygosity for a unique pathogenic intronic allele in the POLR3A gene. This allele was previously reported in compound heterozygous combinations in patients with Wiedemann-Rautenstrauch syndrome, a severe progeroid POLR3A-associated phenotype. We show that homozygosity for this allele is associated with spastic ataxia with hypodontia, and not with progeroid features. These findings contribute to the characterization of genotype-phenotype correlation in POLR3A-related disorders.
Asunto(s)
Anodoncia/genética , Discapacidad Intelectual/genética , Intrones/genética , Espasticidad Muscular/genética , Atrofia Óptica/genética , ARN Polimerasa III/genética , Ataxias Espinocerebelosas/genética , Alelos , Anodoncia/complicaciones , Anodoncia/diagnóstico por imagen , Anodoncia/enzimología , Análisis Mutacional de ADN , Femenino , Mutación del Sistema de Lectura , Humanos , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/diagnóstico por imagen , Discapacidad Intelectual/enzimología , Masculino , Persona de Mediana Edad , Espasticidad Muscular/complicaciones , Espasticidad Muscular/diagnóstico por imagen , Espasticidad Muscular/enzimología , Atrofia Óptica/complicaciones , Atrofia Óptica/diagnóstico por imagen , Atrofia Óptica/enzimología , Ataxias Espinocerebelosas/complicaciones , Ataxias Espinocerebelosas/diagnóstico por imagen , Ataxias Espinocerebelosas/enzimologíaAsunto(s)
Ligasas de Carbono-Nitrógeno con Glutamina como Donante de Amida-N/genética , Discapacidades del Desarrollo/genética , Microcefalia/genética , Espasticidad Muscular/genética , Mutación , Ligasas de Carbono-Nitrógeno con Glutamina como Donante de Amida-N/deficiencia , Discapacidades del Desarrollo/diagnóstico por imagen , Discapacidades del Desarrollo/enzimología , Discapacidades del Desarrollo/patología , Exones , Expresión Génica , Homocigoto , Humanos , Imagen por Resonancia Magnética , Microcefalia/diagnóstico por imagen , Microcefalia/enzimología , Microcefalia/patología , Espasticidad Muscular/diagnóstico por imagen , Espasticidad Muscular/enzimología , Espasticidad Muscular/patología , Secuenciación del ExomaRESUMEN
Selenocysteine synthase (SepSecS) catalyzes the terminal reaction of selenocysteine, and is vital for human selenoproteome integrity. Autosomal recessive inheritance of mutations in SepSecS-Ala239Thr, Thr325Ser, Tyr334Cys and Tyr429*-induced severe, early-onset, neurological disorders in distinct human populations. Although harboring different mutant alleles, patients presented remarkably similar phenotypes typified by cerebellar and cerebral atrophy, seizures, irritability, ataxia, and extreme spasticity. However, it has remained unclear how these genetic alterations affected the structure of SepSecS and subsequently elicited the development of a neurological pathology. Herein, our biophysical and structural characterization demonstrates that, with the exception of Tyr429*, pathogenic mutations decrease protein stability and trigger protein misfolding. We propose that the reduced stability and increased propensity towards misfolding are the main causes for the loss of SepSecS activity in afflicted patients, and that these factors contribute to disease progression. We also suggest that misfolding of enzymes regulating protein synthesis should be considered in the diagnosis and study of childhood neurological disorders.
