Creatine transporter deficiency (CTD) is a rare X-linked disease caused by SLC6A8 variants, which impair ATP-dependent energy metabolism in neurons and myocytes. Although the neurologic and muscular manifestations are well characterized, the cardiac phenotype remains poorly understood. Early clinical reports and a transgenic mouse model have raised concerns about possible associations with corrected QT (QTc) interval prolongation and dilated cardiomyopathy. This study aimed to characterize the cardiac phenotype of male patients with CTD. This cross-sectional study prospectively included male patients with CTD with confirmed SLC6A8 pathogenic variants. A systematic cardiological evaluation was performed, including 12-lead resting electrocardiogram (ECG), ambulatory ECG (Holter monitoring), transthoracic echocardiography, and biological analysis. 23 male patients with CTD (median [interquartile range] age 17.1 years [13.5-20.5]) with 20 distinct SLC6A8 variants were included. Prominent U-waves were observed in 82.6% of resting ECGs and 95% of ambulatory ECGs, and biphasic T-waves in 30.4% and 90%, respectively. No patient had a prolonged QTc interval (median [interquartile range] QTc interval 431 ms [411-443]) when the U-waves were excluded. Repolarization abnormalities were not secondary to electrolyte disorders. No sustained arrhythmias or conduction disorders were observed. No patient reported syncope or cardiac arrest. Transthoracic echocardiography revealed no cardiomyopathy or congenital heart defects. 2 patients had mildly elevated N-terminal pro-brain natriuretic peptide with no clinical or imaging abnormalities. This study highlighted an atypical ventricular repolarization pattern in patients with CTD (prominent U-waves and biphasic T-waves) without QTc interval prolongation. Long-term follow-up data are needed to establish its prognosis, but it must be distinguished from long-QT syndrome. No patient met diagnostic criteria for cardiomyopathy or congenital heart defect.

Type 2 Long QT Syndrome (type 2 LQTS) is a cardiac channelopathy caused by pathogenic variants in the KCNH2 gene, often associated with delayed cardiac repolarization and increased risk of arrhythmias. While its impact is traditionally considered cardiac, emerging studies suggest a potential role of KCNH2 dysfunction in neurogical disorders. We describe monozygotic twin sisters carrying the pathogenic frameshift variant KCNH2 c.2959_2960delCT (p.Leu987Valfs*131; rs748706373), inherited from their asymptomatic father. Clinically, both twins presented with severe language delay, absence of pointing, impaired social interaction, and stereotyped behaviors features consistent with neurogical disorders. Diagnostic diagnostic testing included whole exome sequencing (WES), chromosomal microarray (aCGH), and Fragile X screening. The KCNH2 variant emerged as the sole clinically significant finding. Cardiac evaluation through ECG and 24-hour Holter monitoring revealed no significant QT prolongation or arrhythmic episodes in either the twins or their father. No history of syncope, seizures, or cardiac events was reported. This report supports the variable expressivity and incomplete penetrance of KCNH2 variants in type 2 LQTS and raises the possibility that KCNH2 dysfunction may contribute to neurogical phenotypes manifestations. Causality remains to be established between KCNH2 and neurologic disorders. Though whole-genome sequencing remains to be completed in this pedigree, the potential association between KCNH2 and neurologic disorders is strengthened by the unique monozygotic presentation and the absence of known perinatal complications. Further studies are needed to clarify the association between KCNH2 variants and their contribution to neurological disorders, either through direct neural effects or indirectly via unrecognized perinatal arrhythmic events.

Timothy syndrome (OMIM #601005) is a rare disease caused by variants in the gene CACNA1C. Initially, Timothy syndrome was characterized by a cardiac presentation of long QT syndrome and syndactyly of the fingers and/or toes, all associated with the CACNA1C variant, Gly406Arg. However, subsequent identification of diverse variants in CACNA1C has expanded the clinical spectrum, revealing various cardiac and extra-cardiac manifestations. It remains underexplored whether individuals with the canonical Gly406Arg variants in mutually exclusive exon 8A (Timothy syndrome 1) or exon 8 (Timothy syndrome 2) exhibit overlapping symptoms. Moreover, case reports have indicated that some CACNA1C variants may produce a cardiac-selective form of Timothy syndrome often referred to as non-syndromic long QT type 8 or cardiac-only Timothy syndrome, however few reports follow up on these patients to confirm the cardiac selectivity of the phenotype over time. A survey was administered to the parents of patients with Timothy syndrome, querying a broad range of symptoms and clinical features. Study participants were organized into 5 separate categories based on genotype and initial diagnosis, enabling comparison between groups of patients which have been described differentially in the literature. Our findings reveal that Timothy syndrome patients commonly exhibit both cardiac and extra-cardiac features, with long QT syndrome, neurodevelopmental impairments, hypoglycemia, and respiratory issues being frequently reported. Notably, the incidence of these features was similar across all patient categories, including those diagnosed with non-syndromic long QT type 8, suggesting that the 'non-syndromic' classification may be incomplete. This study represents the first Natural History Study of Timothy syndrome, offering a comprehensive overview of the disease's clinical manifestations. We demonstrate that both cardiac and extra-cardiac features are prevalent across all patient groups, underscoring the syndromic nature of CACNA1C variants. While the critical role of long QT syndrome and cardiac arrhythmias in Timothy syndrome has been well recognized, our findings indicate that hypoglycemia and respiratory dysfunction also pose significant life-threatening risks, emphasizing the need for comprehensive therapeutic management of affected individuals.

