RESUMEN

Mitochondrial diseases are multiorgan system disorders and the brain is the most commonly affected organ. The high-energy requirement of the brain leaves it vulnerable to energy failure. All components of the neuraxis including muscle, the neuromuscular junction, peripheral nerve, spinal cord, and brain can be affected. Genetic mitochondrial disease can be caused by nuclear gene defects and mitochondrial DNA defects. Mitochondrial medicine is rapidly expanding as exome and mtDNA sequencing is identifying new gene defects on a daily basis. This review will focus on primary genetic mitochondrial diseases that impair energy production and affect the nervous system, pathophysiology of disease, classical phenotypes, diagnosis, and treatment.

Asunto(s)

ADN Mitocondrial/genética , Mitocondrias/genética , Enfermedades Mitocondriales/genética , Fenotipo , Animales , Encéfalo/metabolismo , Encéfalo/patología , Humanos , Mutación/genética

RESUMEN

Guanidinoacetate methyltransferase (GAMT) deficiency is a disorder of creatine biosynthesis, characterized by excessive amounts of guanidinoacetate in body fluids, deficiency of creatine in the brain, and presence of mutations in the GAMT gene. We present here 8 new patients with GAMT deficiency along with their clinical, biochemical and molecular data. The age at diagnosis of our patients ranges from 0 to 14 years. The age of onset of seizures usually ranges from infancy to 3 years. However, one of our patients developed seizures at age 5; progressing to myoclonic epilepsy at age 8 years and another patient has not developed seizures at age 17 years. Five novel mutations were identified: c.37ins26 (p.G13PfsX38), c.403G>T (p.D135Y), c.507_521dup15 (p.C169_S173dup), c.402C>G (p.Y134X) and c.610_611delAGinsGAA (p.R204EfsX63). Six patients had the c.327G>A (last nucleotide of exon 2) splice-site mutation which suggests that this is one of the most common mutations in the GAMT gene, second only to the known Portuguese founder mutation, c.59G>C (p.W20S). Our data suggests that the clinical presentation can be variable and the diagnosis may be overlooked due to unawareness of this disorder. Therefore, GAMT deficiency should be considered in the differential diagnosis of progressive myoclonic epilepsy as well as in unexplained developmental delay or regression with dystonia, even if the patient has no history of seizures. As more patients are reported, the prevalence of GAMT deficiency will become known and guidelines for prenatal diagnosis, newborn screening, presymptomatic testing and treatment, will need to be formulated.

Asunto(s)

Errores Innatos del Metabolismo de los Aminoácidos/enzimología , Guanidinoacetato N-Metiltransferasa/deficiencia , Guanidinoacetato N-Metiltransferasa/genética , Adolescente , Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/terapia , Niño , Preescolar , Creatina/deficiencia , Femenino , Humanos , Lactante , Masculino , Mutación , Convulsiones/enzimología , Convulsiones/genética , Convulsiones/terapia

RESUMEN

The mechanism of the muscle toxicity associated with lipid-lowering therapy remains obscure. Pathological and biochemical findings in patients with statin myotoxicity suggest impaired fatty acid oxidation. Exhaled gas analysis can be used to assess substrate utilization including fatty acid oxidation. In order to determine if muscle toxicity due to lipid-lowering therapy might be related to abnormalities in lipid oxidation, exhaled gas analysis was performed in the fasted state on 11 patients subsequent to statin-associated myositis reactions. Results were compared to those of 16 normal controls who were measured both on and off statin therapy. Post-myositis patients showed a depressed anaerobic threshold (AT) (P=0.009) compared to controls while age-adjusted maximal oxygen consumption (VO2max) and ventilatory efficiency (VE/VCO2) were not significantly different. The fasting respiratory exchange ratio (RER) of post-myositis patients off statins was abnormally increased (P=0.00001) as was their S1-slope (P=0.023). Controls demonstrated a significant increase in their RER while taking statins consistent with decreased lipid oxidation (P <0.00001). These findings suggest that abnormal lipid oxidation in certain patients may predispose them to the myotoxicity caused by lipid-lowering therapies.