Asunto(s)
Aminoacil-ARNt Sintetasas/química , Ataxia/genética , Espasticidad Muscular/genética , ARN de Transferencia/química , Convulsiones/genética , Selenocisteína/química , Edad de Inicio , Sustitución de Aminoácidos , Aminoacil-ARNt Sintetasas/genética , Aminoacil-ARNt Sintetasas/metabolismo , Ataxia/enzimología , Ataxia/patología , Atrofia , Sitios de Unión , Cerebelo/enzimología , Cerebelo/patología , Corteza Cerebral/enzimología , Corteza Cerebral/patología , Cristalografía por Rayos X , Humanos , Genio Irritable , Modelos Moleculares , Espasticidad Muscular/enzimología , Espasticidad Muscular/patología , Mutación , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Pliegue de Proteína , Dominios y Motivos de Interacción de Proteínas , Estabilidad Proteica , ARN de Transferencia/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Convulsiones/enzimología , Convulsiones/patología , Selenocisteína/metabolismo , Especificidad por SustratoRESUMEN
BACKGROUND: Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare inborn defect disturbing the remethylation of homocysteine to methionine (<200 reported cases). This retrospective study evaluates clinical, biochemical genetic and in vitro enzymatic data in a cohort of 33 patients. METHODS: Clinical, biochemical and treatment data was obtained from physicians by using a questionnaire. MTHFR activity was measured in primary fibroblasts; genomic DNA was extracted from cultured fibroblasts. RESULTS: Thirty-three patients (mean age at follow-up 11.4 years; four deceased; median age at first presentation 5 weeks; 17 females) were included. Patients with very low (<1.5%) mean control values of enzyme activity (n = 14) presented earlier and with a pattern of feeding problems, encephalopathy, muscular hypotonia, neurocognitive impairment, apnoea, hydrocephalus, microcephaly and epilepsy. Patients with higher (>1.7-34.8%) residual enzyme activity had mainly psychiatric symptoms, mental retardation, myelopathy, ataxia and spasticity. Treatment with various combinations of betaine, methionine, folate and cobalamin improved the biochemical and clinical phenotype. During the disease course, patients with very low enzyme activity showed a progression of feeding problems, neurological symptoms, mental retardation, and psychiatric disease while in patients with higher residual enzyme activity, myelopathy, ataxia and spasticity increased. All other symptoms remained stable or improved in both groups upon treatment as did brain imaging in some cases. No clear genotype-phenotype correlation was obvious. DISCUSSION: MTHFR deficiency is a severe disease primarily affecting the central nervous system. Age at presentation and clinical pattern are correlated with residual enzyme activity. Treatment alleviates biochemical abnormalities and clinical symptoms partially.
Asunto(s)
Homocistinuria/enzimología , Homocistinuria/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/deficiencia , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Espasticidad Muscular/enzimología , Espasticidad Muscular/genética , Ataxia/genética , Betaína/uso terapéutico , Niño , Femenino , Ácido Fólico/uso terapéutico , Estudios de Asociación Genética/métodos , Homocistinuria/tratamiento farmacológico , Humanos , Discapacidad Intelectual/genética , Masculino , Metionina/uso terapéutico , Espasticidad Muscular/tratamiento farmacológico , Mutación/genética , Fenotipo , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/enzimología , Trastornos Psicóticos/genética , Estudios Retrospectivos , Enfermedades de la Médula Espinal/genética , Vitamina B 12/uso terapéuticoAsunto(s)
Discapacidades del Desarrollo/genética , Homocistinuria/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/deficiencia , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Espasticidad Muscular/genética , Edad de Inicio , Preescolar , Discapacidades del Desarrollo/tratamiento farmacológico , Discapacidades del Desarrollo/enzimología , Epilepsia/tratamiento farmacológico , Epilepsia/enzimología , Epilepsia/genética , Femenino , Variación Genética , Heterocigoto , Homocistinuria/tratamiento farmacológico , Homocistinuria/enzimología , Humanos , Lactante , Recién Nacido , Masculino , Espasticidad Muscular/tratamiento farmacológico , Espasticidad Muscular/enzimología , Mutación , Linaje , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/enzimología , Trastornos Psicóticos/genética , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: It has been previously shown that CB1 cannabinoid receptor agonism using cannabis extracts alleviates spasticity in both a mouse experimental autoimmune encephalomyelitis (EAE) model and multiple sclerosis (MS) in humans. However, this action can be associated with dose-limiting side effects. OBJECTIVE: We hypothesised that blockade of anandamide (endocannabinoid) degradation would inhibit spasticity, whilst avoiding overt cannabimimetic effects. METHODS: Spasticity eventually developed following the induction of EAE in either wild-type or congenic fatty acid amide hydrolase (FAAH)-deficient Biozzi ABH mice. These animals were treated with a variety of different FAAH inhibitors and the effect on the degree of limb stiffness was assessed using a strain gauge. RESULTS: Control of spasticity was achieved using FAAH inhibitors CAY100400, CAY100402 and URB597, which was sustained following repeated administrations. Therapeutic activity occurred in the absence of overt cannabimimetic effects. Importantly, the therapeutic value of the target could be definitively validated as the treatment activity was lost in FAAH-deficient mice. Spasticity was also controlled by a selective monoacyl glycerol lipase inhibitor, JZL184. CONCLUSIONS: This study demonstrates definitively that FAAH inhibitors provide a new class of anti-spastic agents that may have utility in treating spasticity in MS and avoid the dose-limiting side effects associated with cannabis use.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Ácidos Araquidónicos/metabolismo , Encéfalo/efectos de los fármacos , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Endocannabinoides/metabolismo , Inhibidores Enzimáticos/farmacología , Espasticidad Muscular/prevención & control , Músculo Esquelético/efectos de los fármacos , Alcamidas Poliinsaturadas/metabolismo , Amidohidrolasas/deficiencia , Amidohidrolasas/genética , Animales , Encéfalo/enzimología , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/enzimología , Encefalomielitis Autoinmune Experimental/fisiopatología , Femenino , Masculino , Ratones , Ratones Biozzi , Ratones Noqueados , Terapia Molecular Dirigida , Monoacilglicerol Lipasas/antagonistas & inhibidores , Monoacilglicerol Lipasas/metabolismo , Espasticidad Muscular/enzimología , Espasticidad Muscular/fisiopatología , Músculo Esquelético/inervación , Factores de TiempoRESUMEN
Mitochondrial myopathies are heterogeneous disorders. They may present at any age with a variable clinical course. We report a 6-year-old boy presenting as spastic cerebral palsy for 4 years, then athetotic movements and loss of milestones. He was eventually found to have NADH dehydrogenase deficiency.
