Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency.

Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy leading to severe metabolic disturbances in infants, which recover spontaneously after 6-months of age. RIRCD is associated with the homoplasmic m.14674T>C mitochondrial DNA mutation; however, only ~ 1/100 carriers develop the disease. We studied 27 affected and 15 unaffected individuals from 19 families and found additional heterozygous mutations in nuclear genes interacting with mt-tRNAGlu including EARS2 and TRMU in the majority of affected individuals, but not in healthy carriers of m.14674T>C, supporting a digenic inheritance. Our transcriptomic and proteomic analysis of patient muscle suggests a stepwise mechanism where first, the integrated stress response associated with increased FGF21 and GDF15 expression enhances the metabolism modulated by serine biosynthesis, one carbon metabolism, TCA lipid oxidation and amino acid availability, while in the second step mTOR activation leads to increased mitochondrial biogenesis. Our data suggest that the spontaneous recovery in infants with digenic mutations may be modulated by the above described changes. Similar mechanisms may explain the variable penetrance and tissue specificity of other mtDNA mutations and highlight the potential role of amino acids in improving mitochondrial disease.

Α rare case of myopathy, lactic acidosis, and severe rhabdomyolysis, due to a homozygous mutation of the ferredoxin-2 (FDX2) gene.

Mitochondrial myopathy is a severe metabolic myopathy related to nuclear or mitochondrial DNA dysfunction. We present a rare case of mitochondrial myopathy, presented with multiple episodes of proximal muscle weakness, lactic acidosis, and severe rhabdomyolysis (CPK 319,990 U/L, lactic acid 22.31 mmol/L, and GFR 3.82 mL/min/1.73m2 ). She was hospitalized in the pediatric intensive care unit due to acute kidney injury, elevated blood pressure, and deterioration of respiratory and cardiac function. Investigation for inherited metabolic disorders showed elevated levels of ammonia, lactic acid to pyruvic acid ratio, and urine ketone bodies. Exome sequencing detected a homozygous pathogenic variant in FDX2 (ENST00000541276:p.Met4Leu/c.10A > T) and a heterozygous variant of uncertain significance in MSTO1 (ENST00000538143:p.Leu137Pro/c.410 T > C). After Sanger sequencing, the p.Met4Leu pathogenic variant in FDX2 (ENST00000541276:p.Met4Leu/c.10A > T) was identified in a heterozygous state in both her parents and sister. Recently, pathogenic variants in the FDX2 gene have been associated with mitochondrial myopathy, lactic acidosis, optic atrophy, and leukoencephalopathy. Only four reports of FDX2-related rhabdomyolysis have been described before, but none of the previous patients had hyperammonemia. This is a rare case of severe mitochondrial myopathy in a pediatric patient related to a pathogenic FDX2 variant, suggesting the need for genetic analysis of the FDX2 gene in cases of suspicion of mitochondrial myopathies.

Exercise testing and prescription in patients with inborn errors of muscle energy metabolism.

Skeletal muscle is a dynamic organ requiring tight regulation of energy metabolism in order to provide bursts of energy for effective function. Several inborn errors of muscle energy metabolism (IEMEM) affect skeletal muscle function and therefore the ability to initiate and sustain physical activity. Exercise testing can be valuable in supporting diagnosis, however its use remains limited due to the inconsistency in data to inform its application in IEMEM populations. While exercise testing is often used in adults with IEMEM, its use in children is far more limited. Once a physiological limitation has been identified and the aetiology defined, habitual exercise can assist with improving functional capacity, with reports supporting favourable adaptations in adult patients with IEMEM. Despite the potential benefits of structured exercise programs, data in paediatric populations remain limited. This review will focus on the utilisation and limitations of exercise testing and prescription for both adults and children, in the management of McArdle Disease, long chain fatty acid oxidation disorders, and primary mitochondrial myopathies.

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.

A case of mitochondrial myopathy and chronic progressive external ophthalmoplegia. / çº¿ç²’ä½“è‚Œç— åˆå¹¶æ ¢æ€§è¿›è¡Œæ€§çœ¼å¤–è‚Œéº»ç—¹1例（英文）.

