Elevated CK Research Articles

Genetic and clinical characteristics of 26 cases with glycogen storage disease type Ⅲ

Objective: To investigate the genetic, clinical, and post-treatment characteristics of patients with glycogen storage disease type Ⅲ (GSD Ⅲ). Methods: A retrospective cohort analysis was performed on the genetic and clinical data of 26 cases with GSD Ⅲ who visited the Children's Hospital affiliated with Fudan University from June 2017 to December 2023. The patients were divided into non-missense variation and missense variation groups according to the types of mutation in the AGL gene.The correlation between genotype and phenotype was analyzed. All patients were treated with uncooked cornstarch after diagnosis. The changes before and after treatment were compared in patients who underwent more than twelve months of follow-up. A P value of <0.05 was used to denote statistical significance. Results: Among the 26 cases enrolled, 13 were female and 13 were male, and the median age of diagnosis was 28 (6 to 134) months. A total of thirty-five different types of AGL gene variation were detected, with c.1735+1G＞T (9/52, 17.3%) as the hotspot variation. The common clinical manifestations were elevated aminotransferases (26/26, 100%), hepatomegaly (25/26, 96.2%), fasting hypoglycemia (25/26, 96.2%), hyperketonemia (16/18, 88.9%), hypertriglyceridemia (TG) (20/26, 76.9%), elevated CK (16/25, 64.0%), and an abnormal electrocardiogram (12/16, 75.0%). Four cases (15.4%) had symptoms of myopathy at diagnosis. Liver biopsy was performed in eighteen cases, among whom 83.3% (15/18) had liver fibrosis≥S2. The number of cases with elevated levels of CK (P＝0.031) and ALT (P＝0.038)was pronounced in the non-missense variation group compared to that in the missense variation group. There were no statistically significant differences in age, height, liver size, degree of fibrosis, fasting blood glucose (Glu) and TG (P>0.05). The median follow-up time of 14 cases was 40.5 (20-73) months, with improvement in body stature, reduced liver size, decreased ALT and TG, and improved Glu. However, four (28.6%) cases had new myopathy symptoms with raised CK (P<0.05) and with advancing age, increased ALT diminished while CK level elevated (P<0.05). Conclusions: The common clinical manifestations at the early stage of the GSD Ⅲdiagnosis are elevated aminotransferases, hepatomegaly, fasting hypoglycemia, hyperketonemia, high triglycerides, elevated CK, and fibrotic liver in China. Myopathy symptoms may arise following uncooked cornstarch treatment; however, there is significant improvement in height, liver-related, and metabolic parameters.

INNV-31. THE USE OF IVOSIDENIB IN PATIENTS WITH ENHANCING IDH1 MUTANT GLIOMAS

Abstract Ivosidenib offers a novel targeted therapy for non-enhancing IDH1 mutated gliomas following initial resection. Potential effects of IDH inhibitors on enhancing disease in clinical settings are not well established. This study characterizes a cohort of patients with IDH1 mutated gliomas with enhancing disease, who were initiated on monotherapy, off-label ivosidenib between October, 2020 to August, 2023. The cohort included 21 patients ages 29 to 73 years, 11 female and 10 male. Diagnoses represented were astrocytoma IDH1 mutant, grade 2-4 (N=9) and oligodendrogliomas IDH1 mutant, grade 2-3 (N=12). Prior treatment exposures included radiation therapy (N=11), temozolomide (N=15), bevacizumab (N=3), and treatment naïve (N=6). Time from diagnosis to ivosidenib initiation was 9.1±2.7 years. Although all patients had enhancing disease, ivosidenib was initiated due to non-enhancing disease progression (N=7), enhancing disease progression (N=13), and temozolomide intolerance (N=1). Size of enhancement by cross-section measured &amp;gt;1cm (N=15) and &amp;lt;1cm (N=6). Best radiographic responses per RANO criteria were partial response (N=3), stable disease (N=11), and progressive disease (N=7). At last contact, eleven patients were maintained on ivosidenib with no evidence of disease progression since initiation with an average treatment duration of 25.5±6.4 months and overall survival of 11.7±3.1 years. Ten patients had disease progression at median 5.2±3.1 months following ivosidenib initiation, three of whom died 16.7 (range 6.8-34.4) months after treatment initiation with an overall survival of 9.4 years (range 4.6-13.6). Adverse events from therapy included diarrhea (N=2), CK elevation (N=4), and QTc prolongation (N=2). No patients discontinued ivosidenib due to adverse events. No significant difference was detected between patients with and without disease progression due to size of enhancement (p=0.4) or prior treatment exposure (p=0.3). Future studies should include biopsies to understand the role of enhancing lesions in treatment response of IDH inhibitors.