Asunto(s)
Parálisis Cerebral/enzimología , Miopatías Mitocondriales/enzimología , NADPH Deshidrogenasa/deficiencia , Atetosis/enzimología , Atetosis/patología , Atetosis/fisiopatología , Ataxia Cerebelosa/enzimología , Ataxia Cerebelosa/patología , Ataxia Cerebelosa/fisiopatología , Parálisis Cerebral/patología , Parálisis Cerebral/fisiopatología , Niño , Humanos , Masculino , Mitocondrias Musculares/enzimología , Miopatías Mitocondriales/patología , Miopatías Mitocondriales/fisiopatología , Destreza Motora/fisiología , Espasticidad Muscular/enzimología , Espasticidad Muscular/patología , Espasticidad Muscular/fisiopatología , Músculos/enzimología , Músculos/patologíaRESUMEN
A number of inherited disorders of cornification have been related to abnormal lipid metabolism. In the recessively inherited Sjögren-Larsson syndrome, defined by the triad of ichthyosis, mental retardation, and spasticity, fatty alcohol:NAD+ oxidoreductase deficiency has recently been reported. These patients accumulate fatty alcohol in the plasma and cultured fibroblasts. A 19-year-old woman with ichthyosis, mental retardation, and mild spasticity is described in whom fatty alcohol metabolism was normal, as determined by plasma octadecanol level and fibroblast fatty alcohol:NAD+ oxidoreductase activity. Ultrastructural studies on skin from the patient revealed morphologically abnormal epidermal lamellar bodies, not unlike those seen in neutral lipid storage disease with ichthyosis. We postulate that this patient has a novel neurocutaneous syndrome that may be secondary to abnormal lipid metabolism.
Asunto(s)
Oxidorreductasas de Alcohol/metabolismo , Ictiosis/patología , Discapacidad Intelectual/patología , Espasticidad Muscular/patología , Adolescente , Alcoholes Grasos/metabolismo , Femenino , Fibroblastos/enzimología , Humanos , Ictiosis/enzimología , Discapacidad Intelectual/enzimología , Lípidos/análisis , Espasticidad Muscular/enzimología , Piel/química , Piel/enzimología , Piel/ultraestructura , Síndrome , Vacuolas/ultraestructuraRESUMEN
A patient is presented who had therapy-resistant epileptic seizures from the 7th day of life. Examination at the age of 17 months revealed a mentally retarded boy with epileptic seizures, generalised myoclonic contractions, and abnormal ocular movements. A cerebral CT scan showed central and cortical atrophy. Lactate levels in serum, cerebrospinal fluid and urine were elevated, the pyruvate level was raised in serum. A quadriceps muscle biopsy revealed aspecific morphologic signs of a myopathy. Biochemical analysis showed decreased substrate oxidation rates in the mitochondria associated with low rates of ATP production. Total and free carnitine levels were decreased. Investigation of the respiratory chain revealed a defect in the proximal part of respiratory chain involving the region of coenzyme Q. Based on clinical and chemical data it is likely that the patient is suffering from a multi-system disorder.
Asunto(s)
Encefalopatías/enzimología , Mitocondrias Musculares/ultraestructura , Espasticidad Muscular/enzimología , Ubiquinona/metabolismo , Acidosis/complicaciones , Adenosina Trifosfato/metabolismo , Epilepsia/complicaciones , Humanos , Lactante , Discapacidad Intelectual/complicaciones , Lactatos/metabolismo , Masculino , Espasticidad Muscular/complicaciones , Mioclonía/complicaciones , NAD/metabolismo , Nistagmo Patológico/complicaciones , Oxidación-Reducción , Piruvatos/metabolismoRESUMEN
We will present 8 children with progressive infantile or juvenile poliodystrophy (Alpers' disease), associated with a defect in pyruvate metabolism. Laboratory studies showed elevated levels of lactate in CSF and, in 4 children, elevated levels in serum. Histopathologic studies revealed lipid storage in liver and/or muscle tissue, sometimes myopathy with abnormal mitochondria and slight axonal degeneration in the peripheral nerve. Autopsy showed the characteristics of progressive poliodystrophy with degeneration and loss of neurons. Electron microscopy of cerebral cortex showed no mitochondrial abnormalities in neurons or astroglia. Biochemical studies in muscle and/or liver and/or cerebral tissue showed different deficiencies in pyruvate metabolism: in the pyruvate dehydrogenase complex, in the second part of the citric acid cycle (after the oxoglutarate dehydrogenase complex), in the NADH oxidation, in cytochrome aa3 and in pyruvate carboxylase.
