RESUMEN
BACKGROUND: Mitochondrial myopathies (MMs) are a group of multi-system diseases caused by abnormalities in mitochondrial DNA (mtDNA) or mutations of nuclear DNA (nDNA). The diagnosis of mitochondrial myopathy (MM) is reliant on the combination of history and physical examination, muscle biopsy, histochemical studies, and next-generation sequencing. Patients with MMs have diverse clinical manifestations. In the contemporary literature, there is a paucity of reports on cardiac structure and function in this rare disease. We report a Chinese man with MM accompanied with both acute right heart failure and left ventricular hypertrophy. CASE PRESENTATION: A 49-year-old man presented with clinical features suggestive of MM, i.e., ophthalmoparesis, weakness of the pharyngeal and extremity muscles, and respiratory muscles which gradually progressed to respiratory insufficiency. He had a family history of mitochondrial myopathy. He had increased levels of serum creatine kinase and lactate. Muscle biopsy of left lateral thigh revealed 8% ragged red fibers (RRF) and 42% COX-negative fibers. Gene sequencing revealed a novel heterozygote TK2 variant (NM_001172644: c.584T>C, p.Leu195Pro) and another heterozygous variant (NM_004614.4:c.156+958G>A; rs1965661603) in the intron of TK2 gene. Based on these findings, we diagnosed the patient as a case of MM. Echocardiography revealed right heart enlargement, pulmonary hypertension, left ventricular hypertrophy, and thickening of the main pulmonary artery and its branches. The patient received non-invasive ventilation and coenzyme Q10 (CoQ10). The cardiac structure and function were restored at 1-month follow-up. CONCLUSIONS: This is the first report of reversible cardiac function impairment and left ventricular hypertrophy in a case of adult-onset MM, nocturnal hypoxia is a potential mechanism for left ventricular hypertrophy in patients with MM.
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Hipertrofia Ventricular Izquierda , Miopatías Mitocondriales , Adulto , Masculino , Humanos , Persona de Mediana Edad , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/genética , Pueblos del Este de Asia , Corazón , Miopatías Mitocondriales/complicaciones , Miopatías Mitocondriales/diagnóstico , Miopatías Mitocondriales/genética , CardiomegaliaRESUMEN
BACKGROUND: Primary muscular disorders (metabolic myopathies, including mitochondrial disorders) are a rare cause of dyspnea. We report a case of dyspnea caused by a mitochondrial disorder with a pattern of clinical findings that can be classified in the known pathologies of mitochondrial deletion syndrome. CASE PRESENTATION: The patient presented to us at 29 years of age, having had tachycardia, dyspnea, and functional impairment since childhood. She had been diagnosed with bronchial asthma and mild left ventricular hypertrophy and treated accordingly, but her symptoms had worsened. After more than 20 years of progressive physical and social limitations was a mitochondrial disease suspected in the exercise testing. We performed cardiopulmonary exercise testing (CPET) with right heart catheterization showed typical signs of mitochondrial myopathy. Genetic testing confirmed the presence of a ~ 13 kb deletion in mitochondrial DNA from the muscle. The patient was treated with dietary supplements for 1 year. In the course of time, the patient gave birth to a healthy child, which is developing normally. CONCLUSION: CPET and lung function data over 5 years demonstrated stable disease. We conclude that CPET and lung function analysis should be used consistently to evaluate the cause of dyspnea and for long-term observation.
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Disnea , Miopatías Mitocondriales , Humanos , Femenino , Niño , Prueba de Esfuerzo , Miopatías Mitocondriales/complicaciones , Miopatías Mitocondriales/diagnóstico , Miopatías Mitocondriales/genética , Mitocondrias , SíndromeRESUMEN
Myopathy, lactic acidosis, and sideroblastic anemia 2 (MLASA2) is an autosomal recessive mitochondrial disorder caused by pathogenic variants in YARS2. YARS2 variants confer heterogeneous phenotypes ranging from the full MLASA syndrome to a clinically unaffected state. Symptom onset is most common in the first decade of life but can occur in adulthood and has been reported following intercurrent illness. Early death can result from respiratory muscle weakness and cardiomyopathy. We report a case of MLASA2 with compound heterozygous YARS2 pathogenic variants; a known pathogenic nonsense variant [NM_001040436.3:c.98C>A (p.Ser33Ter)] and a likely pathogenic missense variant not previously associated with disease [NM_001040436.3:c.948G>T (p.Arg316Ser)]. The proband initially presented with a relatively mild phenotype of myopathy and lactic acidosis. During pregnancy, anemia emerged as an additional feature and in the postpartum period she experienced severe decompensation of cardiorespiratory function. This is the first reported case of pregnancy-related complications in a patient with YARS2-related mitochondrial disease. This case highlights the need for caution and careful counseling when considering pregnancy in mitochondrial disease, due to the risk of disease exacerbation and pregnancy complications.
