Serial Magnetic Resonance Imaging and 1H-Magnetic Resonance Spectroscopy in GABA Transaminase Deficiency: A Case Report.

Gamma-aminobutyric acid transaminase (GABA-T) deficiency is a rare, autosomal recessive disorder characterized by severe psychomotor retardation, early-onset epileptic encephalopathy, intractable seizures, hypotonia, and hyperreflexia. The disease is caused by mutation in the 4-aminobutyrate aminotransferase (ABAT) gene, which encodes an enzyme involved in GABA catabolism. In this chapter, a 10-year follow-up of GABA-T deficiency in a rare case of a long-term survivor patient is discussed. The patient showed a progression of clinical phases with increasing age. In infancy, the patient developed psychomotor retardation and recurrent encephalopathic episodes associated with febrile illness. In early childhood, the patient presented with refractory involuntary and hyperkinetic movements and dystonic hypertonicity. In childhood, the patient gradually progressed into the chronic stable phase of the condition. Magnetic resonance imaging demonstrated high signal intensity on diffusion-weighted images involving the internal and external capsules and cerebral white matter in infancy which disappeared gradually by the age of 3 years, and showed subsequently diffuse brain atrophy in childhood. Using proton magnetic resonance spectroscopy, GABA levels in the basal ganglia were shown to be markedly elevated at the age of 1-2 years, and subsequently decreased with increasing age (toward 5 years). These findings suggest that the encephalopathic episodes in infancy and clinical severity of involuntary and hyperkinetic movements may be correlated with levels of GABA in the basal ganglia. The high levels of GABA in the cerebrospinal fluid remained unaltered, whereas levels of GABA in the serum decreased during childhood. Further investigation of long-term clinical surveillance may improve the understanding of GABA-T deficiency

Glycine measurement using short and long echo time proton magnetic resonance spectroscopy in a neonate with nonketotic hyperglycinemia

Introduction: In nonketotic hyperglycinemia (NKH), 1H-MRS shows a striking increase in brain glycine levels. However, the signal overlap of glycine with myo-inositol makes it difficult to quantify each metabolite separately. Our aim was to investigate glycine measurement with 1H-MRS using different echo times (TE) in a neonate with NKH. Methods: Serial single-voxel 1H-MRS in the centrum semiovale was performed with TE of 30 and 270ms in a neonate with NKH on 6, 19, 44 days of age, and the peak area ratios of glycine plus myo-inositol to creatine ((Gly+mIns)/Cr) was evaluated. Glycine levels of plasma and cerebral spinal fluid (CSF) were also measured on 5, 19, and 44 days of ages. Results: In both TEs, (Gly+mIns)/Cr showed higher values at first, then decreased subsequently; TE 30msec: 1.43, 1.19, and 1.11, TE 270 msec: 1.05, 0.55, and 0.49, respectively. Both glycine levels of plasma and CSF showed similar decreasing: plasma: 1803.9, 353.0, and 140.0 μmol/L, CSF: 321.6, 135.3, and 69.7 μmol/L, respectively. On 6 days, the patient was comatose, and had no spontaneous respiration. On 19 days, he was lethargic but had spontaneous respirations. On 44 days, his consciousness was almost clear.Conclusion: The continuing reduction of (Gly+mIns)/Cr with long-TE corresponded more reliably with glycine levels of plasma and CSF than the change with short-TE. In addition to T2 relaxation time effect, myo-inositol also has J-coupling induced-dephasing effect, which results in small signal in long TE. Therefore myo-inositol signal may have a relatively less contribution to (Gly+mIns) in TE 270ms.The 20th Annual Meeting of Infantile Seizure Society (ISS

Elevation of brain gamma-aminobutyric acid levels is associated with vigabatrin-associated brain abnormalities on magnetic resonance imaging.

Vigabatrin (VGB) is an effective antiseizure medication for West syndrome. It works by irreversibly inhibiting gamma-aminobutyric acid (GABA) transaminase and increasing central GABA levels. Vigabatrin-associated brain abnormalities on magnetic resonance imaging (VABAM) are an adverse effect of VGB that has only been reported in children, but the pathophysiology of this effect is unknown. In this study, we evaluated the relationship of VGB and brain GABA levels as well as the association between VABAM and GABA

A rapid screening with direct sequencing from blood samples for the diagnosis of Leigh syndrome

Large numbers of genes are responsible for Leigh syndrome (LS), making genetic confirmation of LS difficult. We screened our patients with LS using a limited set of 21 primers encompassing the frequently reported gene for the respiratory chain complexes I (ND1–ND6, and ND4L), IV(SURF1), and V(ATP6) and the pyruvate dehydrogenase E1α-subunit. Of 18 LS patients, we identified mutations in 11 patients, including 7 in mDNA (two with ATP6), 4 in nuclear (three with SURF1). Overall, we identified mutations in 61% of LS patients (11/18 individuals) in this cohort. Sanger sequencing with our limited set of primers allowed us a rapid genetic confirmation of more than half of the LS patients and it appears to be efficient as a primary genetic screening in this cohort

DataSheet1_Loss of CAPS2/Cadps2 leads to exocrine pancreatic cell injury and intracellular accumulation of secretory granules in mice.PDF

The type 2 Ca2+-dependent activator protein for secretion (CAPS2/CADPS2) regulates dense-core vesicle trafficking and exocytosis and is involved in the regulated release of catecholamines, peptidergic hormones, and neuromodulators. CAPS2 is expressed in the pancreatic exocrine acinar cells that produce and secrete digestive enzymes. However, the functional role of CAPS2 in vesicular trafficking and/or exocytosis of non-regulatory proteins in the exocrine pancreas remains to be determined. Here, we analyzed the morpho-pathological indicators of the pancreatic exocrine pathway in Cadps2-deficient mouse models using histochemistry, biochemistry, and electron microscopy. We used whole exosome sequencing to identify CADPS2 variants in patients with chronic pancreatitis (CP). Caps2/Cadps2-knockout (KO) mice exhibited morphophysiological abnormalities in the exocrine pancreas, including excessive accumulation of secretory granules (zymogen granules) and their amylase content in the cytoplasm, deterioration of the fine intracellular membrane structures (disorganized rough endoplasmic reticulum, dilated Golgi cisternae, and the appearance of empty vesicles and autophagic-like vacuoles), as well as exocrine pancreatic cell injury, including acinar cell atrophy, increased fibrosis, and inflammatory cell infiltration. Pancreas-specific Cadps2 conditional KO mice exhibited pathological abnormalities in the exocrine pancreas similar to the global Cadps2 KO mice, indicating that these phenotypes were caused either directly or indirectly by CAPS2 deficiency in the pancreas. Furthermore, we identified a rare variant in the exon3 coding region of CADPS2 in a non-alcoholic patient with CP and showed that Cadps2-dex3 mice lacking CAPS2 exon3 exhibited symptoms similar to those exhibited by the Cadps2 KO and cKO mice. These results suggest that CAPS2 is critical for the proper functioning of the pancreatic exocrine pathway, and its deficiency is associated with a risk of pancreatic acinar cell pathology.</p