Impact of newborn screening for fatty acid oxidation disorders on neurological outcome: A Belgian retrospective and multicentric study.

Fatty acid oxidation (FAO) disorders are autosomal recessive genetic disorders affecting either the transport or the oxidation of fatty acids. Acute symptoms arise during prolonged fasting, intercurrent infections, or intense physical activity. Metabolic crises are characterized by alteration of consciousness, hypoglycemic coma, hepatomegaly, cardiomegaly, arrhythmias, rhabdomyolysis, and can lead to death. In this retrospective and multicentric study, the data of 54 patients with FAO disorders were collected. Overall, 35 patients (64.8%) were diagnosed after newborn screening (NBS), 17 patients on clinical presentation (31.5%), and two patients after family screening (3.7%). Deficiencies identified included medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (75.9%), very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (11.1%), long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency (3.7%), mitochondrial trifunctional protein (MTP) deficiency (1.8%), and carnitine palmitoyltransferase 2 (CPT 2) deficiency (7.4%). The NBS results of 25 patients were reviewed and the neurological outcome of this population was compared with that of the patients who were diagnosed on clinical presentation. This article sought to provide a comprehensive overview of how NBS implementation in Southern Belgium has dramatically improved the neurological outcome of patients with FAO disorders by preventing metabolic crises and death. Further investigations are needed to better understand the physiopathology of long-term complications in order to improve the quality of life of patients and to ensure optimal management.

Tracer-based lipidomics enables the discovery of disease-specific candidate biomarkers in mitochondrial ß-oxidation disorders.

Carnitine derivatives of disease-specific acyl-CoAs are the diagnostic hallmark for long-chain fatty acid ß-oxidation disorders (lcFAOD), including carnitine shuttle deficiencies, very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD), long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) and mitochondrial trifunctional protein deficiency (MPTD). The exact consequence of accumulating lcFAO-intermediates and their influence on cellular lipid homeostasis is, however, still unknown. To investigate the fate and cellular effects of the accumulating lcFAO-intermediates and to explore the presence of disease-specific markers, we used tracer-based lipidomics with deuterium-labeled oleic acid (D9-C18:1) in lcFAOD patient-derived fibroblasts. In line with previous studies, we observed a trend towards neutral lipid accumulation in lcFAOD. In addition, we detected a direct connection between the chain length and patterns of (un)saturation of accumulating acylcarnitines and the various enzyme deficiencies. Our results also identified two disease-specific candidate biomarkers. Lysophosphatidylcholine(14:1) (LPC(14:1)) was specifically increased in severe VLCADD compared to mild VLCADD and control samples. This was confirmed in plasma samples showing an inverse correlation with enzyme activity, which was better than the classic diagnostic marker C14:1-carnitine. The second candidate biomarker was an unknown lipid class, which we identified as S-(3-hydroxyacyl)cysteamines. We hypothesized that these were degradation products of the CoA moiety of accumulating 3-hydroxyacyl-CoAs. S-(3-hydroxyacyl)cysteamines were significantly increased in LCHADD compared to controls and other lcFAOD, including MTPD. Our findings suggest extensive alternative lipid metabolism in lcFAOD and confirm that lcFAOD accumulate neutral lipid species. In addition, we present two disease-specific candidate biomarkers for VLCADD and LCHADD, that may have significant relevance for disease diagnosis, prognosis, and monitoring.

Neuropathy, ataxia, retinitis pigmentosa: a case of a mother and two siblings.