Asunto(s)

Anticolesterolemiantes/efectos adversos , Ácidos Grasos/metabolismo , Corazón/fisiopatología , Pulmón/fisiopatología , Miositis/inducido químicamente , Miositis/fisiopatología , Anciano , Anciano de 80 o más Años , Pruebas Respiratorias , Prueba de Esfuerzo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oxidación-Reducción

RESUMEN

OBJECTIVE: To quantify developmental abnormalities in cerebral and cerebellar volume in autism. METHODS: The authors studied 60 autistic and 52 normal boys (age, 2 to 16 years) using MRI. Thirty autistic boys were diagnosed and scanned when 5 years or older. The other 30 were scanned when 2 through 4 years of age and then diagnosed with autism at least 2.5 years later, at an age when the diagnosis of autism is more reliable. RESULTS: Neonatal head circumferences from clinical records were available for 14 of 15 autistic 2- to 5-year-olds and, on average, were normal (35.1 +/- 1.3 cm versus clinical norms: 34.6 +/- 1.6 cm), indicative of normal overall brain volume at birth; one measure was above the 95th percentile. By ages 2 to 4 years, 90% of autistic boys had a brain volume larger than normal average, and 37% met criteria for developmental macrencephaly. Autistic 2- to 3-year-olds had more cerebral (18%) and cerebellar (39%) white matter, and more cerebral cortical gray matter (12%) than normal, whereas older autistic children and adolescents did not have such enlarged gray and white matter volumes. In the cerebellum, autistic boys had less gray matter, smaller ratio of gray to white matter, and smaller vermis lobules VI-VII than normal controls. CONCLUSIONS: Abnormal regulation of brain growth in autism results in early overgrowth followed by abnormally slowed growth. Hyperplasia was present in cerebral gray matter and cerebral and cerebellar white matter in early life in patients with autism.

Asunto(s)

Trastorno Autístico/patología , Encéfalo/crecimiento & desarrollo , Encéfalo/patología , Imagen por Resonancia Magnética , Adolescente , Niño , Preescolar , Humanos , Masculino , Factores de Tiempo

RESUMEN

Serial measurements of nerve conduction velocities and amplitudes were performed in 27 patients with congenital lactic acidemia over 1 year of sodium dichloroacetate (DCA) administration. Patients were treated with oral thiamine (100 mg) and DCA (initial dose of 50 mg/kg) daily. Nerve conduction velocity and response amplitude were measured in the median, radial, tibial, and sural nerves at 0, 3, 6, and 12 months, and plasma DCA pharmacokinetics were measured at 3 and 12 months. Baseline electrophysiologic parameters in this population were generally below normal but as a group were within 2 standard deviations of normal means. Although symptoms of neuropathy were reported by only three patients or their families, nerve conduction declined in 12 patients with normal baseline studies, and worsening of nerve conduction occurred in the two who had abnormalities at baseline. Peripheral neuropathy appears to be a common side effect during chronic DCA treatment, even with coadministration of oral thiamine. Nerve conduction should be monitored during DCA treatment.

Asunto(s)

Ácido Dicloroacético/efectos adversos , Síndrome MELAS/tratamiento farmacológico , Síndrome MELAS/fisiopatología , Neuropatía Mediana/inducido químicamente , Conducción Nerviosa/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Adolescente , Adulto , Niño , Preescolar , Electromiografía , Femenino , Humanos , Lactante , Síndrome MELAS/diagnóstico , Masculino , Neuropatía Mediana/diagnóstico , Conducción Nerviosa/fisiología , Neuronas Aferentes/fisiología , Neuropatía Radial/inducido químicamente , Neuropatía Radial/diagnóstico , Neuropatía Tibial/inducido químicamente , Neuropatía Tibial/diagnóstico