DDDR-24. REAL WORLD EXPERIENCE USING THE IDH INHIBITOR IVOSIDENIB IN IDH MUTANT GLIOMA: TOLERABILITY AND OUTCOMES

Abstract BACKGROUND Mutant isocitrate dehydrogenase (IDHm) inhibitors represent a novel therapeutic strategy for treating IDHm glioma, though their optimal use outside of clinical trials remains undefined. This study describes real world utilization of the IDH1 inhibitor, ivosidenib, in patients with IDHm glioma. METHODS We retrospectively reviewed clinical and radiographic data from IDHm glioma patients treated with ivosidenib monotherapy at Dana-Farber Cancer Institute and Massachusetts General Hospital from 2020-2024. Patients with a baseline MRI at ivosidenib initiation and at least 2 subsequent scans while on ivosidenib were included in radiographic response analysis (452 scans). RESULTS This cohort included 77 patients (39 males) age 17-75 years (median 41). Thirty-eight patients (49%) had astrocytomas and 39 (51%) had oligodendrogliomas; 48 (62%) had grade 2, 26 (34%) grade 3, and 3 (4%) grade 4 gliomas. Twenty-four patients (31%) received ivosidenib as first-line therapy and 53 (69%) received ivosidenib after failing prior treatments. Among those in the radiographic analysis, 4 (6%) demonstrated partial response, 4 (6%) minor response, 44 (62%) stable disease, and 19 (27%) progressive disease (PD). Significantly higher PD rates were seen in those with enhancing disease (p&amp;lt;0.001) or received ivosidenib as subsequent-line therapy (p=0.002); PD rate was similar between grades 2 and 3 in the first-line group (p=0.64). One-year progression free survival was 100% in the first-line group and 66% in the subsequent-line group. At the time of our analyses, 4 patients (5%) had died (all in the subsequent-line group). Infrequent side effects included CK elevation, QTc prolongation, transaminitis, and diarrhea. One patient (1%) was dose reduced and 3 (4%) discontinued drug due to side effects. CONCLUSIONS In this real world IDHm glioma cohort, ivosidenib was well-tolerated. Better response rates were seen in patients without enhancing disease at ivosidenib initiation and those who received the drug as first-line therapy.

8800 A Case of Hypopituitarism Due to Sheehan Syndrome

Abstract Disclosure: N. Akabogu: None. S. Dejhansathit: None. F. Marium: None. B. Stanley: None. E.M. Bazuaye: None. L.S. Krusniak: None. L.G. Kurukulasuriya: None. U.Z. Khan: None. Background: Sheehan syndrome, which is also known as postpartum pituitary infarction, refers to the necrosis of the anterior pituitary gland due to postpartum hypovolemia, hemorrhage, shock, resulting in various degrees of hypopituitarism. The pituitary gland enlarges during pregnancy due to estrogen stimulation and becomes hyper-vascular, making it prone to infarction with postpartum hemorrhage. The initial symptoms include hyponatremia, weakness, weight loss, but the most prominent specific symptoms are inability to nurse and postpartum amenorrhea. Depending on the severity of hypopituitarism, symptoms may develop within the first few days to weeks after delivery or may take months to years to develop. Case presentation: 35year-old Caucasian female with a medical history of gestational diabetes, hyperlipidemia, and hypertension, who presented to the hospital with flu-like symptoms, leg pain, abdominal pain, and proximal muscle weakness. The evaluating hospitalist observed that patient appeared sluggish and spoke with a deep coarse voice, which concerned him for hypothyroidism. Thyroid function test revealed undetectable free T4 with inappropriately normal TSH of 1.38 – consistent with secondary hypothyroidism. Additional history from patient uncovered 9 months history of constant fatigue, weight gain, dry skin, hair loss, cold intolerance, and intermittent ankle swelling. There is no history of brain irradiation or head trauma. She has 4 biological children, and her last childbirth 3years ago was complicated by severe bleeding from her incision site, requiring transfusion of 6 units of blood. She has been amenorrheic since and is neither on birth control nor had hysterectomy. Physical exam showed mildly enlarged tongue, diffuse pallor, dry scaly skin on upper arms, scanty eyebrows, and slowed speech. Further work-up for pituitary insufficiency showed secondary adrenal insufficiency, secondary hypogonadism, low prolactin, and growth hormone deficiency. There was no evidence of AVP deficiency. Other lab and clinical findings were hypoglycemia, hyperlipidemia, elevated CK, elevated Cr, pericardial effusion, and diastolic hypertension. Pituitary MRI showed markedly attenuated and flattened pituitary gland with no focal mass. Patient was given stress dose hydrocortisone and thyroid hormone replacement, initially IV then oral. Following hydrocortisone and thyroid hormone replacement, her diastolic BP, hypoglycemia, CK, and Cr improved. Further management plans include initiating estrogen (plus progesterone) for bone health. Conclusion: Although Sheehan syndrome is rare in developed countries, it does occur. This case emphasizes the importance of detailed history taking, to discover the root of patients’ presentation. Even though TSH is the screening test for thyroid disease, when pituitary etiology is suspected, it is important to also check a free T4. Presentation: 6/1/2024

