Characterization of seizures and EEG findings in creatine transporter deficiency due to SLC6A8 mutation.

Seizures occur in up to 59% of boys with creatine transporter deficiency (CTD). While seizure phenotypes have been previously described, electroencephalogram (EEG) findings have only been reported in several case reports. In this prospective observational study, we report seizure characteristics and EEG findings in combination with neurobehavioral and SLC6A8 pathogenic variants in twenty males with CTD. Eighteen study participants (SP) underwent video-EEG, and seven had follow-up EEG recordings. Seizures typically occurred by age of 2 years. Thirteen (65%) had non-febrile seizures, requiring anti-seizure medications in nine. Four had febrile seizures. Seizures were bilateral tonic-clonic in 7 SP and focal impaired awareness in 5 SP; often responding to 1 to 2 antiseizure medications. EEG showed slowing in 5 SP, beta activity in 6 SP, and focal/multifocal, and/or generalized epileptiform activity in 9 SP. Follow-up EEGs in 7 SP showed emergence of epileptiform activity in 1 SP, and increased activity in 2 SP. In conclusion, seizures were frequent in our cohort but tended to respond to antiseizure medications. Longitudinal follow up provided further insight into emergence of seizures and EEG abnormalities soliciting future studies with long term follow up. Biomarkers of epileptogenicity in CTD are needed to predict seizures in this population.

Corrigendum to "Elevated amyloid beta peptides and total tau in cerebrospinal fluid in individuals with Creatine transporter deficiency".

[This corrects the article DOI: 10.1016/j.ymgmr.2023.101001.].

Elevated amyloid beta peptides and total tau in cerebrospinal fluid in individuals with Creatine transporter deficiency.

Background: Creatine transporter deficiency (CTD) is a rare X-linked disorder of creatine transport caused by pathogenic variants in SLC6A8 (Xq28). The disorder is marked by developmental delay, especially speech delay. The biomarkers Aß40, Aß42 and total tau are abnormal in Alzheimer disease (AD), a common neurodegenerative disorder pathologically characterized by Aß peptide containing amyloid plaques and tau neurofibrillary tangles. Although CTD results in neuronal energy deficiency, the pathological processes underlying the CTD phenotype are not fully characterized. Methods: Cerebral spinal fluid (CSF) was collected as an optional part of a natural history study of CTD. Aß40, Aß42 and total tau levels were quantified in CSF from individuals with CTD and from age-appropriate comparison samples. Neuro3-Plex enzyme-linked immunoassay was performed on a Quanterix SR-X instrument. The Vineland Adaptive Behavior Scale, 3rd Edition was used to determine an overall Adaptive Behavior Composite (ABC) standard score. Results: CSF from 12 individuals with CTD and 23 age appropriate non-CTD comparison samples were analyzed. We found that levels of total tau [t(32) = 4.05, p = 0.0003], Aß40 [t(31) = 6.11, p < 0.0001], and Aß42 [t(32) = 3.20, p = 0.003] were elevated in the participants with CTD relative to the comparison group. Additionally, except for one individual that we considered an outlier, all three biomarkers correlated inversely with the adaptive behavior score (total tau: ρ = -0.60 [-0.88, 0.005]; Aß40: ρ = -0.67 [-0.91, -0.12]; Aß42: ρ = -0.62 [-0.89, -0.02]). Conclusion: We describe here the novel finding of elevated protein biomarkers in the CSF of individuals with CTD. Aß40, Aß42 and total tau are markedly elevated in individuals with CTD compared to comparison samples, and increased levels of these biomarkers inversely correlated with ABC scores. We hypothesize that elevated CSF levels of Aß40 and Aß42 are due to cellular energy deficiency. Elevated CSF total tau levels may indicate ongoing neuronal damage. The observed inverse correlation of Vineland ABC scores with increased biomarker levels needs to be confirmed in a larger CTD cohort; however, our observation of increased Aß40, Aß42 and total tau levels in CSF from individuals with CTD may provide insight into pathological mechanisms contributing to the CTD phenotype and may prove useful as supportive data in future therapeutic trials.

