Disruption of mitochondrial bioenergetics and calcium homeostasis by phytanic acid in the heart: Potential relevance for the cardiomyopathy in Refsum disease.

Refsum disease is an inherited peroxisomal disorder caused by severe deficiency of phytanoyl-CoA hydroxylase activity. Affected patients develop severe cardiomyopathy of poorly known pathogenesis that may lead to a fatal outcome. Since phytanic acid (Phyt) concentrations are highly increased in tissues of individuals with this disease, it is conceivable that this branched-chain fatty acid is cardiotoxic. The present study investigated whether Phyt (10-30 µM) could disturb important mitochondrial functions in rat heart mitochondria. We also determined the influence of Phyt (50-100 µM) on cell viability (MTT reduction) in cardiac cells (H9C2). Phyt markedly increased mitochondrial state 4 (resting) and decreased state 3 (ADP-stimulated) and uncoupled (CCCP-stimulated) respirations, besides reducing the respiratory control ratio, ATP synthesis and the activities of the respiratory chain complexes I-III, II, and II-III. This fatty acid also reduced mitochondrial membrane potential and induced swelling in mitochondria supplemented by exogenous Ca2+, which were prevented by cyclosporin A alone or combined with ADP, suggesting the involvement of the mitochondrial permeability transition (MPT) pore opening. Mitochondrial NAD(P)H content and Ca2+ retention capacity were also decreased by Phyt in the presence of Ca2+. Finally, Phyt significantly reduced cellular viability (MTT reduction) in cultured cardiomyocytes. The present data indicate that Phyt, at concentrations found in the plasma of patients with Refsum disease, disrupts by multiple mechanisms mitochondrial bioenergetics and Ca2+ homeostasis, which could presumably be involved in the cardiomyopathy of this disease.

Funcionamiento Cognitivo Global y Conducta Adaptativa en dos Niñas con Neuropatía Sensitiva Autonómica Hereditaria Tipo IV / Global cognitive and adaptive functioning in two girls with hereditary sensory and autonomic neuropathy type IV

La neuropatía sensitiva autonómica hereditaria tipo IV (HSAN-IV) es una condición neurológica de origen genético extremadamente rara que puede cursar con discapacidad intelectual, sin embargo, hay escasas publicaciones sobre las características del funcionamiento cognitivo global y la conducta adaptativa de los afectados. En este estudio se describe la capacidad cognitiva global y el funcionamiento adaptativo de dos niñas de 12 y 14 años diagnosticadas con HSANIV, incluyendo una caracterización de los procesos de comprensión verbal, razonamiento perceptual, memoria de trabajo y velocidad de procesamiento. Las menores fueron evaluadas mediante la Escala de Inteligencia para niños de Wechsler cuarta edición (WISC-IV) encontrándose en ambos casos un bajo índice de comprensión verbal, una medida del desarrollo cognitivo alcanzado a través de la historia de aprendizaje de las niñas; así como un bajo índice de razonamiento perceptivo, indicador de su capacidad para adaptarse y afrontar situaciones nuevas de forma flexible. Esto se acompaña de dificultad en la manipulación de información en la memoria para la resolución de problemas y enlentecimiento en la velocidad de procesamiento de la información. Adicionalmente, se evaluó su funcionamiento adaptativo mediante el sistema de evaluación de la conducta adaptativa ABAS-II, el cual se caracterizó por fortalezas en habilidades comunicativas, uso de recursos comunitarios y vida en el hogar; con limitaciones en habilidades académicas y de autocuidado. En conclusión, la HSAN-IV es una condición que cursa con discapacidad intelectual con necesidades de apoyo variables en intensidad. En los casos estudiados se encontró discapacidad intelectual con necesidad de apoyo limitado, es decir, los apoyos se requieren de forma regular durante un periodo de tiempo corto pero definido.

