Submitted by Mario BC (mario@bc.ufrpe.br) on 2016-08-03T12:08:22Z No. of bitstreams: 1 Tatiane Rodrigues da Silva.pdf: 904164 bytes, checksum: e0b2a02ffea31eda3f280d8b3c391bea (MD5) / Made available in DSpace on 2016-08-03T12:08:22Z (GMT). No. of bitstreams: 1 Tatiane Rodrigues da Silva.pdf: 904164 bytes, checksum: e0b2a02ffea31eda3f280d8b3c391bea (MD5) Previous issue date: 2014-08-04 / Mineral deficiencies are present throughout the country and represent a major loss factors in productivity creations of ruminants. The objective of this study was to review regarding mineral deficiencies, as well as a survey of clinical cases of copper deficiency in ruminants treated at the Veterinary Hospital of the Federal University of Campina Grande and characterize the status of trace elements in tissues of sheep and goats created in Paraiba semi-arid. Copper deficiency is initially identified in the state of Paraiba evaluated the database Clinic of Large Animal and Animal Pathology Laboratory of the Veterinary Hospital of the Federal University of Campina Grande in the year 1998 to the year 2011. During the survey data were highlighted in goats four delayed enzootic ataxia outbreaks and congenital copper deficiency case (swayback) in cattle and an outbreak of chronic diarrhea associated with hipocuprose. To trace the trace mineral profile was performed to determine the levels of copper, iron, molybdenum and zinc in samples of liver and serum of sheep and goats, raised and slaughtered in the backlands of Paraiba region, the dry and rainy seasons. The characterization of the trace mineral profile were identified in the serum of small ruminants, marginal copper deficiency and severe deficiency of iron and zinc. In hepatic dose found marginal deficiency of copper levels in both species and iron goats. The clinical presentations of copper deficiency in sheep and cattle and serum and liver marginal concentration of this element suggest that supplementation with copper is needed in grazing ruminants in the semiarid region of Paraíba. / As deficiências de minerais estão presentes em todo território nacional e representam um dos principais fatores de perda na produtividade em criações de ruminantes. O objetivo deste trabalho foi fazer uma revisão a respeito das deficiências de minerais, bem como um levantamento de casos clínicos de deficiência de cobre em ruminantes atendidos no Hospital Veterinário da Universidade Federal de Campina Grande e caracterizar o status de microminerais em tecidos de caprinos e ovinos criados no semiárido paraibano. Para identificação da ocorrência de deficiência de cobre no Estado da Paraíba avaliou-se o banco de dados do Ambulatório de Grandes Animais e do Laboratório de Patologia Animal do Hospital Veterinário da Universidade Federal de Campina Grande do ano de 1998 até o ano de 2011. Durante o levantamento de dados foram evidenciados em caprinos quatro surtos de ataxia enzoótica tardia e um caso de deficiência de cobre congênita (swayback) e em bovinos um surto de diarreia crônica associado a hipocuprose. Para traçar o perfil de microminerais foi realizada a determinação dos teores de cobre, ferro, molibidênio e zinco em amostras de fígado e soro de ovinos e caprinos, criados e abatidos na região do sertão paraibano, nas épocas seca e chuvosa. Na caracterização do perfil de microminerais foram identificadas na dosagem sérica de pequenos ruminantes, deficiência marginal de cobre e deficiência acentuada de ferro e zinco. Na dosagem hepática foram encontrados níveis de deficiência marginal de cobre nas duas espécies e ferro nos caprinos. As apresentações clínicas de carência de cobre em caprinos e bovinos e a concentração marginal sérica e hepática deste elemento sugerem que a suplementação com cobre é necessária em ruminantes em pastejo no semiárido da Paraíba.