Mitochondrial myopathy is a group of multi-system diseases in which mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) defects lead to structural and functional dysfunction of mitochondria. The clinical manifestations of mitochondrial myopathy are complex and varied, and the testing for mtDNA and nDNA is not widely available, so misdiagnosis or missed diagnosis is common. Chronic progressive external ophthalmoplegia (CPEO) is a common type of mitochondrial myopathy, which is characterized by blepharoptosis. Here we report a 38-year-old female with mitochondrial myopathy presented with chronic numbness and weakness of the limbs, accompanied by blepharoptosis that was recently noticed. Laboratory and head magnetic resonance imaging (MRI) examinations showed no obvious abnormalities. Muscle and nerve biopsies showed characteristic ragged red fibers (RRFs) and large aggregates of denatured mitochondria. Testing for mtDNA and nDNA showed a known mutation c.2857C>T (p.R953C) and a novel variant c.2391G>C (p.M797I) in the polymerase gamma (POLG)gene, so the patient was diagnosed as mitochondrial myopathy. Clinicians should pay more attention to long-term unexplained skeletal muscle diseases with recent onset blepharoptosis. Histopathologic examination and genetic testing are of great value in the early diagnosis and therapeutic intervention.

Successful plasmapheresis and immunoglobulin treatment for severe lipid storage myopathy: Doing the right thing for the wrong reason.

Three consecutive skeletal muscle biopsies during a several months time-frame, showing different degrees of neutral lipid storage. This is highlighted by Oil-red-O stains (D, E, F) and electron microscopy (G, H, I). Note the impact on mitochondrial morphology with so called 'parking lots (K, L). Zooming 'in and out' into the ultrastructure, using the nanotomy platform provides interesting detailled information (http://nanotomy.org). ​.

Novel truncating variants in FGD1 detected in two Danish families with Aarskog-Scott syndrome and myopathic features.

Aarskog-Scott syndrome (AAS) is a developmental disorder, caused by disease-causing hemizygous variants in the FGD1 gene. AAS is characterized by dysmorphic features, genital malformation, skeletal anomalies, and in some cases, intellectual disability and behavioral difficulties. Myopathy has only been reported once in two affected siblings diagnosed with AAS. Only few adult cases have been reported. This article reports four adults with AAS (three male cases and one female carrier) from two unrelated Danish families, all males presented with variable features suggestive of myopathy. All four carried novel hemizygous pathogenic variants in the FGD1 gene; one family presented with the c.2266dup, p.Cys756Leufs*19 variant while the c.527dup; p.Leu177Thrfs*40 variant was detected in the second family. All males had some mild myopathic symptoms or histological abnormalities. Case 1 had the most severe myopathic phenotype with prominent proximal muscular fatigue and exercise intolerance. In addition, he had multiple deletions of mtDNA and low respiratory chain activity. His younger nephew, case 3, had difficulties doing sports in his youth and had a mildly abnormal muscle biopsy and relatively decreased mitochondrial enzyme activity. The singular case from family 2 (case 4), had a mildly myopathic muscle biopsy, but no overt myopathic symptoms. Our findings suggest that myopathic involvement should be considered in AAS.

Decompensation of cardiorespiratory function and emergence of anemia during pregnancy in a case of mitochondrial myopathy, lactic acidosis, and sideroblastic anemia 2 with compound heterozygous YARS2 pathogenic variants.

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.

Single- and multiple-dose safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of ASP0367, or bocidelpar sulfate, a novel modulator of peroxisome proliferator-activated receptor delta in healthy adults: Results from a phase 1 study.

INTRODUCTION/AIMS: ASP0367, or bocidelpar sulfate, is an orally administered small molecule that potently and selectively modulates peroxisome proliferator-activated receptor δ (PPARδ) to address mitochondrial dysfunction occurring in diseases including primary mitochondrial myopathy and Duchenne muscular dystrophy. The objectives of this first-in-human trial were to evaluate the safety/tolerability, pharmacokinetics, and pharmacodynamics of ASP0367 in healthy participants. METHODS: In this double-blind phase 1 study, adult participants were randomized to single or multiple ascending oral doses of ASP0367 or placebo. The study duration was 1 and 14 days, respectively. Pharmacokinetic parameters under fed conditions were also evaluated. RESULTS: A total of 64 (single-dose cohort) and 37 (multiple-dose cohort) participants were included in the study. After single doses of 1 to 120 mg, ASP0367 was rapidly absorbed, with median time to maximum plasma concentration (tmax ) of 1.50 to 2.24 hours under fasting conditions; ASP0367 concentrations declined in a multiphasic manner after reaching maximum plasma concentration. Under fed conditions, tmax was delayed 1.7 hours. After multiple once-daily doses, mean half-life of ASP0367 10 to 75 mg ranged from 14.1 to 17.5 hours; steady state was reached after 4 days. Negligible accumulation was observed after repeated dosing. No participants receiving ASP0367 discontinued treatment, and all treatment-emergent adverse events were mild to moderate in severity; none were considered drug-related. No clinically significant changes were observed on laboratory or electrocardiographic evaluation. Treatment- and dose-dependent upregulation of six PPARδ target genes was observed with single and multiple doses of ASP0367. DISCUSSION: ASP0367, or bocidelpar sulfate, was well tolerated; rapid absorption, roughly dose-proportional bioavailability, and effects on PPARδ target genes were demonstrated in healthy adult participants.