AIM: We describe the ophthalmic manifestations of Neuropathy, ataxia, retinitis pigmentosa (NARP) syndrome in three related patients. METHODS: We examined a mother and her two children, who were carriers of the mt 8993T>G mutation. The mother, patient I, is the first known carrier within the family pedigree. Patients II and III are her children from a non-carrier father. NARP syndrome and the heteroplasmy levels were established prior to the first referral of the patients to the Ophthalmology department.We performed a visual acuity testing, followed by a biomicroscopic and fundus examination, as well as additional multimodal imaging testing: optical coherence tomography (OCT) and fundus autofluorescence (FAF), and functional testing: electroretinogram and visual field. RESULTS: All patients had the clinical manifestations of NARP syndrome, which were variably expressed symptomatically, on the fundus exams, electroretinogram, and visual fields. CONCLUSIONS: Once genetically established, NARP syndrome, as other mitochondrial disorders, has a very variable progression with different degrees of severity. A multimodal approach involving both neurological and ophthalmological diagnosis of NARP syndrome is necessary in order to establish the course of the disease and the measures to be taken.

Reversible cardiac function and left ventricular hypertrophy in a Chinese man with mitochondrial myopathy: a case report.

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.

Mitochondrial Myopathy in a 21-Year-Old Man Presenting With Bilateral Lower Extremity Weakness and Swelling.

Bilateral lower extremity weakness and swelling can have several causes. Although often underdiagnosed, mitochondrial myopathy is more prevalent in the general population than more commonly suspected diseases, such as Guillain-Barre syndrome. The clinical manifestations of mitochondrial disease can be broadly classified into 3 categories: chronic progressive external ophthalmoplegia, skeletal muscle-central nervous system syndromes, or pure myopathy. Cardiac abnormalities occur in 30% to 32% of cases, mostly in the form of hypertrophic cardiomyopathy, dilated cardiomyopathy, or conduction abnormalities. We report a case of a 21-year-old student who developed bilateral lower limb weakness, pain, and swelling diagnosed with mitochondrial myopathy on muscle biopsy. Initial laboratory tests revealed elevated creatinine kinase, brain natriuretic peptide, troponin, myoglobin, and lactic acid and reduced serum bicarbonate. Cardiac workup revealed systolic heart failure with a reduced ejection fraction. Endomyocardial biopsy revealed punctate foci of lymphocytic myocarditis. However, cardiac magnetic resonance imaging did not reveal either myocarditis or an infiltrative cardiac disease. An extensive autoimmune and infection work-up was negative. A muscle biopsy from the patient's rectus femoris revealed scattered ragged-blue fibers (stained with NADH dehydrogenase), scattered ragged-red fibers on modified Gomori trichrome stain, and cytochrome-c oxidase negative fibers with increased perimysial and endomysial connective tissue, consistent with active and chronic primary mitochondrial myopathy. The patient was treated successfully with furosemide, metoprolol, and methylprednisolone. Adult-onset mitochondrial myopathy is a rare clinical disorder, and our experience stresses the importance of using an inter-disciplinary team approach to diagnose uncommon clinical disorders with widely variable multisystem involvement.

Generalized Muscular Hypermetabolism Caused by Mitochondrial Myopathy Shown on 18 F-FDG PET/CT.

ABSTRACT: An 18-year-old man presented with progressive exercise intolerance and muscle weakness for 1 year with recent acute exacerbation. Laboratory test demonstrated lactic acidosis. 18 F-FDG PET/CT was performed to exclude malignancy and showed generalized muscular hypermetabolism. Muscle biopsy combined with patient's history suggested mitochondrial myopathy. This report illustrates that mitochondrial myopathy may present as generalized muscular hypermetabolism on 18 F-FDG PET/CT and thus should be added to the differential diagnoses.

Clinical Spectrum of Biopsy Proven Mitochondrial Myopathy.

