脳クレアチン欠乏症候群

Creatine, α-N-methyl-guanidino-acetic acid, plays a fundamental role in the storage and regeneration of high-energy phosphate in the brain. Defects in the creatine transporter gene (CRT/SLC6A8) result in a significant reduction in brain creatine levels and severe neurological symptoms such as intellectual disability. Clarifying creatine dynamics in the brain is essential to increase our understanding of CRT deficiency syndrome (CRTD) pathology and the development of CRTD therapeutics. This review comprehensively summarizes the pathophysiological roles of transporters in dynamics of creatine and related guanidine compounds in the brain barriers and brain parenchyma. Brain creatine dynamics are regulated by the cooperative actions of various influx and efflux transporters of creatine, guanidinoacetate, creatinine, and creatine biosynthetic enzymes. These transporters include CRT/SLC6A8 as a creatine/guanidinoacetate/creatinine influx transporter, MCT12/SLC16A12, and SLC22A15 for creatine efflux transport, TauT/SLC6A6, GAT2/SLC6A13, and GAT3/SLC6A11 for guanidinoacetate influx transport, and OCT3/SLC22A3 for creatinine influx transport. Transporters and creatine biosynthetic enzymes, such as arginine-glycine amidinotransferase and guanidinoacetate N-methyltransferase, exhibit cell-type specific spatio-temporal expression at the brain barrier and in neurons, astrocytes, and oligodendrocytes. To date, no effective therapeutics have been developed for the treatment of CRTD. The link between low brain creatine level and the mechanism of neurological dysfunction remains unclear. Creatine prodrugs, molecular chaperones, and adeno-associated virus-based gene therapies are potential therapeutic options for CRTD. Advanced technologies, such as omics and genetic engineering, will open new avenues for CRTD therapeutics.

BACKGROUND: Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is an autosomal recessive lysosomal storage disorder characterized by progressive central nervous system degeneration and behavioral abnormalities. Type A is caused by a deficiency of SGSH. This case report presents the first documented case of Sanfilippo syndrome type A (MPS IIIA) with a homozygous SGSH c.571G > A mutation, associated with severe acute metabolic acidosis. Despite an extensive scoping review, no similar cases were found, highlighting the novelty of this report. CASE PRESENTATION: A 13-year-old girl presented with a 10-year history of global developmental regression and over 7 years of behavioral abnormalities, which had acutely worsened over the preceding three days. On admission, she was unconscious (Glasgow Coma Scale score (GCS): 10) and exhibited tachypnea. Arterial blood gas analysis revealed severe metabolic acidosis (pH 7.039, PaCO₂ 18.8 mmHg, HCO₃⁻ 5.1 mmol/L, base excess − 23.9 mmol/L, lactate 1.6 mmol/L), accompanied by hypernatremia, hyperchloremia, and markedly elevated creatine kinase and myoglobin levels. Lactate and ammonia concentrations were within normal limits. Neuroimaging (MRI) demonstrated cerebral atrophy with prominent sulci. Echocardiography showed mild valvular regurgitation, and skeletal survey suggested multiple bone dysplasias. Initially, central nervous system infection or metabolic encephalopathy was suspected. Following correction of acidosis, fluid resuscitation, and supportive care, she regained consciousness. Whole-exome sequencing identified a homozygous c.571G > A (p. Gly191Arg) mutation in the SGSH gene, with both parents confirmed as heterozygous carriers at the same locus. Significantly reduced heparan N-sulfatase activity confirmed the diagnosis of mucopolysaccharidosis type IIIA (MPS IIIA). CONCLUSIONS: Acute metabolic acidosis can occur in MPS IIIA, particularly during infection or physiological stress. Adolescents presenting with a long history of developmental regression and behavioral disturbances, accompanied by neuroimaging evidence of cerebral atrophy, should prompt strong consideration of MPS III. Combined genetic and enzymatic testing confirmed the diagnosis and guided multidisciplinary care. A comprehensive literature review revealed no previously reported cases of SGSH c.571G > A mutation or MPS IIIA complicated by acute metabolic acidosis, making this the first documented case.

BACKGROUND: The purpose of the Vigilan observational study (ClinicalTrials.gov, NCT02931682) was to prospectively assess the natural history and developmental course of creatine transporter deficiency (CTD). METHODS: Males with CTD aged 6 months to 65 years were evaluated at 6-month intervals for up to 4 years. Evaluations included neurodevelopmental assessments of intellectual functioning, adaptive functioning, challenging behaviors and the onset and progression of medical comorbidities. RESULTS: Fifty participants (median age, 7.6 years) were enrolled. The predominant CTD phenotype consisted of significant intellectual disabilities and limited skill development over time. Most participants had a history of febrile or nonfebrile seizures, gastrointestinal symptoms, and growth failure. All participants learned how to walk, 78% developed at least some verbal speech, and 34% communicated using phrases or sentences. Norm-referenced neurodevelopment assessments indicated declining standardized scores over time; however, absolute scores (i.e., age equivalent person ability scores) indicated that developmental gains were slower than average, particularly among older participants. Between-person differences in neurodevelopmental skills as a function of age did not match within-person change, suggesting a cohort effect. CONCLUSIONS: In this cohort, CTD was associated with significant and persistent intellectual disability. The use of absolute metrics from neurodevelopmental tests (e.g., person ability scores) allowed for the quantification of slow, but present, skill development.

BACKGROUND: 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. OBJECTIVE: This study aimed to characterize the cardiac phenotype of male patients with CTD. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

INTRODUCTION: Lipodystrophy syndromes (LS) represent a clinically and genetically heterogeneous group of disorders of adipose tissue. LS are characterized by a partial or generalized deficiency of adipose tissue and variations in fat distribution throughout the body. Metabolic complications serve as significant determinants of morbidity and mortality in these syndromes. CASE PRESENTATION: The patient was assessed for general lipodystrophy and myopathy findings, and a CAVIN1 mutation was identified by next generation sequencing. Our patient exhibited low leptin and vitamin D levels, categorized as metabolic disorders, alongside increased insulin resistance. Additionally, low insulin-like growth factor 1 levels and delayed puberty were noted as hormonal disorders. Osteoporosis, scoliosis, ventricular extrasystoles, and ventricular tachycardia were observed as morbid conditions during the follow-up. We detected hypoplasia of the anterior cerebral artery and the internal carotid artery, which are seen as ultrarare. A coexistent structural cerebral vascular anomaly has not been previously reported in congenital generalized lipodystrophy type 4. CONCLUSION: Congenital generalized lipodystrophy type 4 should be considered when associated with elevated liver enzyme levels and creatine phosphokinase values. Determining the underlying genetic cause enables an expeditious monitoring and treatment process.