12375 Rhabdomyolysis As A Cause Of PTH-independent Hypocalcemia In A Child With Acute Influenza Infection

Abstract Disclosure: S. Bhattarai: None. K. Halpin: None. Introduction: Hypocalcemia is characterized by low blood calcium level. Normal range for calcium for ages 12- 19-year is 8.5-10.6 mg/dli . Severe hypocalcemia is considered as serum calcium level of &amp;lt;7 mg/dl. Hypoparathyroidism, pseudohypoparathyroidism and Vitamin D deficiency are some of the most common causes encountered by pediatrician endocrinologists. Rhabdomyolysis with hypocalcemia and elevated PTH is a rare presentation that should be considered, particularly for children presenting with acute viral illness. We present a rare case of rhabdomyolysis associated with hypocalcemia not related to hypoparathyroidism. Case: A 12-year-old female presented to the ED with body ache, poor oral intake and vomiting. She was found to be influenza positive. Labs showed hypocalcemia (4.8 mg/dl). She had an undetectable 25-OH vitamin D level (&amp;lt;5 ng/ml) and elevated iPTH level (609 pg/ml). We discussed the possibility of her etiology of hypocalcemia as Vitamin D deficiency although her presentation was atypical at an older age with negative imaging for rickets, hyperphosphatemia (6.0 mg/dl), and normal ALP (334 unit/L). She did not have any phenotypic features of Albright’s hereditary osteodystrophy with normal renal function. She had elevated CK (4829 U/L) supporting rhabdomyolysis secondary to acute influenza as a cause of her hypocalcemia. Rhabdomyolysis, a known complication of influenza infection, causes cell membrane destruction which impairs the normal function of Na-K-ATPase channel leading to increase in intracellular sodium activating Na/Ca exchanger. This in turn causes influx of calcium intracellularly causing hypocalcemia. Additionally, any injury leads to high phosphorus release from cells due to its lysis. High phosphorus is also caused by reduced oxidative metabolism in muscles impairing phosphate use. This excess of phosphate then combines with calcium and causes calcium-phosphate complex in soft tissues. Hyperphosphatemia additionally inhibits 1 alpha hydroxylase limiting formation of calcitriol leading to hypocalcemia. iiConclusion: Our patient had severe hypocalcemia due to influenza-related rhabdomyolysis. Rhabdomyolysis is an important cause of hypocalcemia in children, especially with acute viral illness. Accordingly, it is also important to obtain serum electrolytes in patients presenting with rhabdomyolysis as hypocalcemia may lead to complications like seizures and cardiac arrhythmia. Endnotes:i Roizen, Jeffrey &amp; Shah, Vipul &amp; Levine, Michael &amp; Carlow, Dean. (2013). Determination of Reference Intervals for Serum Total Calcium in the Vitamin D-Replete Pediatric Population. The Journal of clinical endocrinology and metabolism. 98. 10.1210/jc.2013-3105.ii Ding LN, Wang Y, Tian J, Ye LF, Chen S, Wu SM, Shang WB. Primary hypoparathyroidism accompanied by rhabdomyolysis induced by infection: A case report. World J Clin Cases. 2019 Oct 6;7(19) Presentation: 6/2/2024

8188 Pituitary hyperplasia resulting from primary hypothyroidism: A case report

Abstract Disclosure: M. Aziz: None. M.I. Manolas: None. V. Tabatabaie: None. L. Rincon: None. Pituitary hyperplasia resulting from primary hypothyroidism: A case report.Background: Primary hypothyroidism is a common endocrine condition seen in 4.6% of USpopulation (1). We describe an uncommon presentation of prolonged severe primaryhypothyroidism leading to significant hyperplasia of the pituitary gland resembling a pituitarymacroadenoma. Clinical Case: A 34-year male with schizophrenia and Hashimoto’s hypothyroidism diagnosedat the age of 17 presented with hallucinations, chest pain, fatigue, and dyspnea. The patient hada 15-year history of uncontrolled hypothyroidism with persistently elevated TSH with values ashigh as 2,299 (n 0.30-4.20 uU/mL) due to poor adherence to levothyroxine. Initial laboratorystudies revealed hyponatremia (Na 130, n135-145 mEq/L), elevated TSH (&amp;gt;100, n0.30-4.20 uU/mL), undetectable FT4 (&amp;lt;0.4, n0.6-1.5 ng/dL) and elevated CK (5671, n&amp;lt;200 U/L).Levothyroxine was restarted at dose of 150 mcg daily. Head CT performed for evaluation ofaltered mental status and hallucinations revealed hyperdensity within the pituitary gland,concerning for underlying hemorrhage and apoplexy. Neurosurgical consultation was requested,and a pituitary MRI was obtained in preparation for potential surgical intervention. MRI showeda prominent anterior pituitary gland measuring up to 14 mm with homogeneous enhancementwithout evidence of hemorrhage. In the absence of any hemorrhage or definitive mass, thepituitary enlargement was considered secondary to the long-standing history of uncontrolledprimary hypothyroidism leading to pituitary hyperplasia, and surgical intervention was deemedunnecessary. Repeat labs 1 week later showed TSH &amp;gt;100uU/mL, FT4 0.6 ng/dL, CK 2799 andrepeat MRI showed slight decrease in size of the pituitary gland, confirming hyperplasiasecondary to severe, prolonged hypothyroidism. Conclusion: Prolonged primary hypothyroidism can lead to pituitary hyperplasia which can bemistaken as pituitary macroadenoma, leading to unnecessary surgical intervention. Carefulreview of history and TSH trends can help elucidate this diagnosis.