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Acidosis Láctica , Anemia Sideroblástica , Miopatías Mitocondriales , Enfermedades Musculares , Tirosina-ARNt Ligasa , Acidosis Láctica/diagnóstico , Acidosis Láctica/genética , Adulto , Anemia Sideroblástica/complicaciones , Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/genética , Femenino , Humanos , Miopatías Mitocondriales/complicaciones , Miopatías Mitocondriales/diagnóstico , Miopatías Mitocondriales/genética , Enfermedades Musculares/genética , Embarazo , Tirosina-ARNt Ligasa/genéticaRESUMEN
BACKGROUND: Mitochondrial myopathy caused by the long-term use of nucleos(t)ide analogue in patients with chronic hepatitis B (CHB) is mostly characterized by myasthenia and myalgia. Cases with respiratory failure as the prominent manifestation and multisystem symptoms have not been reported. CASE REPORT: We report a case of mitochondrial myopathy associated with the long-term use of entecavir for CHB. The patient was a 54-year-old male who was treated with entecavir for 9 years. During the treatment, hepatitis B virus (HBV) DNA was negative and liver function was normal. However, generalized fatigue, poor appetite, dysosmia and other discomforts gradually presented starting at the 5th year of treatment, and respiratory failure was the prominent manifestation in the later stage of disease progression. The diagnosis was based on histopathology examination. The dysosmia, hypoxemia and digestive tract symptoms were gradually improved after withdrawal of entecavir. DISCUSSION: Mitochondrial myopathy is a rare side effect of entecavir and can be diagnosed by muscle biopsy. Although the incidence is extremely low, but the severe cases can lead to respiratory failure. We should receive adequate attention in clinical practice.
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Hepatitis B Crónica , Miopatías Mitocondriales , Insuficiencia Respiratoria , Antivirales/efectos adversos , Guanina/análogos & derivados , Virus de la Hepatitis B/genética , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Miopatías Mitocondriales/inducido químicamente , Miopatías Mitocondriales/complicaciones , Miopatías Mitocondriales/tratamiento farmacológico , Insuficiencia Respiratoria/tratamiento farmacológico , Resultado del TratamientoRESUMEN
BACKGROUND: MtDNA 3243 A > G mutation leads to mitochondrial myopathies with predominant hyperlactatemia. Given the ubiquitous nature of mitochondria, cellular dysfunction can also appear in tissues with high metabolic turnover; thus, there can be cardiac, digestive, ophthalmologic, and kidney complications. MtDNA 3243 A > G mutation has been shown to be with renal involvement in the previous cases of which are FSGS and tubularinterstitial nephritis. CASE PRESENTATION: We report a case of patient who had the mitochondrial myopathy with mitochondrial DNA (mtDNA) 3243 A > G mutation diagnosed membranous nephropathy by kidney biopsy, which was never reported before. Our patient was found to have chest tightness and shortness of breath with hyperlactatemia and was diagnosed mitochondrial myopathy with mtDNA 3243 A > G mutation 11 months ago. Acute kidney injury occurred with hyperuricemia (urid acid 1011umol/L) which may be associated with mtDNA mutation. Since then, persistent proteinuria was also found and the 24-h urine protein quantitative was around 2 g. Kidney biopsy was performed and the result was consistent with membranous nephropathy, with abnormal mitochondria seen in renal tubules by electron microscopy. CONCLUSIONS: Patients with mitochondrial myopathy could also have renal presentation of membranous nephropathy. Patients with mtDNA mutation may have various renal manifestations so that more attention should be paid on their kidneys.