Hereditary sensory autonomic neuropathy type IV (HSAN-IV) is a neurological condition of extremely rare genetic origin that may be associated with intellectual disability; however, there are few publications about the characteristics of global cognitive functioning and adaptive behaviour of these patients. In this study we describe the global cognitive function and the adaptive behavior of two girls aged 12 and 14 diagnosed with HSAN-IV, including a characterization of the processes of verbal comprehension, perceptual reasoning, working memory and processing speed. The children were assessed using the Wechsler Intelligence Scale for Children - Fourth Edition (WISC-IV), finding in both cases a low level of verbal comprehension, a measure of cognitive development achieved through the girls' learning history; as well as a low rate of perceptual reasoning, indicator of their ability to adapt and face new situations in a flexible way. This is accompanied by difficulty in manipulating information in the memory to solve problems and slow down the speed of information processing. Additionally, its adaptive functioning was evaluated through the Adaptive Behavior Assessment System ABAS-II, which was characterized by strengths in communication skills, use of community resources and life at home; with limitations in academic and self-care skills. In conclusion, HSAN-IV is a condition related with intellectual disability with varying support needs in intensity. In the cases studied, intellectual disability was found with limited need for support, that is, supports are required on a regular basis for a short but defined period.

Marked inhibition of Na+, K(+)- ATPase activity and the respiratory chain by phytanic acid in cerebellum from young rats: possible underlying mechanisms of cerebellar ataxia in Refsum disease.

Refsum disease is an autosomal recessive disorder of peroxisomal metabolism biochemically characterized by highly elevated concentrations of phytanic acid (Phyt) in a variety of tissues including the cerebellum. Reduction of plasma Phyt levels by dietary restriction intake ameliorates ataxia, a common clinical manifestation of this disorder, suggesting a neurotoxic role for this branched-chain fatty acid. Therefore, considering that the underlying mechanisms of cerebellum damage in Refsum disease are poorly known, in the present study we tested the effects of Phyt on important parameters of bioenergetics, such as the activities of the respiratory chain complexes I to IV, creatine kinase and Na(+), K(+)- ATPase in cerebellum preparations from young rats. The activities of complexes I, II, I-III and II-III and Na(+), K(+)- ATPase were markedly inhibited (65-85%) in a dose-dependent manner by Phyt. In contrast, creatine kinase and complex IV activities were not altered by this fatty acid. Therefore, it is presumed that impairment of the electron flow through the respiratory chain and inhibition of Na(+), K(+)- ATPase that is crucial for synaptic function may be involved in the pathophysiology of the cerebellar abnormalities manifested as ataxia in Refsum disease and in other peroxisomal disorders in which brain Phyt accumulates.

Phytanic acid disturbs mitochondrial homeostasis in heart of young rats: a possible pathomechanism of cardiomyopathy in Refsum disease.

Phytanic acid (Phyt) accumulates in tissues and biological fluids of patients affected by Refsum disease. Although cardiomyopathy is an important clinical manifestation of this disorder, the mechanisms of heart damage are poorly known. In the present study, we investigated the in vitro effects of Phyt on important parameters of oxidative stress in heart of young rats. Phyt significantly increased thiobarbituric acid-reactive substances levels (P < 0.001) and carbonyl formation (P < 0.01), indicating that this fatty acid induces lipid and protein oxidative damage, respectively. In contrast, Phyt did not alter sulfhydryl oxidation. Phyt also decreased glutathione (GSH) concentrations (P < 0.05), an important non-enzymatic antioxidant defense. Moreover, Phyt increased 2',7'-dichlorofluorescin oxidation (DCFH) (P < 0.01), reflecting increased reactive species generation. We also found that the induced lipid and protein oxidative damage, as well as the decreased GSH levels and increased DCFH oxidation provoked by this fatty acid were prevented or attenuated by the reactive oxygen species scavengers melatonin, trolox, and GSH, but not by the nitric oxide inhibitor N: (ω)-nitro-L: -arginine methyl ester, suggesting that reactive oxygen species were involved in these effects. Next, we verified that Phyt strongly inhibited NADH-cytochrome c oxidoreductase (complex I-III) activity (P < 0.001) in heart supernatants, and decreased membrane potential and the NAD(P)H pool in heart mitochondria, indicating that Phyt acts as a metabolic inhibitor and as an uncoupler of the electron transport chain. Therefore, it can be presumed that disturbance of cellular energy and redox homeostasis induced by Phyt may possibly contribute to the cardiomyopathy found in patients affected by Refsum disease.

Neurochemical evidence that phytanic acid induces oxidative damage and reduces the antioxidant defenses in cerebellum and cerebral cortex of rats.