WITHDRAWN: Shenmai Injection Exerts the Cardioprotective Effects by Modulating Autophagy-apoptosis via Beclin-1

Background and aimDespite the excellent efficacy of anthracyclines, their clinical application is subject to cardiotoxicity. Studies have shown that Shenmai Injection(SMI) alleviated anthracycline-induced myocardial injury, however, the exact mechanism has not been clarified. Experimental procedureEach intervention was explored by detecting the viability of cardiomyocytes, LDH leakage rate, and CK levels. Finally, the effects of each intervention on autophagy-apoptosis and Beclin-1 were observed by using mCherry-EGFP-LC3B double fluorescence method, Annexin V/propidium iodide (PI), and protein immunoblotting method to explain the mechanism of Shenmai Injection. Key resultsThe viability of H9c2 cells in the model group decreased, accompanied by elevated LDH leakage rate and CK levels after doxorubicin intervention (P<0.01 or P<0.05). In contrast, SMI reversed above situation (P<0.01 or P<0.05). Besides, autophagy and apoptosis up-regulated in the model group (P<0.01), accompanied by upregulated Beclin-1, LC3-II, LC3-II/LC3-I, apoptosis effector proteins Cleaved-Caspase-9, Cleaved-Caspase-9/Caspase-9, Cleaved-Caspase-3, Cleaved-Caspase-3/Caspase-3 expressions and the downregulation of p62 protein, anti-apoptotic protein Bcl2 expressions (P<0.01 or P<0.05). Nonetheless, autophagy and apoptosis were decreased with the help of SMI (P<0.01 or P<0.05). ConclusionSMI alleviated autophagy and apoptosis of damaged cardiomyocytes by regulating Beclin-1.

Clinical Features in Boys with Duchenne/Becker Muscular Dystrophy: A Tertiary Center Experience

Background: Dystrophin-related muscular dystrophies are a group of diseases caused by mutations in the dystrophin gene that are inherited in an X-linked recessive manner. Objectives: We aimed to discuss the clinical, laboratory, genetic, treatment, and prognostic features, as well as diagnostic clues, of our DMD/BMD patients. Methods: The medical records of 39 children who were followed up with DMD/BMD diagnoses at Bursa Uludağ University Faculty of Medicine Child Neurology Clinic between August 2018 and September 2023 were evaluated retrospectively. DMD or BMD is diagnosed by genetic testing or muscle biopsy. Results: All patients were male, and the age of symptom onset was 3.44 ± 2.7 years (range: 1 - 12.2 years). Twenty-two cases were symptomatic, presenting with difficulty walking (N = 17), difficulty climbing stairs (N = 14), and getting tired quickly (N = 11). Seventeen cases were initially asymptomatic, identified through elevated CK, AST, and ALT levels. Conclusions: Early recognition that increased serum transaminase and CK levels reflect muscle disease accelerates the diagnosis of underlying conditions and protects patients from unnecessary, invasive, and costly diagnostic testing.

The first reported familial case of statin-induced immune-mediated necrotizing myopathy associated with anti-hydroxy-3-methylglutaryl-CoA reductase autoantibodies and HLA DRB1*11:01

ABSTRACT Immune-mediated necrotizing myopathy (IMNM) is a rare type of auto-immune myositis, characterized by symmetric muscle pain, proximal weakness, elevated serum CK levels and pathologic findings of necrotized muscle fibers. IMNM may be seronegative, associated with anti-signal recognition particle (SRP) antibodies or anti-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibodies, the last widely related with statin use. This last entity affects only 2 to 3 of 100,000 patients under statins. Recently, patients carrying the class II human leukocyte antigen (HLA) DRB1*11:01 were identified to be more at risk to present IMNM with anti-HMGCR antibodies. We describe the case of a daughter and father diagnosed with HMGCR-IMNM and both carrying HLA DRB1*11:01. To our knowledge, it is the first familial case reported in the literature.

