In vitro effect of N-acetyl-L-cysteine on glutathione and sulfhydryl levels in X-linked adrenoleukodystrophy patients

Introduction: Recent evidence shows that oxidative stress seems to be related with the pathophysiology of X-linked adrenoleukodystrophy (X-ALD), a neurodegenerative disorder. Methods: In the present study, the in vitro effect of N-acetyl-L-cysteine (NAC) on glutathione (GSH) and sulfhydryl levels in X-ALD patients was evaluated. Results: A significant reduction of GSH and sulfhydryl content was observed in X-ALD patients compared to the control group. Furthermore, 5 mM of NAC, in vitro, led to an increase in GSH content and sulfhydryl groups in these patients. Conclusion: These data probably indicate that an adjuvant therapy with the antioxidant NAC could improve the oxidative imbalance in X-ALD patients(AU)

Auditory agnosia as a clinical symptom of childhood adrenoleukodystrophy.

OBJECTIVE: To investigate detailed auditory features in patients with auditory impairment as the first clinical symptoms of childhood adrenoleukodystrophy (CSALD). SUBJECTS AND METHODS: Three patients who had hearing difficulty as the first clinical signs and/or symptoms of ALD. Precise examination of the clinical characteristics of hearing and auditory function was performed, including assessments of pure tone audiometry, verbal sound discrimination, otoacoustic emission (OAE), and auditory brainstem response (ABR), as well as an environmental sound discrimination test, a sound lateralization test, and a dichotic listening test (DLT). The auditory pathway was evaluated by MRI in each patient. RESULTS: Poor response to calling was detected in all patients. Two patients were not aware of their hearing difficulty, and had been diagnosed with normal hearing by otolaryngologists at first. Pure-tone audiometry disclosed normal hearing in all patients. All patients showed a normal wave V ABR threshold. Three patients showed obvious difficulty in discriminating verbal sounds, environmental sounds, and sound lateralization and strong left-ear suppression in a dichotic listening test. However, once they discriminated verbal sounds, they correctly understood the meaning. Two patients showed elongation of the I-V and III-V interwave intervals in ABR, but one showed no abnormality. MRIs of these three patients revealed signal changes in auditory radiation including in other subcortical areas. CONCLUSION: The hearing features of these subjects were diagnosed as auditory agnosia and not aphasia. It should be emphasized that when patients are suspected to have hearing impairment but have no abnormalities in pure tone audiometry and/or ABR, this should not be diagnosed immediately as psychogenic response or pathomimesis, but auditory agnosia must also be considered.

A case of adult-onset adrenoleukodystrophy with frontal lobe dysfunction: a novel point mutation in the ABCD1 gene.

We report the case of a 48-year-old man with adult-onset adrenoleukodystrophy (ALD) who developed dementia with subacute onset. He was abulic, indifferent to his surroundings, and without insight with regards to his own disease. An elevated plasma very long chain fatty acid level and a novel point mutation IVS3+2t>g in the ABCD1 gene confirmed the diagnosis of ALD. Diffusion-weighted MRI revealed a high intensity area in the white matter of the frontal lobes. Severe brain hypoperfusion in the frontal lobes was revealed. We believe that this is a rare case of adult-onset adrenoleukodystrophy with predominant frontal lobe dysfunction.

Treatment of an adrenomyeloneuropathy patient with Lorenzo's oil and supplementation with docosahexaenoic acid--a case report.

This is a case report of adrenomyeloneuropathy (AMN), the adult variant of adrenoleukodystryphy (ALD). The diagnoses in the patient, aged 34, was confirmed via increased serum very long chain fatty acid concentration (VLCFA). Treatment started with the cholesterol lowering drug, atorvastatin, followed by add-on therapy with Lorenzo's oil (LO) and finally supplementation with docosahexaenoic acid (DHA). The magnetic resonance imaging (MRI) scan of the AMN patient before DHA treatment, already showed abnormal white matter in the brain. Although the MRI showed no neurological improvement after 6 months of DHA treatment, no selective progression of demyelination was detected in the AMN patient. Contrary to what was expected, LO failed to sustain or normalize the VLCFA levels or improve clinical symptoms. It was however, shown that DHA supplementation in addition to LO, increased DHA levels in both plasma and red blood cells (RBC). Additionally, the study showed evidence that the elongase activity in the elongation of eicosapentaenoic acid (EPA) to docosapentaenoic acid (DPA) might have been significantly compromised, due to the increased DHA levels.