Master of Science / Department of Human Nutrition / Denis M. Medeiros / Copper deficiency has been linked with many health problems, among them cardiac hypertrophy. Because of its potential for causing oxidative damage, copper within the cell must be bound to chaperone proteins. In this thesis, we examined the role of dietary copper deficiency in the regulation of select copper chaperone proteins in cardiac tissue of rats. Sixteen weanling male Long-Evans rats were randomized into treatment groups, one group receiving a copper deficient diet (< 1 mg Cu/kg diet) and one group receiving a diet containing adequate copper (6 mg Cu/kg diet) for 5 weeks. Rats were sacrificed and a small blood sample was removed to determine hematocrit. Also, heart and liver tissues were removed for subsequent analysis. Rats fed the copper deficient diet had lower body weights but greater heart weights and heart:body weight. Hematocrit levels and liver copper concentrations were markedly decreased in copper deficient rats. These variables indicated that the copper deficient diet did in fact induce a copper deficiency in these animals. Non-myofibrillar proteins from the hearts were removed and separated by SDS-PAGE. Western Blotting was used to determine the concentrations of CTR1, CCS, Cox17, SCO1, Cox1 and Cox4. No changes were observed in the concentrations of CTR1 and Cox17. CCS and SCO1 were up-regulated as a result of copper deficiency, while Cox1 and Cox4 were both down-regulated. However, use of another antibody against Cox subunits suggested that only the nuclear encoded subunits including subunit IV were decreased, but not subunits I and II. These data provide new insight into the cardiac hypertrophy observed in copper deficiency, which suggests that select chaperone proteins may be up-regulated by a dietary copper deficiency.

Submitted by (edna.saturno@ufrpe.br) on 2016-07-29T11:50:01Z No. of bitstreams: 1 Allan Vieira dos Santos Marques.pdf: 717930 bytes, checksum: aa978139a85c2cfa9f5a7df5d8379ad4 (MD5) / Made available in DSpace on 2016-07-29T11:50:01Z (GMT). No. of bitstreams: 1 Allan Vieira dos Santos Marques.pdf: 717930 bytes, checksum: aa978139a85c2cfa9f5a7df5d8379ad4 (MD5) Previous issue date: 2010-02-26 / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / The aim of this research was to know serum and liver concentrations of Cu, Mo, Fe and Zn in sheep and goats slaughtered in the semiarid region of the state of Pernambuco, Northeastern Brazil, during the rainy and dry seasons, and to determine if Cu deficiency that occurs in the region is primary or secondary to high levels of Mo and/or Fe. Serum and liver samples from 141 goats and 141 sheep were submitted to wet digestion in nitric-percloric acid and analyzed by coupled plasma atomic absorption spectrophotometry. The mean concentration of serum Cu in sheep was 9.22±2.34 μmol/L in the dry period and 10.03±2.89 μmol/L in the rainy period, but females had significantly higher values (10.92±2.56 μmol/L) than males (9.42±2.67 μmol/L). Mean Cu concentrations in the liver were 185.1±88.28 mg per kg of dry matter (mg/kg) in the dry period and 137.95±87.04 mg/kg in the rainy period, and females had significantly higher concentrations (218.61±93.49 mg/kg) than males (133.45±92.37 mg/kg). In goats serum concentrations of Cu were of 11.74±2.36 μmol/L in the dry period and 11.05±2.74 μmol/L in the rainy period, and females (12.10±2.67 μmol/L) had higher concentrations than males (10.14±1.80 μmol/L). Liver concentrations were 155.2±93.40 mg/kg in the dry period and of 149.37±62.33 mg/kg in the rainy period. Mean serum concentrations of Cu in sheep (9.85±2.71 μmol/L) were significantlyt lower than in goats (11.37±2.57 μmol/L), but there were no differences in liver concentrations of Cu between sheep (158.45±83.05 mg/kg) and goats (152.46±79.58 mg/kg). Based in Cu serum and liver concentrations, and in the sporadic occurrence of enzootic ataxia, Cu suplementation is recommended in grazing sheep and goats during the dry and the rainy seasons. In sheep, serum concentrations of Fe were 36.99±15 μmol/L in the dry season and 34.52±14.86 μmol/L in the rainy season, with significant differences between females (29.92±11.06 μmol/L) and males (37.85±15.68 μmol/L). Liver Fe concentrations