A case of mitochondrial DNA depletion syndrome type 11 - expanding the genotype and phenotype.

Mitochondrial DNA depletion syndrome type 11 (MTDPS11) is caused by pathogenic variants in MGME1 gene. We report a woman, 40-year-old, who presented slow progressive drop eyelid at 11-year-old with, learning difficulty and frequent falls. Phisical examination revealed: mild scoliosis, elbow hyperextensibility, flat feet, chronic progressive external ophthalmoplegia with upper eyelid ptosis, diffuse hypotonia, and weakness of arm abduction and neck flexion. Investigation evidenced mild serum creatine kinase increase and glucose intolerance; second-degree atrioventricular block; mild mixed-type respiratory disorder and atrophy and granular appearance of the retinal pigment epithelium. Brain magnetic resonance showed cerebellar atrophy. Muscle biopsy was compatible with mitochondrial myopathy. Genetic panel revealed a homozygous pathogenic variant in the MGME1 gene, consistent with MTDPS11 (c.862C>T; p.Gln288*). This case of MTDPS11 can contribute to the phenotypic characterization of this ultra-rare mitochondrial disorder, presenting milder respiratory and nutritional involvement than the previously reported cases, with possible additional features.

Muscle fiber conduction velocity in situ revisited: A new approach to an ancient technique.

The aim of this study was to measure the muscle fiber conduction velocity (MFCV) in situ in the tibialis anterior muscle in healthy subjects. A total of 36 subjects matched for age and sex were studied. The MFCV was measured with a concentric needle by intramuscular monopolar needle electrical activation at a distance of 50 mm. The mean consecutive difference (MCD) of <5 µs was obtained after a median of 62 muscle fiber action potentials (MFAPs), confirming a direct muscle fiber activation. The measuring latency was at the median point of ascending depolarizing line of the MFAP. The calculated MFCV from 784 MFAPs was 4.10 ± 0.66 m/s, 3.99 ± 0.57 for female subjects (95%, 2.85 to 5.13), and 4.20 ± 0.73 for male subjects (95%, 2.74 to 5.67). The MFCV was 5.22% faster in male subjects. The calculated fast-to-slow MFCV ratio (F/S ratio) was 1.47 for female subjects (95%, 1.27 to 2.54) and 1.67 for male subjects (95%, 1.31 to 3.74). Aging significantly increased the F/S ratio. As the MFCVs mainly depend on the muscle diameter, their assessment is a quick and helpful tool for estimating it. Its variability by the F/S ratio is also a powerful tool in the follow-up of some neuromuscular disorders.

Concentric needle jitter: Reference values in stimulated Tibialis Anterior muscle.

Calculating the reference values for jitter parameters utilizing a disposable concentric needle have been already done for the most often tested muscles. Jitter, expressed as the mean consecutive difference (MCD), was measured in the Tibialis Anterior (TA), not routinely tested muscle. Jitter measurement was taken using the intramuscular microaxonal stimulation technique in 32 healthy subjects. The mean MCD and the mean MCD of the 27th value from the 32 subjects had a normal distribution and were 19.79 ± 2.72 µs and 26.88 ± 3.56 µs, respectively. The suggested limit for the mean MCD is ≥ 26 µs and for the individual values is > 34 µs.

Jitter Evaluation in Distant and Adjacent Muscles after Botulinum Neurotoxin Type A Injection in 78 Cases.