AIMS: In the present work we investigated the in vitro effects of phytanic acid (Phyt), that accumulates in Refsum disease and other peroxisomal diseases, on important parameters of oxidative stress in cerebellum and cerebral cortex from young rats. MAIN METHODS: The parameters thiobarbituric acid-reactive substances levels (TBA-RS; lipid peroxidation), carbonyl formation and sulfhydryl oxidation (protein oxidative damage) and the concentrations of the most important nonenzymatic antioxidant defense reduced glutathione (GSH) were determined. KEY FINDINGS: It was observed that Phyt significantly increased TBA-RS levels in both cerebral structures. This effect was prevented by the antioxidants alpha-tocopherol and melatonin, suggesting the involvement of free radicals. Phyt also provoked protein oxidative damage in both cerebellum and cerebral cortex, as determined by increased carbonyl content and sulfhydryl oxidation. Furthermore, Phyt significantly diminished the concentrations of GSH, while melatonin and alpha-tocopherol treatment totally blocked this effect. We also verified that Phyt does not behave as a direct acting oxidant, since Phyt did not oxidize commercial solutions of GSH and reduced cytochrome c to Phyt in a free cell medium. SIGNIFICANCE: Our data indicate that oxidative stress is elicited in vitro by Phyt, a mechanism that may contribute at least in part to the pathophysiology of Refsum disease and other peroxisomal disorders where Phyt is accumulated.

In vitro evidence that phytanic acid compromises Na(+),K(+)-ATPase activity and the electron flow through the respiratory chain in brain cortex from young rats.

Phytanic acid (Phyt) tissue concentrations are increased in Refsum disease and other peroxisomal disorders characterized by neurologic damage and brain abnormalities. The present work investigated the in vitro effects of Phyt, at concentrations found in these peroxisomal disorders, on important parameters of energy metabolism in brain cortex of young rats. The parameters analyzed were CO(2) production from labeled acetate and glucose, the activities of the citric acid cycle enzymes citrate synthase, aconitase, isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, fumarase and malate dehydrogenase, as well as of the respiratory chain complexes I-IV, creatine kinase and Na(+),K(+)-ATPase. Our results show that Phyt did not alter citric acid cycle enzyme activities, or CO(2) production from acetate, reflecting no impairment of the functionality of the citric acid cycle. In contrast, respiratory chain activities were reduced at complexes I, II, I-III, II-III and IV. Membrane synaptical Na(+),K(+)-ATPase activity was also reduced by Phyt, with no alteration of creatine kinase activity. Considering the importance of the electron flow through the respiratory chain for brain energy metabolism (oxidative phosphorylation) and of Na(+),K(+)-ATPase activity for maintaining membrane potential necessary for neurotransmission, the data indicate that Phyt impairs brain bioenergetics at the level of energy formation, as well as neurotransmission. It is presumed that Phyt-induced impairment of these important systems may be involved at least in part in the neurological damage found in patients affected by disorders in which brain Phyt concentrations are increased.

Experiencia diagnóstica y de atención integral de enfermedad de Refsum en el Hospital Pablo Tobón Uribe / Diagnostic and comprehensive health care experience on Refsum disease at Hospital Pablo Tobón Uribe

Objetivo: Describir la experiencia clínica y de diagnóstico de la enfermedad de Refsum con base en las guías de atención por un grupo interdisciplinario de errores innatos del metabolismo. Tipo de estudio: Reporte de caso. Métodos: Se realizó revisión retrospectiva de la historia clínica y seguimiento al paciente remitido al Hospital Pablo Tobón Uribe, con sospecha clínica de error innato de metabolismo, con enfermedad de Refsum, a quien se le implementó guía de atención integral para esta patología. Conclusiones: La utilización de la guía de atención clínica diagnóstica y terapéutica integral de errores innatos del metabolismo facilitó el abordaje temprano del paciente al igual que de apoyo para la familia, mejorando la calidad de vida.

Objective: To describe the clinical and diagnostic experience regarding Refsum disease of an interdisciplinary group focusing on children diagnosed with innate errors of metabolism. Type of study: Case report. Methods: Retrospective and systematic review of medical records and follow -up of a patient who was referred to HPTU withclinical suspicion of inborn error of metabolism, Refsum disease, who was included in the implementation of a comprehensive health care guideline of this disease. Conclusions: the use of a comprehensive diagnosis and therapeutic guideline of innate errors of metabolism approach facilitates early approach to the patient and give family support improving their quality of life.