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Glomerulonefritis Membranosa , Hiperlactatemia , Miopatías Mitocondriales , ADN Mitocondrial/genética , Femenino , Glomerulonefritis Membranosa/complicaciones , Glomerulonefritis Membranosa/diagnóstico , Glomerulonefritis Membranosa/genética , Humanos , Hiperlactatemia/complicaciones , Hiperlactatemia/patología , Riñón/patología , Masculino , Miopatías Mitocondriales/complicaciones , Miopatías Mitocondriales/diagnóstico , Miopatías Mitocondriales/genéticaRESUMEN
Peripheral neuropathy is a known irreversible long-term complication of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) and mitochondrial trifunctional protein deficiency (MTPD), two inherited disorders of mitochondrial long-chain fatty acid oxidation. The underlying pathophysiology of neuropathy is still not fully understood. We report electrophysiological studies and neurological findings in a series of 8 LCHAD-deficient and 11 MTP-deficient patients. The median age at time of the study was 8.0 years (0.5-25 years). The overall prevalence of neuropathy was 58% with neuropathic symptoms being slightly more common in MTPD compared to LCHADD (70% vs 50%, respectively). Onset of neuropathy was significantly earlier in MTPD patients compared to LCHADD patients (median age at onset 4.7 vs 15.3 years, respectively, P = .047). In four patients, isolated peripheral neuropathy was the first and only presenting symptom, and in all four the diagnosis was missed by newborn screening. About half of the patients (45.5%) had a sensorimotor neuropathy, while 27.3% showed a pure motor form and another 27.3% an isolated sensory form. Despite early diagnosis by newborn screening and early initiation of therapy, peripheral neuropathy cannot be prevented in all patients with LCHADD/MTPD and has severe impact on the life of affected patients. Electrophysiology classifies LCHADD/MTPD neuropathy as axonal with secondary demyelination. A novel observation is that in patients with acute, fulminant onset of neuropathy, symptoms can be partly reversible. Further studies are needed to elucidate the underlying pathophysiology of axonal damage and possible therapeutic targets.
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Cardiomiopatías/complicaciones , Errores Innatos del Metabolismo Lipídico/complicaciones , Miopatías Mitocondriales/complicaciones , Proteína Trifuncional Mitocondrial/deficiencia , Enfermedades del Sistema Nervioso/complicaciones , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Enfermedades del Sistema Nervioso Periférico/etiología , Rabdomiólisis/complicaciones , Adolescente , Adulto , Factores de Edad , Cardiomiopatías/diagnóstico , Cardiomiopatías/patología , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/patología , Masculino , Miopatías Mitocondriales/diagnóstico , Miopatías Mitocondriales/patología , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/patología , Enfermedades del Sistema Nervioso Periférico/patología , Fenotipo , Rabdomiólisis/diagnóstico , Rabdomiólisis/patología , Adulto JovenRESUMEN
Frailty is a syndrome characterized by decreased reserves across multiple physiologic systems resulting in functional limitations and vulnerability to new stressors. Physical frailty develops over years in community-dwelling older adults but presents or worsens within days in the intensive care unit (ICU) because common mechanisms governing age-related physical frailty are often exacerbated by critical illness. The hallmark of physical frailty is a combined loss of muscle mass, force, and endurance. About one-third of ICU patients have frailty before hospitalization, which increases their risk for both short- and long-term disability and mortality. While there are several valid ways to measure clinical frailty in patients before or after an ICU admission, the mechanistic underpinnings of frailty in critically ill patients and ICU survivors have not been thoroughly investigated. Furthermore, therapeutic interventions to treat frailty during and after time in the ICU are lacking. In this narrative review, we examine studies that identify potential biological mechanisms underlying the development and propagation of physical frailty in both aging and critical illness (eg, inflammation, mitochondrial myopathy, and neuroendocrinopathy). We discuss specific aspects of these frailty mechanisms in older adults, critically ill patients, and ICU survivors that may represent therapeutic targets. Consistent with complexity underlying frailty, this syndrome is unlikely to result from an excess of a single harmful mediator or deficit of a single protective mediator. Rather, frailty occurs in the presence of an incompletely understood state of multisystem dysregulation. We further describe knowledge gaps that warrant clinical and translational research in frailty and critical care with an overall goal of developing effective frailty treatments in critically ill patients and ICU survivors.