Defining the landscape of TIA1 and SQSTM1 digenic myopathy

TIA1/SQSTM1 myopathy is one of the few digenic myopathies. We describe four new French adult male patients carrying the TIA1 p.Asn357Ser and SQSTM1 p.Pro392Leu variant and review the literature to include 20 additional cases to define the spectrum of the disease. These twenty-four patients (75% males) had late-onset (52,6 ± 10,1 years), mainly asymmetric, distal ankle and hand finger extension weakness (75%), mild CK elevation (82.4%) and myopathic EMG. Two of the four French patients had sensorimotor axonal polyneuropathy and an additional one had neurogenic changes in muscle biopsy. Muscle biopsy showed rimmed vacuoles (44.4%), myofibrillar disorganization (16.7%) or both (38.9%), with P62/TDP43 aggregates. The TIA1 p.Asn357Ser variant was present in all patients and the SQSTM1 p.Pro392Leu was the most frequent (71%) of the four reported SQSTM1 variants. We reviewed the distal myopathy gene panels of Pitié-Salpêtrière's hospital cohort finding a prevalence of 11/414=2.7% of the TIA1 p.Asn357Ser variant, with two patients having an alternative diagnosis (TTN and MYH7) with atypical phenotypes, resembling some of the features seen in TIA1/SQSTM1 myopathy. Overall, TIA1/SQSTM1 myopathy has a homogenous phenotype reinforcing the pathogenicity of its digenic variants. We confirm an increased burden of the TIA1 p.Asn357Ser variant in distal myopathy patients which could act as a genetic modifier.

LGG-55. DIFFERENTIAL TOXICITY PROFILE OF INDIVIDUAL MEK INHIBITORS: A MULTI-INSTITUTION RETROSPECTIVE REVIEW

Abstract BACKGROUND Most pediatric low-grade gliomas (pLGGs) are driven by molecular aberrations in the mitogen-activated protein kinase pathway (MAPK), which can be targeted by novel agents such as MEK inhibitors (MEKi.) However, MEKi use is accompanied by a varied side effect profile, with the most severe dose-limiting effects involving dermatologic, cardiac, and ophthalmic toxicities. METHODS Multi-institutional retrospective chart review of patients less than 25 years of age who underwent MEKi monotherapy between 2015-2022 was conducted. Data was collected from 4 sites, including Connecticut Children’s, St. Louis Children’s Hospital, Cardinal Glennon Children’s Hospital, and Children’s Hospital of Philadelphia. RESULTS Ninety-six patients were included in the analysis; 54 (56.4%) with brain tumors and 56 (58.3%) with germline mutation in NF-1. Forty-nine (51%) received trametinib, 42 (43.8%) selumetinib, 5 (5%) binimetinib. Of 42 patients with skin toxicity data available, 35 (83%) had cutaneous toxicity, with the most prevalent being acneiform rash (40.0%), followed by maculopapular rash (28.6%) and eczematous dermatitis (11.4%). The mean number of cutaneous skin toxicities was 2.4 (trametinib group = 2.2, selumetinib group = 2.6). Eighteen of 96 (18.8%) patients experienced cardiac toxicity, of which 11 (61.1%), experienced reduction in left ventricular ejection fraction (6 trametinib, 5 selumetinib), 4 (22.2%) developed pericardial effusions. 10 of 96 (10.4%) patients experienced ophthalmic toxicities, most commonly blurred vision (30.0%). Other toxicities included elevated CK (36, 37.5%), anemia (32, 33.3%), and eosinophilia (17, 17.7%). CONCLUSION There was not an observable clinically relevant difference in toxicities between MEKi, with skin toxicity the most prevalent. The prevalence of cardiac toxicity in the patient cohort reinforces the need for appropriate monitoring via echocardiography. MEKi remain an excellent option for therapy for LGG but with the need for continued supportive care and monitoring.

P.042 Anti-HMG Coenzyme A reductase antibody (anti-HMGCR) myopathy: case review of two pediatric patients from a single center

Background: Necrotizing anti-HMGCR myopathy is rare in children. Pediatric cases are not typically associated with statin use or malignancy. Methods: Retrospective chart review (January 2009 to December 2023) identified cases of anti-HMGCR myopathy at our hospital. Results: Two patients were identified. Patient A, presented at 8 yo with a 2 year history of proximal muscle weakness. His CK was 4,840 U/L (normal &lt;205 U/L) with a high anti-HMGCR antibody titre. His Childhood Myositis Assessment Scale (CMAS) score was 33/52. Monthly IVIG was started and his muscle strength and CK improved. Two years later, weekly methotrexate was started for persistent mild CK elevation (602 to 869 U/L). At 11 years old, 3 years after diagnosis, his CMAS score was 47 and he could participate in soccer with mild fatigue. Patient B, presented at 8 yo with acute proximal weakness, rash and CMAS 13/52. His CK was 20,185 U/L with elevated anti-HMGCR antibody titre. He received oral corticosteroids, weekly methotrexate and monthly IVIG. At 10 yo, 2 years after diagnosis, he is asymptomatic with CMAS 51. He is maintained on methotrexate monotherapy. Conclusions: Anti-HMGCR antibody myopathy requires prompt diagnosis to obviate muscle necrosis and long-term complications. Our patients showed clinical and CMAS improvement with treatment.