Phenotype of patients with peroxisomal disorders subdivided into sixteen complementation groups.

OBJECTIVE: To use the technique of complementation analysis to help define genotype and classify patients with clinical manifestations consistent with those of the disorders of peroxisome assembly, namely the Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and rhizomelic chondrodysplasia punctata (RCDP). STUDY DESIGN: Clinical findings, peroxisomal function, and complementation groups were examined in 173 patients with the clinical manifestations of these disorders. RESULTS: In 37 patients (21%), peroxisome assembly was intact and isolated deficiencies of one of five peroxisomal enzymes involved in the beta-oxidation of fatty acids or plasmalogen biosynthesis were demonstrated. Ten complementation groups were identified among 93 patients (54%) with impaired peroxisome assembly and one of three phenotypes (ZS, NALD, or IRD) without correlation between complementation group and phenotype. Forty-three patients (25%) had impaired peroxisome assembly associated with the RCDP phenotype and belonged to a single complementation group. Of the 173 patients, 10 had unusually mild clinical manifestations, including survival to the fifth decade or deficits limited to congenital cataracts. CONCLUSIONS: At least 16 complementation groups, and hence genotypes, are associated with clinical manifestations of disorders of peroxisome assembly. The range of phenotype is wide, and some patients have mild involvement.

Síndromes mas frecuentes asociadosa a retinosis pigmentaria en Cuba / Most frequent syndromes asocciated to retinitis pigmentosa in Cuba

Propósito: Determinar los Síndromes más frecuentes Asociados a Retinosis Pigmentaria en Cuba y señalar algunas de sus características oftalmológicas. Método: Se caracterizaron clínicamente y clasificaron 245 enfermos de RP que compartiendo su cuadro oftalmológico conformaban síndromes complejos asociados. Se estimó su prevalencia y forma de progresión basados en análisis del campo visual y de la agudeza visual, así como también se correlacionaron estos últimos con los hallazgos del examen físico oftalmológico. Resultados: La prevalencia de RP asociada en Cuba fue de un 9,2 por ciento entre la población de enfermos de RP. Predominó la herencia autosómica recesiva en un 72,5 por ciento entre la población de enfermos de RP. Predominó la herencia autosómica recesiva en un 72,6 por ciento de los casos. Los Síndromes de Usher y Bardet-Biedl fueron los más frecuentes con un 64,1 por ciento y 13,9 por ciento, respectivamente. Otros Síndromes encontrados fueron el Kearns Sayre (2,4 por ciento), Strumpell Loraine (2 por ciento), el Rud, Refsum, Marphan y otras degeneraciones del sistema nervioso central que se encontraron en un 17,6 por ciento. Analizados en conjunto, el cuadro de RP sin pigmento se encontró en un 8,9 por ciento. Distintos grados de compromiso macular se determinaron en un 54 por ciento, predominando el edema cistoide y la atrofia epitelial. En un 69,4 por ciento el debut de la enfermedad fue precoz, entre 5 a 10 años de edad y un 75 por ciento de los enfermos estudiados se encontraban en un estadio final de la enfermedad. Conclusiones: La frecuencia de presentación de la RP Asociada en Cuba es ligeramente superior a la reportada en la literatura, así como precoz fue el debut de los síntomas, lo que se debe a la labor de pesquisaje

Artritis psoriasica asociada a acroosteolisis y neuropatia perférica

El diagnóstico de artritis psoriásica se hace cuandopsoriasis y artritis de presentan juntas, sin nódulos subcutáneos y usualmente seronegativa para factor reumatoideo (FR) (1). Wright en 1991 (2) simplificó la clasificación en tres grupos. Revisamos la literatura y no encontramos informes de neuropatía periférica ni osteólisi de la tibia, peroné y tarso en artritis psoriática. Informamos el caso de una paciente con las anteriores manifestaciones clínicas

Biochemical abnormalities in rhizomelic chondrodysplasia punctata.

