脳クレアチン欠乏症候群

BACKGROUND: There is a pressing demand to implement a standard acquisition and post-processing approach for proton magnetic resonance spectroscopy performed in children within the clinical setting. Clinical magnetic resonance spectroscopy data is needed to characterize and understand phenotypes and track treatment response, especially in rare genetic disorders with distinct metabolite signatures. For instance, infants and children with cerebral creatine deficiency syndromes are too often misdiagnosed, which leads to delay in life-changing supplementation especially for those with synthesis deficiencies. Quantitative information about brain creatine concentrations is useful in characterizing these syndromes, potentially tracking relevant biomarkers in relation to treatment response, and guiding future clinical trial designs for patients. METHODS: Spectroscopists began discussions about the usage of magnetic resonance spectroscopy in late 2024 with the leadership of the Association for Creatine Deficiencies (ACD). The ACD is a charitable organization established by parents of children with creatine deficiencies to provide patient, family, and public education, to advocate for early intervention through newborn screening, and to promote and fund medical research for treatments and cures for Cerebral Creatine Deficiency Syndromes. The ACD hosts a patient registry where families complete surveys and upload medical reports. Upon review of radiologist reports, the group noted the variability in acquisition, post-processing and interpretation across patient studies and clinical imaging sites. A team of spectroscopists reviewed the literature, identified common parameters across vendors and developed a harmonized approach that can serve as a starting point for imaging sites adopting magnetic resonance spectroscopy or a supplement to those already using it. KEY MESSAGE: This paper is a call for the usage and provides a recommendation of a minimum standard single voxel proton magnetic resonance spectroscopy approach that can be implemented for rapidly evaluating pediatric patients with neurodevelopmental delays consistent with genetic etiologies.

Metabolic diseases caused by transporter dysfunction are inherited disorders resulting from defects in membrane transport proteins. These proteins allow the passage of nutrients, ions, and other molecules across cell membranes. If there is a malfunction, substances do not enter the cell, are not reabsorbed, or are not distributed correctly, even if present in normal amounts. Intracellular metabolism is normal; the problem lies in the movement of the molecule. These diseases are caused by mutations in genes that encode transporters and impair intestinal absorption (Menkes disease), renal reabsorption (cystinuria), or the passage of substances to specific tissues such as the brain (type I glucose transporter deficiency), muscle (mitochondrial carnitine transporter deficiency), or liver (Wilson disease). They are generally autosomal recessive inherited diseases with highly varied clinical manifestations, including seizures, developmental delay, intellectual disability, autism, and movement disorders. In the text we review some of the most common diseases of interest to neuropediatricians. Many of these diseases have early biochemical or molecular diagnosis and therapeutic options that improve the prognosis.

This study aimed to investigate the effects of Zhenwu Decoction(ZWT) on cardiac fibrosis in mice with heart-kidney Yang deficiency-induced chronic heart failure(CHF). The research further explored the therapeutic mechanisms of ZWT in CHF treatment in the hope of providing novel insights for TCM approaches to managing heart-kidney Yang deficiency-induced heart failure. Sixty C57BL/6 mice were randomly divided into the following groups: the control group(normal untreated mice),the DOX group(doxorubicin-induced CHF model),the low-dose ZWT group(ZWT-L,4.7 g·kg~(-1)),the medium-dose ZWT group(ZWT-M,9.3 g·kg~(-1)),the high-dose ZWT group(ZWT-H,18.6 g·kg~(-1)),and the dopamine group(DA,positive control). The CHF mouse model was established over a 4-week period, which was followed by an additional 4-week treatment regimen. After 8 weeks, the spontaneous locomotor activity of mice was assessed, and TCM syndrome scoring was performed. Mouse serum samples were collected and analyzed to measure the levels of cardiac-specific biomarkers including cardiac troponin Ⅰ(cTn-Ⅰ),brain natriuretic peptide(BNP), creatine kinase-MB isoenzyme(CK-MB), creatine kinase(CK),lactate dehydrogenase(LDH),triiodothyronine(T3),succinate dehydrogenase(SDH) and myocardial cyclic adenosine monophosphate(cAMP). Cardiac tissue was collected for pathological examination. Western blot and real-time quantitative polymerase chain reaction(RT-PCR) were used to detect the expression of myocardial cAMP-dependent protein kinase catalytic subunit(PKA C),protein kinase A(PKA),ryanodine receptor 2(RyR2),phospholamban(PLB),B-cell lymphoma-2(Bcl-2),caspase-3,cleaved caspase-3 and Bcl-2-associated X protein(Bax). The experimental results indicated that, compared with the control group, the DOX group exhibited significantly elevated TCM syndrome scores accompanied by decreased heart rate, reduced body weight, and increased cardiac index(P<0.05); serum levels of CK, CK-MB, BNP, cTn-Ⅰ, LDH and myocardial cAMP were significantly increased(P<0.05), while SDH and T3 levels were decreased(P<0.05); meanwhile, myocardial interstitial fibrosis was aggravated and myocardial hypertrophy appeared; the expression of PKA C, PKA, caspase-3, cleaved caspase-3, Bax and phosphorylation of RyR2 were increased(P<0.05), the expression of Bcl-2 and phosphorylation of PLB were decreased compared with the DOX group, the ZWT treated groups demonstrated reduced TCM syndrome scores, increased heart rate, improved body weight, and decreased cardiac index. Additionally, serum levels of CK, CK-MB, BNP, cTn-Ⅰ, LDH and myocardial cAMP were decreased(P<0.05), while SDH and T3 levels were increased(P<0.05); myocardial hypertrophy and fibrosis were also improved; the expression of PKA C, PKA, Bax, caspase-3, cleaved caspase-3 and phosphorylation of RyR2 was reduced(P<0.05), and the expression of Bcl-2 and phosphorylation of PLB were increased(P<0.05). These findings suggested that ZWT may exert therapeutic effects on CHF by regulating sarcoplasmic reticulum calcium-related proteins, reducing apoptosis, and improving cardiac function.

