Objective: Plasma assay for very long- chain fatty acids has made it possibl e to perform large- scale screening of at- risk individuals to identify asympt omatic patients with X- linked adrenoleukodystrophy (X- ALD)....Objective: Plasma assay for very long- chain fatty acids has made it possibl e to perform large- scale screening of at- risk individuals to identify asympt omatic patients with X- linked adrenoleukodystrophy (X- ALD). We evaluated the burden of undiagnosed adrenal insufficiency in 49 such patients (age, 4.5 ± 3 .5 years). Study design: Serum adrenocorticotropic hormone (ACTH) and standard- dose ACTH stimulation test were performed at the baseline and followed prospect ively until initiation of adrenal replacement therapy (follow- up, 2 ± 1.7 ye ars). Results: At baseline, 39 (80% ) patients had impaired adrenal function, s erum ACTH levels were elevated in 34 (69% ) patients, and ACTH stimulation test was abnormal in 21(43% ) patients. There was a moderate association between Se rum ACTH and age at baseline, (r = 0.32, P = .05). By the end of follow- up, 86 % of patients had borderline or overt adrenal insufficiency (age of onset, 4.8 ± 3.7 years). Conclusions: We detected a high prevalence of unrecognized adre nocortical insufficiency in asymptomatic boys with X- ALD. It is known to be a frequent cause of morbidity and can be prevented by careful monitoring, early id entification of impaired adrenal reserve, and timely initiation of therapy. It m anifests early and before onset of neurologic symptoms, suggesting X- ALD as a candidate disorder for neonatal screening.展开更多
Background: Various studies have demonstrated abnormal neuropsychological function in boys with the childhood cerebral phenotype of X-linked adrenoleukodystrophy. Not much is known about the cognitive function of neur...Background: Various studies have demonstrated abnormal neuropsychological function in boys with the childhood cerebral phenotype of X-linked adrenoleukodystrophy. Not much is known about the cognitive function of neurologically asymptomatic boys with X-linked adrenoleukodystrophy who have normal brain magnetic resonance imaging results. Objective: To describe the cognitive profile of 52 neurologically asymptomatic boys with X-linked adrenoleukodystrophy (mean± SD age, 6.7± 3.6 years). Methods: Neuropsychological tests included evaluation of IQ (full-scale IQ, verbal IQ, and performance IQ), 5 major cognitive domains (language, visuospatial skills, perception, visuomotor or graphomotor skills, memory, and attention or executive function), adaptive skills, and academic achievement. Standardized z scores relative to ageappropriate published norms were generated. Association between age and cognitive performance was evaluated using nonparametric Spearman rank correlation and robust median regression adjusting for full-scale IQ and socioeconomic status. Results: All but 4 patients had normal cognitive function. There was a negative correlation between age and visual perception as well as age and visuomotor skills after adjustment for full-scale IQ and socioeconomic status. Conclusions: This study provides, to our knowledge, the first evidence of overall normal cognitive function in neurologically and radiologically normal boys with X-linked adrenoleukodystrophy, indicating no evidence of neurodevelopmental abnormalities despite the inherent ABCD1 mutation. Subtle deterioration with age was observed in some functional domains. This suggests that prevention and timely institution of therapy can potentially preserve cognitive function seen in patients with the cerebral X-linked adrenoleukodystrophy phenotype. X-linked adrenoleukodystrophy should be considered a candidate disorder for neonatal screening.展开更多
Background: Gait abnormalities and sensorimotor disturbances are principal defects in adrenomyeloneuropathy (AMN). However, to our knowledge, their association with overall impairment and neuroanatomical changes has n...Background: Gait abnormalities and sensorimotor disturbances are principal defects in adrenomyeloneuropathy (AMN). However, to our knowledge, their association with overall impairment and neuroanatomical changes has not been defined. Objectives: To understand how sensorimotor impairments create mobility deficits and to analyze how these impairments are related to specific metrics of axonal integrity. Design: Cross-sectional study assessing impairments, including vibration sensation, strength, spasticity, and global measures of walking and balance. Fractional anisotropy was measured to evaluate the integrity of the corresponding brainstem tracts. Participants: Men with AMN and healthy control