Postural tremor in L-2-hydroxyglutaric aciduria is associated with cerebellar atrophy.

OBJECTIVE: In this study, we performed analysis of brainstem reflexes and movement disorders using surface polymyogram in L-2-hydroxyglutaric aciduria (L2HGA). We also reviewed all cases in the literature with detailed clinical and radiological description to analyze the anatomical correlates of involuntary movements. PATIENTS AND METHOD: We performed surface electromyography of appropriate muscles, long-loop reflexes, and somatosensory evoked potentials and analyzed the neuroimaging findings in patients with L2HGA and recorded blink reflex (BR), auditory startle response (ASR), and startle response after somatosensory stimuli (SSS) in patients and healthy subjects. We also performed a systematic literature search to identify the association of neuroimaging findings and movements disorders in previous patients with L2HGA. RESULTS: Thirteen patients were enrolled in the study. Among them, ten had low-amplitude postural tremor with a frequency between 4 and 7 Hz. The tremor was predominant on distal parts of the upper extremities. Postural tremor was accompanied by negative myoclonus in one-third. The BR, ASR, and SSS, all, were hypoactive. There was a close association of postural tremor with cerebellar atrophy in patients who participated in this study and by the analysis of the previously reported patients. CONCLUSIONS: Low-amplitude postural tremor is common in L2HGA. It is related with cerebellar atrophy. Although the neuroimaging shows no overt lesions at the brainstem, there is a functional inhibition at this level.

Adrenal steroids reference ranges in infancy determined by LC-MS/MS.

BACKGROUND: Interpretation of the results of steroid hormone measurements is challenging at early infancy. The liquid chromatography-tandem mass spectrometry (LC-MS/MS) method provides a powerful tool for diagnosing steroidogenesis disorders. We aimed to develop normative data for a 14-steroid panel and four adrenal enzyme activity indices, determined by LC-MS/MS from 3 days to 6 months of age. METHODS: Age- and sex-specific plasma steroid concentrations were calculated in 324 healthy full-term neonates and infants (151 females). Percentile curves were devised. Steroid ratios were evaluated as biomarkers of adrenal enzyme activities. The steroid profiles of four patients with adrenal enzyme deficiencies were included to test the diagnostic efficiency. RESULTS: Nine steroids showed age, but none showed sex specificity. The concentrations of progestins and androgens were higher at 7-14 days than at 3-7 days. After the first month, adrenal androgen concentrations decreased significantly. Adrenal enzyme activities changed towards increasing cortisol over the first 6 months. There were several-fold differences in diagnostic steroids and related adrenal enzyme activity indices between the patients and the healthy group. CONCLUSIONS: The majority of adrenal steroids show age-related variations in the neonatal period and early infancy. Our data will enable accurate interpretation of steroid measurements for etiologic diagnosis of disorders of steroidogenesis. IMPACT: LC-MS/MS method is capable of quantitating numerous analytes simultaneously, which provides an integrated picture of adrenal steroidogenesis in a small amount of sample. The development of LC-MS/MS-based normative data of steroid hormones in healthy infants is crucial to differentiate physiologic alterations from steroidogenic defects during the first 3-6 months of infancy. Previous studies had limitations due to the small numbers of samples available by sex and by age groups. Our detailed normative data and percentile curves will enable accurate interpretation of steroid measurements for etiologic diagnosis of disorders of steroidogenesis without the need for further invasive testing.

Evaluation of clinical, neuroradiologic, and genotypic features of patients with L-2-hydroxyglutaric aciduria.

