Genome-Wide Analysis of Exertional Rhabdomyolysis in Sickle Cell Trait Positive African Americans.

Sickle cell trait (SCT), although generally a benign carrier state of hemoglobin S (HbAS), is a risk factor for exertional rhabdomyolysis (ERM), a rare but potentially fatal consequence of highly intense physical exercise, particularly among active-duty military personnel and high-performance athletes. The association between SCT and ERM is poorly understood. The objective of this study was to elucidate the genetic basis of ERM in an SCT-positive African American cohort. SCT-positive African Americans with a personal history of ERM (cases, n = 30) and without history of ERM (controls, n = 53) were enrolled in this study. Whole-genome sequencing was performed on DNA samples isolated from peripheral white blood cells. Participants' demographic, behavioral, and medical history information was obtained. An additional 131 controls were extracted from SCT-positive subjects of African descent from the 1000 Genomes Project. SCT carriers with ERM were characterized by myotoxicity features, significant muscle involvement dominated by muscle weakness, and severe pain and substantial increase in serum creatine kinase, with a mean value of 50,480 U/L. A distinctive feature of the SCT individuals with ERM was exertional collapse, which was reported in 53.3% of the cases in the study cohort. An important factor for the development of ERM was the duration and frequency of strenuous physical activity in the cases compared to the controls. Whole-genome sequencing identified 79,696 protein-coding variants. Genome-wide association analysis revealed that the p.C477R, rs115958260 variant in the SLC44A3 gene was significantly associated with ERM event in SCT-positive African Americans. The study results suggest that a combination of vigorous exercise and a genetic predisposing factor is involved in ERM.

Major clinical events and healthcare resource use among patients with long-chain fatty acid oxidation disorders in the United States: Results from LC-FAOD Odyssey program.

Major clinical events (MCEs) related to long-chain fatty acid oxidation disorders (LC-FAOD) in triheptanoin clinical trials include inpatient or emergency room (ER) visits for three major clinical manifestations: rhabdomyolysis, hypoglycemia, and cardiomyopathy. However, outcomes data outside of LC-FAOD clinical trials are limited. The non-interventional cohort LC-FAOD Odyssey study examines data derived from US medical records and patient reported outcomes to quantify LC-FAOD burden according to management strategy including MCE frequency and healthcare resource utilization (HRU). Thirty-four patients were analyzed of which 21 and 29 patients had received triheptanoin and/or medium chain triglycerides (MCT), respectively. 36% experienced MCEs while receiving triheptanoin versus 54% on MCT. Total mean annualized MCE rates on triheptanoin and MCT were 0.1 and 0.7, respectively. Annualized disease-related inpatient and ER events were lower on triheptanoin (0.2, 0.3, respectively) than MCT (1.2, 1.0, respectively). Patients were managed more in an outpatient setting on triheptanoin (8.9 annualized outpatient visits) vs MCT (7.9). Overall, this shows that those with LC-FAOD in the Odyssey program experienced fewer MCEs and less HRU in inpatient and ER settings during triheptanoin-treated periods compared with the MCT-treated periods. The MCE rate was lower after initiation of triheptanoin, consistent with clinical trials.

Fatal Case of Exercise Collapse Associated with Sickle Cell Trait with Novel Underlying LAMA2 Mutation.

ABSTRACT: Sickle cell trait is typically thought to be an asymptomatic carrier state, but it is rarely associated with exertional rhabdomyolysis in cases termed Exercise Collapse Associated with Sickle Cell Trait (ECAST). In a subset of these cases, underlying disease contributes to the development and/or severity of the ensuing medical complications. We describe the first ever case of ECAST reported in a previously asymptomatic, multiply deployed, highly physically active service member with an underlying heterozygous LAMA2 mutation. Moreover, the mutation identified via whole exome sequencing is a novel, likely pathogenic variant that has yet to be described in the literature.

Molecular insight into CREBBP and TANGO2 variants causing intellectual disability.

