Late Onset Subacute Profound Biotinidase Deficiency Caused by a Novel Homozygous Variant c.466-3T>G in the BTD Gene

Biotinidase defciency (BD) is an autosomal recessive disorder caused by bi-allelic mutation in the BTD gene. Clinical manifestations in BD mainly depends on residual biotinidase enzyme activity, although there are some exceptions. Broadly BD disorders are classifed as profound BD and partial BD. Further profound BD can be early onset, late onset, and sometimes may be asymptomatic. Clinically late-onset profound BD can present with spectrum of manifestations ranging from single organ to multiple organ involvement, typically afecting function of brain, eye, ear, and skin. Here, a frst-born child to consanguineous parents with late-onset profound BD presenting with hyperventilation secondary to lactic acidosis, hypotonia, evolving spasticity, and abnormal neuroimaging fndings caused by novel homozygous variant, c.466-3T>G in the BTD gene is reported.

Lactic acidosis associated with standard dose linezolid in a kidney recipient with impaired renal function

Abstract Severe lactic acidosis, a mitochondrial toxicity caused by the recommended standard dosage of linezolid (LZD), may occur in patients with impaired renal function. We describe an adult male who underwent kidney transplantation with stably impaired renal function, severe dyspnea, and abdominal discomfort. He received a standard oral dose of LZD (600 mg twice daily) and azithromycin for three weeks with a reduced immunosuppressant dose due to pulmonary non-tuberculosis mycobacterial infection. He was alert and afebrile, with a blood pressure of 140/60 mmHg. Pertinent laboratory data showed: pH 7.12, PaCO2 13.6 mmHg; HCO3- 4.3 mmol/L and serum lactate 18.4 mmol/L. His trough serum LZD concentration reached toxic levels (21.4 μg/mL). With hemodialysis, his clinical symptoms improved, with a decline in serum LZD (9.8μg/mL) and lactate (3.2 mmol/L). Chronic standard dose LZD in patients with impaired renal function can lead to life-threatening lactic acidosis, especially in coexisting conditions that reduce LZD metabolism.

Toxicidad por metformina, más allá de la falla renal y la acidosis láctica: reporte de dos casos / Metformin toxicity, beyond renal failure and lactic acidosis: report of 2 cases / Toxicidade da metformina, além de insuficiência renal e acidose láctica: relato de dois casos

El suicidio es un problema de salud pública grave, vincula frecuentemente al consumo de medicamentos. La metformina es un fármaco antihiperglicemiante de fácil acceso y la sobredosis implica riesgos metabólicos, entre ellos, la acidosis láctica es el principal. Teniendo en cuenta la frecuencia de su consumo, es necesario que el personal de salud conozca los riesgos que implica la intoxicación y los signos y síntomas iniciales, pues del manejo adecuado dependerá un pronóstico favorable. El objetivo de este reporte es evidenciar los riesgos metabólicos renales-hemodinámicos, asociados a la toxicidad por metformina, además de resaltar la necesidad de considerar el uso temprano de la terapia de remplazo renal y de concientizar a los clínicos de que exponer a los pacientes a un medicamento, es también exponerlo a efectos adversos o a abuso con fines autolesivos.

Suicide is a serious public health problem that increases worldwide. In Medellín, its incidence is on the rise, and the most frequent mechanism is the ingestion of drugs. Metformin is an antihyperglycemic medication that is easily accessible and frequently used, because it is part of the first line of management of type 2 diabetes mellitus. One of the complications associated with its use is lactic acidosis, which can lead to serious toxicity. Therefore, it is necessary for the health personnel to be aware of the signs and symptoms that can initially appear in the case of intoxication, since a favorable prognosis depends on adequate management. The objective of this report is to present two clinical cases that evidence the wide spectrum of toxicity secondary to the use of metformin and to review the available evidence of the approach to this poisoning, emphasizing the importance of early use of renal replacement therapy.

O suicídio é um grave problema de saúde pública, frequentemente relacionado ao consu-mo de drogas. A metformina é um anti-hiperglicêmico de fácil acesso e a sobredosagem envolve riscos metabólicos, entre eles, a acidose láctica é o principal. Considerando a frequência de seu consumo, é necessário que o pessoal de saúde conheça os riscos das intoxicações e os sinais e sintomas iniciais, pois um prognóstico favorável dependerá de manejo adequado. O objetivo deste relatório é demonstrar os riscos metabólicos renais-hemodinâmicos associados à toxicidade da metformina, além de destacar a necessidade de considerar o uso precoce da terapia de substituição renal e alertar os médicos sobre o que expor os pacientes a um medicamento. a efeitos adversos ou abuso para fins autolesivos.