Auditory function in adrenomyeloneuropathy.

Auditory brainstem responses (ABR), ipsilateral and contralateral acoustic reflexes and the masking level difference for speech (MLD) were studied in 29 patients with adrenomyeloneuropathy (AMN). Abnormalities were seen for all ABR components with Waves V and III affected to the greatest degree. For male patients with AMN, the I-III, III-V and I-V interpeak latency intervals were abnormal for a majority of patients. For female patients with AMN, the I-V and III-V interpeak latency intervals were abnormal for a majority of patients with the I-III interval less affected. Contralateral acoustic reflexes were elevated or absent for approximately 50% of ears. Ipsilateral acoustic reflexes were abnormal for 25% of ears. MLDs were significantly reduced in 72% of patients. When considered in terms of the earliest ABR wave abnormality, the earlier components of the ABR (i.e., Waves III and I) were the initial components impaired for the majority of ears. Word recognition in quiet was relatively unimpaired for all subjects. Despite the presence of marked ABR abnormalities, patients with AMN denied the presence of significant difficulty hearing.

Transcranial magnetic stimulation after conditioning stimulation in two adrenomyeloneuropathy patients: delayed but facilitated motor-evoked potentials.

Two male patients were diagnosed with adrenomyeloneuropathy. Their chief problems were progressive spastic paraparesis, sensory impairment, hyperpigmentation and testis atrophy. Transcranial magnetic stimulation (TMS) does not easily elicit motor-evoked potentials (MEPs) in patients with a central nervous system dysfunction, even though a few methods, such as contraction of the target muscles and the Jendrassik maneuver (JM), are used in the attempt to facilitate them. In these two patients, we used a conditioning method (prior electrical stimulation over the cutaneous nerve of the left index finger) in order to facilitate MEPs, elicited by TMS, in the left tibialis anterior muscle. In patient 1, facilitation of MEPs was present at conditioning-test (C-T) intervals in the range 60-220 ms, with the maximal MEP recorded at C-T 160 ms; in patient 2, it occurred in the C-T interval range 110-140 ms, with the maximal MEP recorded at C-T 130 ms. By means of conditioning electrical stimulation, we can facilitate MEPs elicited by TMS in those subjects in whom MEPs are minimal or difficult to elicit even using the conventional JM or muscle contraction. The facilitation of MEPs by conditioning stimuli allowed us not only to assess central motor conduction time, but also to demonstrate the preserved continuity of the corticospinal tract in these two patients.

Auditory brainstem response findings and peripheral auditory sensitivity in adrenoleukodystrophy.

Measurements of the auditory brainstem response (ABR) were obtained in 96 individuals with X-linked adrenoleukodystrophy (X-ALD). The patients were divided into five diagnostic groups on the basis of neurologic diagnosis. The five groups were cerebral childhood and adolescent, pure adrenomyeloneuropathy (pure AMN), adrenomyeloneuropathy cerebral (AMN cerebral), Addison's only and symptomatic female heterozygotes. Results indicated the presence of marked ABR abnormalities for all groups most frequently involving Wave V, followed by Wave III and Wave I. Abnormalities of all interpeak latency intervals (i.e., I-III, III-V and I-V) were observed for all groups. ABR abnormalities were most frequently seen in the AMN-cerebral and pure AMN groups but were also common in the symptomatic female heterozygote group. The ABRs in the cerebral childhood and adolescent group were the least impaired of the five groups examined. Age was found to be a significant independent predictor of bilateral ABR abnormalities but VLCFA levels, MRI Loes score, and duration of symptoms were not found to be independent predictors of bilateral ABR abnormalities after adjusting for ALD phenotype. Patients with AMN were significantly more likely to have bilateral ABR abnormalities than the cerebral childhood and adolescent group after adjusting for age, duration of symptoms, EDSS score, VLCFA levels and MRI Loes scores. The prevalence of peripheral hearing loss was not found to exceed that present in age and sex matched normal control groups derived from the NHANES (1999-2000), indicating a lack of association between peripheral hearing loss and X-linked adrenoleukodystrophy. It was concluded that: (1) auditory sensitivity in X-ALD is not significantly impaired; (2) ABR abnormalities are a frequent finding and may be caused by abnormalities of fiber tracts in the region of the lateral lemniscus and inferior colliculus; and, (3) the abnormalities progress slowly and appear to be associated mainly with the AMN phenotype.