RESUMEN

Recent reports of mitochondrial disease in infants whose mothers were treated in pregnancy with nucleoside analogues are of concern. Chronic nucleoside analogue treatment of adults has long been known to cause mitochondrial DNA depletion with the risk of multisystem disease. Combination nucleoside analogue treatment regimens may have the greatest risk of toxicity. This paper briefly presents the underlying biochemical etiologies and phenotypes of some common genetic mitochondrial diseases in order to provide a comparison with reports of infant toxicity. A standardized method for the diagnosis and evaluation of mitochondrial disease is discussed. A hypothesis, with predictions of the effects of antenatal nucleoside analogue treatment on the fetus, is presented and future directions for research on this problem are suggested.

Asunto(s)

Fármacos Anti-VIH/efectos adversos , Infecciones por VIH/prevención & control , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Miopatías Mitocondriales/inducido químicamente , Miopatías Mitocondriales/genética , Complicaciones del Embarazo/tratamiento farmacológico , Efectos Tardíos de la Exposición Prenatal , Zidovudina/efectos adversos , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/transmisión , Humanos , Recién Nacido , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Miopatías Mitocondriales/clasificación , Embarazo

RESUMEN

We report a family with a heterogeneous group of neurologic disorders associated with the mitochondrial DNA G8363A transfer ribonucleic acid (RNA)Lys mutation. The phenotype of one child in the family was consistent with autism. During his second year of life, he lost previously acquired language skills and developed marked hyperactivity with toe-walking, abnormal reciprocal social interaction, stereotyped mannerisms, restricted interests, self-injurious behavior, and seizures. Brain magnetic resonance imaging (MRI) and repeated serum lactate studies were normal. His older sister developed signs of Leigh syndrome with progressive ataxia, myoclonus, seizures, and cognitive regression. Her laboratory studies revealed increased MRI T2-weighted signal in the putamen and posterior medulla, elevated lactate in serum and cerebrospinal fluid, and absence of cytochrome c oxidase staining in muscle histochemistry. Molecular analysis in her revealed the G8363A mutation of the mitochondrial transfer RNA(Lys) gene in blood (82% mutant mitochondrial DNA) and muscle (86%). The proportions of mutant mitochondrial DNA from her brother with autism were lower (blood 60%, muscle 61%). It is likely that the origin of his autism phenotype is the pathogenic G8363A mitochondrial DNA mutation. This observation suggests that certain mitochondrial point mutations could be the basis for autism in some individuals.

Asunto(s)

Trastorno Autístico/genética , ADN Mitocondrial/genética , Enfermedad de Leigh/genética , Mutación Puntual , ARN de Transferencia de Lisina/genética , Adulto , Trastorno Autístico/fisiopatología , Trastorno Autístico/psicología , Niño , Preescolar , Análisis Mutacional de ADN , Epilepsia/genética , Femenino , Genotipo , Humanos , Discapacidades para el Aprendizaje/genética , Masculino , Músculo Esquelético/patología , Linaje , Fenotipo , Índice de Severidad de la Enfermedad

RESUMEN

A patient with 2-oxoadipic aciduria and 2-aminoadipic aciduria presented at 2 years of age with manifestations typical of organic acidemia, episodes of ketosis and acidosis, progressive to coma. This resolved and the key metabolites disappeared from the urine and blood. At 9 years of age she developed typical Kearns-Sayre syndrome with complete heart block, retinopathy, and ophthalmoplegia. Southern blot revealed a deletion in the mitochondrial genome.