Acidosis láctica asociada a metformina / Metformin-associated lactic acidosis

Resumen La acidosis láctica es una reacción adversa relacionada con metformina y la principal etiología de acidosis metabólica. Se ha reportado una incidencia anual de acidosis láctica de 4,3 casos por cada 100 000 usuarios de este medicamento, lo cual es una cifra considerable teniendo en cuenta que cerca de 150 millones de pacientes diagnosticados con diabetes mellitus tipo 2 usan el medicamento. Se reporta el caso de una paciente de 81 años con diabetes mellitus tipo 2 manejada con metformina que, sumado a la presencia de múltiples comorbilidades, favoreció al desarrollo de acidosis láctica.

Abstract Lactic acidosis is an adverse reaction related to metformin and is the main etiology of metabolic acidosis. An annual incidence of lactic acidosis of 4.3 cases per 100 000 users of this drug has been reported, which is a considerable amount considering that about 150 million patients diagnosed with type 2 diabetes mellitus use the drug. We report the case of an 81-year-old patient with type 2 diabetes mellitus managed with metformin which, added to the presence of multiple comorbidities, favored the development of lactic acidosis.

Intravascular large B-cell lymphoma presenting with fever and refractory acidosis

Intravascular large B-cell lymphoma (IVLBCL) is a rare form of diffuse large B-cell lymphoma, characterized by malignant B-cells primarily localized to the lumina of small- and medium-sized blood vessels without lymphadenopathy. Two patients initially presented with fever of unknown origin and persistent lactic acidosis without evidence of tissue hypoxia. Neither patient had an identifiable source of infection and both underwent peripheral blood smear demonstrating leukocytosis with a neutrophilic predominance and thrombocytopenia without evidence of hematologic malignancy. One had previously had a bone marrow biopsy which was unremarkable. Both patients' condition deteriorated rapidly, progressing to multiorgan failure requiring pressors and mechanical ventilation, which ultimately resulted in cardiopulmonary arrest. At autopsy, each patient demonstrated malignant lymphocytoid cells, staining positive for CD20, localized to the lumina of small- and medium-sized vessels in multiple organs, including the lungs, liver, spleen, and kidneys, among others, allowing for the diagnosis of IVLBCL. IVLBCL is exceedingly rare, which in combination with significant variability in presentation, can make identification and diagnosis challenging. Diagnosis requires biopsy, therefore a high index of suspicion is needed to obtain an adequate tissue sample, whether pre- or postmortem. In the presented cases, both patients exhibited type B lactic acidosis with an unknown etiology that was ultimately determined at autopsy.

A study to assess the clinicopathological spectrum of acute complications of diabetes mellitus type II

Background: The acute metabolic complications of diabetes consist of diabetic ketoacidosis (DKA), hyperosmolar non-ketotic coma (HNC), lactic acidosis (LA), and hypoglycemia. All of these are associated with significant morbidity and mortality. These can easily be prevented by early recognition and prompt management. Therefore, this study was conducted to assess the clinicopathological spectrum of acute complications of diabetes mellitus type II.Methods: This observational, analytical study was conducted on 100 patients aged more than 18 years admitted in the ICU with acute complication of Diabetes mellitus Type II. Medical history was recorded. Physical examination and investigations were done and recorded.Results: The mean age of the study population was 55.26±13.13 years. Hypoglycemia was more common (63%) than DKA (37%). Fever and sweating had the overall highest incidence (and were more in patients with hypoglycemia) while stupor, nausea and abdominal pain had the lowest incidence (and were more in patients with DKA). On examination, only one patient of DKA was drowsy. Mean temperature, pulse and respiratory rate were higher in the patients having DKA while blood pressure was higher in patients having hypoglycemia.Conclusions: It can be effectively concluded from the present study that DKA and hypoglycaemia have a broad spectrum of clinicopathological features. But the incidences vary widely. This may help in early recognition of the impending complication and thereby enabling prompt management of the same, reducing the associated morbidity and mortality.

Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes / myoclonus epilepsy with ragged-red fibers /Leigh overlap syndrome caused by mitochondrial DNA 8344A>G mutation / 北京大学学报(医学版)