Bicalutamide and third-generation aromatase inhibitors in testotoxicosis.

Testotoxicosis, a form of gonadotropin-independent precocious puberty, results from an activating mutation of the luteinizing hormone receptor expressed in testicular Leydig cells. Affected males experience early testosterone secretion, virilization, advancing bone age, and resultant short stature. Recently, the use of combination therapy with a potent antiandrogen agent (bicalutamide) and a third-generation aromatase inhibitor (anastrozole or letrozole) was reported to yield encouraging short-term results. We present here the results of longer-term treatment (4.5 and 5 years) with this combination therapy in 2 boys who demonstrated that it is well tolerated, slows bone-age advancement in the face of continued linear growth, and prevents progression of virilization.

Results of a second year of therapy with the 12-month histrelin implant for the treatment of central precocious puberty.

Background. Gonadotropin releasing hormone analogs (GnRHas) are standard of care for central precocious puberty (CPP). The histrelin subcutaneous implant is safe and effective in the treatment of CPP for one year. Objective. The study evaluates a second year of therapy in children with CPP who received a new implant after one year of treatment. Methods. A prospective one-year study following an initial 12-month treatment period was conducted. Results. Thirty-one patients (29 girls) aged 7.7 +/- 1.5 years received a second implant. Eighteen were naïve to GnRHa therapy at first implantation. Peak LH declined from 0.92 +/- 0.58 mIU/mL at 12 months to 0.51 +/- 0.33 mIU/mL at 24 months (P < .0001) in naïve subjects, and from 0.74 +/- 0.50 mIU/mL at 12 months to 0.45 +/- 0.35 mIU/mL at 24 months (P = .0081) in previously treated subjects. Predicted adult height increased by 5.1 cm at 24 months (P = .0001). Minor implant site reactions occurred in 61%, while minor difficulties with explantation occurred in 32.2% of subjects. Conclusion. The histrelin implant demonstrates profound hypothalamic-pituitary-gonadal axis suppression when a new implant is placed for a second year of treatment. Prospective follow-up of this therapeutic modality for the treatment of CPP is needed.

The impact of assay sensitivity in the assessment of diseases and disorders in children.

Accurate measurement of the low levels of testosterone (T) and estradiol (E(2)) present in normal children and in children with disorders of puberty and sexual development is critical both for appropriate diagnosis and treatment and for clinical research studies. However, measurement of these levels lacks needed precision because of inadequate sensitivity of most commercially available assays and poor accuracy at the low levels found in normal childhood and most disorders. While immunoassays presently do not appear to have the potential to provide more accurate measurements, isotope dilution-gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry techniques offer promise to meet this need to improve clinical care and research.

Unexpected recovery of ovarian function many years after bone marrow transplantation.

Premature ovarian failure as a consequence of childhood cancer treatment is considered permanent when present long after the initial insult. We report spontaneous recovery of ovarian function occurring 8 years after bone marrow transplantation in a girl with history of leukemia and growth hormone deficiency. Clinical management challenges are discussed.

Thyroid stimulating immunoglobulin is often negative in children with Graves' disease.

BACKGROUND: The diagnosis of Graves' disease (GD) is typically confirmed with a thyroid stimulating immunoglobulin (TSI) titer. While TSI is reported to be positive in >90% of patients with GD, our anecdotal experience suggests that TSI negative GD may be more common in children. AIM: To investigate the incidence of TSI negative GD in our population and to compare patients with TSI negative vs TSI positive GD. METHODS: Charts of children with GD seen in our pediatric endocrinology clinic over the past 5 years were reviewed. RESULTS: Fifty-seven patients with GD were included. TSI was negative in 43% of patients. No significant differences were found in children with TSI negative vs TSI positive GD. CONCLUSIONS: In patients with GD, the finding of a negative TSI titer usually creates diagnostic uncertainty. However, the fact that nearly half of our patients with GD were TSI negative suggests that this is common in children.