Asunto(s)

Adipatos/orina , Síndrome de Kearns-Sayre/orina , Ácido 2-Aminoadípico/sangre , Ácido 2-Aminoadípico/orina , Adipatos/sangre , Adulto , Población Negra/genética , Niño , Preescolar , Coma/sangre , Coma/genética , Coma/orina , ADN Mitocondrial/sangre , ADN Mitocondrial/genética , Femenino , Humanos , Concentración de Iones de Hidrógeno , Síndrome de Kearns-Sayre/sangre , Síndrome de Kearns-Sayre/genética , Cetosis/sangre , Cetosis/genética , Cetosis/orina , Degeneración Macular/sangre , Degeneración Macular/genética , Degeneración Macular/orina , Masculino , Eliminación de Secuencia/genética

RESUMEN

BACKGROUND: The mitochondrial DNA polymerase gamma is the principal polymerase required for mitochondrial DNA replication. Primary or secondary deficiencies in the activity of DNA polymerase gamma may lead to mitochondrial DNA depletion. We describe a sensitive and robust clinical assay for this enzyme. METHODS: The assay was performed on mitochondria isolated from skeletal muscle biopsies. High-molecular weight polynucleotide reaction products were captured on ion-exchange paper, examined qualitatively by autoradiography, and quantified by scintillation counting. RESULTS: Kinetic analysis of DNA polymerase gamma by this method showed a K(m) for dTTP of 1.43 micromol/L and a K(i) for azidothymidine triphosphate of 0.861 micromol/L. The assay was linear from 0.1 to 2 microgram of mitochondrial protein. The detection limit was 30 units (30 fmol dTMP incorporated in 30 min). The linear dynamic range was three orders of magnitude; 30-30 000 units. Imprecision (CV) was 6.4% within day and 12% between days. Application of this assay to a mixed population of 38 patients referred for evaluation of mitochondrial disease revealed a distribution with a range of 0-2506 U/microgram, reflecting extensive biologic variation among patients with neuromuscular disease. CONCLUSION: This assay provides a useful adjunct to current laboratory methods for the evaluation of patients with suspected mitochondrial DNA depletion syndromes.

Asunto(s)

ADN Mitocondrial/análisis , ADN Polimerasa Dirigida por ADN/análisis , Animales , Autorradiografía , Bovinos , Cromatografía por Intercambio Iónico , Cromatografía en Papel , ADN Polimerasa gamma , Humanos , Mitocondrias Cardíacas/química , Músculo Esquelético/química , Reproducibilidad de los Resultados , Sensibilidad y Especificidad

RESUMEN

Parkinson's disease (PD) is a degenerative neurological disorder. Recent studies have demonstrated reduced activity of complex I of the electron transport chain in brain and platelets from patients with PD. Platelet mitochondria from parkinsonian patients were found to have lower levels of coenzyme Q10 (CoQ10) than mitochondria from age/sex-matched controls. There was a strong correlation between the levels of CoQ10 and the activities of complexes I and II/III. Oral CoQ10 was found to protect the nigrostriatal dopaminergic system in one-year-old mice treated with MPTP, a toxin injurious to the nigrostriatal dopaminergic system. We further found that oral CoQ10 was well absorbed in parkinsonian patients and caused a trend toward increased complex I activity. These data suggest that CoQ10 may play a role in cellular dysfunction found in PD and may be a potential protective agent for parkinsonian patients.

Asunto(s)

Antioxidantes/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Ubiquinona/análogos & derivados , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Administración Oral , Animales , Plaquetas/metabolismo , Coenzimas , Humanos , Ratones , Mitocondrias/metabolismo , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Enfermedad de Parkinson Secundaria/fisiopatología , Ubiquinona/administración & dosificación , Ubiquinona/fisiología , Ubiquinona/uso terapéutico

RESUMEN

Deficiency of mitochondrial DNA polymerase gamma activity was found in a patient with mtDNA depletion and Alpers' syndrome. Metabolic evaluation revealed fasting hypoglycemia, dicarboxylic aciduria, and reduced activity of the electron transport chain in skeletal muscle. The patient died in early childhood of fulminant hepatic failure, refractory epilepsy, lactic acidemia, and coma. mtDNA content was 30% of normal in skeletal muscle and 25% in the liver. The activity of mtDNA polymerase gamma was undetectable.