OBJECTIVE@#Mitochondrial deoxyribonucleic acid (mtDNA) 8344 A>G (m.8344A>G) mutation is the common mutation associated with mitochondrial myoclonus epilepsy with ragged-red fibers (MERRF) syndrome. Herein we report a rare case with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes/MERRF/Leigh (MELAS/MERRF/Leigh) overlap syndrome caused by m.8344A>G mutation.@*METHODS@#The clinical and imaging data of the patient were collected and an open muscle biopsy was carried out. We further employed molecular genetic analyses to detect mtDNA mutation in the proband and his mother. And then a clinical and neuroimaging follow-up was performed.@*RESULTS@#This patient was a 25-year-old male, who developed exercise intolerance since the age of 6. At age 10, he suffered from acute episodes of hemianopia, and cranial magnetic resonance imaging (MRI) showed occipital stroke-like lesions and cranial magnetic resonance spectroscopy (MRS) revealed a lactate peak corresponding to the lesion. After that the patient presented slowly progressive psychomotor decline. He had myoclonic seizures and cerebellar ataxia since the age of 12. At age 21, he was admitted to our hospital because of confusion and cranial MRI revealed symmetrical lesions in bilateral posterior putamen, thalami and midbrain. Then repeated MRI showed progression of original lesions and new frontal multiple stroke-like lesions. Symptomatic and rehabilitation treatment relieved his condition. Follow-up cranial MRI at age 24 showed the lesions in basal ganglia and thalami diminished, and the midbrain lesions even completely vanished. Muscle pathology indicated the presence of numerous scattered ragged-red fibers (RRF), suggestive of a mitochondrial disorder. Polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) detected the m.8344A>G mutation of the MT-TK gene encoding mitochondrial transfer RNA for lysine in the patient's blood. Next generation sequencing (NGS) of the whole mitochondrial genome identified that the proportion of m.8344A>G was 90%, and no other mtDNA mutation was detected. Sanger sequencing further identified this mutation both in the proband and his mother's blood, although the mutation load was much lower in his mother's blood with approximately 10% heteroplasmy.@*CONCLUSION@#The present study is the first to describe a patient with m.8344A>G mutation in association with the MELAS/MERRF/Leigh overlap syndrome, which expands the phenotypic spectrum of the m.8344A>G mutation.

Acidosis lactica secundaria a intoxicacion por metformina, reporte de caso clinico / Lactic acidosis secondary to metformin poisoning, clinical case report

La metformina es un medicamento ampliamente utilizado como tratamiento de primera línea en diabetes mellitus tipo 2, su mecanismo de acción incluye impedir la elaboración de glucosa hepática, disminuye el transporte de glucosa a nivel intestinal entre otros. Uno de sus efectos adversos es la acidosis láctica, la mortalidad en estos pacientes aún es elevada a pesar de tratamientos modernos con terapia de sustitución renal. Presentación del caso: Presentamos el caso de una paciente femenina de 16 años que ingresó al servicio de emergencia debido a intoxicación con metformina (30 tabletas de 500mg) secundario a intento autolítico. La paciente se presentó somnolienta, con ruidos hidroaéreos aumentados, y relajación de esfínteres. Los controles gasométricos mostraron cifras de lactato en ascenso, llegando a valores de hasta 19,5 mmol/L. Paciente requirió ventilación mecánica invasiva motivo por el cual, ingresó al servicio de Terapia Intensiva para manejo de fallo multiorgánico, se inició tratamiento sustitutivo renal con ciclos prolongados. Paciente fue dada de alta del servicio de terapia intensiva en su quinto día de hospitalización y continuó su tratamiento multidisciplinar a cargo del servicio de medicina interna. Conclusiones: La metformina al ser un medicamento ampliamente usado a nivel mundial, todo servicio de emergencias debería estar preparado para identificar los casos de intoxicación por este fármaco. Dentro de las intervenciones se incluye: fluidoterapia, drogas vasoactivas, soporte ventilatorio invasivo, bicarbonato de sodio y terapia de reemplazo renal; todas ellas se brindaron a nuestra paciente con resultados exitosos.

Metformin is a medicine used as first-line treatment in type 2 diabetes mellitus, its mechanism of action includes among others: preventing the production of hepatic glucose, decreases the transport of glucose at intestinal level. One of its adverse effects is lactic acidosis, especially when its used in autolytic attempts. Mortality in these patients is still high despite modern treatment with renal replacement therapy. Case presentation: We present the case of a 16-year-old female patient who entered the emergency service due to metformin poisoning (30 tablets of 500mg) secondary to autolytic attempt. The patient was drowsy, with increased hydroaereal noises, and relaxation of sphincters. Gasometric controls showed rising lactate figures, reaching values of up to 19.5 mmol/L. Patient required invasive mechanical ventilation which is why, entered the intensive therapy service for management of multiorgan failure, renal replacement treatment was initiated with prolonged cycles. Patient was discharged from intensive care on her fifth day of hospitalization and continued her treatment in charge of the internal medicine service. Conclusions: Metformin being a widely used medicine worldwide, every emergency service should be prepared to identify cases of this drug. Interventions include: fluid therapy, vasoactive drugs, invasive ventilatory support, sodium bicarbonate, and renal replacement therapy; All of them were provided to our patient with successful results.