subjects. Results: Individuals with sensory loss only showed minimal walking deficits. Concomitant strength and sensory loss resulted in slower walking, with abnormal knee control; increased spasticity led to an exaggerated trunk motion and a knee-flexed (crouched) posture. Hip strength was an independent predictor of walking velocity in subjects with AMN. Subjects with sensory loss only had greater sway amplitudes during standing balance testing, which did not worsen with additional impairments. There were significant associations among sway amplitude, great toe vibration sense, and dorsal column fractional anisotropy. Brainstem fractional anisotropy in AMN was significantly negatively correlated with impairment, indicating that overall tract integrity is associated with sensorimotor abnormalities in AMN. Conclusions: Impairment measures capture specific abnormalities in walking and balance that can be used to direct rehabilitation therapy in AMN. Tract-specific magnetic resonance imaging metrics, such as fractional anisotropy (used herein to evaluate structure-function relationships), significantly reflect disease severity in AMN.展开更多
Background: Adrenomyeloneuropathy (AMN) is the adult variant of X-linked adre noleukodystrophy. The disease pathology is usually limited to spinal cord and pe ripheral nerves, and when this is the case, it is referred...Background: Adrenomyeloneuropathy (AMN) is the adult variant of X-linked adre noleukodystrophy. The disease pathology is usually limited to spinal cord and pe ripheral nerves, and when this is the case, it is referred to as “pure" AMN. Hi stopathology shows cerebral involvement even in pure AMN; however, not much is k nown about the nature, extent, and clinical relevance of these findings. Objecti ve: To investigate brain involvement in AMN patients with normal MRI, employing multislice MR spectroscopic imaging. Methods: Twelve men with pure AMN were comp ared with 19 age-matched healthy volunteers.Metabolite ratios (N-acetylasparta te [NAA]/choline [Cho],NAA/creatine [Cr], and Cho/Cr) were measured from seven b rain regions. Global metabolite ratios were generated as an average of these sev en regional ratios. The Expanded Disability Status Scale (EDSS) was used for neu rologic evaluation. Results: The patients with AMN showed reduced global NAA/Cho (AMN 1.40 ±0.16 vs controls 1.75 ±0.34; p = 0.003) and global NAA/Cr (AMN 2.3 2 ±0.13 vs controls 2.62 ±0.43; p = 0.03). Regionally, NAA/Cho was lowered in the internal capsule(AMN 1.30 ±0.20 vs controls 1.69 ±0.37; p = 0.002) and inp arieto-occipital white matter (AMN 1.45 ±0.19 vs controls 1.78 ±0.55; p = 0.0 4). NAA/Cr was lowered in parieto-occipital white matter (AMN 2.34 ±0.31 vs co ntrols 2.83 ±0.71; p= 0.04). EDSS demonstrated an inverse association with glob al NAA/Cr (r = -0.65, p = 0.02) and NAA/Cr in centrum semiovale(r = -0.73, p = 0.006) and in parieto-occipital white matter (r= -0.64, p = 0.02). Cho/Cr was not significantly elevated.Conclusions: 1H-MR spectroscopic imaging is able to detect biochemical abnormalities sugge stive of axonal damage even in the brains of patients with pure adrenomyeloneuro pathy. The axonopathy is most prominent in internal capsule and parietooccipital white matter and may contribute to clinical disability.展开更多
文摘Objective: Plasma assay for very long- chain fatty acids has made it possibl e to perform large- scale screening of at- risk individuals to identify asympt omatic patients with X- linked adrenoleukodystrophy (X- ALD). We evaluated the burden of undiagnosed adrenal insufficiency in 49 such patients (age, 4.5 ± 3 .5 years). Study design: Serum adrenocorticotropic hormone (ACTH) and standard- dose ACTH stimulation test were performed at the baseline and followed prospect ively until initiation of adrenal replacement therapy (follow- up, 2 ± 1.7 ye ars). Results: At baseline, 39 (80% ) patients had impaired adrenal function, s erum ACTH levels were elevated in 34 (69% ) patients, and ACTH stimulation test was abnormal in 21(43% ) patients. There was a moderate association between Se rum ACTH and age at baseline, (r = 0.32, P = .05). By the end of follow- up, 86 % of patients had borderline or overt adrenal insufficiency (age of onset, 4.8 ± 3.7 years). Conclusions: We detected a high prevalence of unrecognized adre nocortical insufficiency in asymptomatic boys with X- ALD. It is known to be a frequent cause of morbidity and can be prevented by careful monitoring, early id entification of impaired adrenal reserve, and timely initiation of therapy. It m anifests early and before onset of neurologic symptoms, suggesting X- ALD as a candidate disorder for neonatal screening.