Objectives: Clinical spectrum of mitochondrial myopathy extends beyond chronic progressive external ophthalmoplegia (CPEO). While information on encephalomyopathies is abundant, clinical data on predominant myopathic presentation of mitochondrial disorders are lacking. Materials and Methods: Clinical, electrophysiological, biochemical, and follow-up data of patients with predominant myopathic presentation and muscle biopsy confirmed primary mitochondrial myopathy was obtained. We excluded known syndromes of mitochondrial cytopathies and encephalomyopathies. Results: Among 16 patients, 7 had CPEO, 4 had CPEO with limb-girdle muscle weakness (LGMW), and 5 had isolated LGMW. Systemic features included seizures with photosensitivity (n = 3), diabetes (n = 1), cardiomyopathy (n = 1), and sensorineural hearing loss (n = 1) and were more common in isolated LGMW. Elevated serum creatine kinase (CK) and lactate levels and electromyography (EMG) myopathic potentials were more frequent with LGMW. During follow-up, LGMW had more severe progression of weakness. Conclusion: We identified three subsets of mitochondrial myopathy with distinct clinical features and evolutionary patterns. Isolated LGMW was seen in 30% of patients and would represent severe end of the spectrum.

Metabolic Myopathies.

PURPOSE OF REVIEW: Metabolic myopathies are disorders that affect skeletal muscle substrate oxidation. Although some drugs and hormones can affect metabolism in skeletal muscle, this review will focus on the genetic metabolic myopathies. RECENT FINDINGS: Impairments in glycogenolysis/glycolysis (glycogen storage disease), fatty acid transport/oxidation (fatty acid oxidation defects), and mitochondrial metabolism (mitochondrial myopathies) represent most metabolic myopathies; however, they often overlap clinically with structural genetic myopathies, referred to as pseudometabolic myopathies. Although metabolic myopathies can present in the neonatal period with hypotonia, hypoglycemia, and encephalopathy, most cases present clinically in children or young adults with exercise intolerance, rhabdomyolysis, and weakness. In general, the glycogen storage diseases manifest during brief bouts of high-intensity exercise; in contrast, fatty acid oxidation defects and mitochondrial myopathies usually manifest during longer-duration endurance-type activities, often with fasting or other metabolic stressors (eg, surgery, fever). The neurologic examination is often normal between events (except in the pseudometabolic myopathies) and evaluation requires one or more of the following tests: exercise stress testing, blood (eg, creatine kinase, acylcarnitine profile, lactate, amino acids), urine (eg, organic acids, myoglobin), muscle biopsy (eg, histology, ultrastructure, enzyme testing), and targeted (specific gene) or untargeted (myopathy panels) genetic tests. SUMMARY: Definitive identification of a specific metabolic myopathy often leads to specific interventions, including lifestyle, exercise, and nutritional modifications; cofactor treatments; accurate genetic counseling; avoidance of specific triggers; and rapid treatment of rhabdomyolysis.

Highly asymmetrical distribution of muscle wasting correlates to the heteroplasmy in a patient carrying a large-scale mitochondrial DNA deletion: a novel pathophysiological mechanism for explaining asymmetry in mitochondrial myopathies.

Mitochondrial diseases are a heterogeneous group of pathologies, caused by missense mutations, sporadic large-scale deletions of mitochondrial DNA (mtDNA) or mutations of nuclear maintenance genes. We report the case of a patient in whom extended muscle pathology, biochemical and genetic mtDNA analyses have proven to be essential to elucidate a unique asymmetrical myopathic presentation. From the age of 34 years on, the patient has presented with oculomotor disorders, right facial peripheral palsy and predominantly left upper limb muscle weakness and atrophy. By contrast, he displayed no motor weakness on the right hemi-body, and no sensory symptoms, cerebellar syndrome, hypoacusis, or parkinsonism. Cardiac function was normal. CK levels were elevated (671 UI/L). Electroneuromyography (ENMG) and muscle MRI showed diffuse myogenic alterations, more pronounced on the left side muscles. Biopsy of the left deltoid muscle showed multiple mitochondrial defects, whereas in the right deltoid, mitochondrial defects were much less marked. Extended mitochondrial biochemical and molecular workup revealed a unique mtDNA deletion, with a 63.4% heteroplasmy load in the left deltoid, versus 8.1% in the right one. This case demonstrates that, in mitochondrial myopathies, heteroplasmy levels may drastically vary for the same type of muscle, rising the hypothesis of a new pathophysiological mechanism explaining asymmetry in hereditary myopathies.