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Enfermedad Crítica/terapia , Fragilidad/complicaciones , Fragilidad/terapia , Inflamación/terapia , Miopatías Mitocondriales/terapia , Sistemas Neurosecretores/fisiopatología , Anciano , Anciano Frágil , Hospitalización , Humanos , Inflamación/complicaciones , Unidades de Cuidados Intensivos , Miopatías Mitocondriales/complicaciones , Sistemas Neurosecretores/patología , Admisión del Paciente , Fenotipo , Calidad de Vida , Resultado del TratamientoRESUMEN
INTRODUCTION: Mitochondrial trifunctional protein deficiency (MTPD) is a long-chain fatty acid oxidation disorder characterized by co-existence of rhabdomyolysis episodes and peripheral neuropathy. Two phenotypes are described: generalized mitochondrial trifunctional protein deficiency (gMTPD) and isolated long-chain-3-hydroxyacyl-CoA dehydrogenase deficiency (iLCHADD) that is always associated with the c.1528G>C mutation. Peripheral neuropathy of MTPD is commonly described in children as axonal, length-dependent and sensorimotor. OBJECTIVES: To report clinical and electrophysiological features of four independent adult MTPD patients with peripheral neuropathy. RESULTS: Onset of the disease was characterized in all patients by rhabdomyolysis episodes occurring during childhood preceded by severe hypoglycemic episodes in three patients. Peripheral nerve involvement manifesting as sensory ataxia appeared later, during adolescence or adulthood. In all cases, electroneuromyogram showed no length-dependent sensory potentials decrease characteristic of sensory neuronopathy ("ganglionopathy"). All patients harbored at least one c.1528G>C mutation. DISCUSSION: We describe MTPD as a newly hereditary etiology of sensory neuronopathy in adults, specifically in patients with c.1528G>C mutation. MTPD should be screened for by performing plasma acylcarnitines in patients with chronic sensory neuronopathy and additional suggestive features such as exercise intolerance or retinopathy.
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Cardiomiopatías/complicaciones , Cardiomiopatías/diagnóstico , Errores Innatos del Metabolismo Lipídico/complicaciones , Errores Innatos del Metabolismo Lipídico/diagnóstico , Miopatías Mitocondriales/complicaciones , Miopatías Mitocondriales/diagnóstico , Proteína Trifuncional Mitocondrial/deficiencia , Enfermedades del Sistema Nervioso/complicaciones , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Enfermedades del Sistema Nervioso Periférico/etiología , Rabdomiólisis/complicaciones , Rabdomiólisis/diagnóstico , Adulto , Factores de Edad , Cardiomiopatías/patología , Femenino , Humanos , Errores Innatos del Metabolismo Lipídico/patología , Masculino , Persona de Mediana Edad , Miopatías Mitocondriales/patología , Enfermedades del Sistema Nervioso/patología , Enfermedades del Sistema Nervioso Periférico/patología , Fenotipo , Rabdomiólisis/patología , Adulto JovenRESUMEN
Oral nucleoside analogs (NAs) reduce hepatitis B virus (HBV) replication by inhibiting HBV DNA polymerase. However, NAs can also affect human mitochondrial DNA (mtDNA) polymerase, which can lead to mtDNA depletion (quantitative abnormality). Indeed, several mitochondrial myopathy cases have been reported in which a reduced mtDNA copy number was induced by oral NAs for hepatitis B. Herein, we report a case of toxic myopathy with multiple mtDNA deletions (qualitative abnormality) associated with long-term use of NAs for hepatitis B. A 68-year-old woman, who underwent long-term treatment with lamivudine and adefovir for chronic hepatitis B, developed proximal muscle weakness in the four extremities. Neurological examination showed mild proximal muscle weakness and atrophy in the four extremities. Upon admission to our hospital, her blood lactate/pyruvate ratio during an aerobic exercise test was elevated. Myogenic patterns were observed in lower limb muscles on electromyographic examination. Muscle magnetic resonance imaging revealed diffuse atrophy of proximal muscles in the four extremities with no signal changes. A biopsy from the biceps brachii muscle showed an abnormally large variation in fiber size, scattered muscle fibers with decreased cytochrome c oxidase activity, and ragged-red fibers. Analysis of mtDNA from skeletal muscle revealed no decrease in copy number but increased incidence of multiple deletions, including a deletion of 4977 base pairs (known as the common deletion) reflecting oxidative stress-induced mtDNA damage. This case study indicates that long-term oral antiviral therapy for hepatitis B can induce chronic oxidative damage to mtDNA resulting in qualitative mtDNA abnormalities and toxic myopathy.