BACKGROUND: Creatine deficiency syndromes (CDS) are rare inborn errors of creatine biosynthesis or transport, predominantly affecting the central nervous system. This study aimed to evaluate the clinical features, neuroimaging findings, cardiac involvement and treatment outcomes of patients with CDS, while also increasing awareness of CDS in the differential diagnosis of autism spectrum disorder and developmental delay. METHODS: Patients diagnosed with CDS and followed at the Pediatric Metabolism Departments of Çukurova University and Adana City Hospital between 2014 and 2024 were retrospectively analysed. Demographic data, age at symptom onset and diagnosis, clinical findings, laboratory results, brain magnetic resonance imaging, magnetic resonance spectroscopy, genetic analyses, cardiological evaluations and treatment outcomes were recorded. RESULTS: Eight patients were included: two with arginine-glycine amidinotransferase (AGAT) deficiency, four with guanidinoacetate methyltransferase (GAMT) deficiency and two with creatine transporter deficiency (CTD). Developmental and speech delay were present in all patients. Seizures were observed in six patients and were controlled with antiepileptic therapy. Behavioural disorders, including autistic features, were detected in five patients. Brain MRS revealed reduced cerebral creatine peaks in evaluated patients. Cardiac evaluations showed no abnormalities in any patient. Follow-up MRS performed after treatment initiation in six patients demonstrated a marked increase in cerebral creatine peaks in three patients. CONCLUSION: CDS should be considered in patients with unexplained neurodevelopmental delay, epilepsy and autistic features. Early diagnosis and timely treatment are associated with improved outcomes.

BACKGROUND: TANGO2 deficiency disorder is an ultra-rare autosomal recessive condition characterized by life-threatening metabolic crises with rhabdomyolysis and cardiac arrhythmias. Patients with 22q11.2 deletion syndrome are at increased risk when a pathogenic variant occurs in the remaining allele, yet this dual diagnosis remains underrecognized as clinicians often attribute all manifestations to the primary genetic condition. We report a case of a child with confirmed 22q11.2 deletion syndrome in whom a coexisting variant in the TANGO2 gene was diagnosed at the age of 5 after first metabolic crisis with rhabdomyolysis. CASE PRESENTATION: A girl with 22q11.2 deletion syndrome diagnosed in infancy exhibited global developmental delay and chronic excessive sleepiness attributed to her established diagnosis. At age 5, she experienced her first metabolic crisis during pneumonia with severe rhabdomyolysis (creatine kinase >100,000 U/L), features inconsistent with isolated 22q11.2 deletion syndrome. Two additional metabolic crises occurred at age 7 before exome sequencing revealed a hemizygous TANGO2 variant c.536G>A, confirming TANGO2 deficiency. A previously unreported hemizygous missense variant c.536G>A (p.Gly138Glu) in the TANGO2 gene (NM_152906.7) was identified and verified by NGS-based deep amplicon sequencing and Sanger direct sequencing; segregation analysis confirmed paternal inheritance with the maternal allele deleted within the 22q11.2 region. Following diagnosis, B-vitamin supplementation, coenzyme Q10, L-carnitine, and gastrostomy tube placement were initiated to ensure consistent hydration and prevent prolonged periods without nutrition, a known crisis trigger. The patient achieved 4 years of crisis-free stability with reduced daytime sleepiness. At age 11, she remains stable without further crises. CONCLUSIONS: This case demonstrates that exome sequencing should be pursued early when atypical features emerge in patients with established genetic diagnoses. The sustained crisis-free period following gastrostomy placement supports proactive nutritional intervention in TANGO2 patients with feeding difficulties. Clinicians must recognize that microdeletion syndrome patients can harbor variants unmasking additional autosomal recessive conditions requiring distinct management.