Asunto(s)

ADN Mitocondrial/metabolismo , ADN Polimerasa Dirigida por ADN/deficiencia , Esclerosis Cerebral Difusa de Schilder/enzimología , Esclerosis Cerebral Difusa de Schilder/genética , Ataxia/etiología , Biopsia , Corteza Cerebelosa/enzimología , Corteza Cerebelosa/patología , Análisis Mutacional de ADN , ADN Polimerasa gamma , ADN Mitocondrial/análisis , ADN Polimerasa Dirigida por ADN/metabolismo , Esclerosis Cerebral Difusa de Schilder/complicaciones , Electroencefalografía , Transporte de Electrón , Epilepsia/diagnóstico , Epilepsia/etiología , Resultado Fatal , Humanos , Lactante , Fallo Hepático/etiología , Fallo Hepático/genética , Fallo Hepático/patología , Imagen por Resonancia Magnética , Masculino , Mitocondrias/enzimología , Mitocondrias/genética , Músculo Esquelético/enzimología , Músculo Esquelético/patología

RESUMEN

Abnormal accumulations of lipid droplets, localized predominantly in histochemical type 1 fibers, were observed in fresh frozen sections of muscle biopsies from 25 dogs with myalgia, weakness, and muscle atrophy. Compared to controls, lactic acidemia, hyperalaninemia, lactic and pyruvic aciduria, variably increased urinary excretion of carnitine esters, and muscle carnitine deficiency were present. These findings support a metabolic block in oxidative metabolism resulting in lactic acidemia in dogs with lipid storage myopathy.

Asunto(s)

Ácidos/orina , Aminoácidos/sangre , Carnitina/metabolismo , Enfermedades de los Perros/metabolismo , Metabolismo de los Lípidos , Enfermedades Musculares/veterinaria , Animales , Enfermedades de los Perros/patología , Perros , Femenino , Masculino , Músculos/metabolismo , Músculos/patología

Asunto(s)

Carbohidratos de la Dieta/administración & dosificación , Encefalomiopatías Mitocondriales/dietoterapia , Adolescente , Adulto , Niño , Ayuno , Fructosa , Prueba de Tolerancia a la Glucosa , Humanos , Ácido Láctico/sangre , Masculino

RESUMEN

We report a pilot study of three oral doses of coenzyme Q10 (CoQ10) (200 mg administered two, three, or four times per day for 1 month) in 15 subjects with Parkinson's disease. Oral CoQ10 caused a substantial increase in the plasma CoQ10 level. It was well tolerated, but at the highest dose (200 mg four times per day) mild, transient changes in the urine were noted. CoQ10 did not change the mean score on the motor portion of the Unified Parkinson's Disease Rating Scale. There was a trend toward an increase in complex I activity in the subjects.

Asunto(s)

Mitocondrias/enzimología , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Ubiquinona/análogos & derivados , Absorción , Administración Oral , Anciano , Citrato (si)-Sintasa/sangre , Coenzimas , Relación Dosis-Respuesta a Droga , Portadores de Fármacos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mitocondrias/efectos de los fármacos , NAD(P)H Deshidrogenasa (Quinona)/sangre , Enfermedad de Parkinson Secundaria/fisiopatología , Proyectos Piloto , Índice de Severidad de la Enfermedad , Ubiquinona/efectos adversos , Ubiquinona/farmacocinética , Ubiquinona/uso terapéutico , Vitamina E

RESUMEN

Bone density analysis, dietary intake, and anthropometrics were compared in 20 subjects with Rett syndrome (RS), 25 normal control subjects, and 11 girls with cerebral palsy. Bone mineral density, bone mineral content, and spine (bone) mineral density were significantly reduced in the RS group. When weight and age were kept constant, the bone density was still reduced in the patients with RS. Subjects with RS are at risk for osteoporosis.