Appropriateness of metformin prescription for type 2 diabetes mellitus patients with chronic kidney disease (Stages 3-5)

@#Introduction: Metformin is the first-line pharmacological therapy for type 2 diabetes mellitus (T2DM). Guidelines recommend metformin to be given at reduced dosages for those with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 and omitted in those with eGFR<30 mL/min/1.73m2. Lactic acidosis is a known complication of those on metformin. This study aimed to determine the appropriateness of metformin prescription in T2DM patients with chronic kidney disease (CKD) stages 3-5 in a tertiary centre in Malaysia. Materials and Methods: A cross-sectional design using retrospective secondary data of T2DM patients on metformin attending nephrology and diabetic clinics in the year 2017. eGFR calculated using the CKD-EPI formula identified those in CKD stage 3-5 defined using the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative criteria. Metformin prescription was considered appropriate when the metformin maximum daily dosage does not exceed 1500 mg in CKD stage 3a and 1000 mg in CKD stage 3b and metformin stopped in CKD stages 4 and 5. Results: A total of 143 patients were included. Majority were in the elderly age group (62.9%), male (60.8%) and had concurrent hypertension (85.3%). Median HbA1c was 8.3% (67 mmol/mol) with most patients (88.8%) having HbA1c above 6.5% (48 mmol/ mol). Majority (92.3%) were categorised as stage 3 CKD. Eleven (7.7%) subjects had inappropriate metformin prescription. Seven of nine (78%) subjects in CKD stage 4 were on metformin with a maximum daily dose of 500 mg to1000 mg. Three patients had serum lactate measured. Conclusion: The majority of CKD patients had appropriate metformin prescription. However, a considerable number of CKD stage 4 patients continued to be on metformin. The many benefits of metformin may be a reason why it is still continued against recommendations. Only three patients had lactate measured which, although may suggest that lactic acidosis is not a common occurrence, the potential for metformin-associated lactic acidosis especially in those at risk should be considered.

Intoxicación aguda intencional por metformina en una adolescente: a propósito de un caso clínico / Intentional acute metformin overdose in an adolescent. Case report / Intoxicação intencional aguda com metformina num adolescente. Relato de caso

Resumen: Las intoxicaciones agudas en los servicios de emergencia pediátrica ocupan un lugar importante dentro de la patología de urgencia por su potencial riesgo vital. El Centro de Información y Asesoramiento Toxicológico (CIAT) recibe anualmente un promedio de 10.000 consultas, el 45% corresponde a pacientes menores de 15 años. Del total de consultas (41.465) en el período 2003-2006, el 5,4% correspondieron a circunstancias voluntarias suicidas en el grupo etario de 10-15 años. Los medicamentos fueron los agentes más frecuentemente involucrados. Describimos el caso de una adolescente con una intoxicación aguda grave intencional suicida con metformina. Las manifestaciones clínicas más importantes fueron náuseas, vómitos, dolor abdominal, hipotensión mantenida, bradicardia transitoria, acidosis metabólica, hiperlactacidemia e hipoglicemia sintomática. No se evidenció la presencia de hipoglicemiantes orales, ni fármacos cardiovasculares en el escenario. La ingesta de metformina presenta habitualmente al inicio síntomas poco específicos, desarrollando acidosis láctica hasta 8 horas posingesta. Los síntomas graves en la intoxicación con metformina no son frecuentes. La presencia de síntomas digestivos con acidosis metabólica y lactato elevado debe hacer sospechar una intoxicación por metformina. La hipotensión es un signo ominoso que requiere soporte hemodinámico urgente y mantenido, siendo de mal pronóstico. Otra preocupación después de una sobredosis de metformina es la progresión a la acidosis láctica. Esta situación metabólica determinará el pronóstico, dado que es conocido el efecto deletéreo en la función cardiovascular. La muerte después de la aparición de acidosis láctica puede ser rápida en ausencia de hemodiálisis.

Summary: Acute intoxications have a key role in pediatric emergency services, due to its potential life threat. The Montevideo Poison Control Center annually receives an average of 10,000 consultations per year, 45% from patients under 15 years of age. Of the total number of consultations (41,465) in 2003-2006, 5.4% accounted for voluntary suicidal circumstances in the 10 -15 year-old age group. Medications were the most frequent agents used. We hereby describe the case of a teenager who used Metformin to intend am intentional severe acute poisoning suicide. The main clinical manifestations were nausea, vomiting, abdominal pain, maintained hypotension, transient bradycardia, metabolic acidosis, hyperlactatemia and symptomatic hypoglycemia. There was no evidence of oral hypoglycemic agents or cardiovascular drugs at stake. Metformin intake usually shows symptoms that are not very specific at first, and lactic acidosis usually occurs up to 8 hours after the intake. Metformin poisoning symptoms are rarely severe. The presence of digestive symptoms, metabolic acidosis and elevated lactate should suggest Metformin poisoning. Hypotension is an ominous sign that requires urgent and continuous hemodynamic support and it is often poorly diagnosed. Another concern after Meformin overdose is the progression to lactic acidosis. This metabolic situation will determine the prognosis to be adopted, due to the deleterious effect on cardiovascular function. In absence of hemodialysis, death after the onset of lactic acidosis can be rapid.