Biochemical studies with emphasis on peroxisomal functions were conducted in six patients with well-documented rhizomelic chondrodysplasia punctata (RCDP) and compared with findings in patients with Zellweger syndrome and neonatal adrenoleukodystrophy (ALD). Patients with RCDP had three characteristic biochemical abnormalities: (1) profound defect in plasmalogen (ether lipid) synthesis, which is significantly greater than the analogous defect in Zellweger syndrome or neonatal ALD; (2) reduction of phytanic acid oxidation activity to 1% to 5% of control, similar to that observed in Refsum disease, Zellweger syndrome, and neonatal ALD; (3) presence of the unprocessed form of peroxisomal 3-oxoacyl-coenzyme A thiolase in the postmortem liver of two patients. Other peroxisomal functions were normal, including levels of very long chain fatty acids, pipecolic acid, and bile acid intermediates, and immunoblot studies of peroxisomal acyl-CoA oxidase and bifunctional enzyme in postmortem liver. Unlike what is observed in Zellweger syndrome and neonatal ALD, catalase activity in cultured skin fibroblasts was sedimentable, indicating that peroxisome structure is not grossly deficient in RCDP. The biochemical abnormalities in RCDP were consistent and set it apart from all the other known peroxisomal disorders.

Síndrome de Refsum: relato e discussäo de um caso / Refsum's syndrome: report and discussion of a case

Relata-se um caso com diagnóstico clínico da Síndrome de Refsum, revisando-se os aspectos clínicos e terapêuticos essenciais desta infrequente enfermidade

Dysmorphic syndrome with phytanic acid oxidase deficiency, abnormal very long chain fatty acids, and pipecolic acidemia: studies in four children.

We describe a relatively new syndrome in four children with characteristic facial dysmorphism, sensorineural hearing loss, severe visual impairment with retinitis pigmentosa, hypotonia, hepatomegaly, and severe developmental delay. Two patients had intracranial hemorrhage secondary to a vitamin K-responsive clotting defect; both had steatorrhea. Liver biopsy specimens in two children showed an accentuated lobular architecture with prominent fibrous bands in the portal area. In one, the ultrastructure showed accumulation of abnormal substances and occasional trilaminar structures in hepatocytes and other cells. All four patients had elevated serum phytanic acid concentrations (0.3 to 2.7 mg/dl, normal less than 0.2 mg/dl) and deficient fibroblast phytanic acid oxidase activity (0.1 to 6.7 pmol/mg protein/hr, normal 23 to 87 pmol/mg protein/hr). Serum pipecolic acid was 7 to 55 times normal, and the ratio of C26/C22 very long chain fatty acids was increased (0.10 to 0.22; normal less than 0.03). This characteristic syndrome has been described in several children and called infantile Refsum disease or phytanic acid storage disease. Its relationship to neonatal adrenoleukodystrophy, hyperpipecolic acidemia, and Zellweger syndrome is discussed.

Enfermedad de Refsum / Refsum's disease

La enfermedad de Refsum es un defecto congénito del metabolismo graso que se hereda en forma autosómica recesiva. Aunque es una entidad infrecuente, el mecanismo fisiopatológico ha sido intensivamente estudiado y se demostró la acumulación en tejidos de ácido fitánico. Presentamos el segundo caso comunicado en la Argentina, un joven varón con los hallazgos típicos de degeneración tapetorretiniana, neuropatia periférica crónica y ataxia moderada. El ácido fitánico correspondió al 10,3% del total de los ácidos grasos séricos. El conocimiento y diagnóstico de este trastorno metabólico es particularmente importante puesto que se ha comprobado que la progresión natural puede ser detenida mediante la eliminación de alimentos ricos en ácido fitánico de la dieta de los enfermos

Enfermedad de Refsum / Refsums disease

La enfermedad de Refsum es un defecto congénito del metabolismo graso que se hereda en forma autosómica recesiva. Aunque es una entidad infrecuente, el mecanismo fisiopatológico ha sido intensivamente estudiado y se demostró la acumulación en tejidos de ácido fitánico. Presentamos el segundo caso comunicado en la Argentina, un joven varón con los hallazgos típicos de degeneración tapetorretiniana, neuropatia periférica crónica y ataxia moderada. El ácido fitánico correspondió al 10,3% del total de los ácidos grasos séricos. El conocimiento y diagnóstico de este trastorno metabólico es particularmente importante puesto que se ha comprobado que la progresión natural puede ser detenida mediante la eliminación de alimentos ricos en ácido fitánico de la dieta de los enfermos (AU)