were significantly lower in the dry season (186.20±30.02 mg/kg) than in the rainy season (229.25±83.15 mg/kg), with no differences between females and males. In goats, serum concentrations of Fe were 25.61±9.35 μmol/L in the dry season and 24.57±6.96 μmol/L in the rainy season, and liver concentrations were of 170.52±56.91 mg/kg in the dry season and 139.73±51.30 mg/kg in the rainy season; there were no significant differences between females and males. Serum levels of Fe were significantly higher in sheep (35.58±14.89 μmol/L) than in goats (25.06±8.10 μmol/L). Also Fe concentrations of the liver were higher in sheep (210.53±121.99 mg/kg) than in goats (156.1±55.99 mg/kg). Considering that serum and hepatic concentrations of Fe are between normal ranges or marginal it is suggested that the low Cu concentrations are not related with high Fe ingestion. In sheep serum concentrations of Mo were 0.33±0.18 μmol/L in the dry season and 0.3±0.15 μmol/L in the rainy season and liver concentrations were 8.27±3.97 in the dry season and 7.96±4.07 in the rainy season. In goats, serum concentrations of Mo were 0.31±0.12 μmol/L in the dry season and 0.26±0.10 μmol/L in the rainy season, and liver concentrations were 7.17±4.09 mg/kg in the dry season and 5.8±4.14 mg/kg in the rainy season. There were no significant differences in serum and liver Mo concentrations between sheep and goats and between males and females. Despite the variations found in this study and also in reference values, it is suggested that the low or marginal Cu concentrations are not due to high Mo intake. In sheep serum concentrations of Zn were significantly lower during the dry season (9.79±3.02 μmol/L) than in the rainy season (13.48±7.22 μmol/L). Also Zn concentrations in the liver were significantly lower in the dry season (109.96±30.23 mg/kg) than in rainy season (139.1±60.45 mg/kg). In goats, serum Zn concentrations were 12.01±9.61 μmol/L in the dry season and 11.6±4.93 μmol/L in the rainy season, and liver concentrations were 134.2±26.58 mg/kg in the dry season and 131.45±76.55 mg/kg in the rainy season. There were no significant differences between serum and liver concentrations of Zn between sheep and goats or between males and females. Taking into account that serum and liver Zn concentrations in sheep and goats are considered marginal, supplementation with this mineral it suggested in grazing sheep and goats, mainly during the dry season. / Objetivou-se conhecer os teores de Cu, Mo, Fe e Zn em soro e fígado de ovinos e caprinos, nas épocas de chuva e seca, criadas no semi-árido do estado de Pernambuco, e estabelecer se a carência de Cu é causada por deficiência primária de Cu ou secundária à ingestão de quantidades excessivas de Fe ou Mo. Amostras de soro e fígado de 141 ovinos e 141 caprinos foram submetidas à digestão úmida em ácido nítrico-perclórico e analisados em espectrofotômetro de absorção atômica acoplado a plasma. A concentração sérica média de Cu em ovinos foi de 9,22±2,34 μmol/L na seca e 10,03±2,89 μmol/L na chuva, sendo que as fêmeas tiveram valores significativamente maiores (10,92±2,56 μmol/L) do que os machos (9,42±2,67 μmol/L). Os valores de Cu em fígado foram de 185,1±88,28 mg/kg da MS na seca e 137,95±87,04 mg/kg na chuva e as fêmeas tiveram valores significativamente maiores (218,61±93,49 mg/kg) do que os machos (133,45±92,37 mg/kg). Em caprinos os valores séricos de Cu foram de 11,74±2,36 μmol/L na seca e 11,05±2,74 μmol/L na chuva, sendo que as fêmeas tiveram maiores valores (12,10±2,67 μmol/L) que os machos (10,14±1,80 μmol/L). Os teores do fígado foram de 155,2±93,40 mg/kg na seca e 149,37±62,33 mg/kg na chuva. Os teores séricos de cobre em ovinos foram significativamente menores que o dos caprinos, mas não se observaram diferenças nos teores hepáticos de Cu entre ovinos e caprinos. Baseado nesses valores, considerados marginais, e na ocorrência de surtos de ataxia enzoótica em caprinos e ovinos na região, recomenda-se a suplementação com Cu, em animais a campo, tanto na seca quanto na chuva. Os teores séricos de Fe em ovinos foram de 36,99±15 μmol/L na seca e de 34,52±14,86 μmol/L na chuva, diferindo entre fêmeas (29,92±11,06 μmol/L) e machos (37,85±15,68 μmol/L). Os teores do fígado foram significativamente menores