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Long term follow-up in GAMT deficiency - Correlation of therapy regimen, biochemical and in vivo brain proton MR spectroscopy data.

ABSTRACT: GAMT deficiency is a rare autosomal recessive disease within the group of cerebral creatine deficiency syndromes. Cerebral creatine depletion and accumulation of guanidinoacetate (GAA) lead to clinical presentation with intellectual disability, seizures, speech disturbances and movement disorders. Treatment consists of daily creatine supplementation to increase cerebral creatine, reduction of arginine intake and supplementation of ornithine for reduction of toxic GAA levels. This study represents the first long-term follow-up over a period of 14 years, with detailed clinical data, biochemical and multimodal neuroimaging findings. Developmental milestones, brain MRI, quantitative single voxel ¹H magnetic resonance spectroscopy (MRS) and biochemical analyses were assessed. The results reveal insights into the dose dependent effects of creatine/ornithine supplementation and expand the phenotypic spectrum of GAMT deficiency. Of note, the creatine concentrations, which were regularly monitored over a long follow-up period, increased significantly over time, but did not reach age matched control ranges. Our patient is the second reported to show normal neurocognitive outcome after an initial delay, stressing the importance of early diagnosis and treatment initiation.

SUBMITTER: Marten LM

PROVIDER: S-EPMC10926185 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Long term follow-up in GAMT deficiency - Correlation of therapy regimen, biochemical and <i>in vivo</i> brain proton MR spectroscopy data.

Marten Lara M LM Krätzner Ralph R Salomons Gajja S GS Fernandez Ojeda Matilde M Dechent Peter P Gärtner Jutta J Huppke Peter P Dreha-Kulaczewski Steffi S

Molecular genetics and metabolism reports 20240118

GAMT deficiency is a rare autosomal recessive disease within the group of cerebral creatine deficiency syndromes. Cerebral creatine depletion and accumulation of guanidinoacetate (GAA) lead to clinical presentation with intellectual disability, seizures, speech disturbances and movement disorders. Treatment consists of daily creatine supplementation to increase cerebral creatine, reduction of arginine intake and supplementation of ornithine for reduction of toxic GAA levels. This study represent ...[more]

PMID: 38469086

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Project description:Background and purposeSevere and progressive neurologic disease remains a problem for patients with hyperphenylalaninemia due to a deficiency of tetrahydrobiopterin (BH4), even with early diagnosis and despite treatment with BH4 and neurotransmitter precursors. Few reports have included the associated imaging characteristics. Our purpose was to describe the imaging features of BH4-deficient patients identified by neonatal screening in a Taiwanese population and to correlate the imaging features with the treatment.MethodsThis study analyzed the cases of eight BH4-deficient patients who were examined by MR imaging and MR spectroscopy. Analysis of the findings was correlated with the clinical findings.ResultsOne patient whose intelligence quotient score was lower than those of the other seven patients experienced seizures in conjunction with central white matter signal changes on MR images and a lactate peak on MR spectroscopy. Lactate peak was revealed in another patient who had marked elevations of N-acetylaspartate:creatine and N-acetylaspartate:choline ratios. Although most patients had a higher than average N-acetylaspartate:creatine or N-acetylaspartate:choline ratio, the patient who had decreases of both ratios possessed the highest intelligence quotient scores among the eight patients. In addition, the myoinositol:choline ratio correlated positively with the average BH4 dosage (P =.027, r = 0.027) and the choline:creatine ratio correlated negatively with the average 5-hydroxytryptophan dosage (P =.035, r = -0.742).ConclusionCompared with classical phenylketonuria, patients with BH4 deficiency have fewer white matter changes revealed by MR imaging but more changes revealed by MR spectroscopy. MR spectroscopy is a potential method with which to monitor the dosages of supplements used to treat this disorder. In addition, MR spectroscopy may be helpful in gaining understanding of the neurophysiological changes that occur in association with this disease.

Project description:Background and purposeThe characterization of peripheral nerve sheath tumors is challenging. The purpose here was to investigate the diagnostic value of quantitative proton MR spectroscopy at 3T for the characterization of peripheral nerve sheath tumors as benign or malignant, compared with PET.Materials and methodsTwenty participants with 24 peripheral nerve sheath tumors underwent MR spectroscopy by use of a point-resolved sequence (TE, 135 ms). Six voxels were placed in 4 histologically proven malignant peripheral nerve sheath tumors and 22 voxels in 20 benign peripheral nerve sheath tumors (9 histologically proven, 11 with documented stability). The presence or absence of a trimethylamine signal was evaluated, the trimethylamine concentration estimated by use of phantom replacement methodology, and the trimethylamine fraction relative to Cr measured. MR spectroscopy results for benign and malignant peripheral nerve sheath tumors were compared by use of a Mann-Whitney test, and concordance or discordance with PET findings was recorded.ResultsIn all malignant tumors and in 9 of 18 benign peripheral nerve sheath tumors, a trimethylamine peak was detected, offering the presence of trimethylamine as a sensitive (100%), but not specific (50%), marker of malignant disease. Trimethylamine concentrations (2.2 ± 2.8 vs 6.6 ± 5.8 institutional units; P < .049) and the trimethylamine fraction (27 ± 42 vs 88 ± 22%; P < .012) were lower in benign than malignant peripheral nerve sheath tumors. A trimethylamine fraction threshold of 50% resulted in 100% sensitivity (95% CI, 58.0%-100%) and 72.2% (95% CI, 59.5%-75%) specificity for distinguishing benign from malignant disease. MR spectroscopy and PET results were concordant in 12 of 16 cases, (2 false-positive results for MR spectroscopy and PET each).ConclusionsQuantitative measurement of trimethylamine concentration by use of MR spectroscopy is feasible in peripheral nerve sheath tumors and shows promise as a method for the differentiation of benign and malignant lesions. Trimethylamine presence within a peripheral nerve sheath tumor is a sensitive marker of malignant disease, but quantitative measurement of trimethylamine content is required to improve specificity.

Dataset Information

Long term follow-up in GAMT deficiency - Correlation of therapy regimen, biochemical and in vivo brain proton MR spectroscopy data.

Publications

Long term follow-up in GAMT deficiency - Correlation of therapy regimen, biochemical and <i>in vivo</i> brain proton MR spectroscopy data.

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