Resumo: As intoxicações agudas têm um papel fundamental nos serviços de emergência pediátrica, devido a seu potencial de ameaça à vida. O Centro de Controle de Intoxicações de Montevidéu recebe anualmente uma média de 10.000 consultas por ano, 45% de pacientes com menos de 15 anos de idade. Do total de consultas (41.465) em 2003-2006, 5,4% aconteceram por circunstâncias de suicídio voluntário nas idades de 10 a 15 anos. Os agentes mais frequentemente utilizados foram os medicamentos. Descrevemos aqui o caso de um adolescente que usou Metformina para intentar um suicídio intencional por intoxicação aguda grave. As principais manifestações clínicas foram náuseas, vómitos, dor abdominal, hipotensão mantida, bradicardia transitória, acidose metabólica, hiperlactatemia e hipoglicemia sintomática. Não houve evidência de hipoglicemiantes orais ou drogas cardiovasculares. A ingestão de Metformina geralmente apresenta sintomas que não são específicos no início, e a acidose láctica geralmente ocorre até 8 horas após a ingestão. Os sintomas de envenenamento por Metformina raramente são graves. A presença de sintomas digestivos, acidose metabólica e lactato elevado pode sugerir intoxicação por Metformina. A hipotensão é uma sinal de risco que requer suporte hemodinâmico urgente e contínuo e, muitas vezes, é pouco diagnosticado. Outra preocupação após a overdose de Meformina é a progressão para a acidose láctica. Essa situação metabólica determinará o prognóstico a ser adotado, devido ao efeito deletério sobre a função cardiovascular. No caso de ausência de hemodiálise, a morte após o início da acidose láctica pode ser rápida.

Twenty-one-year follow-up of variable onset MELAS syndrome with heteroplasmic nt3243A>G mtDNA mutation: A case report

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a maternally inherited mitochondrial disorder of which m.3243A>G is the most commonly associated mutation, resulting in an inability to meet the energy requirements of various organs. MELAS poses a diagnostic challenge owing to its multiple organ involvement and great clinical variability due to its heteroplasmic nature. We report three cases from a family who were initially misdiagnosed with myasthenia gravis or undiagnosed. Although there is no optimal consensus treatment approach for patients with MELAS because of the disease's heterogeneity, our 21-year-long therapy regimen of l-arginine, l-carnitine, and coenzyme Q10 supplementation combined with dietary management appeared to provide noticeable protection from the symptoms and complications. Prompt early diagnosis is important, as optimal multidisciplinary management and early intervention may improve outcomes.

A case of middle-aged mitochondrial encephalomyopathy with multiple cerebrovascular stenosis / 中国脑血管病杂志

A case of middle-age-onset mitochondrial encephalomyopathy,lactic acidosis and stroke-like episodes (MELAS) type mitochondrial myopathy was retrospectively analyzed, and clinical features and diagnostic criteria of MELAS with multiple cerebrovascular stenosis in the middle-aged were summarized. The patient was a middle-aged woman who suffered from repeated headaches and limb convulsions and admitted by Xuanwu Hospital Capital Medical University. She had various risk factors of atherosclerosis. Related examination revealed multiple intracranial vascular stenosis. The lesions could be caused by the stenotic vessels. Therefore, the first diagnosis was ' acute cerebral infarction' after admission. But the clinical symptoms were characterized by ' relapse-remission'. The patient also suffered from headaches, seizures, and cognitive decline. There was past history of ' neurological deafness' and hearing loss in both ears. Magnetic resonance imaging (MRI) showed that ischemic lesions were distributed in the cortex. So further examinations were conducted. She was diagnosed as MELAS-type mitochondrial myopathy by head MR, magnetic resonance spectroscopy (MRS) and genetic examination. Neurotrophic factors, mitochondria-protection,anti-epilepsy,and relief therapy were given. The genetics and clinical manifestations of MELAS-type of mitochondrial myopathy are broadly heterogeneous. For middle-age-onset patients who have various atherosclerotic risk factors and stroke-like symptoms, doctors should be cautious about the mitochondrial disease by dynamically observing patient's clinical symptoms and head MRI, and perform pathology and gene mutation examination for comprehensive analysis. Only in this way,can we timely consider the possibility of mitochondrial encephalomyopathy and correctly make diagnosis as early as possible.