BACKGROUND: Intellectual disability (ID) can be associated with different syndromes such as Rubinstein-Taybi syndrome (RSTS) and can also be related to conditions such as metabolic encephalomyopathic crises, recurrent,with rhabdomyolysis, cardiac arrhythmias and neurodegeneration. Rare congenital RSTS1 (OMIM 180849) is characterized by mental and growth retardation, significant and duplicated distal phalanges of thumbs and halluces, facial dysmorphisms, and an elevated risk of malignancies. Microdeletions and point mutations in the CREB-binding protein (CREBBP) gene, located at 16p13.3, have been reported to cause RSTS. By contrast, TANGO2-related metabolic encephalopathy and arrhythmia (TRMEA) is a rare metabolic condition that causes repeated metabolic crises, hypoglycemia, lactic acidosis, rhabdomyolysis, arrhythmias and encephalopathy with cognitive decline. Clinicians need more clinical and genetic evidence to detect and comprehend the phenotypic spectrum of this disorder. METHODS: Exome sequencing was used to identify the disease-causing variants in two affected families A and B from District Kohat and District Karak, Khyber Pakhtunkhwa. Affected individuals from both families presented symptoms of ID, developmental delay and behavioral abnormalities. The validation and co-segregation analysis of the filtered variant was carried out using Sanger sequencing. RESULTS: In the present study, two families (A and B) exhibiting various forms of IDs were enrolled. In Family A, exome sequencing revealed a novel missense variant (NM 004380.3: c.4571A>G; NP_004371.2: p.Lys1524Arg) in the CREBBP gene, whereas, in Family B, a splice site variant (NM 152906.7: c.605 + 1G>A) in the TANGO2 gene was identified. Sanger sequencing of both variants confirmed their segregation with ID in both families. The in silico tools verified the aberrant changes in the CREBBP protein structure. Wild-type and mutant CREBBP protein structures were superimposed and conformational changes were observed likely altering the protein function. CONCLUSIONS: RSTS and TRMEA are exceedingly rare disorders for which specific clinical characteristics have been clearly established, but more investigations are underway and required. Multicenter studies are needed to increase our understanding of the clinical phenotypes, mainly showing the genotype-phenotype associations.

Experience with carnitine palmitoyltransferase II deficiency: diagnostic challenges in the myopathic form.

OBJECTIVES: Carnitine palmitoyltransferase II (CPT II) deficiency is an autosomal recessive disorder of long-chain fatty acid oxidation. Three clinical phenotypes, lethal neonatal form, severe infantile hepatocardiomuscular form, and myopathic form, have been described in CPT II deficiency. The myopathic form is usually mild and can manifest from infancy to adulthood, characterised by recurrent rhabdomyolysis episodes. The study aimed to investigate the clinical features, biochemical, histopathological, and genetic findings of 13 patients diagnosed with the myopathic form of CPT II deficiency at Ege University Hospital. METHODS: A retrospective study was conducted with 13 patients with the myopathic form of CPT II deficiency. Our study considered demographic data, triggers of recurrent rhabdomyolysis attacks, biochemical metabolic screening, and molecular analysis. RESULTS: Ten patients were examined for rhabdomyolysis of unknown causes. Two patients were diagnosed during family screening, and one was diagnosed during investigations due to increased liver function tests. Acylcarnitine profiles were normal in five patients during rhabdomyolysis. Genetic studies have identified a c.338C>T (p.Ser113Leu) variant homozygous in 10 patients. One patient showed a novel frameshift variant compound heterozygous with c.338C>T (p.Ser113Leu). CONCLUSIONS: Plasma acylcarnitine analysis should be preferred as it is superior to DBS acylcarnitine analysis in diagnosing CPT II deficiency. Even if plasma acylcarnitine analysis is impossible, CPT2 gene analysis should be performed. Our study emphasizes that CPT II deficiency should be considered in the differential diagnosis of recurrent rhabdomyolysis, even if typical acylcarnitine elevation does not accompany it.

Raised CK and acute kidney injury following intense exercise in three patients with a history of exercise intolerance due to homozygous mutations in SLC2A9.