na seca (186,20±30,02 mg/kg) do que na chuva (229,25±83,15 mg/kg), não havendo diferenças entre machos e fêmeas. Em caprinos os teores séricos de Fe foram de 25,61±9,35 μmol/L na seca e de 24,57±6,96 μmol/L na chuva e os teores do fígado de 170,52±56,91 mg/kg na seca e de 139,73±51,30 mg/kg na chuva. Nesta espécie não houve diferenças nos teores séricos e hepáticos de Fe entre machos e fêmeas. Os teores séricos e hepáticos de Fe foram significativamente maiores em ovinos do que em caprinos. Considerando que as concentrações séricas e hepáticas de Fe encontram-se dentro da normalidade ou são marginais sugere-se que as concentrações marginais de Cu não estejam diretamente relacionadas com o excesso de Fe. Os teores séricos de Mo em ovinos foram de 0,33±0,18 μmol/L na seca e 0,3±0,15 μmol/L na chuva e os teores no fígado de 8,27±3,97 na seca e 7,96±4,07 na chuva. Os teores séricos de Mo em caprinos foram de 0,31±0,12 μmol/L na seca e de 0,26±0,10 μmol/L na chuva e os do fígado de 7,17±4,09 mg/kg na seca e 5,8±4,14 mg/kg na chuva. Os teores médios de Mo de soro e fígado em ovinos, 0,31±0,17 μmol/L e 8,10±4,01 mg/kg, respectivamente, foram semelhantes aos teores séricos e hepáticos de caprinos, de 0,28±0,11 μmol/L e 6,53±4,13 mg/kg, respectivamente. Tanto em ovinos quanto em caprinos não houve diferenças significantes nos teores do soro e fígado entre machos e fêmeas. Apesar das variações encontradas tanto neste trabalho quanto nos dados da literatura os resultados sugerem que os teores marginais de Cu não são devidos a teores altos de Mo. Em ovinos os valores de Zn no soro foram significativamente diferentes na seca (9,79±3,02 μmol/L) do que na chuva (13,48±7,22 μmol/L). No fígado os valores de Zn foram, também, significativamente diferentes na seca (109,96±30,23 mg/kg) do que na chuva (139,1±60,45 mg/kg). Em caprinos os teores de Zn no soro foram de 12,01±9,61 μmol/L na seca e 11,6±4,93 μmol/L na chuva e os do fígado foram de 134,2±26,58 mg/kg na seca e 131,45±76,55 mg/kg na chuva. Os teores séricos e hepáticos de Zn foram semelhantes em caprinos e ovinos. Considerando que os teores de Zn sérico encontram-se abaixo dos valores considerados como marginais e os hepáticos dentro do limite de normalidade, embora próximos ao limite inferior da referência, recomenda-se a suplementação com Zn, principalmente durante o período da seca.

Hintergrund: Der Morbus Wilson ist eine seltene, angeborene Störung des Kupferstoffwechsels, bei welcher es zu Akkumulationen von Kupfer und infolgedessen zu Schäden in verschiedenen Organen des menschlichen Körpers kommt. Die Therapie besteht vor allem darin, den Kupferspiegel medikamentös zu senken. In einzelnen Fällen wurde der Kupferspiegel während der Therapie so weit gesenkt, dass bei den Patient*innen neurologische Symptome auftraten (sogenannte Kupfermangel-Myeloneuropathien). Kupfer ist ein essenzieller Kofaktor mehrerer Enzyme im menschlichen Körper, so auch der Cytochrom-c-Oxidase, welche einen wichtigen Bestandteil der mitochondrialen Atmungskette und damit der zellulären Energiegewinnung darstellt. Die Bestimmung ihrer Aktivität ist bisher für verschiedene Zellen und Gewebe etabliert worden, ein standardisierter Assay für die Bestimmung in Thrombozyten existiert jedoch nicht. Fragestellung: Für die optimale Bestimmung der Cytochrom-c-Oxidase-Aktivität in Thrombozyten sollen bereits existierende Methoden angepasst werden. Ziel dieser Arbeit ist es, die Aktivität der Cytochrom-c-Oxidase bei Morbus Wilson-Patient*innen unter kupfersenkender Therapie zu untersuchen und auf einen Zusammenhang zum Serum-Kupferspiegel zu prüfen. Die Frage, ob eine zu starke Kupfersenkung durch die Therapie des Morbus Wilson zu einer verringerten Cytochrom-c-Oxidase-Aktivität führt und ob diese Myeloneuropathien hervorruft, soll somit beantwortet werden. Material und Methodik: Es wurden 36 Morbus Wilson-Patient*innen unter kupfersenkender Therapie und 20 gesunde Kontrollproband*innen untersucht. Es erfolgte eine Blutabnahme für die Gewinnung der Thrombozyten sowie für die Bestimmung des Serum-Kupferspiegels. Die Bestimmung der Aktivität der Cytochrom-c-Oxidase erfolgte spektralphotometrisch in Thrombozyten. Des Weiteren wurde die Aktivität des Komplex-II der Atmungskette bestimmt, da dieser nicht