To study the jitter parameters in the distant (DM) and the adjacent muscle (AM) after botulinum neurotoxin type A (BoNT/A) injection in 78 patients, jitter was measured by voluntary activation in DM (n = 43), and in AM (n = 35). Patients were receiving BoNT/A injections as a treatment for movement disorders. Mean age 65.1 years (DM) and 61.9 years (AM). The mean jitter was abnormal in 13.9% (maximum 41.4 µs) of DM, and 40% (maximum 43.7 µs) of AM. Impulse blocking was sparse. We found no correlation of the mean jitter to age, BoNT/A most recent injection (days/units), number of muscles injected, total BoNT/A units summated, number of total BoNT/A sessions, beta-blockers/calcium channel blockers use, and cases with local spread symptoms such as eyelid drop/difficulty swallowing. Maximum mean jitter (41.4/43.7 µs) for DM/AM occurred 61 and 131 days since the most recent BoNT/A, respectively. The far abnormal mean jitter (32.6/36.9 µs) occurred 229 and 313 days since the most recent BoNT/A. We suggested that jitter measurement can be done after BoNT/A in a given muscle other than the injected one, after 8 (DM) and 11 (AM) months, with reference >33 µs and >37 µs, respectively.

Quantitation of muscle pathology abnormalities in 18 patients with mitochondrial disorders / Quantificação das anormalidades patológicas musculares em 18 pacientes com desordens mitocondriais

ABSTRACT INTRODUCTION: Mitochondrial disorders can lead to the accumulation of mitochondria in muscle fibers, as indicated by ragged red (RRF) or ragged blue fibers when stained with modified Gomori trichrome or succinate dehydrogenase (SDH+), respectively, and, absence of activity of cytochrome c oxidase, COX negative fibers (COX-). The combined COX-SDH stain (COMBO+) can reveal even more COX-deficient fibers. OBJECTIVE: To quantify RRFs, SDH+, COX-, and COMBO+ fibers in muscle biopsies with mitochondrial findings. MATERIAL AND METHODS: We retrospectively selected 18 muscle biopsies with mitochondrial abnormalities based on the Walker criteria (percentage of RRFs/COX- fibers, and clinical picture), and/or the Sleigh criteria (percentage of RRFs, SDH+, and COX- fibers). RESULTS: Females represented 83.3%, with a mean age of 38.6 years (5 months-70 years). Patients were diagnosed with chronic progressive external ophthalmoplegia (CPEO, 66.7%), proximal myopathy (22.2%), idiopathic hyperCKemia (11.1%), Kearns-Sayre syndrome (5.6%), mitochondrial encephalomyopathy with ragged red fibers and stroke-like episodes (5.6%), and a dystrophic pattern (5.6%). Some cases of CPEO were combined with proximal myopathy. The quantitative pathologic findings were: RRFs, 3.95% ± 3.17%; SDH+, 7.55% ± 6.1%; COX-, 10.9% ± 7.2%; COMBO+, 14.22% ± 12.79%. We found a slight variation in the diameter of muscle fibers, no necrosis or proliferative connective tissue, few fibers with internal nuclei, and some cases with fiber type grouping. CONCLUSION: Pathologic events, grouped in ascending order of frequency, were RRFs, SDH+ fibers, COX- fibers, and COMBO+ fibers. These data emphasize the importance of the COMBO technique in revealing occult COX deficiency in muscle fibers.