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Antivirales/efectos adversos , Hepatitis B Crónica/tratamiento farmacológico , Miopatías Mitocondriales/inducido químicamente , Miopatías Mitocondriales/patología , Adenina/efectos adversos , Adenina/análogos & derivados , Administración Oral , Anciano , ADN Mitocondrial , Femenino , Eliminación de Gen , Hepatitis B Crónica/complicaciones , Humanos , Lamivudine/efectos adversos , Miopatías Mitocondriales/complicaciones , Miopatías Mitocondriales/genética , Músculo Esquelético/patología , Organofosfonatos/efectos adversosRESUMEN
BACKGROUND: Mitochondrial myopathies (MMs) are mainly presented with chronic muscle weakness and accompanied with other syndromes. MM with acute respiratory insufficiency is rare. AIMS: To reveal the clinical, pathological and molecular characteristics of a life-threatening MM. METHODS: Muscle biopsy and enzyme staining were performed in skeletal muscles. Mitochondrial DNA (mtDNA) sequencing was analyzed and heteroplasmy were quantified by pyrosequencing. RESULTS: All three patients had tachycardia, acute lactic acidosis, dyspnea and sudden severe muscle weakness. Two patients had calf edema and abdominal pain, and one had a heart attack. Electromyography in two patients showed dramatically decreased axonal amplitudes of motor nerves. Muscle biopsies showed ragged red fibers and dramatic mitochondrial abnormality. A mtDNA m.3243A>G mutation was identified in Patient 1 (mutation load: 29% in blood and 73% in muscle) and Patient 3 (79% in blood and 89% in muscle). A mtDNA m.8344A>G mutation was found in Patient 2 (mutation load 80.4% in blood). CONCLUSION: MM characterized by lactic acidosis, respiratory failure and acute motor axonal neuropathy is life threatening.
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Miopatías Mitocondriales/complicaciones , Polineuropatías/complicaciones , Insuficiencia Respiratoria/complicaciones , Adolescente , Adulto , Análisis Mutacional de ADN , ADN Mitocondrial/genética , Electromiografía , Femenino , Humanos , Masculino , Miopatías Mitocondriales/genética , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Mutación/genética , Polineuropatías/genética , Insuficiencia Respiratoria/genética , Adulto JovenRESUMEN
BACKGROUND: Mitochondrial myopathies represent a group of disorders caused by mitochondrial defects that disrupt energy production. Most patients have issues from infancy to early childhood. Pregnancy in women with mitochondrial myopathy is uncommon and the management for these parturients is full of challenges. CASE PRESENTATION: A 36-year-old woman with mitochondrial myopathy was scheduled for caesarean section under a combined spinal-epidural anaesthesia and multi-model analgesia. The parturient was safe and the delivery was performed safely and smoothly, but there were some complications after surgery due to the complex condition of the patient. After consultation with and treatment from multiple disciplines, both the parturient and neonate were well and discharged. CONCLUSION: It is important that patients with mitochondrial diseases are comprehensively assessed and monitored perioperatively.
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Anestesia Epidural , Anestesia Obstétrica , Anestesia Raquidea , Cesárea , Miopatías Mitocondriales/complicaciones , Adulto , Femenino , Humanos , EmbarazoRESUMEN
BACKGROUND: Pure exercise intolerance associated with exclusive affection of skeletal muscle is a very rare phenotype of patients with mitochondrial myopathy. Moreover, the exercise intolerance in these rare patients is yet not well explored, as most of known cases have not been assessed by objective testing, but only by interview. We report a patient with a mitochondrial DNA (mtDNA) mutation that gives rise to an exclusive myopathy associated with exercise intolerance and ophthalmoplegia. We quantified the patient's exercise intolerance through detailed exercise testing. CASE PRESENTATION: A 39-year-old man presented with exercise intolerance and chronic progressive external ophthalmoplegia. Sequencing of the entire mtDNA identified a m.12,294G > A mutation in the MT-TL2 gene. The mutation was heteroplasmic in skeletal muscle (75%) while undetectable in blood, urinary sediment, and buccal mucosa as well as in tissues from the patient's mother. The mutation affected a highly conserved site in the anticodon stem of the mitochondrial transfer RNA Leucine (CUN) molecule and lead to a severe combined respiratory chain defect. Exercise physiological studies in the patient demonstrated a significantly reduced maximal oxygen uptake of 20.4 ml O2 × min-1 × kg-1 (about half of normal) as well as threefold elevated lactate/pyruvate ratios. CONCLUSION: The findings of our study support that the m.12,294G > A mutation is pathogenic. Likely, the mutation arose sporadically in early embryogenesis after differentiation of the mesoderm into muscle progenitor cells, leading to a pure myopathic phenotype.