kupferabhängig ist und seine Aktivität daher bei Kupfermangel nicht eingeschränkt sein sollte. Zusätzlich ermöglichte die Berechnung des Quotienten der Cytochrom-c-Oxidase-Aktivität und der Komplex-II-Aktivität die Erfassung sehr geringer Aktivitätseinschränkungen der Cytochrom-c-Oxidase. Im Rahmen dieser Dissertation wurde die spektralphotometrische Messung dieser beiden Enzymaktivitäten in Thrombozyten entwickelt und optimiert. Zur Justierung der Enzymaktivitäten bei unbekannter Mitochondrienmenge diente die Aktivität der ausschließlich in Mitochondrien vorkommenden Citratsynthase. Die so bestimmten Enzymaktivitäten wurden mittels SPSS zwischen Wilson-Patient*innen und Kontrollproband*innen verglichen und untereinander sowie mit dem Serum-Kupferspiegel auf Zusammenhänge untersucht. Ferner wurden die Morbus Wilson-Patient*innen klinisch auf Anzeichen für Myeloneuropathien untersucht, um die Untersuchungsergebnisse anschließend auf einen Zusammenhang zu der Cytochrom-c-Oxidase-Aktivität zu prüfen. Ergebnisse: Der auf den Untersuchungen von Kirby et al. beruhende Assay für die spektralphotometrische Bestimmung der Cytochrom-c-Oxidase-Aktivität in isolierten Mitochondrien konnte durch die Zugabe von 0,3 mM Dodecylmaltosid für die Messung in Thrombozyten erfolgreich optimiert werden. Ebenso wurde der Assay für die Komplex-II-Aktivität durch die Zugabe von 1 mg/ml BSA für die Bestimmung in Thrombozyten erweitert (Kirby et al., 2007). Die Aktivität der Cytochrom-c-Oxidase der Wilson-Patient*innen war signifikant niedriger als die der Kontrollgruppe, während die Kontrollgruppe eine signifikant höhere Komplex-II-Aktivität aufwies. Der Quotient von Cytochrom-c-Oxidase-Aktivität und Komplex-II-Aktivität war in der Patient*innengruppe folglich ebenfalls signifikant erniedrigt. In der Analyse aller untersuchten Proben zeigte sich ein signifikanter Zusammenhang zwischen Serum-Kupferspiegel und Cytochrom-c-Oxidase-Aktivität, welcher in der Betrachtung der Subgruppen (Wilson Patient*innen und Kontrollproband*innen) jedoch nicht nachgewiesen werden konnte. Keiner der untersuchten Patient*innen wies klinische Anzeichen für Myeloneuropathien auf. Schlussfolgerung: Der optimierte Assay der Cytochrom-c-Oxidase-Aktivität und Komplex-II-Aktivität in Thrombozyten erlaubt die zuverlässige Bestimmung der Atmungskettenaktivität in einem einfach zugänglichen Gewebe und ist damit für vielfältige Fragestellungen einsetzbar, wenn Einflüsse medizinischer Maßnahmen auf die mitochondriale Funktion untersucht werden sollen. Mit 36 Morbus Wilson-Patient*innen umfasst diese Arbeit eine der bisher größten untersuchten Patient*innengruppen dieses seltenen Krankheitsbildes. Der erniedrigte Quotient der Cytochrom-c-Oxidase-Aktivität und Komplex-II-Aktivität ist als Bestätigung einer Cytochrom-c-Oxidase-Einschränkung bei Morbus Wilson-Patient*innen unter kupfersenkender Therapie zu werten. Die Korrelation zwischen dem Serum-Kupferspiegel und der Cytochrom-c-Oxidase-Aktivität sowie die Aktivitätsreduktion der Cytochrom-c-Oxidase in der Patient*innengruppe ist eine wichtige Erkenntnis für die zukünftige Überwachung und gegebenenfalls Anpassung der Therapie von Morbus Wilson. Der Zusammenhang zwischen der Cytochrom-c-Oxidase-Aktivität und Myeloneuropathien sollte an Patient*innen mit Myeloneuropathien weiter untersucht werden. Es wurde jedoch gezeigt, dass Kupfermangel und niedrige Cytochrom-c-Oxidase-Aktivitäten nicht unbedingt mit Myeloneuropathien einhergehen. Therapie-induzierte Kupfermangel-Myeloneuropathien gilt es weiterhin zu vermeiden. / Background: Wilson’s disease is a rare, congenital disorder of copper metabolism, which leads to accumulations of copper and consequent damage in various organs of the human body. The therapy consists mainly in lowering the copper level by medication. In individual cases, the copper level was lowered during the therapy to such an extent that the patients developed neurological symptoms (so-called copper deficiency myeloneuropathies). Copper is an essential cofactor of several enzymes in the human body, including cytochrome c oxidase, which is an important component of the mitochondrial respiratory chain and thus of cellular energy production. The determination of its activity has been established so far for various