RESUMO INTRODUÇÃO: Desordens mitocondriais são usualmente caracterizadas por: 1. acúmulo de mitocôndria nas fibras musculares que aparecem como fibras vermelhas rasgadas (FVR) ou azuis rasgadas quando coradas, respectivamente, pelo tricrômio modificado de Gomori ou pelo succinato desidrogenase (SDH+); 2. ausência de atividade da citocromo c oxidase (COX), originando fibras COX negativa (COX-). A combinação de colorações COX e SDH pode revelar ainda mais fibras COX deficiente (COMBO+). Objetivos: Quantificar FVR, SDH+, COX- e COMBO+ em biópsias musculares com anormalidades mitocondriais. MATERIAL E MÉTODOS: Foram analisadas retrospectivamente 18 biópsias com anormalidades mitocondriais com base no critério de Walker (percentagem de FVR/ COX- e quadro clínico) e/ou critério de Sleigh (percentagem de FVR, SDH+ e COX-). RESULTADOS: Sexo feminino representou 83, 3% e média de idade 38, 6 anos (5 meses a 70 anos). Oftalmoplegia externa progressiva crônica (OEPC) representou 66, 7%; miopatia proximal, 22, 2%; hiperCKemia idiopática, 11, 1%; síndrome de Kearns-Sayre, 5, 6%; encefalopatia mitocondrial com FVR e episódios semelhantes a acidente vascular cerebral, 5, 6%; e padrão distrófico, 5, 6%. Alguns casos de OEPC estavam associados à miopatia proximal. Achados patológicos quantitativos: FVR, 3, 95% ± 3, 17%; SDH+, 7, 55% ± 6, 1%; COX-, 10, 9% ± 7, 2%; COMBO+, 14, 22% ± 12, 79%. Encontramos leve variação de calibre das fibras musculares sem necrose ou proliferação de tecido conjuntivo, poucas fibras com núcleos internos e alguns casos com agrupamento de fibras. CONCLUSÃO: As anormalidades patológicas nas fibras musculares em ordem ascendente de frequência foram: FVR, SDH+, COX- e COMBO+. Nossos achados enfatizam a importância da técnica COMBO (COX + SDH) para aumento na frequência de fibras musculares COX deficiente ocultas.

Time perception and age.

UNLABELLED: Our internal clock system is predominantly dopaminergic, but memory is predominantly cholinergic. Here, we examined the common sensibility encapsulated in the statement: "time goes faster as we get older". OBJECTIVE: To measure a 2 min time interval, counted mentally in subjects of different age groups. METHOD: 233 healthy subjects (129 women) were divided into three age groups: G1, 15-29 years; G2, 30-49 years; and G3, 50-89 years. Subjects were asked to close their eyes and mentally count the passing of 120 s. RESULTS: The elapsed times were: G1, mean = 114.9 ± 35 s; G2, mean = 96.0 ± 34.3 s; G3, mean = 86.6 ± 34.9 s. The ANOVA-Bonferroni multiple comparison test showed that G3 and G1 results were significantly different (P < 0.001). CONCLUSION: Mental calculations of 120 s were shortened by an average of 24.6% (28.3 s) in individuals over age 50 years compared to individuals under age 30 years.

Time perception and age / Percepção do tempo e idade

ABSTRACT Our internal clock system is predominantly dopaminergic, but memory is predominantly cholinergic. Here, we examined the common sensibility encapsulated in the statement: “time goes faster as we get older”. Objective To measure a 2 min time interval, counted mentally in subjects of different age groups. Method 233 healthy subjects (129 women) were divided into three age groups: G1, 15-29 years; G2, 30-49 years; and G3, 50-89 years. Subjects were asked to close their eyes and mentally count the passing of 120 s. Results The elapsed times were: G1, mean = 114.9 ± 35 s; G2, mean = 96.0 ± 34.3 s; G3, mean = 86.6 ± 34.9 s. The ANOVA-Bonferroni multiple comparison test showed that G3 and G1 results were significantly different (P < 0.001). Conclusion Mental calculations of 120 s were shortened by an average of 24.6% (28.3 s) in individuals over age 50 years compared to individuals under age 30 years.

RESUMO Nosso sistema de relógio interno é predominantemente dopaminérgico, mas a memória é predominantemente colinérgica. Neste estudo, examinamos a assertiva comum que “o tempo passa mais rápido para pessoas mais velhas”. Objetivo Medir o intervalo de tempo 2 min contados mentalmente em pessoas de diferentes faixas etárias. Método 233 pessoas saudáveis (129 mulheres) foram divididos em três grupos: G1, 15-29 anos; G2, 30-49 anos; e G3, 50-89 anos. Foi solicitado que contassem mentalmente, com os olhos fechados, a passagem de 120 s. Resultados Os tempos aferidos foram: G1, média = 114,9 ± 35 s; G2, média = 96,0 ± 34,3 s; G3, média = 86,6 ± 34,9 s. A comparação entre os tempos de G3 e G1 (teste de comparação múltipla ANOVA-Bonferroni) foi muito significante (P < 0,001). Conclusão Cálculo mental de 120 s foi encurtado em média 24,6% (28,3 s) em pessoas maiores que 50 anos quando comparado com pessoas menores que 30 anos.