Diagnóstico clínico y bioquímico del síndrome de leigh en cinco pacientes colombianos / Clinical and biochemical diagnosis of leigh syndrome in five colombian patients / Diagnóstico clínico e bioquímico da síndrome de leigh em cinco pacientes colombianos

Resumen El síndrome de Leigh (SL) es una enfermedad neurodegenerativa, descrita como una encefalomielopatía necrotizante subaguda, y es una de las enfermedades de origen mitocondrial más frecuentes. El SL es causado por el déficit en la producción de energía, originada en defectos en los genes que codifican alguno de los complejos mitocondriales; el gen afectado puede ser de codificación tanto nuclear como mitocondrial, lo que explica que se encuentren diferentes mecanismos de herencia, incluyendo autosómica recesiva y herencia materna, lo que, a su vez, hace más difícil su diagnóstico molecular. Clínicamente se presenta con regresión del desarrollo cognitivo y pérdida de habilidades motoras con trastorno de movimiento, de rápida progresión. El diagnóstico se basa en la demostración bioquímica de la elevación del ácido láctico y de la relación lactato/piruvato, así como hallazgos en las neuroimágenes por resonancia magnética que muestran lesiones focales, bilaterales y simétricas en ganglios basales o tallo cerebral asociadas a leucoencefalopatía y atrofia cerebral. Se reportan cinco casos con diagnóstico clínico y bioquímico del SL que ejemplifican la variabilidad clínica y gravedad encontrada en este grupo de pacientes.

Summary Leigh syndrome (LS) is a neurodegenerative disease, described as a subacute necrotizing encephalomyelopathy and is one of the most frequent diseases of mitochondrial origin. LS is caused by a deficit in the energy production due to defects in the genes that encode some of the mitochondrial complexes. The affected gene can be due to either nuclear and/or mitochondrial coding, which explains why there are different ways of inheriting the disease, including autosomal recessive and maternal inheritance, which makes its molecular diagnosis even more difficult. Clinically, LS is characterized by regression in cognitive development and motor abilities, as well as movement disorders of rapid progression. Its diagnosis is based on the biochemical demonstration of an increase in lactic acid and lactate / pyruvate ratio, as well as magnetic resonance neuroimaging findings showing focal, bilateral and symmetric lesions in basal ganglia or brainstem associated with leukoencephalopathy and cerebral atrophy. Five cases are reported with clinical and biochemical diagnosis of LS that exemplify the clinical variability and severity found in this group of patients.

Resumo A síndrome de Leigh (SL) é uma doença neurodegenerativa, descrita como uma encefalomielopatia necrotizante subaguda e é uma das doenças de origem mitocondrial mais frequente. A SL é causada pelo déficit na produção de energia originada em defeitos nos genes que codificam algum dos complexos mitocondriais; o gene afetado pode ser de codificação tanto nuclear como mitocondrial, o que explica que se encontrem diferentes mecanismos de herança, incluindo autossômica recessiva e herança materna, o que torna mais difícil seu diagnóstico molecular. Clinicamente se apresenta com regressão do desenvolvimento do desenvolvimento cognitivo e perda de habilidades motoras com transtorno de movimento, de rápida progressão. O diagnóstico se baseia na demonstração bioquímica da elevação do ácido láctico e da relação lactato/piruvato, assim como descobertas nas neuro imagens por ressonância magnética que mostram lesões focais, bilaterais e simétricas em gânglios basais ou talo cerebral associadas a leucoencefalopatia e atrofia cerebral. Reportam-se cinco casos com diagnóstico clínico e bioquímico da SL que exemplificam a variabilidade clínica e gravidade encontrada neste grupo de pacientes.

Importância da transfaunação no tratamento da acidose láctica ruminal aguda induzida em cabras e ovelhas / Value of transfaunation for the treatment of induced ruminal lactic acidosis in goats and sheep