Asunto(s)
Ciclo del Ácido Cítrico , Transporte de Electrón , Enfermedades Neuromusculares/enzimología , Parálisis/enzimología , Trastornos Psicomotores/enzimología , Adolescente , Encéfalo/enzimología , Dióxido de Carbono/metabolismo , Niño , Preescolar , Fibroblastos/enzimología , Humanos , Lactatos/metabolismo , Ácido Láctico , Leucocitos/enzimología , Hígado/enzimología , Hipotonía Muscular/enzimología , Espasticidad Muscular/enzimología , NADH Deshidrogenasa/metabolismo , Complejo Piruvato Deshidrogenasa/metabolismo , Piruvatos/metabolismo , Ácido PirúvicoRESUMEN
Spasmodic torticollis remains an ill-understood disease. A central deficit in neurotransmitter activity in the basal ganglia may be present in this disorder. In the present study, dopamine-beta-hydroxylase (DBH) activity has been evaluated in the plasma of patients suffering from spasmodic torticollis and in their sibship in 4 informative families. In 1 of these families, 2 brothers are affected with torticollis and they have high plasma DBH levels. In the 3 other families the plasma DBH values are within normal ranges in the probands and their first-degree relatives. The genetic study of plasma DBH activity allowed to discriminate between two forms of spasmodic torticollis, one, which is most likely linked to familial torsion dystonia, appears to be associated with altered dopaminergic activity, while the other, nonfamilial with normal sympathetic activity, is probably an idiopathic or sporadic form of spasmodic torticollis.
Asunto(s)
Dopamina beta-Hidroxilasa/sangre , Espasticidad Muscular/enzimología , Tortícolis/enzimología , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Espasticidad Muscular/genética , Linaje , Tortícolis/genéticaRESUMEN
Leucocyte Glutamate Dehydrogenase (GDH) activity was measured in 44 patients with various forms of ataxia and 44 age and sex-matched normal controls. The only significant change found was a moderate decrease in activity in Friedreich's ataxia and a few patients with OPCA. This decreased activity is not primary to the disease but probably reflects a regulatory defect affecting mitochondrial membranes in these patients.
Asunto(s)
Ataxia/genética , Glutamato Deshidrogenasa/sangre , Leucocitos/enzimología , Ataxia/enzimología , Atrofia , Encefalopatías/enzimología , Enfermedades Cerebelosas/enzimología , Ataxia de Friedreich/enzimología , Humanos , Espasticidad Muscular/enzimología , Espasticidad Muscular/genética , Núcleo OlivarAsunto(s)
Enfermedades de los Bovinos , Espasticidad Muscular/veterinaria , Músculos/patología , Animales , Aspartato Aminotransferasas/sangre , Bovinos , Enfermedades de los Bovinos/enzimología , Enfermedades de los Bovinos/patología , Creatina Quinasa/sangre , L-Lactato Deshidrogenasa/sangre , Espasticidad Muscular/enzimología , Espasticidad Muscular/patologíaRESUMEN
Muscle fiber composition and oxidative and glycolytic enzymatic activity have been studied with complete traumatic transection of the spinal cord and spastic paralysis of the lower extremities. Muscle sample were taken by means of needle biopsy from the vastus lateralis, gastrocnemius, and soleus muscles. Biopsies were also taken for comparison from the deltoid muscle. Fibers staining darkly for alkaline stable myofibrillar ATP-ase (type II) dominated or were the only fibers identified in the paralysed muscles. The deltoid muscles of the same patients had a rather even mixture of type I and II fibers. Staining pattern was reversed after acid preincubation (pH 4.3). Mean diameters in the paralysed muscles were reduced for both fiber types. All fibers stained relatively weakly for NADH-diaphorase. Succinyldehydrogenase activity was low and phosphofructokinase activity usually moderately reduced. The findings imply that neuronal influence on the muscular fibers had led to a change in the staining characteristics of the muscle fibers. Such a change migh indicate altered contractile characteristics, though the detailed nature of the observed findings in still unclear.