The effect of Lorenzo's oil on oxidative stress in X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder biochemically characterized by the accumulation of very long chain fatty acids (VLCFA), particularly hexacosanoic acid (C(26:0)) and tetracosanoic acid (C(24:0)), in tissues and biological fluids. Although patients affected by this disorder predominantly present central and peripheral demyelination as well as adrenal insufficiency, the mechanisms underlying the brain damage in X-ALD are poorly known. The current treatment of X-ALD with glyceroltrioleate (C(18:1))/glyceroltrierucate (C(22:1)) (Lorenzo's oil, LO) combined with a VLCFA-poor diet normalizes VLCFA concentrations, but the neurological symptoms persist or even progress in symptomatic patients. Considering that free radical generation is involved in various neurodegenerative disorders and that in a previous study we showed evidence that oxidative stress is probably involved in the pathophysiology of X-ALD symptomatic patients, in the present study we evaluated various oxidative stress parameters, namely thiobarbituric acid reactive species (TBA-RS) and total antioxidant reactivity (TAR) in plasma, as well as the activities of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) in erythrocytes from symptomatic and asymptomatic X-ALD patients and verified whether LO treatment and a VLCFA restricted diet could change these parameters. We observed a significant increase of plasma TBA-RS in symptomatic and asymptomatic X-ALD patients, reflecting induction of lipid peroxidation even before the disease was manifested. In addition, LO treatment did not alter this profile. Furthermore, plasma TAR measurement of X-ALD patients was not different from that of controls. Similarly, the antioxidant enzyme activities CAT, SOD and GPx were not altered in erythrocyte from X-ALD patients as compared to controls. We also examined the in vitro effects of hexacosanoic acid (C(26:0)) and tetracosanoic acid (C(24:0)) alone or combined with oleic (C(18:1))/erucic (C(22:1)) acids on various oxidative stress parameters in cerebral cortex of young rats, namely chemiluminescence, TBA-RS, TAR, CAT, SOD and GPx in order to investigate whether those fatty acids were able to induce oxidative stress. We found that there was a significant increase of TBARS and of chemiluminescence in rat cerebral cortex exposed to C(26:0)/C(24:0), and that the addition of C(18:1)and C(22:1) to the assays did not prevent this effect. Furthermore, TAR measurement was not altered by C(26:0) and C(24:0) acids in rat cerebral cortex. Taken together, our results indicate that lipid peroxidation occurs in X-ALD and that LO treatment does not attenuate or prevent free radical generation in these patients. Therefore, it may be presumed that antioxidants should be considered as an adjuvant therapy for X-ALD patients.

[Diet therapy in the treatment of neuropediatric disorders]. / Dietas médicas en el tratamiento de las enfermedades neuropediátricas.

OBJECTIVES: This review focuses on the dietary treatment of four neuropediatric disorders: 1) X-linked adrenoleukodystrophy (X-ALD); 2) attention deficit disorders (ADD); 3) refractory epilepsy; and 4) inborn errors of metabolism. DEVELOPMENT: The use of Lorenzo's oil in the treatment of X-ALD has been controversial since no clear efficacy has been demonstrated because of a lack of controlled studies. Although this treatment normalizes the levels of very-long chain fatty acids in children with the cerebral form of X-ALD, the neurological symptoms persist or progress. The dietary treatment of ADD with or without hyperactivity consists of elimination diets such as the Feingold diet and megavitamins. Although the results of several controlled studies are contradictory, there is no scientific evidence that sugar, artificial food colorings or sweeteners are responsible for behavior or learning problems in children. The ketogenic diet has been effective for the control of refractory epilepsy such as infantile spasms and myoclonic seizures. Important side effects include gastrointestinal complaints, metabolic complications, poor growth and nutrition, liver abnormalities and renal calculi. The early identification and treatment of inborn errors of metabolism require prompt diagnosis and correction of metabolic abnormalities. Restriction of protein and fats may be necessary in certain neurometabolic disorders. A variety of special formulas is available to meet the nutritional requirements and avoid offending substances in neurometabolic patients. CONCLUSIONS: Dietary treatment plays an important role in the management of certain neuropediatric disorders, such as the use of special formulas in inborn errors of metabolism and the ketogenic diet in refractory epilepsy. The efficacy of Lorenzo's oil in the cerebral form of X-ALD and of the elimination of artificial food colorings and sweeteners in ADD remain to be proved.