Expressão de antígenos MHC classe I e de células CD4 e CD8 na polimiosite e dermatomiosite / MHC class I antigens, CD4 and CD8 expressions in polymyositis and dermatomyositis

Objetivo: Analisar as frequências de expressão dos antígenos de complexo principal de histocompatibilidade classe I (MHC-I) e células CD4 e CD8 no músculo esquelético na polimiosite (PM) e dermatomiosite (DM). Métodos: Estudo retrospectivo de 34 casos de PM, oito casos de DM e 29 controles com miopatias não inflamatórias. Resultados: Os antígenos MHC-I expressaram-se no sarcolema e/ou sarcoplasma em 79,4% dos casos de PM, 62,5% dos casos de DM e 27,6% dos controles (a expressão de CD4 foi observada em 76,5%, 75% e 13,8%, respectivamente). Quando os antígenos de MHC-I foram coexpressados com CD4, houve elevada suspeita de PM/DM (principalmente PM). Em 14,3% dos casos de PM/DM, observou-se a expressão isolada dos antígenos MHC-I, sem células inflamatórias. Conclusão: A expressão dos antígenos MHC-I e a positividade do CD4 podem aumentar a suspeita diagnóstica de PM/DM. Não foi observado infiltrado celular em 14,3% dos casos. .

Objective: To analyze the frequencies of the expression of major histocompatibility complex class I (MHC-I) antigens, and CD4 and CD8 cells in skeletal muscle in polymyositis (PM) and dermatomyositis (DM). Methods: This was a retrospective study of 34 PM cases, 8 DM cases, and 29 control patients with non-inflammatory myopathies. Results: MHC-I antigens were expressed in the sarcolemma and/or sarcoplasm in 79.4% of PM cases, 62.5% of DM cases, and 27.6% of controls (CD4 expression was observed in 76.5%, 75%, and 13.8%, respectively). There was a high suspicion of PM/DM (mainly PM) in participants in whom MHC-I antigens and CD4 were co-expressed. In 14.3% of PM/DM cases, we observed MHC-I antigens expression alone, without inflammatory cells. Conclusion: MHC-I antigens expression and CD4 positivity might add to strong diagnostic suspicion of PM/DM. No cellular infiltration was observed in approximately 14.3% of such cases. .

[MHC class I antigens, CD4 and CD8 expressions in polymyositis and dermatomyositis]. / Expressão de antígenos MHC classe I e de células CD4 e CD8 na polimiosite e dermatomiosite.

OBJECTIVE: To analyze the frequencies of the expression of major histocompatibility complex class I (MHC-I) antigens, and CD4 and CD8 cells in skeletal muscle in polymyositis (PM) and dermatomyositis (DM). METHODS: This was a retrospective study of 34 PM cases, 8 DM cases, and 29 control patients with non-inflammatory myopathies. RESULTS: MHC-I antigens were expressed in the sarcolemma and/or sarcoplasm in 79.4% of PM cases, 62.5% of DM cases, and 27.6% of controls (CD4 expression was observed in 76.5%, 75%, and 13.8%, respectively). There was a high suspicion of PM/DM (mainly PM) in patients in whom MHC-I antigens and CD4 were co-expressed. In 14.3% of PM/DM cases, we observed MHC-I antigens expression alone, without inflammatory cells. CONCLUSION: MCH-I antigens expression and CD4 positivity might add to strong diagnostic suspicion of PM/DM. No cellular infiltration was observed in 14.3% of such cases.