Acute rhabdomyolysis (AR) leading to acute kidney injury has many underlying etiologies, however, when the primary trigger is exercise, the most usual underlying cause is either a genetic muscle disorder or unaccustomed intense exercise in a healthy individual. Three adult men presented with a history of exercise intolerance and episodes of acute renal impairment following intense exercise, thought to be due to AR in the case of two, and dehydration in one. The baseline serum CK was mildly raised between attacks in all three patients and acutely raised during attacks in two of the three patients. Following referral to a specialized neuromuscular centre, further investigation identified very low serum urate (<12 umol/L). In all three men, genetic studies confirmed homozygous mutations in SLC2A9, which encodes for facilitated glucose transporter member 9 (GLUT9), a major regulator of urate homeostasis. Hereditary hypouricaemia should be considered in people presenting with acute kidney injury related to intense exercise. Serum urate evaluation is a useful screening test best undertaken after recovery.

Novel OBSCN variants associated with a risk to exercise-intolerance and rhabdomyolysis.

Obscurin, encoded by the OBSCN gene, is a muscle protein consisting of three main splice isoforms, obscurin-A, obscurin-B, and obscurin kinase-only protein (also known as KIAA1639 or Obsc-kin). Obscurin is located at the M-band and Z-disks and interacts with titin and myomesin. It plays an important role in the stability and maintenance of the A- and M-bands and the subsarcolemmal organization of the microtubule network. Furthermore, obscurin is involved in Ca2+ regulation and sarcoplasmic reticulum function and is connected to several other muscle proteins. OBSCN gene variants have been reported to be relatively common in inherited cardiomyopathies. Here we reported two young patients with a history of cramps, myalgia, exercise intolerance, rhabdomyolysis, and myoglobinuria without any evidence of concomitant cardiomyopathy in association with novel OBSCN variants (c.24822C>A and c.2653+1G>C). Obscurin-deficient muscle fibers seem to have increased susceptibility to damage triggered by exercise that may lead to rhabdomyolysis. More studies are needed to clarify the diverse clinical phenotypes and the pathophysiology of OBSCN gene variants.

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.

Intrinsic and extrinsic regulation of rhabdomyolysis susceptibility by Tango2.

Rhabdomyolysis is a clinical emergency characterized by severe muscle damage, resulting in the release of intracellular muscle components, which leads to myoglobinuria and, in severe cases, acute kidney failure. Rhabdomyolysis is caused by genetic factors linked to increased disease susceptibility in response to extrinsic triggers. Recessive mutations in TANGO2 result in episodic rhabdomyolysis, metabolic crises, encephalopathy and cardiac arrhythmia. The underlying mechanism contributing to disease onset in response to specific triggers remains unclear. To address these challenges, we created a zebrafish model of Tango2 deficiency. Here, we demonstrate that the loss of Tango2 in zebrafish results in growth defects, early lethality and increased susceptibility of skeletal muscle defects in response to extrinsic triggers, similar to TANGO2-deficient patients. Using lipidomics, we identified alterations in the glycerolipid pathway in tango2 mutants, which is critical for membrane stability and energy balance. Therefore, these studies provide insight into key disease processes in Tango2 deficiency and have increased our understanding of the impacts of specific defects on predisposition to environmental triggers in TANGO2-related disorders.

TANGO2 Deficiency Disorder: Two Cases of Developmental Delay Preceding Metabolic Crisis.

BACKGROUND: TANGO2 deficiency disorder is a rare genetic disease caused by biallelic defects in TANGO2 gene. METHODS: We report the clinical phenotype of two children with TANGO2 deficiency disorder. RESULTS: Patient 1 is a female child presenting with developmental delay and microcephaly during the second year of life, who evolved with severe cognitive impairment, facial dysmorphisms, spastic paraparesis, and atonic seizures. At age 13 years, she was hospitalized due to an episode of rhabdomyolysis complicated with cardiac arrhythmia and hypothyroidism. Patient 2 is a female child with dysmorphic facial features, cleft palate, and developmental delay who was diagnosed with DiGeorge syndrome. At age three years, she presented with an acute episode of severe rhabdomyolysis in the context of human herpesvirus 6 infection. After the resolution of this acute episode, she maintained recurrent muscle weakness with axial hypotonia and progressive spasticity of the lower extremities. In both patients, diagnosis of TANGO2 deficiency disorder was only confirmed after an acute metabolic crisis. CONCLUSIONS: A high index of suspicion for TANGO2 deficiency disorder is needed in patients with developmental delay or other neurological symptoms and episodic rhabdomyolysis.