Pathological Features in Paediatric Patients with TK2 Deficiency.

Thymidine kinase (TK2) deficiency causes mitochondrial DNA depletion syndrome. We aimed to report the clinical, biochemical, genetic, histopathological, and ultrastructural features of a cohort of paediatric patients with TK2 deficiency. Mitochondrial DNA was isolated from muscle biopsies to assess depletions and deletions. The TK2 genes were sequenced using Sanger sequencing from genomic DNA. All muscle biopsies presented ragged red fibres (RRFs), and the prevalence was greater in younger ages, along with an increase in succinate dehydrogenase (SDH) activity and cytochrome c oxidase (COX)-negative fibres. An endomysial inflammatory infiltrate was observed in younger patients and was accompanied by an overexpression of major histocompatibility complex type I (MHC I). The immunofluorescence study for complex I and IV showed a greater number of fibres than those that were visualized by COX staining. In the ultrastructural analysis, we found three major types of mitochondrial alterations, consisting of concentrically arranged lamellar cristae, electrodense granules, and intramitochondrial vacuoles. The pathological features in the muscle showed substantial differences in the youngest patients when compared with those that had a later onset of the disease. Additional ultrastructural features are described in the muscle biopsy, such as sarcomeric de-structuration in the youngest patients with a more severe phenotype.

Acipimox in Mitochondrial Myopathy (AIMM): study protocol for a randomised, double-blinded, placebo-controlled, adaptive design trial of the efficacy of acipimox in adult patients with mitochondrial myopathy.

BACKGROUND: Mitochondrial disease is a heterogenous group of rare, complex neurometabolic disorders. Despite their individual rarity, collectively mitochondrial diseases represent the most common cause of inherited metabolic disorders in the UK; they affect 1 in every 4300 individuals, up to 15,000 adults (and a similar number of children) in the UK. Mitochondrial disease manifests multisystem and isolated organ involvement, commonly affecting those tissues with high energy demands, such as skeletal muscle. Myopathy manifesting as fatigue, muscle weakness and exercise intolerance is common and debilitating in patients with mitochondrial disease. Currently, there are no effective licensed treatments and consequently, there is an urgent clinical need to find an effective drug therapy. AIM: To investigate the efficacy of 12-week treatment with acipimox on the adenosine triphosphate (ATP) content of skeletal muscle in patients with mitochondrial disease and myopathy. METHODS: AIMM is a single-centre, double blind, placebo-controlled, adaptive designed trial, evaluating the efficacy of 12 weeks' administration of acipimox on skeletal muscle ATP content in patients with mitochondrial myopathy. Eligible patients will receive the trial investigational medicinal product (IMP), either acipimox or matched placebo. Participants will also be prescribed low dose aspirin as a non-investigational medical product (nIMP) in order to protect the blinding of the treatment assignment. Eighty to 120 participants will be recruited as required, with an interim analysis for sample size re-estimation and futility assessment being undertaken once the primary outcome for 50 participants has been obtained. Randomisation will be on a 1:1 basis, stratified by Fatigue Impact Scale (FIS) (dichotomised as < 40, ≥ 40). Participants will take part in the trial for up to 20 weeks, from screening visits through to follow-up at 16 weeks post randomisation. The primary outcome of change in ATP content in skeletal muscle and secondary outcomes relating to quality of life, perceived fatigue, disease burden, limb function, balance and walking, skeletal muscle analysis and symptom-limited cardiopulmonary fitness (optional) will be assessed between baseline and 12 weeks. DISCUSSION: The AIMM trial will investigate the effect of acipimox on modulating muscle ATP content and whether it can be repurposed as a new treatment for mitochondrial disease with myopathy. TRIAL REGISTRATION: EudraCT2018-002721-29 . Registered on 24 December 2018, ISRCTN 12895613. Registered on 03 January 2019, https://www.isrctn.com/search?q=aimm.