Phenotype variability and natural history of X-linked myopathy with excessive autophagy.

X-linked myopathy with excessive autophagy (XMEA) linked to the VMA21 gene leads to autophagy failure with progressive vacuolation and atrophy of skeletal muscles. Current knowledge of this rare disease is limited. Our objective was to define the clinical, radiological, and natural history of XMEA. We conducted a retrospective study collecting clinical, genetic, muscle imaging, and biopsy data of XMEA patients followed in France and reviewed the literature for additional cases. Eighteen males had genetically confirmed XMEA in France, carrying four different VMA21 variants. Mean age at disease onset was 9.4 ± 9.9 (range 1-40) years. In 14/18 patients (77.8%), onset occurred during childhood (< 15years); however in four patients, the disease started in adulthood. Patients had anterior and medial compartment thigh muscle weakness, distal contractures (56.3%), elevated CK levels (1287.9 ± 757.8U/l) and autophagic vacuoles with sarcolemmal features on muscle histopathology. Muscle MRI (n = 10) showed a characteristic pattern of lower limb muscle involvement. In 11 patients, outcome measures were available for an average follow-up period of 10.6 ± 9.8years and six of them show disease progression. Mean change of functional outcomes was 0.5 ± 1.2 points for Brooke and 2.2 ± 2.5 points for Vignos score, 7/16 patients (43.8%) needed a walking aid and 3/16 (18.8%) were wheelchair-bound (median age of 40years old, range 39-48). The variant c.164-7T > G was associated with a later onset of symptoms. Respiratory insufficiency was common (57.1%) but cardiac involvement rare (12.5%). XMEA has variable age of onset, but a characteristic clinical, histopathological, and muscle imaging presentation, guiding the diagnosis. Although slowly, motor disability progresses with time, and relevant genotype-phenotype correlations will help design future clinical trials.

Creatine kinase elevation in chronic hepatitis B patients with telbivudine therapy: influence of telbivudine plasma concentration and single nucleotide polymorphisms of TK2, RRM2B, and NME4.

To study the correlations of genetic variants of telbivudine phosphorylase kinases and telbivudine plasma concentration with creatine kinase elevation in chronic hepatitis B patients who received telbivudine. An observational study was performed in China chronic hepatitis B patients receiving telbivudine therapy at 600mg once daily. Plasma concentration was measured 12h after taking telbivudine using ultra-performance liquid chromatography-tandem mass spectrometry and SNPs located in RRM2B, TK2, and NME4 was detected by MALDI-TOF mass spectrometry. All statistical analyses were performed with R 4.3.1 and all graphs were drawn by Origin 2023b and P value < 0.05 was considered statistically significant. A total of 140 patients receiving telbivudine therapy were recruited with a median plasma concentration of 952.49 (781.07-1238.98) ng/mL. The value of plasma concentration was proportional to the grade of creatine kinase elevation and the best telbivudine plasma concentration threshold to discriminate the grade 3/4 CK elevation was 1336.61ng/mL. Multivariate analysis revealed that plasma concentration and rs3826160 were the independent risk factor of telbivudine-induced creatine kinase elevation. Patients with TC and CC genotype in rs3826160 not only had a higher incidence of creatine kinase elevation but also a higher plasma concentration than TT genotype carriers. Chronic hepatitis B patients with TC and CC genotype in rs3826160 have high telbivudine plasma concentration are at risk of elevated creatine kinase.

Novel Biomarkers for Limb Girdle Muscular Dystrophy (LGMD).

To identify novel biomarkers as an alternative diagnostic tool for limb girdle muscular dystrophy (LGMD). LGMD encompasses a group of muscular dystrophies characterized by proximal muscles weakness, elevated CK levels and dystrophic findings on muscle biopsy. Heterozygous CAPN3 mutations are associated with autosomal dominant LGMD-4, while biallelic mutations can cause autosomal recessive LGMD-1. Diagnosis is currently often based on invasive methods requiring muscle biopsy or blood tests. In most cases Western blotting (WB) analysis from muscle biopsy is essential for a diagnosis, as muscle samples are currently the only known tissues to express the full-length CAPN3 isoform. We analyzed CAPN3 in a cohort including 60 LGMD patients. Selected patients underwent a complete neurological examination, electromyography, muscle biopsy, and skin biopsies for primary fibroblasts isolation. The amount of CAPN3 was evaluated by WB analysis in muscle and skin tissues. The total RNA isolated from muscle, fibroblast and urine was processed, and cDNA was used for qualitative analysis. The expression of CAPN3 was investigated by qRT-PCR. The CAPN3 3D structure has been visualized and analyzed using PyMOL. Among our patients, seven different CAPN3 mutations were detected, of which two were novel. After sequencing CAPN3 transcripts from fibroblast and urine, we detected different CAPN3 isoforms surprisingly including the full-length transcript. We found comparable protein levels from fibroblasts and muscle tissue; in particular, patients harboring a novel CAPN3 mutation showed a 30% reduction in protein compared to controls from both tissues. Our findings showed for the first time the presence of the CAPN3 full-length transcript in urine and skin samples. Moreover, we demonstrated surprisingly comparable CAPN3 protein levels between muscle and skin samples, thus allowing us to hypothesize the use of skin biopsy and probably of urine samples as an alternative less invasive method to assess the amount of CAPN3 when molecular diagnosis turns out to be inconclusive.