AIM: L-2-hydroxyglutaric aciduria is a slowly progressive neurometabolic disorder caused by an enzymatic deficiency of L-2-hydroxyglutarate dehydrogenase. Here, we aimed to evaluate the clinical, neuroradiologic, and genotypic characteristics of patients with L-2-hydroxyglutaric aciduria who were followed in our outpatient clinic. MATERIAL AND METHODS: Twenty-five patients with L-2-hydroxyglutaric aciduria were enrolled in the study. Data regarding demographic, clinical, and neuroradiologic findings and molecular analysis were evaluated retrospectively. RESULTS: The mean age of patients at the time of diagnosis was 12.09±8.02 years, whereas the mean age at the time of the first symptoms was 39.47±29.96 months. Diagnostic delay was found as 9.95±7.78 years. Developmental delay, decrease in school success, and seizures were the most common initial symptoms; however, behavioral problems and seizures became more prominent in the disease course. At the time of diagnosis, mental retardation and at least one pathologic cerebellar finding were detected in all symptomatic patients. Three patients developed brain tumors. The most common neuroimaging findings were subcortical white matter changes and cerebellar dentate nucleus involvement. In one patient, there was only isolated basal ganglia involvement without white matter lesions. Patients with similar genotypic features exhibited different clinical and radiologic findings. CONCLUSION: Although clinical symptoms appear early in L-2-hydroxyglutaric aciduria, there is approximately a ten-year delay in diagnosis. In subjects in whom brain tumor is detected in early childhood, L-2-hydroxyglutaric aciduria should be considered in the differential diagnosis in the presence of mental retardation accompanied by developmental delay, cerebellar and pyramidal findings, and behavior disorders in a wide spectrum ranging from autism spectrum disorder to psychosis. In patients with L-2-hydroxyglutaric aciduria, incipient headache, tinnitus, altered consciousness, and seizures can be indicative of brain tumors.

Evaluation of the effect of chenodeoxycholic acid treatment on skeletal system findings in patients with cerebrotendinous xanthomatosis.

AIM: The primary purpose of the present study is to evaluate the effect of chenodeoxycholic acid treatment on skeletal system findings in patients with cerebrotendinous xanthomatosis. MATERIAL AND METHODS: This retrospective study was conducted between June 2013 and December 2018 with seven patients with cerebrotendinous xanthomatosis in Cerrahpasa Medical Faculty Pediatric Nutrition and Metabolism Department. The clinical, epidemiologic, and genotypic features of the patients were reviewed in detail and the following items, especially related with skeletal system involvement, were recorded from medical data: history of a bone fracture, plasma calcium, phosphate, alkaline phosphatase and 25-hydroxy-vitamin D concentrations, bone mineral density values of the posteroanterior lumbar spine (L1-L4), and femoral neck before and after chenodeoxycholic acid treatment. RESULTS: Regarding the bone mineral metabolism, plasma calcium, phosphate, alkaline phosphatase levels were found in normal ranges in all patients. Plasma 25-hydroxy-vitamin D evaluation at the time of diagnosis showed deficiency in three patients and insufficiency in three patients. Following chenodeoxycholic acid therapy, 25-hydroxy-vitamin D deficiency persisted in only one patient, but insufficiency was observed in four patients. According to the bone mineral density assessments, four patients had Z-scores below the expected range for age both at initial examination and after chenodeoxycholic acid therapy. No significant difference was observed between plasma 25-hydroxy-vitamin D levels and bone mineral density Z-scores before or after treatment. CONCLUSION: This study elucidates the necessity of additional medical treatment as a part of chenodeoxycholic acid therapy to improve skeletal system findings in cerebrotendinous xanthomatosis.