O objetivo deste trabalho foi avaliar a importância da transfaunação no tratamento e recuperação de cabras e ovelhas com acidose lática ruminal aguda (ALRA) induzida experimentalmente. Seis cabras (41,2±5,6kg) e seis ovelhas (46,8±4,57kg), não gestantes e não lactantes, receberam 15g de sacarose por quilo de peso corporal para indução da enfermidade. A ALRA foi induzida duas vezes em cada animal, com intervalo de 30 dias após recuperação total da primeira indução. Os procedimentos terapêuticos consistiram na remoção do conteúdo ruminal líquido por lavagem e sifonamento com auxílio de sondagem esofágica, e na correção da acidose metabólica com soluções eletrolíticas, contendo lactato ou bicarbonato de sódio, infundidas por via intravenosa. A transfaunação fez parte de apenas um dos tratamentos de cada animal e consistiu na administração por sondagem esofágica de 2L de suco ruminal de um bovino sadio. A recuperação completa foi avaliada por exames físicos e exames do suco ruminal realizados até quatro dias após os procedimentos terapêuticos. A eficácia dos protocolos de tratamento, com ou sem transfaunação, foi comparada. O protocolo de indução foi efetivo em induzir a enfermidade e as cabras e ovelhas apresentaram sinais clínicos de intensidade máxima (apatia, atonia ruminal, distensão abdominal, diarreia de consistência pastosa a líquida e desidratação moderada) 16 horas após a administração intrarruminal de sacarose, sem distinção entre as espécies. Neste momento, as características do suco ruminal mostraram-se semelhantes aos quadros típicos de ALRA. A frequência de movimentos ruminais se normalizou no terceiro dia após os procedimentos terapêuticos, sem diferença entre as espécies, e independente de terem recebido a transfaunação ou não. A transferência de suco ruminal também não acelerou a recuperação do apetite, que foi considerado normal somente no quarto dia após os procedimentos terapêuticos, em ambas as espécies. Em relação ao líquido ruminal, quando receberam a transfaunação, os caprinos e ovinos apresentaram recuperação das características de cor, odor e consistência mais rapidamente do que quando não receberam. A atividade fermentativa da microbiota ruminal não sofreu influência da transfaunação e se normalizou dois e três dias após os procedimentos terapêuticos nas ovelhas e cabras, respectivamente. A transfaunação promoveu o retorno mais rápido da população de protozoários ruminais, que já foram observados 24 horas após os procedimentos terapêuticos, em ambas as espécies. Quando os animais não receberam a transfaunação, o retorno dos protozoários só ocorreu no segundo dia após os procedimentos terapêuticos. A recuperação completa dos animais estudados ocorreu em até quatro dias, independente da realização da transfaunação ou não. Conclui-se que a transferência de suco ruminal não pode ser considerada medida crucial para o tratamento e convalescença de caprinos e ovinos acometidos por de ALRA.(AU)

The aim of this study was to evaluate the value of transfaunation in the treatment and recovery of goats and sheep with acute rumen lactic acidosis (ARLA) experimentally induced. Six goats (41.2±5.6kg) and six sheep (46.8±4.57kg), non-pregnant and non-lactating, received 15g of sucrose per kilogram of body weight for the disease induction. The ARLA was induced in each animal twice with an interval of 30 days after full recovery of the first induction. Therapeutic procedures consisted in removal of the rumen fluid content by washing and siphoning with an esophageal tube and correction of metabolic acidosis with intravenous electrolyte solutions containing sodium lactate or sodium bicarbonate. The transfaunation was part of only one of each animal treatment and consisted in administration of two liters of rumen fluid colleted from a healthy cow. Complete recovery was assessed by physical examinations and rumen fluid examinations up to four days after therapeutic procedures. The efficacy of treatment protocols, with or without transfaunation was compared. The protocol used was effective in induce the disease and goats and sheep showed clinical signs of maximum intensity (apathy, rumen stasis, abdominal distension, diarrhea and moderate dehydration) 16 hours after the intraruminal administration of sucrose. At this moment, the characteristics of ruminal fluid were similar to the typical ARLA. The frequency of ruminal movements became normal on the third day after therapeutic procedures, with no difference between species, and regardless transfaunation. The ruminal fluid transfer did not accelerate the recovery of appetite, considered normal only on the fourth day after treatment in both species. When transfauntation was received, goats and sheep showed recovery of characteristics of color, odor and consistency faster than when they did not receive. The fermentative activity of the rumen microbiota was not impacted by transfaunation and normalized two and three days after therapeutic procedures in sheep and goats, respectively. The transfaunation promoted faster return of the protozoa population, which was observed 24 hours after therapeutic procedures in both species. When the animals did not receive transfaunation, the protozoa returns occurred only on the second day after therapeutic procedures. Full recovery of the animals occurred within four days, regardless of transfaunation. In conclusion, the ruminal fluid transfer can not be considered crucial for the treatment and convalescence of goats and sheep affected by ARLA.(AU)

Atypical Radiologic Manifestation of NARP Mimicking MELAS: a Case Report

Neurogenic weakness, ataxia and retinitis pigmentosa (NARP) syndrome is a rare maternally inherited mitochondrial disorder. Radiologic findings in NARP syndrome are varied; they include cerebral and cerebellar atrophy, basal ganglia abnormalities, and on rare occasions, leukoencephalopathy. This article describes an extremely rare case of NARP syndrome mimicking mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS).