P-76 Down Syndrome and Thyroid hormone levels - how low can you go?

Abstract Introduction Down syndrome (DS) is the most common chromosomal condition among live-born infants. It is associated with intellectual disability as well as medical issues ranging from congenital heart disease, obstructive sleep apnea, celiac disease, to endocrinopathies, namely thyroid disorders. The spectrum of thyroid dysfunction in patients with DS include congenital hypothyroidism, subclinical hypothyroidism, acquired hypothyroidism, and hyperthyroidism. Identifying medical comorbidities in these patients can be crucial to optimize their quality of life. Clinical Case This is the case of a male patient, 30 years old, caucasian, institutionalized, with DS and known medical history of esophageal dilation, macroglossia, valvular heart disease with mild aortic insufficiency and left ventricular moderated hypertrophy, macrocytic anemia, and pulmonary embolism 10 months earlier. Due to pallor, somnolence, fatigue, thin and fragile hair, and bradycardia, blood tests were requested and revealed an elevated TSH (385.20 mUI/L, N 0.27-4.20) with undetectable free T4 levels (&amp;lt;0.5 pmol/L, N 12.0-22.0), macrocytic anemia (Hb 11.4 g/dL; MCV 102 fL), renal dysfunction (creatinine 1.73 mg/dL) and hypercholesterolemia (total cholesterol 310 mg/dL; LDL 236 mg/dL). The chest X-ray revealed an heart silhouette enlargement and the echocardiogram showed left ventricular hypertrophy with preserved ejection fraction, diastolic dysfunction, and mild pericardial effusion. The thyroid ultrasound revealed a globally reduced gland, with diffuse hyperechogenicity and heterogeneity, suggesting thyroiditis. The patient was referred to the emergency department and the additional study revealed the presence of anti-TPO and anti-TG antibodies and a severe CK elevation (9280 UI/L, N 46-171). The patient, although lethargic, presented with normal blood pressure, heart rate, and body temperature during the hospital admission. Searching our national health system database, it was found the patient already had TSH elevation with undetectable free T4 levels at least 12 years before, in another hospital, but had lost follow-up there after the blood tests, and therefore remaining undiagnosed and untreated. Oral levothyroxine reposition was started, first with 50 micrograms and then 100 micrograms and the patient was discharged after 5 days with follow-up at the Endocrinology department. Two months later, there were already clinical and laboratory changes, with improved level of consciousness and normalized free T4 levels. Conclusion Although hypothyroidism is a common and widely recognized condition, this case emphasizes how challenging the diagnosis can be in a person with DS. Knowing that this syndrome is associated with several organic dysfunctions, namely endocrine disorders with non-specific clinical manifestations, there must be a high level of suspicion in order to screen, diagnose, and treat the comorbidities that may appear.

Diagnostic accuracy and the first genotype-phenotype correlation in glycogen storage disease type V.

Glycogen storage disease type V (GSDV) is an autosomal recessive metabolic condition caused by pathogenic PYGM variants. This is an underdiagnosed condition as it presents with exercise intolerance in children. We reviewed the GSDV cases of a tertiary hospital center to assess diagnostic timing/accuracy, as well as potential clinical/analytical predictors of such factors. We retrospectively reviewed all GSDV cases with follow-up in both Pediatric and Adult Metabolic Diseases consultations. We included 28 cases and assessed their hospital record for clinical information. Over 90% of our cases had late diagnoses, with more than 50% being diagnosed in adulthood despite symptom onset in preschool (very late diagnosis). Diagnostic age was lower in patients exhibiting myoglobinuria. Interestingly, patients with a positive family history of GSDV had similar rates of very late diagnoses, likely since the index case was already detected very late in life. Finally, we observe that the R50* variant is associated with increased myoglobinuria and CK elevation, in a dosage-dependent manner. We concluded that GSDV is severely underdiagnosed, and that some clinical and analytical aspects of the condition can be more indicative of this diagnosis. Furthermore, we propose for the first time a genotype-phenotype correlation in GSDV. GSDV is a pediatric-onset metabolic disorder that is mostly diagnosed late in the adult age and commonly misdiagnosed. We observed the first genotype-phenotype correlation in GSDV, regarding the common R50* variant. Awareness of GSDV for pediatricians and the overall medical community is vital.