A G1528C Hadha knock-in mouse model recapitulates aspects of human clinical phenotypes for long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.

Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a fatty acid oxidation disorder (FAOD) caused by a pathogenic variant, c.1528 G > C, in HADHA encoding the alpha subunit of trifunctional protein (TFPα). Individuals with LCHADD develop chorioretinopathy and peripheral neuropathy not observed in other FAODs in addition to the more ubiquitous symptoms of hypoketotic hypoglycemia, rhabdomyolysis and cardiomyopathy. We report a CRISPR/Cas9 generated knock-in murine model of G1528C in Hadha that recapitulates aspects of the human LCHADD phenotype. Homozygous pups are less numerous than expected from Mendelian probability, but survivors exhibit similar viability with wildtype (WT) littermates. Tissues of LCHADD homozygotes express TFPα protein, but LCHADD mice oxidize less fat and accumulate plasma 3-hydroxyacylcarnitines compared to WT mice. LCHADD mice exhibit lower ketones with fasting, exhaust earlier during treadmill exercise and develop a dilated cardiomyopathy compared to WT mice. In addition, LCHADD mice exhibit decreased visual performance, decreased cone function, and disruption of retinal pigment epithelium. Neurological function is affected, with impaired motor function during wire hang test and reduced open field activity. The G1528C knock-in mouse exhibits a phenotype similar to that observed in human patients; this model will be useful to explore pathophysiology and treatments for LCHADD in the future.

Clinical phenotype associated with variants in TANGO2: A case study.

Transport and Golgi organization 2 (TANGO2) disease is a severe inherited disorder that presents with multiple symptoms and a broad spectrum of phenotypes, including metabolic crisis, encephalopathy, cardiac arrhythmia, and hypothyroidism. The clinical picture of a TANGO2 gene biallelic mutation involves encephalopathy and rhabdomyolysis and is marked by cardiac rhythm disorders and neurological regression. The presentation of encephalopathy varies and can range from isolated language delay and cognitive impairment to multiple disabilities and spastic quadriparesis. A TANGO2 gene mutation causes serious illness with a limited life expectancy due to the unpredictable risk of cardiac rhythm disorder and death, particularly during rhabdomyolysis. Clinicians must therefore consider the TANGO2 gene when confronted with rhabdomyolysis in a patient suffering from an early developmental disorder. Currently, managing this disease is purely symptomatic. Here, we report the clinical features of a 10-year-old girl with mutations in the TANGO2 gene. Unique to our case was the lack of elevated creatine kinase during the early acute crises of cardiac failure and multi-organ failure, as well as the lack of any prior mental retardation associated with the aberrant heart rhythm.

NGS-Based Genetic Analysis in a Cohort of Italian Patients with Suspected Inherited Myopathies and/or HyperCKemia.

Introduction/Aims HyperCKemia is considered a hallmark of neuromuscular diseases. It can be either isolated or associated with cramps, myalgia, weakness, myoglobinuria, or rhabdomyolysis, suggesting a metabolic myopathy. The aim of this work was to investigate possible genetic causes in order to help diagnose patients with recurrent hyperCKemia or clinical suspicion of inherited metabolic myopathy. Methods A cohort of 139 patients (90 adults and 49 children) was analyzed using a custom panel containing 54 genes associated with hyperCKemia. Results A definite genetic diagnosis was obtained in 15.1% of cases, while candidate variants or variants of uncertain significance were found in a further 39.5%. Similar percentages were obtained in patients with infantile or adult onset, with some different causative genes. RYR1 was the gene most frequently identified, either with single or compound heterozygous variants, while ETFDH variants were the most common cause for recessive cases. In one patient, mRNA analysis allowed identifying a large LPIN1 deletion missed by DNA sequencing, leading to a certain diagnosis. Conclusion These data confirm the high genetic heterogeneity of hyperCKemia and metabolic myopathies. The reduced diagnostic yield suggests the existence of additional genes associated with this condition but also allows speculation that a significant number of cases presenting with hyperCKemia or muscle symptoms are due to extrinsic, not genetic, factors.