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ADN Mitocondrial/genética , Tolerancia al Ejercicio/genética , Miopatías Mitocondriales/genética , Oftalmoplejía/genética , Adulto , Transporte de Electrón , Prueba de Esfuerzo , Humanos , Masculino , Miopatías Mitocondriales/complicaciones , Miopatías Mitocondriales/patología , Mutación , Músculo Cuádriceps/enzimología , Músculo Cuádriceps/patologíaRESUMEN
PURPOSE: To assess long-term effects of genotype on chorioretinopathy severity in patients with mitochondrial trifunctional protein (MTP) disorders. DESIGN: Retrospective case series. PARTICIPANTS: Consecutive patients with MTP disorders evaluated at a single center from 1994 through 2015, including 18 patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) and 3 patients with trifunctional protein deficiency (TFPD). METHODS: Local records from all visits were reviewed. Every participant underwent a complete ophthalmic examination and was evaluated by a metabolic physician and dietitian. Nine patients underwent ancillary funduscopic imaging including optical coherence tomography (OCT) and OCT angiography. MAIN OUTCOME MEASURES: The primary outcome measure was best-corrected visual acuity at the final visit. Secondary outcome measures included spherical equivalent refraction, visual fields, electroretinography B-wave amplitudes, and qualitative imaging findings. RESULTS: Participants were followed up for a median of 5.6 years (range 0.3-20.2 years). The median age of LCHADD participants at initial and final visits was 2.3 and 11.9 years, whereas that for TFPD participants at initial and final visits was 4.7 and 15.5 years, respectively. Four long-term survivors older than 16 years were included (3 with LCHADD and 1 with TFPD). The LCHADD participants demonstrated a steady decline in visual acuity from an average of 0.23 logarithm of the minimum angle of resolution (logMAR; Snellen equivalent, 20/34) at baseline to 0.42 logMAR (Snellen equivalent, 20/53) at the final visit, whereas TFPD patients maintained excellent acuity throughout follow-up. Participants with LCHADD, but not TFPD, showed an increasing myopia with a mean decrease in spherical equivalent refraction of 0.24 diopters per year. Visual fields showed sensitivity losses centrally associated with defects on OCT. Multimodal imaging demonstrated progressive atrophy of the outer retina in LCHADD, often preceded by the formation of outer retinal tubulations and choriocapillaris dropout. Electroretinography findings support the more severe clinical profile of LCHADD patients compared with TFPD patients; the function of both rods and cones are attenuated diffusely in LCHADD patients, but are within normal limits for TFPD patients. CONCLUSIONS: Despite improved survival with early diagnosis, medical management, and dietary treatment, participants with the LCHADD subtype of MTP disorder continue to demonstrate visually disabling chorioretinopathy. Multimodal imaging is most consistent with choriocapillaris loss exceeding photoreceptor loss.
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Cardiomiopatías/complicaciones , Enfermedades de la Coroides/etiología , Predicción , Errores Innatos del Metabolismo Lipídico/complicaciones , Miopatías Mitocondriales/complicaciones , Proteína Trifuncional Mitocondrial/deficiencia , Proteína Trifuncional Mitocondrial/genética , Enfermedades del Sistema Nervioso/complicaciones , Rabdomiólisis/complicaciones , Agudeza Visual , Adolescente , Adulto , Cardiomiopatías/diagnóstico , Cardiomiopatías/genética , Niño , Preescolar , Enfermedades de la Coroides/diagnóstico , Enfermedades de la Coroides/genética , Electrorretinografía , Femenino , Angiografía con Fluoresceína , Estudios de Seguimiento , Fondo de Ojo , Genotipo , Humanos , Lactante , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/genética , Masculino , Miopatías Mitocondriales/diagnóstico , Miopatías Mitocondriales/genética , Proteína Trifuncional Mitocondrial/metabolismo , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/genética , Pronóstico , Estudios Retrospectivos , Rabdomiólisis/diagnóstico , Rabdomiólisis/genética , Tomografía de Coherencia Óptica , Campos Visuales , Adulto JovenRESUMEN
INTRODUCTION: Neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) is caused by m.8993T>G/C mutations in the mitochondrial adenosine triphosphate synthase subunit 6 gene (MT-ATP6). Traditionally, heteroplasmy levels between 70% and 90% lead to NARP, and >90% result in Leigh syndrome. METHODS: In this study we report a 30-year-old man with NARP and m.8993T>G in MT-ATP6. RESULTS: Although the patient carried the mutation in homoplasmic state in blood with similarly high levels in urine (94%) and buccal swab (92%), he presented with NARP and not the expected, more severe Leigh phenotype. The mutation could not be detected in any of the 3 analyzed tissues of the mother, indicating a large genetic shift between mother and offspring. Nerve biopsy revealed peculiar endoneurial Schwann cell nuclear accumulations, clusters of concentrically arranged Schwann cells devoid of myelinated axons, and degenerated mitochondria. CONCLUSIONS: We emphasize the phenotypic variability of the m.8993T>G MT-ATP6 mutation and the need for caution in predictive counseling in such patients. Muscle Nerve 54: 328-333, 2016.