Age-Based Characteristics of West Syndrome in Patients with Mitochondrial Disease / 대한소아신경학회지

PURPOSE: West syndrome is a severe form of age-specific epilepsy that typically affects infants younger than 2 years of age with mitochondrial disease. We aimed to examine age-specific characteristics of the syndrome in these patients. METHODS: We retrospectively analyzed 54 patients with West syndrome diagnosed with mitochondrial disease between March 2006 and March 2016. We compared treatment strategies and diagnostic and clinical variables between patients with early-onset ( < 6 months of age) and late-onset (≥6 months of age) seizures. RESULTS: Seizure was the first symptom in 30 (90.9%) and 13 (65%) patients of the early-onset and late-onset groups, respectively (P=0.046). Delayed development was observed in 3 (9.1%) and 7 (35%) patients of the early-onset and late-onset groups, respectively (P=0.023). Lactate levels were normal in 17 patients (55%) of the early-onset group and 5 (25%) of the late-onset group (P=0.036), while initial brain magnetic resonance imaging (MRI) findings were normal in 23 (67.6%) and 8 (40%) patients of the early-onset and late-onset groups, respectively. Final MRI findings were abnormal in 32 patients (94.1%) of the early-onset group and 18 (90%) of the late-onset group (P=0.036). Although ketogenic diets reduced seizure frequency in both groups, the difference was not significant. CONCLUSION: There is no significant difference in epilepsy-related variables when patients are divided based on a cut-off age of 6 months. However, differences in the first symptom at onset and MRI findings were observed. Although lactate levels were not of significant diagnostic value in the early-onset group, they may be in the late-onset group.

Un caso raro de acidosis láctica persistente / A rare case of persistent lactic acidosis

Resumen Comunicamos el caso de una paciente de 72 años de edad con diagnóstico de diabetes mellitus 2 en tratamiento con metformina. Ingresó por dolor abdominal, diarrea, fiebre y somnolencia. Se integraron a su ingreso los diagnósticos de sepsis grave con foco infeccioso gastrointestinal, necrosis tubular aguda con criterios dialíticos de urgencia, además de acidosis láctica grave secundaria a choque séptico y metformina. Recibió tratamiento inicial con soluciones cristaloides, antibióticos intravenosos, bicarbonato intravenoso, infusión de vasopresor, ventilación mecánica y tratamiento hemodialítico. La evolución clínica fue satisfactoria de manera inicial; sin embargo, persistió con hiperlactatemia grave a pesar de tres sesiones de hemodiálisis, presión arterial media por arriba de 65 mmHg con dosis mínima de vasopresor y pruebas de función hepática normales. En el reabordaje diagnóstico la TAC de abdomen documentó múltiples y extensos infartos hepáticos secundarios a trombosis de la arteria hepática, no documentados en la TAC abdominal realizada a su ingreso.

Abstract This paper reports the case of a 72-year-old female patient with type 2 diabetes mellitus treated with metformin. She was admitted for abdominal pain, diarrhea, fever and somnolence. The initial diagnoses were severe sepsis, acute kidney injury with dialysis criteria and severe lactic acidosis secondary to septic shock and metformin. The medical treatment was with crystalloid solutions, intravenous antibiotics, intravenous bicarbonate infusion, vasopressors, mechanical ventilation and hemodialysis. The clinical course was initially satisfactory; however, the patient persisted with severe hyperlactatemia despite 3 hemodialysis sessions, mean arterial pressure above 65 mmHg with minimum dose of vasopressor and normal liver function tests. In the control abdominal CT, multiple and extensive hepatic infarcts were documented secondary to hepatic artery thrombosis, not observed in the abdominal CT performed at hospital admission.

Arginine and Citrulline for the Treatment of MELAS Syndrome

Abstract Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a maternally inherited mitochondrial disease with a broad spectrum of manifestations. In addition to impaired energy production, nitric oxide (NO) deficiency occurs in MELAS syndrome and leads to impaired blood perfusion in microvasculature that can contribute to several complications including stroke-like episodes, myopathy, and lactic acidosis. The supplementation of NO precursors, L-arginine and L-citrulline, increases NO production and hence can potentially have therapeutic utility in MELAS syndrome. L-citrulline raises NO production to a greater extent than L-arginine; therefore, L-citrulline may have a better therapeutic effect. The clinical effect of L-citrulline has not yet been studied and clinical studies on L-arginine, which are limited, only evaluated the stroke-like episodes' aspects of the disease. Controlled studies are still needed to assess the clinical effects of L-arginine and L-citrulline on different aspects of MELAS syndrome.

Mutation analysis of an adult patient with fructose-1,6-bisphosphatase deficiency in a Chinese family / 中华内分泌代谢杂志

The gene mutations of a patient with fructose-1,6-bisphosphatase (FBPase) deficiency and her parents were analyzed and her clinical manifestations, laboratory tests, and genetic characteristics were reviewed. The molecular analysis of FBP1 gene showed a G residue duplication at base 960 in exon 7(c. 960dupG) in this patient while her parents carried the heterozygous c. 960dupG mutation. The prominent clinical feature of this patient was the benign course of the disease with age. However, acute attack could be triggered by stress, long-time fasting, a large amounts of fructose intake, etc. The typical clinical manifestations were severe lactic acidosis, hypoglycemia, and elevated liver enzymes.