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.

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.

The roles of PARK gene family in myopathy.

The causative gene family of Parkinson's disease, PARK, plays important roles in the regulation of skeletal myopathy and is also involved in multiple biological processes, such as the modification of motor neurons, the transmission of nerve signals at the nerve-muscle junction, the regulation of skeletal muscle energy metabolism and mitochondrial quality, and the expression of myogenesis factors. PARK gene family regulates skeletal muscle mass, functions through a multi-level regulatory system, and plays a key role in the occurrence and development of skeletal myopathy. In this review, we summarize the structural characteristics, functions, and research of the PARK gene family in skeletal myopathy, providing a theoretical foundation and future research direction for in-depth study of the molecular mechanism for skeletal myopathy and giving references to further study on the role of PARK family in the development, the pathology, clinical diagnosis, and treatment of skeletal myopathy.

Molecular pathophysiology of human MICU1 deficiency.

AIMS: MICU1 encodes the gatekeeper of the mitochondrial Ca2+ uniporter, MICU1 and biallelic loss-of-function mutations cause a complex, neuromuscular disorder in children. Although the role of the protein is well understood, the precise molecular pathophysiology leading to this neuropaediatric phenotype has not been fully elucidated. Here we aimed to obtain novel insights into MICU1 pathophysiology. METHODS: Molecular genetic studies along with proteomic profiling, electron-, light- and Coherent anti-Stokes Raman scattering microscopy and immuno-based studies of protein abundances and Ca2+ transport studies were employed to examine the pathophysiology of MICU1 deficiency in humans. RESULTS: We describe two patients carrying MICU1 mutations, two nonsense (c.52C>T; p.(Arg18*) and c.553C>T; p.(Arg185*)) and an intragenic exon 2-deletion presenting with ataxia, developmental delay and early onset myopathy, clinodactyly, attention deficits, insomnia and impaired cognitive pain perception. Muscle biopsies revealed signs of dystrophy and neurogenic atrophy, severe mitochondrial perturbations, altered Golgi structure, vacuoles and altered lipid homeostasis. Comparative mitochondrial Ca2+ transport and proteomic studies on lymphoblastoid cells revealed that the [Ca2+ ] threshold and the cooperative activation of mitochondrial Ca2+ uptake were lost in MICU1-deficient cells and that 39 proteins were altered in abundance. Several of those proteins are linked to mitochondrial dysfunction and/or perturbed Ca2+ homeostasis, also impacting on regular cytoskeleton (affecting Spectrin) and Golgi architecture, as well as cellular survival mechanisms. CONCLUSIONS: Our findings (i) link dysregulation of mitochondrial Ca2+ uptake with muscle pathology (including perturbed lipid homeostasis and ER-Golgi morphology), (ii) support the concept of a functional interplay of ER-Golgi and mitochondria in lipid homeostasis and (iii) reveal the vulnerability of the cellular proteome as part of the MICU1-related pathophysiology.

Clinical features of mtDNA-related syndromes in adulthood.

Mitochondrial diseases are the most common inheritable metabolic diseases, due to defects in oxidative phosphorylation. They are caused by mutations of nuclear or mitochondrial DNA in genes involved in mitochondrial function. The peculiarity of "mitochondrial DNA genetics rules" in part explains the marked phenotypic variability, the complexity of genotype-phenotype correlations and the challenge of genetic counseling. The new massive genetic sequencing technologies have changed the diagnostic approach, enhancing mitochondrial DNA-related syndromes diagnosis and often avoiding the need of a tissue biopsy. Here we present the most common phenotypes associated with a mitochondrial DNA mutation with the recent advances in diagnosis and in therapeutic perspectives.

Immune-mediated necrotizing myopathy: Unusual presentations of a treatable disease.