Expanding the phenotype of DNMT3A as a cause a congenital myopathy with rhabdomyolysis.

Pathogenic variants in DNMT3A are most commonly associated with Tatton-Brown-Rahman Syndrome (TBRS), but includes other phenotypes such as Heyn-Sproul-Jackson syndrome and acute myeloid leukemia (AML). We describe a patient presenting to the neuromuscular clinic with a de novo missense variant in DNMT3A where the striking clinical feature is that of a congenital myopathy with associated episodes of rhabdomyolysis, severe myalgias and chest pain along with phenotypic features associated with TBRS. Muscle biopsy showed minor myopathic features and cardiac investigations revealed mildly impaired bi-ventricular systolic function. We confirmed the DNA methylation profile matched haplo-insufficient TBRS cases, consistent with a loss of methyltransferase activity. Our report emphasizes the phenotypic overlap of patients with syndromic disorders presenting to neuromuscular clinics and limitations of gene panels in establishing a molecular diagnosis.

Limb-girdle myopathy and mild intellectual disability: The expanding spectrum of TANGO2-related disease.

TANGO2-related disease is an autosomal recessive multisystem disease associated with developmental delay and infancy-onset recurrent metabolic crises with early mortality. Several studies have reported dysfunction in endoplasmic reticulum-to-Golgi traffic and mitochondrial homoeostasis as the underlying pathophysiology. We report a 40-year-old woman affected by limb-girdle weakness and mild intellectual disability caused by the recurrent deletion of exons 3-9 in homozygosity in the TANGO2 gene. Physical examination revealed hyperlordosis, waddling gait, calf pseudohypertrophy, and Aquilian tendon retractions. Laboratory investigations revealed elevation of serum biomarkers suggestive of mitochondrial dysfunction together with hypothyroidism. At the age of 24, the patient suffered a metabolic crisis with severe rhabdomyolysis and malignant cardiac arrhythmia. After recovery, no metabolic or arrhythmic crisis has recurred. Muscle histology two years later revealed increased endomysial fibrosis and other myopathic changes. Our findings illustrate the mildest end of the phenotypic spectrum of TANGO2-related disease and reveal further aspects related to chronic muscle damage in this disorder.

Type 2 polysaccharide storage myopathy in Quarter Horses is a novel glycogen storage disease causing exertional rhabdomyolysis.

BACKGROUND: Both type 1 (PSSM1) and type 2 polysaccharide storage myopathy (PSSM2) are characterised by aggregates of abnormal polysaccharide in skeletal muscle. Whereas the genetic basis for PSSM1 is known (R309H GYS1), the cause of PSSM2 in Quarter Horses (PSSM2-QH) is unknown and glycogen concentrations not defined. OBJECTIVES: To characterise the histopathological and biochemical features of PSSM2-QH and determine if an associated monogenic variant exists in genes known to cause glycogenosis. STUDY DESIGN: Retrospective case control. METHODS: Sixty-four PSSM2-QH, 30 PSSM1-QH and 185 control-QH were identified from a biopsy repository and clinical data, histopathology scores (0-3), glycogen concentrations and selected glycolytic enzyme activities compared. Coding sequences of 12 genes associated with muscle glycogenoses were identified from whole genome sequences and compared between seven PSSM2-QH and five control-QH. RESULTS: Exertional rhabdomyolysis in PSSM2-QH occurred predominantly in barrel racing and working cow/roping performance types and improved with regular exercise and a low starch/fat-supplemented diet. Histopathological scores, including the amount of amylase-resistant polysaccharide (PSSM2-QH 1.4 ± 0.6, PSSM1-QH 2.1 ± 0.3, control-QH 0 ± 0, p < 0.001), and glycogen concentrations (PSSM2-QH 129 ± 62, PSSM1-QH 175 ± 9, control-QH 80 ± 27 mmol/kg, p < 0.0001) were intermediate in PSSM2-QH with significant differences among groups. In PSSM2-QH, abnormal polysaccharide had a less filamentous ultrastructure than PSSM1-QH and phosphorylase and phosphofructokinase activities were normal. Seventeen of 30 PSSM2-QH with available pedigrees descended from one of three stallions within four generations. Of the 29 predicted high or moderate impact genetic variants identified in candidate genes, none were present in only PSSM2-QH and absent in control-QH. MAIN LIMITATIONS: Analyses of PSSM2-QH and PSSM1-QH were performed on shipped samples, controls on frozen samples. CONCLUSIONS: PSSM2-QH is a novel glycogen storage disorder that is not the result of a mutation in genes currently known to cause muscle glycogenoses in other species.