Asunto(s)

Enfermedades Óseas Metabólicas/complicaciones , Síndrome de Rett/complicaciones , Adolescente , Adulto , Antropometría , Densidad Ósea , Enfermedades Óseas Metabólicas/etiología , Calcificación Fisiológica , Niño , Preescolar , Ingestión de Energía , Femenino , Humanos , Enfermedades Metabólicas/complicaciones , Índice de Severidad de la Enfermedad

RESUMEN

A 6-yr-old boy presented with muscle weakness, lactic acidemia, and insulin-dependent diabetes mellitus (IDDM). Using PCR and restriction enzyme analysis, he was found to have the classical A3248G mitochondrial DNA (mtDNA) mutation frequently associated with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). The mutation was confirmed by sequencing muscle mtDNA. The mutation in mtDNA from muscle, lymphoblasts, and blood was clearly demonstrable by standard methods using ethidium bromide staining. His mother also had IDDM, but no A3243G mutation could be detected in her blood or transformed lymphoblasts using the same PCR technique. When PCR was carried out in the presence of [32P]deoxycytidine triphosphate, subsequent autoradiography detected the presence of the mutation at low levels in mtDNA from the mother's lymphoblasts and blood. Study of the mother's muscle showed a mitochondrial myopathy, despite the fact that she was asymptomatic. We emphasize that the increased sensitivity of radiolabeled PCR may be necessary to detect small percentages of heteroplasmic A3243G mtDNA mutation in blood from diabetic subjects. Otherwise the incidence of mtDNA mutations in both IDDM and non-insulin dependent diabetes may be underestimated.

Asunto(s)

Diabetes Mellitus Tipo 1/complicaciones , Síndrome MELAS/complicaciones , Síndrome MELAS/genética , Mutación , Reacción en Cadena de la Polimerasa/métodos , Adulto , Autorradiografía , Niño , ADN Mitocondrial/genética , Transporte de Electrón , Etidio , Femenino , Colorantes Fluorescentes , Humanos , Síndrome MELAS/metabolismo , Masculino , Microscopía Electrónica , Mitocondrias Musculares/metabolismo , Músculos/patología , Radioisótopos de Fósforo

RESUMEN

The activities of complex I and complex II/III in platelet mitochondria are reduced in patients with early, untreated Parkinson's disease. Coenzyme Q10 is the electron acceptor for complex I and complex II. We found that the level of coenzyme Q10 was significantly lower in mitochondria from parkinsonian patients than in mitochondria from age- and sex-matched control subjects and that the levels of coenzyme Q10 and the activities of complex I and complex II/III were significantly correlated.

Asunto(s)

Complejo III de Transporte de Electrones/metabolismo , Mitocondrias/enzimología , Complejos Multienzimáticos/metabolismo , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Oxidorreductasas/metabolismo , Enfermedad de Parkinson/enzimología , Succinato Deshidrogenasa/metabolismo , Ubiquinona/análogos & derivados , Plaquetas/enzimología , Coenzimas , Complejo II de Transporte de Electrones , Femenino , Humanos , Masculino , Enfermedad de Parkinson/sangre , Valores de Referencia , Ubiquinona/metabolismo

RESUMEN

Neuroanatomic, pathologic, and neurobehavioral studies point to a cerebellar and parietal abnormality in autism. We used a standardized protocol to examine neurologic function in 28 pediatric autistic subjects and 24 pediatric normal healthy volunteer controls. As a group, the autistic subjects had quantitative measures from magnetic resonance imaging suggesting hypoplasia or hyperplasia of the cerebellar vermis, as well as measurements of posterior corpus callosum suggesting abnormalities of posterior cortex. In groups of tests that reflect cerebellar and parietal function, the neurologic abnormalities detectable by clinical examination were significantly greater for autistic subjects than for normal controls. These studies confirm that the structural and behavioral deficit in autism does lead to abnormalities that can be detected on the clinical neurologic examination.