INTRODUCTION/AIMS: Immune-mediated necrotizing myopathy (IMNM) is an immune-mediated myopathy typically presenting with progressive subacute weakness and characteristic, but nonspecific, myopathological findings. Atypical cases however can mimic other inherited or acquired myopathies, depriving patients of treatment. We describe a cohort of such patients. METHODS: We retrospectively identified IMNM patients who either previously carried a diagnosis of an inherited myopathy established on clinicopathological grounds or whose muscle biopsies displayed atypical features suggestive of a different myopathy. RESULTS: Among 131 IMNM patients, seven previously unreported patients (5%) met one of the above criteria. Three patients were diagnosed with limb-girdle muscular dystrophy on the basis of a chronic progressive course of weakness and family history of myopathy or cardiomyopathy. The other four patients displayed atypical histological features (two prominent mitochondrial abnormalities, one myofibrillar pathology, and one granulomatous inflammation). Immunostaining of biopsies from 12 additional IMNM patients did not identify myofibrillar pathology. The patient with granulomatous inflammation was known to have pulmonary sarcoidosis. Genetic testing for inherited myopathies was unrevealing. Antibodies against 3-hydroxy-3-methylglutaryl-CoA reductase or signal recognition particle were identified in 5 and 1 patients, respectively. Four patients presented with slowly progressive weakness over 3-13 y, while weakness was subacute over ≤6 mo in three patients. All patients responded to immunomodulatory therapy. DISCUSSION: Atypical clinical and histological features can occur in IMNM patients, causing delays in diagnosis and treatment. Clinicians should, therefore, consider IMNM in the differential diagnosis of unexplained proximal myopathies in spite of atypical clinical and myopathological findings.

A novel exercise testing algorithm to diagnose mitochondrial myopathy.

INTRODUCTION: Oxygen uptake efficiency slope (OUES) is a noninvasive cardiopulmonary exercise testing (CPET) measurement based on oxygen uptake (V˙O2 ) and minute ventilation (V˙E) and is a marker of the efficiency of oxygen utilization by the body. However, it has not been studied in mitochondrial disorders. We explored noninvasive CPET parameters, including OUES, as a way to reliably diagnose mitochondrial myopathy. METHODS: We performed cycle ergometer maximal exercise testing on definite and suspected mitochondrial myopathy subjects (MM-D and MM-S) and their age- and sex-matched controls. OUES was corrected for body surface area (OUES/BSA) to eliminate the effect of body size. RESULTS: A total of 40 participants, including 20 MM-D (n = 13; 6 males; aged 14-64 years) and 7 MM-S (5 males, aged 11-30 years) subjects and 20 controls, completed the study. MM-D subjects showed lower aerobic fitness than controls. OUES/BSA was lower in MM-D subjects, suggesting inefficient oxygen utilization. Area under the curve (AUC) and 95% confidence interval (CI) for OUES/BSA (AUC, 0.91; 95% CI, 0.80-1.00), peak V˙O2 percent predicted (AUC, 0.95; 95% CI, 0.86-1.00), and V˙O2 /work slope (AUC, 0.94; 95% CI, 0.85-1.00) showed excellent ability to diagnose mitochondrial myopathy in MM-D subjects. We applied a diagnostic approach based on the parameters just noted to MM-S subjects and their controls and were able to support or disprove the diagnosis of mitochondrial myopathy. DISCUSSION: We proposed and applied an approach based on the aformentioned three CPET parameters to diagnose mitochondrial myopathy reliably and found it to be clinically useful.

No effect of resveratrol in patients with mitochondrial myopathy: A cross-over randomized controlled trial.

Mitochondrial myopathies (MM) are caused by mutations that typically affect genes involved in oxidative phosphorylation. Main symptoms are exercise intolerance and fatigue. Currently, there is no specific treatment for MM. Resveratrol (RSV) is a nutritional supplement that in preclinical studies has been shown to stimulate mitochondrial function. We hypothesized that RSV could improve exercise capacity in patients with MM. The study design was randomized, double-blind, cross-over and placebo-controlled. Eleven patients with genetically verified MM were randomized to receive either 1000 mg/day RSV or placebo (P) for 8 weeks followed by a 4-week washout and then the opposite treatment. Primary outcomes were changes in heart rate (HR) during submaximal cycling exercise and peak oxygen utilization (VO2 max) during maximal exercise. Secondary outcomes included reduction in perceived exertion, changes in lactate concentrations, self-rated function (SF-36) and fatigue scores (FSS), activities of electron transport chain complexes I and IV in mononuclear cells and mitochondrial biomarkers in muscle tissue among others. There were no significant differences in primary and secondary outcomes between treatments. Mean HR changes were -0.3 ± 4.3 (RSV) vs 1.8 ± 5.0 bpm (P), P = .241. Mean VO2 max changes were 0.7 ± 1.4 (RSV) vs -0.2 ± 2.3 mL/min/kg (P), P = .203. The study provides evidence that 1000 mg RSV daily is ineffective in improving exercise capacity in adults with MM. These findings indicate that previous in vitro studies suggesting a therapeutic potential for RSV in MM, do not translate into clinically meaningful effects in vivo.