AMAÇ: Bu çalismanin temel amaci serebrotendinöz ksantomatozis tanili hastalarda kullanilan kenodeoksikolik asit tedavisinin iskelet sistemi bulgulari üzerine olan etkisini tanimlamaktir. GEREÇ VE YÖNTEMLER: Bu geriye dönük çalismaya Haziran 2013 ve Aralik 2018 yillari arasinda Cerrahpasa Tip Fakültesi Çocuk Metabolizma ve Beslenme Bilim Dali'nda izlenen serebrotendinoz ksantomatozis tanili yedi hasta alindi. Hastalara ait klinik, epidemiyolojik ve genotipik özellikler geriye dönük incelendi ve özellikle iskelet sistemini ilgilendiren kemik kirigi öyküsü, kenodeoksikolik asit tedavisi öncesi ve sonrasinda plazma kalsiyum, fosfat, alkalen fosfataz, 25-hidroksi-vitamin D düzeyleri, posteroanterior lomber vertebra (L1-L4) ve femur boynu kemik mineral dansitelerine ait bilgiler kaydedildi. BULGULAR: Kemik mineral metabolizmasinin degerlendirilmesi açisindan ölçülen plazma kalsiyum, fosfat, alkalen fosfataz seviyeleri tüm hastalarda normal sinirlardaydi. Tani aninda yapilan plazma 25-hidroksi-vitamin D degerlendirilmesi; üç hastada eksiklik, üç hastada yetersizlik ile uyumluydu. Kenodeoksikolik asit tedavisi sonrasinda 25-hidroksi-vitamin D eksikligi bir hastada devam ederken, dört hastada yetersizlik saptandi. Kemik mineral dansitometri degerlendirmelerinde, dört hastada kemik mineral dansitesi Z-skorlarinin baslangiç aninda ve tedavi sonunda yasa göre düsük olarak devam ettigi görüldü. 25-hidroksi-vitamin D ve kemik mineral dansitometrisi Z-skorlari arasinda tedavi öncesi ve sonrasinda istatistiksel olarak anlamli farklilik izlenmedi. ÇIKARIMLAR: Bu çalismada, serebrotendinöz ksantomatozis tanili hastalarda iskelet sistemi bulgularinin iyilestirilmesi amaciyla kenodeoksikolik asit tedavisine ek olarak farkli medikal tedavilerin gerekli olabilecegi üzerinde durulmustur.

Acquired modification of sphingosine-1-phosphate lyase activity is not related to adrenal insufficiency.

BACKGROUND: Congenital sphingosine-1-phosphate (S1P) lyase deficiency due to biallelic mutations in SGPL1 gene has recently been described in association with primary adrenal insufficiency and steroid-resistant nephrotic syndrome. S1P lyase, on the other hand, is therapeutically inhibited by fingolimod which is an oral drug for relapsing multiple sclerosis (MS). Effects of this treatment on adrenal function has not yet been evaluated. We aimed to test adrenal function of MS patients receiving long-term fingolimod treatment. METHODS: Nineteen patients (14 women) with MS receiving oral fingolimod (Gilenya®, Novartis) therapy were included. Median age was 34.2 years (range; 21.3-44.6 years). Median duration of fingolimod treatment was 32 months (range; 6-52 months) at a dose of 0.5 mg/day. Basal and ACTH-stimulated adrenal steroid measurements were evaluated simultaneously employing LC-MS/MS based steroid panel. Basal steroid concentrations were also compared to that of sex- and age-matched healthy subjects. Cortisol and 11-deoxycortisol, 11-deoxycorticosterone and dehydroepiandrosterone were used to assess glucocorticoid, mineralocorticoid and sex steroid producing pathways, respectively. RESULTS: Basal ACTH concentrations of the patients were 20.8 pg/mL (6.8-37.8 pg/mL) (normal range; 5-65 pg/mL). There was no significant difference in the basal concentrations of cortisol, 11-deoxycortisol, 11-deoxycorticosterone and dehydroepiandrosterone between patients and controls (p = 0.11, 0.058, 0.74, 0.15; respectively). All patients showed adequate cortisol response to 250 mcg IV ACTH stimulation (243 ng/mL, range; 197-362 ng/mL). There was no significant correlation between duration of fingolimod treatment and basal or ACTH-stimulated cortisol or change in cortisol concentrations during ACTH stimulation test (p = 0.57, 0.66 and 0.21, respectively). CONCLUSION: Modification and inhibition of S1P lyase activity by the long-term therapeutic use of fingolimod is not associated with adrenal insufficiency in adult patients with MS. This suggests that S1P lyase has potentially a critical role on adrenal development rather than the function of a fully mature adrenal gland.