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Ataxia/genética , Miopatías Mitocondriales/genética , ATPasas de Translocación de Protón Mitocondriales/genética , Debilidad Muscular/genética , Retinitis Pigmentosa/genética , Adulto , Ataxia/complicaciones , Humanos , Imagen por Resonancia Magnética , Masculino , Mitocondrias/patología , Mitocondrias/ultraestructura , Miopatías Mitocondriales/complicaciones , Miopatías Mitocondriales/diagnóstico por imagen , Debilidad Muscular/complicaciones , Mutación/genética , Retinitis Pigmentosa/complicaciones , Retinitis Pigmentosa/diagnóstico por imagen , Nervio Sural/patología , Nervio Sural/ultraestructuraRESUMEN
AIM: There have been few studies on long-term electroretinographic findings in patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD). This study correlated long-term electroretinographic findings with age, metabolic control and clinical symptoms. METHODS: We examined 12 Swedish patients with LCHADD. Visual acuity testing, fundus examinations, optical coherence tomography and electroretinography were performed. The results were correlated to age, the levels of 3-hydroxyacylcarnitine and acylcarnitine and clinical metabolic control. RESULTS: Blindness or moderate visual impairment was found in two patients. Retinal pigmentation, atrophy and fibrosis were present in 11, seven and one of the patients, respectively, and optical coherence tomography showed retinal thinning in three of the six patients examined. Electroretinography was performed on 11 of the 12 patients. It was pathological, with reduced rod and cone responses, in five patients, subnormal in four and was related to poor clinical metabolic control and severe neonatal symptoms. Repeated electroretinographies revealed reduced function with increasing age. CONCLUSION: More than 80% of the LCHADD patients developed pathological or subnormal retinal function. This was more pronounced in patients with neonatal symptoms, but ameliorated by strict dietary treatment. Annual ophthalmological follow-ups, with electroretinography every second or third year, are recommended.
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Cardiomiopatías/complicaciones , Electrorretinografía , Errores Innatos del Metabolismo Lipídico/complicaciones , Miopatías Mitocondriales/complicaciones , Proteína Trifuncional Mitocondrial/deficiencia , Enfermedades del Sistema Nervioso/complicaciones , Enfermedades de la Retina/etiología , Rabdomiólisis/complicaciones , Adolescente , Adulto , Cardiomiopatías/dietoterapia , Cardiomiopatías/fisiopatología , Niño , Preescolar , Estudios de Cohortes , Humanos , Errores Innatos del Metabolismo Lipídico/dietoterapia , Errores Innatos del Metabolismo Lipídico/fisiopatología , Masculino , Miopatías Mitocondriales/dietoterapia , Miopatías Mitocondriales/fisiopatología , Enfermedades del Sistema Nervioso/dietoterapia , Enfermedades del Sistema Nervioso/fisiopatología , Enfermedades de la Retina/diagnóstico , Rabdomiólisis/dietoterapia , Rabdomiólisis/fisiopatología , Adulto JovenRESUMEN
Defects in peroxisomes such as those associated with Zellweger syndrome (ZS) can influence diverse intracellular metabolic pathways, including mitochondrial functioning. We report on an 8-month-old female infant and a 6-month-old female infant with typical clinical, radiological and laboratory features of Zellweger syndrome; light microscopic and ultrastructural evidence of mitochondrial pathology in their muscle biopsies; and homozygous pathogenic mutations of the PEX16 gene (c.460 + 5G > A) and the PEX 12 gene (c.888_889 del p.Leu297Thrfs*12), respectively. Additionally, mitochondrial respiratory chain enzymology analysis in the first girl showed a mildly low activity in complexes II-III and IV. We also review five children previously reported in the literature with a presumptive diagnosis of ZS and additional mitochondrial findings in their muscle biopsies. In conclusion, this is the first study of patients with a molecularly confirmed peroxisomal disorder with features of a concomitant mitochondrial myopathy and underscores the role of secondary mitochondrial dysfunction in Zellweger syndrome, potentially contributing to the clinical phenotype.
