phosphocreatine and Developmental-Disabilities

Mutations in nuclear and mitochondrial DNA impacting mitochondrial function result in disease manifestations ranging from early death to abnormalities in all major organ systems and to symptoms that can be largely confined to muscle fatigue. The definitive diagnosis of a mitochondrial disorder can be difficult to establish. When the constellation of symptoms is suggestive of mitochondrial disease, neuroimaging features may be diagnostic and suggestive, can help direct further workup, and can help to further characterize the underlying brain abnormalities. Magnetic resonance imaging changes may be nonspecific, such as atrophy (both general and involving specific structures, such as cerebellum), more suggestive of particular disorders such as focal and often bilateral lesions confined to deep brain nuclei, or clearly characteristic of a given disorder such as stroke-like lesions that do not respect vascular boundaries in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode (MELAS). White matter hyperintensities with or without associated gray matter involvement may also be observed. Across patients and discrete disease subtypes (e.g., MELAS, Leigh syndrome, etc.), patterns of these features are helpful for diagnosis. However, it is also true that marked variability in expression occurs in all mitochondrial disease subtypes, illustrative of the complexity of the disease process. The present review summarizes the role of neuroimaging in the diagnosis and characterization of patients with suspected mitochondrial disease.

Topics: Adenosine Triphosphate; Aspartic Acid; Brain; Child; Developmental Disabilities; Diagnosis, Differential; Humans; Image Processing, Computer-Assisted; Lactic Acid; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Mitochondrial Diseases; Phosphocreatine

Our study evaluated the effect of creatine and homoarginine in AGAT- and GAMT-deficient mice after simvastatin exposure. Balestrino and Adriano suggest that guanidinoacetate might explain the difference between AGAT- and GAMT-deficient mice in simvastatin-induced myopathy. We agree with Balestrino and Adriano that our data shows that (1) creatine possesses a protective potential to ameliorate statin-induced myopathy in humans and mice and (2) homoarginine did not reveal a beneficial effect in statin-induced myopathy. Third, we agree that guanidinoacetate can be phosphorylated and partially compensate for phosphocreatine. In our study, simvastatin-induced damage showed a trend to be less pronounced in GAMT-deficient mice compared with wildtype mice. Therefore, (phospo) guanidinoacetate cannot completely explain the milder phenotype of GAMT-deficient mice, but we agree that it might contribute to ameliorate statin-induced myopathy in GAMT-deficient mice compared with AGAT-deficient mice. Finally, we agree with Balestino and Adriano that AGAT metabolites should further be evaluated as potential treatments in statin-induced myopathy.

Topics: Amidinotransferases; Amino Acid Metabolism, Inborn Errors; Animals; Creatine; Developmental Disabilities; Glycine; Guanidinoacetate N-Methyltransferase; Homoarginine; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intellectual Disability; Mice; Muscular Diseases; Phosphocreatine; Speech Disorders

Skeletal muscles require energy either at constant low (e.g., standing and posture) or immediate high rates (e.g., exercise). To fulfill these requirements, myocytes utilize the phosphocreatine (PCr)/creatine (Cr) system as a fast energy buffer and shuttle. We have generated mice lacking L-arginine:glycine amidino transferase (AGAT), the first enzyme of creatine biosynthesis. These AGAT(-/-) (d/d) mice are devoid of the PCr/Cr system and reveal severely altered oxidative phosphorylation. In addition, they exhibit complete resistance to diet-induced obesity, which is associated with a chronic activation of AMP-activated protein kinase in muscle and white adipose tissue. The underlying metabolic rearrangements have not yet been further analyzed. Here, we performed gene expression analysis in skeletal muscle and a serum amino acid profile of d/d mice revealing transcriptomic and metabolic alterations in pyruvate and glucose pathways. Differential pyruvate tolerance tests demonstrated preferential conversion of pyruvate to alanine, which was supported by increased protein levels of enzymes involved in pyruvate and alanine metabolism. Pyruvate tolerance tests suggested severely impaired hepatic gluconeogenesis despite increased availability of pyruvate and alanine. Furthermore, enzymes of serine production and one-carbon metabolism were significantly up-regulated in d/d mice, indicating increased de novo formation of one-carbon units from carbohydrate metabolism linked to NAD(P)H production. Besides the well-established function of the PCr/Cr system in energy metabolism, our transcriptomic and metabolic analyses suggest that it plays a pivotal role in systemic one-carbon metabolism, oxidation/reduction, and biosynthetic processes. Therefore, the PCr/Cr system is not only an energy buffer and shuttle, but also a crucial component involved in numerous systemic metabolic processes.

Topics: Adipose Tissue, White; Amidinotransferases; Amino Acid Metabolism, Inborn Errors; Animals; Developmental Disabilities; Intellectual Disability; Metabolome; Mice; Mice, Knockout; Muscle, Skeletal; Obesity; Oxidative Phosphorylation; Phosphocreatine; Speech Disorders; Transcriptome

The brain pathophysiological abnormalities underlying autism remain unclear. Neuroimaging and histological studies suggest cellular abnormalities early in the course of the disease.. To measure the in vivo chemical profile of gray and white matter tissues in autism.. Cross-sectional spectroscopic imaging study comparing 3- to 4-year-old children with autism spectrum disorder (ASD) with age-matched comparison groups of children with delayed development (DD) and typical development (TD).. The University of Washington Diagnostic Imaging Sciences Center, Seattle.. Forty-five 3- to 4-year-old children with ASD, 12 age-matched children with DD, and 10 age-matched children with TD.. Estimates of gray and white matter concentrations for choline-containing compounds (Cho), creatine plus phosphocreatine, N-acetylaspartate (NAA), and myo-inositol (mI). Transverse relaxation times for Cho, creatine plus phosphocreatine, and NAA expressed relative to control subjects with TD were examined to evaluate tissue compactness.. The children with ASD demonstrated decreased gray matter concentrations of Cho (P < .001), creatine plus phosphocreatine (P = .02), NAA (P = .02), and mI (P = .008) compared with children with TD. Gray matter Cho transverse relaxation was also prolonged for the ASD sample compared with the TD group (P = .01). The children with ASD demonstrated significantly decreased levels of Cho (P = .04) and mI (P = .008) and trend-level NAA (P = .09) in gray matter compared with the DD group. For white matter, both children with ASD and children with DD showed a similar pattern of NAA and mI level decreases (for children with ASD vs children with TD: NAA, P = .03; mI, P = .04; for children with DD vs children with TD, NAA, P = .03; mI, P = .07). In several analyses, cerebral volume contributed significantly as a covariate.. Reduced gray matter chemical concentrations and altered Cho transverse relaxation, in a pattern distinct from that in children with DD, suggest decreased cellularity, or density, at this early time point in ASD. Possibly reflecting shared developmental features, white matter results were common to ASD and DD groups. The relationship between cerebral volume and neurochemistry at this early time point may indicate processes related to unit scaling.

Topics: Aspartic Acid; Autistic Disorder; Brain; Brain Chemistry; Child, Preschool; Choline; Creatine; Cross-Sectional Studies; Developmental Disabilities; Echo-Planar Imaging; Female; Humans; Image Processing, Computer-Assisted; Inositol; Magnetic Resonance Spectroscopy; Male; Phosphocreatine; Tissue Distribution