Correlation between single-nucleotide polymorphisms and statin-induced myopathy: a mixed-effects model meta-analysis.

PURPOSE: A meta-analysis was performed to evaluate the correlation between single-nucleotide polymorphisms (SNPs) and risk of statin-induced myopathy (SIM). METHODS: We retrieved the studies published on SIM until April 2019 from the PubMed, Embase, and Cochrane Library databases. We collected data from 32 studies that analyzed 10 SNPs in five genes and included 21,692 individuals and nine statins. RESULTS: The analysis of the heterozygous (p = 0.017), homozygous (p = 0.002), dominant (p = 0.005), and recessive models (p = 0.009) of SLCO1B1 rs4149056 showed that this SNP increases the risk of SIM. Conversely, heterozygous (p = 0.048) and dominant models (p = 0.030) of SLCO1B1 rs4363657 demonstrated that this SNP is associated with a reduced risk of SIM. Moreover, an increased risk of SIM was predicted for carriers of the rs4149056 C allele among simvastatin-treated patients, whereas carriers of the GATM rs9806699 A allele among rosuvastatin-treated patients had a lower risk of SIM. CONCLUSION: The meta-analysis revealed that the rs4149056 and rs4363657 SNPs in SLCO1B1 and the rs9806699 SNP in GATM are correlated with the risk of SIM.

Homozygous mutations in C1QBP as cause of progressive external ophthalmoplegia (PEO) and mitochondrial myopathy with multiple mtDNA deletions.

Biallelic mutations in the C1QBP gene have been associated with mitochondrial cardiomyopathy and combined respiratory-chain deficiencies, with variable onset (including intrauterine or neonatal forms), phenotypes, and severity. We studied two unrelated adult patients from consanguineous families, presenting with progressive external ophthalmoplegia (PEO), mitochondrial myopathy, and without any heart involvement. Muscle biopsies from both patients showed typical mitochondrial alterations and the presence of multiple mitochondrial DNA deletions, whereas biochemical defects of the respiratory chain were present only in one subject. Using next-generation sequencing approaches, we identified homozygous mutations in C1QBP. Immunoblot analyses in patients' muscle samples revealed a strong reduction in the amount of the C1QBP protein and varied impairment of respiratory chain complexes, correlating with disease severity. Despite the original study indicated C1QBP mutations as causative for mitochondrial cardiomyopathy, our data indicate that mutations in C1QBP have to be considered in subjects with PEO phenotype or primary mitochondrial myopathy and without cardiomyopathy.

Anoctamin 5 (ANO5) muscular dystrophy-three different phenotypes and a new histological pattern.

OBJECTIVE: Anoctamin 5 (ANO5) is a putative intracellular calcium-activated chloride channel. Recessive mutations in ANO5 may present from asymptomatic hyperCKemia and exercise-induced myalgia to proximal and/or distal muscle weakness. Here we describe the clinical, pathological, and molecular findings of three unrelated patients with ANO5-related muscular dystrophy. METHODS: In this retrospective study, we analyzed our database which includes 1700 muscle biopsies performed for diagnostic purposes from October 2004 to February 2019. Patients were attended by two myology experts, who performed and analyzed the muscle biopsies. Muscle biopsies were frozen in cooled isopenthane, cryostat sectioned, and routinely stained and reacted (minimum 16 stainings). A custom panel, including 115 genes (Nextera Rapid Capture, Illumina) and whole-exome sequencing analysis, was used for next-generation sequencing in cases without a definite pathological diagnosis. RESULTS: Three patients were diagnosed with ANO5-related muscular dystrophy, with all presenting the common exon 5 mutation c.191dup plus a compound heterozygous missense mutation. They showed three different phenotypes (distal myopathy, LGMD2L, and asymptomatic hyperCKemia). Curiously, all three muscle biopsies showed different patterns, but numerous ragged-red fibers with little endomysial inflammation and partial invasion cell by T lymphocytes were observed in one. CONCLUSION: ANO5-related muscular dystrophy is a heterogeneous disease with different clinical phenotypes as well as different histological patterns, which may even mimic a mitochondrial myopathy. The results of this study provide further knowledge of the clinical, histological, and pathological features related to ANO5 mutations.