Effectiveness of Robotic-Assisted Gait Training and Aquatic Physical Therapy in a Child With Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency: A Case Report.

PURPOSE: The purpose of this case study is to describe the outpatient rehabilitation program for a 15-year-old girl with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD). SUMMARY OF KEY POINTS: The child presented with sudden-onset muscle weakness and fatigue with resultant dependence for all mobility and self-care. After 12 months of therapy, which included aquatic interventions and robotic-assisted gait training, the patient demonstrated independence with transfers, ambulation with a rolling walker, and stair navigation. Functional mobility, gross motor skills, and participation in activities of daily living significantly improved per the Gross Motor Function Measure and the Pediatric Evaluation of Disability Inventory. STATEMENT OF CONCLUSION AND RECOMMENDATIONS FOR CLINICAL PRACTICE: This is the first case in the literature to outline an outpatient physical therapy treatment plan to address mobility deficits secondary to exacerbation of LCHADD. This patient's rehabilitative course will hopefully add to future research and provide patients with guidelines for their recovery.

Kidney manifestations of mitochondrial disorders.

Mitochondria are intracellular organelles involved in a number of key biologic processes in the cell, including energy production, redox signaling, calcium homeostasis, inflammation, senescence, innate immune response, and mitophagy. Mitochondrial cytopathies include a heterogeneous group of diseases that are characterized by impaired oxidative phosphorylation, leading to multi-organ involvement and progressive clinical deterioration. Mitochondrial cytopathies can result from mitochondrial or nuclear DNA mutations. Mitochondrial defects play an important role in the pathogenesis of nephropathies as tubular syndromes, interstitial nephritis, focal and segmental glomerulosclerosis and diabetic nephropathy. The role of mitochondria in a pathogenesis of nephrotoxicity and kidney carcinogenesis is also discussed (Tab. 2, Fig. 7, Ref. 100). Keywords: mitochondrial nephropathy, interstitial nephritis, glomerulosclerosis, diabetic nephropathy, nephrotoxicity, mitochondrial cytopathies.

Genetic diversity in Kashubs: the regional increase in the frequency of several disease-causing variants.

Differential distribution of genetic variants' frequency among human populations is caused by the genetic drift in isolated populations, historical migrations, and demography. Some of these variants are identical by descent and represent founder mutations, which - if pathogenic in nature - lead to the increased frequency of otherwise rare diseases. The detection of the increased regional prevalence of pathogenic variants may shed light on the historical processes that affected studied populations and can help to develop effective screening and diagnostic strategies as a part of personalized medicine. Here, we discuss the specific genetic diversity in Kashubs, the minority group living in northern Poland, reflected in the biased distribution of some of the repetitively found disease-causing variants. These include the following: (1) c.662A > G (p.Asp221Gly) in LDLR, causing heterozygous familial hypercholesterolemia; (2) c.3700_3704del in BRCA1, associated with hereditary breast and ovarian cancer syndrome; (3) c.1528G > C (p.Glu510Gln) in HADHA, seen in long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) deficiency, and (4) c.1032delT in NPHS2, associated with steroid-resistant nephrotic syndrome.

Approach to the diagnosis of metabolic myopathies.

Metabolic myopathies are a diverse group of genetic disorders that result in impaired energy production. They are individually rare and several have received the 'orphan disorder' status. However, collectively they constitute a relatively common group of disorders that affect not only the skeletal muscle but also the heart, liver, and brain among others. Mitochondrial disorders, with a frequency of 1/8000 population, are the commonest cause of metabolic myopathies. Three main groups that cause metabolic myopathy are glycogen storage disorders (GSD), fatty acid oxidation defects (FAOD), and mitochondrial myopathies. Clinically, patients present with varied ages at onset and neuromuscular features. While newborns and infants typically present with hypotonia and multisystem involvement chiefly affecting the liver, heart, kidney, and brain, patients with onset later in life present with exercise intolerance with or without progressive muscle weakness and myoglobinuria. In general, GSDs result in high-intensity exercise intolerance while, FAODs, and mitochondrial myopathies predominantly manifest during endurance-type activity, fasting, or metabolically stressful conditions. Evaluation of these patients comprises a meticulous clinical examination and a battery of investigations which includes- exercise stress testing, metabolic and biochemical screening, electrophysiological studies, neuro-imaging, muscle biopsy, and molecular genetics. Accurate and early detection of metabolic myopathies allows timely counseling to prevent metabolic crises and helps in therapeutic interventions. This review summarizes the clinical features, diagnostic tests, pathological features, treatment and presents an algorithm to diagnose these three main groups of disorders.