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Mitocondrias/patología , Miopatías Mitocondriales/diagnóstico , Síndrome de Zellweger/diagnóstico , Femenino , Homocigoto , Humanos , Lactante , Imagen por Resonancia Magnética , Miopatías Mitocondriales/complicaciones , Miopatías Mitocondriales/genética , Mutación , Síndrome de Zellweger/complicaciones , Síndrome de Zellweger/genéticaRESUMEN
Acute fatty liver of pregnancy (AFLP) is a devastating disorder of the maternal liver in the third trimester. Recent studies have demonstrated an association between AFLP and fetal fatty acid oxidation disorders. Here, we report a case of AFLP caused by fetal mitochondrial trifunctional protein (TFP) deficiency. A 21-year-old parous woman presented with nausea, genital bleeding and abdominal pain at 33 weeks of gestation. Laboratory data revealed hepatic failure and disseminated intravascular coagulopathy. The patient underwent emergency cesarean section and was diagnosed with AFLP from the clinical characteristics. She was successfully treated with frequent plasma exchange. The newborn presented severe heart failure and died on the 39th day after birth. Tandem mass spectrometry indicated long-chain fatty acid oxidation disorder. Gene analysis demonstrated homozygous mutation in exon 13 of HADHB, the gene responsible for mitochondrial TFP deficiency. The parents carried a heterozygous mutation at the same location in HADHB.
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Cardiomiopatías/complicaciones , Hígado Graso/etiología , Insuficiencia Cardíaca/complicaciones , Errores Innatos del Metabolismo Lipídico/complicaciones , Miopatías Mitocondriales/complicaciones , Proteína Trifuncional Mitocondrial/deficiencia , Enfermedades del Sistema Nervioso/complicaciones , Complicaciones del Embarazo/etiología , Rabdomiólisis/complicaciones , Cardiomiopatías/genética , Resultado Fatal , Hígado Graso/terapia , Femenino , Insuficiencia Cardíaca/genética , Humanos , Recién Nacido , Errores Innatos del Metabolismo Lipídico/genética , Miopatías Mitocondriales/genética , Proteína Trifuncional Mitocondrial/genética , Subunidad beta de la Proteína Trifuncional Mitocondrial/genética , Mutación , Enfermedades del Sistema Nervioso/genética , Intercambio Plasmático , Embarazo , Complicaciones del Embarazo/terapia , Rabdomiólisis/genética , Adulto JovenRESUMEN
Mitochondrial myopathies are inborn metabolism defect diseases manifested by symptoms reflecting failure of the final step in the mitochondrial respiratory chain. Clinical expression of these conditions can vary widely, but typically includes organ systems with a high energy demand, such as striated muscle, myocardium, and nervous and liver tissues. In contrast, cutaneous manifestations are rare and are non-specific, most commonly presenting as pigmentation disorders. In this case report, we present a case of Alpers syndrome accompanied by hyperpigmentation and atrophy in skin folds.
Asunto(s)
Hiperpigmentación/etiología , Miopatías Mitocondriales/complicaciones , Piel/patología , Atrofia/diagnóstico , Atrofia/etiología , Diagnóstico Diferencial , Humanos , Hiperpigmentación/diagnóstico , Lactante , Masculino , Miopatías Mitocondriales/diagnóstico , Músculo Esquelético/patologíaRESUMEN
INTRODUCTION: A 61-year-old woman with a 5-year history of progressive muscle weakness and atrophy had a muscle biopsy characterized by a combination of dystrophic features (necrotic fibers and endomysial fibrosis) and mitochondrial alterations [ragged-red, cytochrome c oxidase (COX)-negative fibers]. METHODS: Sequencing of the whole mtDNA, assessment of the mutation load in muscle and accessible nonmuscle tissues, and single fiber polymerase chain reaction. RESULTS: Muscle mitochondrial DNA (mtDNA) sequencing revealed a novel heteroplasmic mutation (m.4403G>A) in the gene (MTTM) that encodes tRNA(Met). The mutation was not present in accessible nonmuscle tissues from the patient or 2 asymptomatic sisters. CONCLUSIONS: The clinical features and muscle morphology in this patient are very similar to those described in a previous patient with a different mutation, also in MTTM, which suggests that mutations in this gene confer a distinctive "dystrophic" quality. This may be a diagnostic clue in patients with isolated mitochondrial myopathy.