Thrombotic microangiopathy (TMA) in association with RNA exosome encoding mutations has only recently been recognized. Here, we present an infant (female) with an EXOSC5 mutation (c.230_232del p.Glu77del) associated with the clinical phenotype known as CABAC syndrome (cerebellar ataxia, brain abnormalities, and cardiac conduction defects), including pontocerebellar hypoplasia, who developed renal TMA. At the age of four months, she presented with signs of septic illness, after which she developed TMA. A stool culture showed rotavirus as a potential trigger. The patient received eculizumab once, alongside supportive treatment, while awaiting diagnostic analysis of TMA, including genetic complement analysis, all of which were negative. Eculizumab was withdrawn and the patient's TMA recovered quickly. A review of the literature identified an additional four patients (age < 1 year) who developed TMA after a viral trigger in the presence of mutations in EXOSC3. The recurrence of TMA in one of these patients with an EXOSC3 mutation while on eculizumab treatment underscores the apparent lack of responsiveness to C5 inhibition. In conclusion, mutations in genes influencing the RNA exosome, like EXOSC3 and EXOSC5, characterized by neurodevelopment and neurodegenerative disorders could potentially lead to TMA in the absence of complement dysregulation. Hence, these patients were likely non-responsive to eculizumab.

A couple was referred for prenatal counseling at the gestational age of 35 weeks of a male fetus (II-2) with sinus bradycardia and suspected first degree atrioventricular block with left ventricular noncompaction (LVNC). A previous pregnancy for the couple of a female fetus (II-1) was diagnosed prenatally as sinus bradycardia at the gestational age of 30 weeks. Both fetuses were confirmed to have long QT syndrome (LQTS) with LVNC after birth, and died of heart failure during infancy. The genetic cause of the combined cardiovascular disorders was investigated by trio whole-exome sequencing and Sanger sequencing on DNA extracted from parental blood samples and umbilical cord serum of the proband. Compound heterozygous variants were identified in the endoplasmic reticulum membrane protein complex subunit 1 gene (EMC1, NM_015047.3), including paternally inherited c.245C>T (p. Thr82Met) and maternally inherited c.1459delC (p. Arg487Alafs*49). Pathogenic variants in EMC1 have been associated with a recessive neurodevelopmental disorder, whereas Emc10 knockout mice exhibit cardiovascular issues. The present study shows that EMC1 variation potentially causes the overlapping phenotypes of LVNC and LQTS and may expand the spectrum of diseases caused by EMC1 variation. Single large-scale mitochondrial DNA deletion syndromes (SLSMDSs) comprise overlapping clinical phenotypes including Kearns-Sayre syndrome (KSS), KSS spectrum, Pearson syndrome (PS), chronic progressive external ophthalmoplegia (CPEO), and CPEO-plus. KSS is a progressive multisystem disorder with onset before age 20 years characterized by pigmentary retinopathy, CPEO, and cardiac conduction abnormality. Additional features can include cerebellar ataxia, tremor, intellectual disability or cognitive decline, dementia, sensorineural hearing loss, oropharyngeal and esophageal dysfunction, exercise intolerance, muscle weakness, and endocrinopathies. Brain imaging typically shows bilateral lesions in the globus pallidus and white matter. KSS spectrum includes individuals with KSS in addition to individuals with ptosis and/or ophthalmoparesis and at least one of the following: retinopathy, ataxia, cardiac conduction defects, hearing loss, growth deficiency, cognitive impairment, tremor, or cardiomyopathy. Compared to CPEO-plus, individuals with KSS spectrum have more severe muscle involvement (e.g., weakness, atrophy) and overall have a worse prognosis. PS is characterized by pancytopenia (typically transfusion-dependent sideroblastic anemia with variable cell line involvement), exocrine pancreatic dysfunction, poor weight gain, and lactic acidosis. PS manifestations also include renal tubular acidosis, short stature, and elevated liver enzymes. PS may be fatal in infancy due to neutropenia-related infection or refractory metabolic acidosis. CPEO is characterized by ptosis, ophthalmoplegia, oropharyngeal weakness, variable proximal limb weakness, and/or exercise intolerance. CPEO-plus includes CPEO with additional multisystemic involvement including neuropathy, diabetes mellitus, migraines, hypothyroidism, neuropsychiatric manifestations, and optic neuropathy. Rarely, an SLSMDS can manifest as Leigh