A case report of mitochondrial myopathy with membranous nephropathy.

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.

Respiratory failure as the prominent manifestation of entecavir-associated mitochondrial myopathy: a case report.

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.

Stroke and stroke-like episodes in inborn errors of metabolism: Pathophysiological and clinical implications.

Inborn errors of metabolism causing stroke (ischemic or haemorrhagic) or stroke-like episodes (e.g., that are also called "metabolic strokes" and include acute brain lesions not related with alterations of blood flow) cover a wide range of diseases in which acute metabolic decompensations after trigger events (e.g., fever, dehydration, sepsis etc.) may have a variable frequency. The early diagnosis of these conditions is essential because, despite their rarity, effective symptomatic treatments may be available for acute settings (e.g., arginine for Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes- MELAS) while in other cases disease modifying therapies may be useful to prevent stroke occurrence, recurrence, or relapse (e.g., Fabry disease). The detection of a non-vascular distribution of lesions and the diffuse use of 1HMRS are often diriment in the differential of ischemic and metabolic strokes. This review summarized the main clinical features and the pathophysiological mechanisms of stroke and stroke-like episodes in inborn errors of metabolism presenting with stroke as part of natural history of the disease. These conditions belong to different etiological groups, such as organic acidurias, mitochondrial encephalopathies, homocystinuria and remethylation disorders, urea cycle disorders, lysosomal diseases (e.g. Fabry disease, glycogen storage disease), congenital disorders of glycosylation, neurotransmitter disorders, adenosine deaminase 2 deficiency and few other neurometabolic disorders.

Expression pattern of mitochondrial respiratory chain enzymes in skeletal muscle of patients with mitochondrial myopathy associated with the homoplasmic m.14674T>C variant.

Two homoplasmic variants in tRNAGlu (m.14674T>C/G) are associated with reversible infantile respiratory chain deficiency. This study sought to further characterize the expression of the individual mitochondrial respiratory chain complexes and to describe the natural history of the disease. Seven patients from four families with mitochondrial myopathy associated with the homoplasmic m.14674T>C variant were investigated. All patients underwent skeletal muscle biopsy and mtDNA sequencing. Whole-genome sequencing was performed in one family. Western blot and immunohistochemical analyses were used to characterize the expression of the individual respiratory chain complexes. Patients presented with hypotonia and feeding difficulties within the first weeks or months of life, except for one patient who first showed symptoms at 4 years of age. Histopathological findings in muscle included lipid accumulation, numerous COX-deficient fibers, and mitochondrial proliferation. Ultrastructural abnormalities included enlarged mitochondria with concentric cristae and dense mitochondrial matrix. The m.14674T>C variant in MT-TE was identified in all patients. Immunohistochemistry and immunoblotting demonstrated pronounced deficiency of the complex I subunit NDUFB8. The expression of MTCO1, a complex IV subunit, was also decreased, but not to the same extent as NDUFB8. Longitudinal follow-up data demonstrated that not all features of the disorder are entirely transient, that the disease may be progressive, and that signs and symptoms of myopathy may develop during childhood. This study sheds new light on the involvement of complex I in reversible infantile respiratory chain deficiency, it shows that the disorder may be progressive, and that myopathy can develop without an infantile episode.