328. One-Day Holiday: An Approach to Managing Daptomycin-Induced CK Elevations in OPAT

Abstract Background Daptomycin can be ideal for outpatient parenteral antimicrobial therapy (OPAT) due to its once-daily dosing, tolerability, and lack of nephrotoxicity compared to vancomycin. Though infrequent, skeletal myopathy with associated elevation of serum creatinine kinase (CK) is a clinically significant adverse effect associated with daptomycin. Risk factors associated with CK elevations include initial dose, obesity, chronic kidney disease, and statin use. Based on a case series by Burdette et. al, the UNC OPAT Program manages asymptomatic mild-to-moderate CK elevations by either a one-day dose holiday with continuation of the same dose or one-day daptomycin holiday followed by dose reduction. We assessed the effectiveness of this strategy for allowing continuation of daptomycin in our patient population.Figure 1:Daptomycin and CK Elevations FlowchartTable 1:Baseline Demographics Methods A total of 396 patients received daptomycin in the OPAT Program from March 2015 to January 2023. We analyzed associated baseline risk factors for patients with CK elevations above 500 U/L and management strategies (e.g., one-day holiday, dose reduction, and/or drug discontinuation). CK elevations were defined as mild (500-999 U/L), moderate (1000-1999 U/L), or severe (≥ 2000 U/L). Results Of the 396 patients on daptomycin, 36 (9%) experienced a CK elevation &amp;gt; 500 U/L. 34 (94%) patients required further management. 58% of patients were asymptomatic, with 55% having mild CK elevation. Most reported symptoms were muscle/joint pain. On average, CK elevations occurred 18 days (± 9) into therapy, with a shorter time to CK elevation for severe (11 days ± 2) and moderate elevation (14 days ± 6). Lab abnormalities were managed within one day. Of the 7 patients that had a one-day holiday only, 5 experienced CK improvement. Of the 8 patients with a one-day holiday + dose reduction, 6 showed CK improvement. No patient with dose reductions had readmission during treatment course and one had infection recurrence within 90 days. Conclusion The one-day holiday +/- dose reduction adjustment strategy for management of CK elevations allowed for continuation of daptomycin without compromising treatment or leading to hospital readmission. Timely evaluation of safety labs and dose adjustment strategies are key in managing CK elevations for OPAT patients receiving daptomycin. Disclosures Asher J. Schranz, MD, MPH, WoltersKluwer: Honoraria Alan C. Kinlaw, PhD, Genentech: Grant/Research Support

Clinicopathological characteristics of gastric cancer patients with dermatomyositis and analysis of perioperative management: a case series study.

This study aimed to investigate the clinical characteristics of gastric cancer (GC) patients with dermatomyositis (DM) and summarize the perioperative outcomes. The clinical and pathological data of five patients diagnosed with co-occurring DM and GC (DM-GC group) were retrospectively analyzed, who were admitted to the Department of Gastrointestinal Surgery at Ren ji Hospital, Shanghai Jiao Tong University, between January 2012 and April 2023. Their data were compared with 618 GC patients (GC-1 group) from September 2016 to August 2017 and 35 GC patients who were meticulously screened from 14,580 GC cases from January 2012 and April 2023. The matching criteria included identical gender, age, tumor location, TNM stage, and surgical procedure (7 GC patients were matched for each DM-GC patient). Analysis indicated that the DM-GC group comprised four female and one male patient. The female proportion was significantly higher (P = 0.032) than that of GC-1 group. In DM-GC group, four DM patients were diagnosed as GC within 12 months. One DM patients was diagnosed as GC within 15 months. Among them, four patients presented with varying degrees of skin rashes, muscle weakness while one patient had elevated CK levels as the typical symptom. Similarly, the preoperative tumor markers (CA-199 and CA-125) in the DM-GC group were significantly higher than normal levels (CA-199: 100 vs. 28.6%, P = 0.002; CA-125: 40 vs. 2.9%, P = 0.003) compared to GC-2 group. Moreover, postoperative complication incidence and the length of hospital stay were significantly higher in the DM-GC than GC-2 group [complication rate: 40 vs. 8.6%, P = 0.047; hospital stay: 15 days (range: 9-28) vs. 9 days (range: 8-10), P = 0.021]. GC Patients with dermatomyositis are more prone to experience postoperative complications and longer hospital stay.

Unusual Presentation of Rhabdomyolysis &amp; Acute Kidney Injury in a Young Patient with Associated Pancreatitis of Un-Known Etiology

A case of 41-year-old patient presented with left lower leg cellulitis, laboratory investigations showed elevated CK levels of more than 193000 U/L, high pancreatic enzymes level namely amylase &amp; lipase, significant electrolyte and acid base abnormalities. Diagnosis of Rhabdomyolysis made based on CK level results in acute pancreatitis. This patient developed acute renal failure with all above in mind, he stayed inpatient for 19 days. The purpose of this case report is to highlight the unusually high CK with unusual association of acute pancreatitis leading to rhabdo¬myolysis and the associated morbidity.