Lactato basal sanguíneo em indivíduos não diabéticos e diabéticos: mensuração por meio de tiras / Basal blood lactate in non-diabetics and diabetics’ patients: measurementby means of test-strip method

Lactato resulta da glicólise anaeróbica e sua dosagem é usualmente realizada após coleta de sangue venoso. Não há relatos de valores de referência para mensuração por meio de fitas após uso de lancetas na extremidade do dedo. O objetivo principal do estudo é mensurar o lactato sanguíneo por meio de fitas em voluntários normais e em diabéticos. Foram constituídos 2 grupos: normal, composto por 69 voluntários sadios, com média de idade de 41,3 ± 17,5 anos (15 a 86), 27 masculino e 42 feminino, e diabéticos, composto por 31 doentes, com média de idade de 52,1 ± 14,8 anos (13 a 76), 10 masculino e 21 feminino. Gota de sangue após jejum de 12 horas foi colocada em fita e os valores do lactato e glicose mensurados em aparelhos portáteis, Accutrend® Lactate e Accutrend® GCT . No grupo normal o lactato sanguíneo foi 2,7 ± 0,95 mmol/L (1,0 a 5,2), com limite superior de normalidade de 4,6 mmol/L (95%). No grupo de diabéticos foi 3,94 ± 1,27 mmol/L (1,7 a 7,0). Houve diferença estatisticamente significativa entre os grupos (P<0,0001) e não foi encontrada correlação entre os níveis de glicose e lactato em ambos os grupos. Os valores de referência de lactato sanguíneo mensurado por meio de fitas foram mais elevados e tiveram maior variação em relação à dosagem usual; indivíduos diabéticos tem nível sanguíneo mais elevado em relação aos normais, mas sem correlação com o nível glicêmico.

Lactate results from anaerobic glycolysis, and it is usually measured after a vein puncture. There are noknown reports on reference values for lactate measure through strips after a blood drop from digit. The main purpose of the study is to get reference values for blood lactate using strips in normal subjects and patients with diabetes. Two groups were constituted: control with 69 health subjects with mean age of41.3 ± 17.5 years (15 - 86), 42 females and 27 males, and 32 patients with diabetes melito with mean age of52.1 ± 14.8 years (13 - 76), 21 females and 10 males. Blood lactate and glucose were measured after 12 hour-fasting through a blood drop on a strip for immediate reading on portable Accutrend® Lactate and Accutrend® GCT. Control group: lactate 2.7 ± 0.95 mmol/L (1.0 - 5.2) and upper limit of normality 4.6mmol/L (95%). Diabetic group: lactate 3.94 ± 1.27 mmol/L (1.7 - 7.0). There was a significant difference between groups (P<0.0001) and there was no correlation between lactate and glucose values in bothgroups. The reference values of blood lactate measured by the test-strip method were higher and had a greater variation from the usual dosage; diabetics’ patients have higher blood levels compared to normal ones, but no correlation with the glucose level.

Methylenetetrahydrofolate reductase gene polymorphism and its association with coronary artery disease.

CONTEXT AND OBJECTIVE: Obstructive coronary artery disease (CAD) is characterized by the deposition of atherosclerotic plaque on the coronary artery wall. Its manifestations depend on interactions between environmental and genetic risk factors. The aim of this work was to analyze the frequency of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in patients with CAD and its association with plasma homocysteine levels. Risk factors for CAD were also evaluated. DESIGN AND SETTING: Retrospective with blind quantitative analysis, at Hospital de Base, Faculdade de Medicina de São José do Rio Preto. METHODS: One hundred and twenty-seven individuals were studied. All completed a questionnaire to analyze risk factors for CAD. MTHFR polymorphism was investigated by restriction fragment length analysis and correlated with the number of affected arteries and degree of arterial obstruction determined by coronary cineangiography, and with plasma homocysteine levels measured by liquid chromatography/sequential mass spectrometry. RESULTS: Smoking (p = 0.02) and high-density lipoprotein cholesterol (p = 0.01) were associated with CAD. The C allele was the most prevalent in patients (0.61) and controls (0.66). There was no correlation between MTHFR/C677T polymorphism and plasma homocysteine levels. However, in patients with the TT genotype there was a correlation with the prevalence of coronary obstruction greater than 95% (p = 0.02) and the presence of two affected arteries (p = 0.04). CONCLUSIONS: The TT genotype is associated with coronary artery obstruction greater than 95% and the presence of two affected arteries. This confirms the relationship between genetic variants in specific patient subgroups and cardiovascular diseases.