cells and tissues, but a standardized assay for its determination in platelets does not exist. Purpose: For the optimal determination of cytochrome c oxidase activity in platelets, existing methods will be adapted. The aim of this work is to investigate the activity of cytochrome c oxidase in Wilson’s disease patients under copper-lowering therapy and to test for a correlation to serum copper levels. The question of whether excessive copper lowering by Wilson’s disease therapy leads to reduced cytochrome c oxidase activity and whether this possibly causes myeloneuropathies will thus be answered. Material and Methods: 36 Wilson’s disease patients under copper-lowering therapy and 20 healthy control subjects were studied. Blood was drawn for platelet collection and determination of serum copper levels. The activity of cytochrome c oxidase was determined spectrophotometrically in platelets. Furthermore, the activity of complex II of the respiratory chain was determined, since this is not copper-dependent and its activity should therefore not be limited in copper deficiency. In addition, calculation of the quotient of cytochrome c oxidase activity and complex II activity allowed detection of very low activity limitations of cytochrome c oxidase. In this dissertation, the spectrophotometric measurement of these two enzyme activities in platelets was developed and optimized. The activity of citrate synthase, which occurs exclusively in mitochondria, was used to adjust the enzyme activities when amount of mitochondria was unknown. The enzyme activities determined in this way were compared between Wilson’s disease patients and control subjects using SPSS and examined for correlations with each other and with serum copper levels. Furthermore, the Wilson’s disease patients were clinically examined for signs of myeloneuropathies, in order to subsequently examine the examination results for a correlation to the cytochrome c oxidase activity. Results: The assay for spectrophotometric determination of cytochrome c oxidase activity in isolated mitochondria, based on studies of Kirby et al, was successfully optimized for measurement in platelets by the addition of 0.3 mM dodecylmaltoside. Similarly, the assay for complex II activity was enhanced by the addition of 1 mg/ml BSA for determination in platelets (Kirby et al., 2007). The activity of cytochrome c oxidase of Wilson patients was significantly lower than that of the control group, with the control group had a significantly higher complex II activity. Consequently, the quotient of cytochrome c oxidase activity and complex II activity was also significantly lower in the Wilson patient group. A significant correlation between serum copper level and cytochrome c oxidase activity was found in the analysis of all samples examined, which, however, could not be proven in the examination of the subgroups (Wilson patients and control subjects). None of the patients examined showed clinical signs of myeloneuropathies. Conclusion: The optimized assay of cytochrome c oxidase activity and complex II activity in platelets allows reliable determination of respiratory chain activity in an easily accessible tissue and is thus applicable to a variety of questions when influences of medical interventions on mitochondrial function are to be investigated. With 36 Wilson's disease patients, this work includes one of the largest groups of patients of this rare disease studied so far. The decreased quotient of cytochrome c oxidase activity and complex II activity is a confirmation of cytochrome c oxidase impairment in Wilson’s disease patients on copper-lowering therapy. The correlation between serum copper level and cytochrome c oxidase activity as well as the reduction of cytochrome c oxidase activity in the patient group is an important finding for future monitoring and, if necessary, adjustment of Wilson’s disease therapy. The relationship between cytochrome c oxidase activity and myeloneuropathies should be further investigated in patients with myeloneuropathies. However, it has been shown that copper deficiency and low cytochrome c oxidase activities are not necessarily associated with myeloneuropathies. Therapy-induced copper deficiency myeloneuropathies should continue to be avoided.