CONTEXTO: Ambos os tipos 1 e 2 de miopatia por acúmulo de polissacarídeo (PSSM) são caracterizados por agregados de polissacarídeos anormais no músculo esquelético. Enquanto a base genética do PSSM 1 é conhecida (R309H GYS1), a causa do PSSM2 em cavalos Quarto de Milha (PSSM2-QH) é desconhecida, e a concentração de glicogênio não é definida. OBJETIVOS: Identificar as características histopatológicas e bioquímicas do PSSM-QH e determinar se há uma variante monogênica em genes conhecidos por causar glicogenose. DELINEAMENTO DO ESTUDO: Caso controlado retrospectivo. METODOLOGIA: 64 PSSM2-QH, 30 PSSM1-QH e 185 QH controles foram identificados em um arquivo de dados. Informação clínica, achados histológicos (escala 0-3), concentração de glicogênio e atividade enzimática de algumas enzimas glicolíticas foram comparadas. Sequências codificadas de 12 genes associados com glicogenose muscular foram identificados nas sequências genômicas completas, e comparadas entre 7 PSSM2-QH e 5 QH controles. RESULTADOS: Rabdomiólise por exercício em PSSM2-QH ocorreu predominantemente em cavalos de corrida de tambor e cavalos de team roping/trabalho com gado, e melhorou com exercício regular e uma dieta com baixo amido e alta gordura. A escala histopatológica, incluindo a quantidade de polissacarídeos resistentes à amilase (PSSM2-QH 1.4 ± 0.6, PSSM1-QH 2.1 ± 0.3, controle-QH 0 ± 0, P < 0.001), e concentrações de glicogênio (PSSM2-QH 129 ± 62, PSSM1-QH 175 ± 9, controle-QH 80 ± 27 mmol/kg, P < 0.0001) foram intermediárias em PSSM2-QH com diferença significante entre grupos. Em PSSM2-QH, polissacarídeo anormal teve uma ultraestrutura menos filamentosa do que PSSM1-QH e as atividades de fosforilase e fosfofrutoquinase foram normais. Dezessete dos 30 PSSM2-QH com pedigree disponível descendiam de 1 de 3 garanhões dentro de 4 gerações. Das 29 variações genéticas preditas a terem impacto moderado ou alto como genes candidatos, nenhuma estava presente apenas em PSSM2-QH e ausente no grupo controle-QH. PRINCIPAIS LIMITAÇÕES: As análises feitas nas amostras de PSSM2-QH e PSSM1-QH foram realizadas em amostras enviadas por correio, e as amostras dos animais controles eram amostras congeladas. CONCLUSÕES: PSSM2-QH é uma nova doença por acúmulo de glicogênio que não é o resultado de uma mutação nos genes conhecidos por causarem glicogenose muscular em outras espécies.

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.

Enriched Pathways of Calcium Regulation, Cellular/Oxidative Stress, Inflammation, and Cell Proliferation Characterize Gluteal Muscle of Standardbred Horses between Episodes of Recurrent Exertional Rhabdomyolysis.