syndrome, which is characterized as developmental delays, neurodevelopmental regression, lactic acidosis, and bilateral symmetric basal ganglia, brain stem, and/or midbrain lesions on MRI. The diagnosis of an SLSMDS is established in a proband with characteristic clinical features by identification of a mitochondrial DNA (mtDNA) deletion ranging in size from 1.1 to 10 kb on molecular genetic testing. SLSMDSs can be identified in DNA from blood, buccal cells, and urine in affected children; analysis of skeletal muscle tissue may be required to detect an SLSMDS in an affected adult. Targeted therapy: Folinic acid supplementation in individuals with KSS with low 5-methyltetrahydrofolate in CSF or white matter abnormalities on brain MRI. Supportive care: Consider mitochondrial supplement therapies such as coenzyme Q10 and antioxidants; optimize nutrition and exercise regimen to prevent acute decompensation; physical and occupational therapy for myopathy and/or ataxia; standard treatment with anti-seizure medication; hearing aids or cochlear implants for sensorineural hearing loss; developmental and educational support; feeding therapy; consider gastrostomy tube placement if poor weight gain, choking, or aspiration risk is present; dilation of the upper esophageal sphincter to alleviate cricopharyngeal achalasia; prophylactic placement of cardiac pacemaker in individuals with cardiac conduction block, with consideration of an implantable cardioverter defibrillator; hormone replacement therapy per endocrinologist; electrolyte monitoring and replacement for renal tubular acidosis; eyelid slings and/or ptosis repair for severe ptosis; eye ointment for dry eyes; eyeglass prisms for diplopia; transfusion therapy for individuals with PS with sideroblastic anemia; replacement of pancreatic enzymes for exocrine pancreatic insufficiency; ventilatory support for respiratory abnormalities that may occur in individuals with Leigh syndrome; standard treatment of anxiety and/or depression; social work support and care coordination as needed. Surveillance: Annual neurology assessment for ataxia, neuropathy, seizures, and myopathy; annual audiology evaluation; annual assessment of developmental progress, educational needs, and cognitive issues; annual evaluation by a neuro-ophthalmologist and/or retinal specialist and oculoplastics; measurement of growth parameters and evaluation of nutritional status and safety of oral intake at each visit; annual assessment of mobility and self-help skills with physical medicine, occupational therapy, and/or physical therapy; EKG and echocardiogram every six to 12 months; annual assessment with an endocrinologist; BUN and creatinine, with consideration of cystatin C in those with low muscle mass; complete blood count in those with PS to assess transfusion needs with additional labs per hematologist, and ferritin for those needing recurrent transfusions as needed; annual complete blood count in those with other SLSMDSs; fecal fat and fecal elastase as needed based on symptoms; monitor for evidence of aspiration and respiratory insufficiency at each visit; assess family needs at each visit. Agents/circumstances to avoid: Volatile anesthetic hypersensitivity may occur. Avoid prolonged treatment with propofol (>30-60 minutes). Medications should be reviewed with a physician familiar with mitochondrial disorders including a thorough individualized assessment of risk vs benefit as several medications may be toxic to mitochondria. SLSMDSs are almost never inherited, suggesting that these disorders are typically caused by a de novo single large-scale mitochondrial DNA deletion (SLSMD) that occurs in the mother's oocytes during germline development or in the embryo during embryogenesis. If the mother is clinically unaffected and the proband represents a simplex case (i.e., a single affected family member), the empiric risk to the sibs of a proband is very low (at or below 1%). If the mother is affected, the recurrence risk to sibs is estimated to be approximately 4% (one in 24 births). Maternal transmission to more than one child has not been reported to date. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are scientifically possible but technically prohibitive as next-generation sequencing methodology does not accurately quantify heteroplasmy level of an SLSMD and droplet digital quantitative PCR cannot reliably detect less than 10% heteroplasmy levels of an SLSMD. Further, prenatal testing is not clinically available due to the inability to accurately interpret the clinical prognosis based on prenatal diagnostic results of an SLSMD.