Asunto(s)

Trastorno Autístico/fisiopatología , Cerebelo/anomalías , Cerebelo/fisiopatología , Lóbulo Parietal/anomalías , Lóbulo Parietal/fisiopatología , Adolescente , Adulto , Trastorno Autístico/complicaciones , Trastorno Autístico/diagnóstico , Niño , Femenino , Marcha , Humanos , Discapacidad Intelectual/complicaciones , Imagen por Resonancia Magnética , Masculino , Hipotonía Muscular/complicaciones , Índice de Severidad de la Enfermedad

RESUMEN

Low concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) of patients with progressive myoclonus epilepsy (PME) suggest hypofunctional serotonergic neurotransmission. To study this hypothesis, we enrolled 6 patients with PME [Unverricht-Lündborg disease (U-L), mitochondrial encephalomyopathy, or Lafora disease] in a controlled, double-blinded, dose-ranging, cross-over add-on pilot clinical trial of 5-hydroxy-L-tryptophan (L-5-HTP) plus carbidopa after 2 other patients had received open-label L-5-HTP for compassionate use. Prestudy CSF 5-HIAA concentrations were low (< 20 ng/ml) in 6 patients regardless of the etiology of PME. One patient with U-L disease showed clinical improvement and a fivefold increase in CSF 5-HIAA, and 1 with Lafora disease showed a twofold increase in CSF 5-HIAA without improvement. A patient with Lafora disease reported enough improvement in myoclonus-evoked convulsions to continue chronic use of the drug. One patient with mitochondrial encephalomyopathy developed status epilepticus during treatment with L-5-HTP. As a group, patients had no statistically significant changes in myoclonus evaluation scale scores, subjective and objective measures of ataxia, seizure frequency, antiepileptic drug (AED) levels, or routine blood tests. These data suggest a serotonergic abnormality regardless of the underlying etiology of PME, but one that seldom responds to acute treatment with L-5-HTP.

Asunto(s)

5-Hidroxitriptófano/uso terapéutico , Epilepsias Mioclónicas/tratamiento farmacológico , Adolescente , Adulto , Carbidopa/uso terapéutico , Estudios Cruzados , Método Doble Ciego , Quimioterapia Combinada , Epilepsias Mioclónicas/líquido cefalorraquídeo , Epilepsias Mioclónicas/metabolismo , Femenino , Humanos , Ácido Hidroxiindolacético/líquido cefalorraquídeo , Masculino , Encefalomiopatías Mitocondriales/líquido cefalorraquídeo , Encefalomiopatías Mitocondriales/tratamiento farmacológico , Encefalomiopatías Mitocondriales/metabolismo , Proyectos Piloto , Serotonina/metabolismo

RESUMEN

A novel point mutation in the ND6 subunit of complex I at position 14,459 of the mitochondrial DNA (MTND6*LDY T14459A) was identified as a candidate mutation for the highly tissue-specific disease. Leber's hereditary optic neuropathy plus dystonia. Since the MTND6*LDYT14459A mutation was identified in a single family, other pedigrees with the mutation are needed to confirm its association with the disease. Clinical, biochemical, and genetic characterization is reported in two additional pedigrees. Leber's hereditary optic neuropathy developed in two family members in one pedigree. The daughter had clinically silent basal ganglia lesions. In a second pedigree, a single individual presented with childhood-onset generalized dystonia and bilateral basal ganglia lesions. Patient groups that included individuals with Leigh's disease, dystonia plus complex neurodegeneration, and Leber's hereditary optic neuropathy did not harbor the MTND6*LDYT14459A mutation, suggesting that this mutation displays a high degree of tissue specificity, thus producing a narrow phenotypic range. These results confirm the association of the MTND6*LDYT14459A mutation with Leber's hereditary optic neuropathy and/or dystonia. As the first genetic abnormality that has been identified to cause generalized dystonia, this mutation suggests that nuclear DNA or mitochondrial DNA mutations in oxidative phosphorylation genes are important considerations in the pathogenesis of dystonia.

Asunto(s)

ADN Mitocondrial/genética , Distonía/genética , Atrofias Ópticas Hereditarias/genética , Mutación Puntual , Adolescente , Adulto , Distonía/enzimología , Femenino , Humanos , Persona de Mediana Edad , Atrofias Ópticas Hereditarias/enzimología