Certain Standardbred racehorses develop recurrent exertional rhabdomyolysis (RER-STD) for unknown reasons. We compared gluteal muscle histopathology and gene/protein expression between Standardbreds with a history of, but not currently experiencing rhabdomyolysis (N = 9), and race-trained controls (N = 7). Eight RER-STD had a few mature fibers with small internalized myonuclei, one out of nine had histologic evidence of regeneration and zero out of nine degeneration. However, RER-STD versus controls had 791/13,531 differentially expressed genes (DEG). The top three gene ontology (GO) enriched pathways for upregulated DEG (N = 433) were inflammation/immune response (62 GO terms), cell proliferation (31 GO terms), and hypoxia/oxidative stress (31 GO terms). Calcium ion regulation (39 GO terms), purine nucleotide metabolism (32 GO terms), and electron transport (29 GO terms) were the top three enriched GO pathways for down-regulated DEG (N = 305). DEG regulated RYR1 and sarcoplasmic reticulum calcium stores. Differentially expressed proteins (DEP ↑N = 50, ↓N = 12) involved the sarcomere (24% of DEP), electron transport (23%), metabolism (20%), inflammation (6%), cell/oxidative stress (7%), and other (17%). DEP included ↑superoxide dismutase, ↑catalase, and DEP/DEG included several cysteine-based antioxidants. In conclusion, gluteal muscle of RER-susceptible Standardbreds is characterized by perturbation of pathways for calcium regulation, cellular/oxidative stress, inflammation, and cellular regeneration weeks after an episode of rhabdomyolysis that could represent therapeutic targets.

Recent advances in our understanding of genetic rhabdomyolysis.

PURPOSE OF REVIEW: This review summarizes recent advances in our understanding of the genetics of rhabdomyolysis. RECENT FINDINGS: Rhabdomyolysis is the acute breakdown of myofibres resulting in systemic changes that can be life-threatening. Environmental triggers, including trauma, exercise, toxins and infections, and/or gene defects can precipitate rhabdomyolysis. A schema (aptly titled RHABDO) has been suggested for evaluating whether a patient with rhabdomyolysis is likely to harbour an underlying genetic defect. It is becoming increasingly recognized that defects in muscular dystrophy and myopathy genes can trigger rhabdomyolysis, even as the sole or presenting feature. Variants in genes not previously associated with human disease have been identified recently as causative of rhabdomyolysis, MLIP , MYH1 and OBSCN . Our understanding of the pathomechanisms contributing to rhabdomyolysis have also improved with an increased awareness of the role of mitochondrial dysfunction in LPIN1 , FDX2 , ISCU and TANGO2 -mediated disease. SUMMARY: An accurate genetic diagnosis is important for optimal clinical management of the patient, avoiding associated triggers and genetic counselling and cascade screening. Despite recent advances in our understanding of the genetics contributing to rhabdomyolysis, many patients remain without an accurate genetic diagnosis, suggesting there are many more causative genes, variants and disease mechanisms to uncover.

Severe rhabdomyolysis in neuronal ceroid lipofuscinosis type 7.

Neuronal ceroid lipofuscinosis (CLN) 7 typically presents with motor and cognitive decline, seizures (myoclonus) and vision loss. Atypical manifestations such as, ataxia, Rett-like findings, microcephaly, personality disorders, extrapyramidal symptoms, stereotypical hand movements and autistic behaviors had been reported. A 7-year-old male patient referred with the diagnosis of sepsis and a medical history of afebrile seizure at the age of 3 years, and sleep problems and aggressive behavior at the age of 4 years. Dance-like movements were noted in his arms and legs. Laboratory tests identified elevated creatine kinase, and diffuse acanthocytes in a peripheral blood smear. A genetic analysis for chorea-acanthocytosis was conducted but no pathogenic variant was detected in the VPS13A gene. A homozygous deletion in the MFSD8 gene was detected with whole exome sequencing. Upon the initiation of treatment for the septic shock, the CK level regressed to normal value and the acanthocytes in the peripheral blood smear disappeared. Acanthocytosis and rhabdomyolysis were attributed to sepsis. This report suggest that CLN7 should be kept in mind in neurodegenerative findings with similar clinical findings and in the presence of choreo-athetotic movements.