Methylenetetrahydrofolate reductase gene polymorphism and its association with coronary artery disease

CONTEXT AND OBJECTIVE: Obstructive coronary artery disease (CAD) is characterized by the deposition of atherosclerotic plaque on the coronary artery wall. Its manifestations depend on interactions between environmental and genetic risk factors. The aim of this work was to analyze the frequency of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in patients with CAD and its association with plasma homocysteine levels. Risk factors for CAD were also evaluated. DESIGN AND SETTING: Retrospective with blind quantitative analysis, at Hospital de Base, Faculdade de Medicina de São José do Rio Preto. METHODS: One hundred and twenty-seven individuals were studied. All completed a questionnaire to analyze risk factors for CAD. MTHFR polymorphism was investigated by restriction fragment length analysis and correlated with the number of affected arteries and degree of arterial obstruction determined by coronary cineangiography, and with plasma homocysteine levels measured by liquid chromatography/sequential mass spectrometry. RESULTS: Smoking (p = 0.02) and high-density lipoprotein cholesterol (p = 0.01) were associated with CAD. The C allele was the most prevalent in patients (0.61) and controls (0.66). There was no correlation between MTHFR/C677T polymorphism and plasma homocysteine levels. However, in patients with the TT genotype there was a correlation with the prevalence of coronary obstruction greater than 95 percent (p = 0.02) and the presence of two affected arteries (p = 0.04). CONCLUSIONS: The TT genotype is associated with coronary artery obstruction greater than 95 percent and the presence of two affected arteries. This confirms the relationship between genetic variants in specific patient subgroups and cardiovascular diseases.

CONTEXTO E OBJETIVO: A doença arterial coronariana (DAC) caracteriza-se pelo depósito de placa aterosclerótica na parede arterial coronária. Sua manifestação é dependente da interação entre fatores de risco ambientais e genéticos. O objetivo deste trabalho é analisar a freqüência do polimorfismo MTHFR/C677T em pacientes com doença arterial coronária e sua associação com o nível de Hcy plasmática. Fatores de risco para DAC também foram avaliados. TIPO DE ESTUDO: Retrospectivo com análise cega quantitativa, no Hospital de Base, Faculdade de Medicina de São José do Rio Preto. MÉTODOS: Foram estudados 127 indivíduos. Todos responderam a um questionário para análise dos fatores de risco para DAC. O polimorfismo MTHFR/C677T, investigado por análise de comprimento de fragmentos de restrição, foi correlacionado com número de artérias afetadas e grau de obstrução arterial, determinadas pela cinangiocoronariografia, e com o nível de Hcy plasmática. RESULTADOS: Tabagismo (p = 0,02) and HDLc (p = 0,01) foram associados com DAC. O alelo C foi o mais prevalente em pacientes (0,61) e controles (0,66; p = 0,49). O polimorfismo MTHFR/C677T não apresentou associação com níveis de Hcy plasmática. Entretanto, nos pacientes com genótipo TT observou-se a prevalência de obstrução coronariana acima de 95 por cento (p = 0,02) e a presença de duas artérias lesadas (p = 0,04). CONCLUSÕES: Associou-se o genótipo TT com o grau de obstrução arterial coronária acima de 95 por cento e a presença de duas artérias lesadas; confirma-se, assim, a relação de variantes genéticas em subgrupos específicos de pacientes com doenças cardiovasculares.