文摘Background: Various studies have demonstrated abnormal neuropsychological function in boys with the childhood cerebral phenotype of X-linked adrenoleukodystrophy. Not much is known about the cognitive function of neurologically asymptomatic boys with X-linked adrenoleukodystrophy who have normal brain magnetic resonance imaging results. Objective: To describe the cognitive profile of 52 neurologically asymptomatic boys with X-linked adrenoleukodystrophy (mean± SD age, 6.7± 3.6 years). Methods: Neuropsychological tests included evaluation of IQ (full-scale IQ, verbal IQ, and performance IQ), 5 major cognitive domains (language, visuospatial skills, perception, visuomotor or graphomotor skills, memory, and attention or executive function), adaptive skills, and academic achievement. Standardized z scores relative to ageappropriate published norms were generated. Association between age and cognitive performance was evaluated using nonparametric Spearman rank correlation and robust median regression adjusting for full-scale IQ and socioeconomic status. Results: All but 4 patients had normal cognitive function. There was a negative correlation between age and visual perception as well as age and visuomotor skills after adjustment for full-scale IQ and socioeconomic status. Conclusions: This study provides, to our knowledge, the first evidence of overall normal cognitive function in neurologically and radiologically normal boys with X-linked adrenoleukodystrophy, indicating no evidence of neurodevelopmental abnormalities despite the inherent ABCD1 mutation. Subtle deterioration with age was observed in some functional domains. This suggests that prevention and timely institution of therapy can potentially preserve cognitive function seen in patients with the cerebral X-linked adrenoleukodystrophy phenotype. X-linked adrenoleukodystrophy should be considered a candidate disorder for neonatal screening.
文摘Background: Gait abnormalities and sensorimotor disturbances are principal defects in adrenomyeloneuropathy (AMN). However, to our knowledge, their association with overall impairment and neuroanatomical changes has not been defined. Objectives: To understand how sensorimotor impairments create mobility deficits and to analyze how these impairments are related to specific metrics of axonal integrity. Design: Cross-sectional study assessing impairments, including vibration sensation, strength, spasticity, and global measures of walking and balance. Fractional anisotropy was measured to evaluate the integrity of the corresponding brainstem tracts. Participants: Men with AMN and healthy control subjects. Results: Individuals with sensory loss only showed minimal walking deficits. Concomitant strength and sensory loss resulted in slower walking, with abnormal knee control; increased spasticity led to an exaggerated trunk motion and a knee-flexed (crouched) posture. Hip strength was an independent predictor of walking velocity in subjects with AMN. Subjects with sensory loss only had greater sway amplitudes during standing balance testing, which did not worsen with additional impairments. There were significant associations among sway amplitude, great toe vibration sense, and dorsal column fractional anisotropy. Brainstem fractional anisotropy in AMN was significantly negatively correlated with impairment, indicating that overall tract integrity is associated with sensorimotor abnormalities in AMN. Conclusions: Impairment measures capture specific abnormalities in walking and balance that can be used to direct rehabilitation therapy in AMN. Tract-specific magnetic resonance imaging metrics, such as fractional anisotropy (used herein to evaluate structure-function relationships), significantly reflect disease severity in AMN.
文摘Background: Adrenomyeloneuropathy (AMN) is the adult variant of X-linked adre noleukodystrophy. The disease pathology is usually limited to spinal cord and pe ripheral nerves, and when this is the case, it is referred to as “pure" AMN. Hi stopathology shows cerebral involvement even in pure AMN; however, not much is k nown about the nature, extent, and clinical relevance of these findings. Objecti ve: To investigate brain involvement in AMN patients with normal MRI, employing multislice MR spectroscopic imaging. Methods: Twelve men with pure AMN were comp ared with 19 age-matched healthy volunteers.Metabolite ratios (N-acetylasparta te [NAA]/choline [Cho],NAA/creatine [Cr], and Cho/Cr) were measured from seven b rain regions. Global metabolite ratios were generated as an average of these sev en regional ratios. The Expanded Disability Status Scale (EDSS) was used for neu rologic evaluation. Results: The patients with AMN showed reduced global NAA/Cho (AMN 1.40 ±0.16 vs controls 1.75 ±0.34; p = 0.003) and global NAA/Cr (AMN 2.3 2 ±0.13 vs controls 2.62 ±0.43; p = 0.03). Regionally, NAA/Cho was lowered in the internal capsule(AMN 1.30 ±0.20 vs controls 1.69 ±0.37; p = 0.002) and inp arieto-occipital white matter (AMN 1.45 ±0.19 vs controls 1.78 ±0.55; p = 0.0 4). NAA/Cr was lowered in parieto-occipital white matter (AMN 2.34 ±0.31 vs co ntrols 2.83 ±0.71; p= 0.04). EDSS demonstrated an inverse association with glob al NAA/Cr (r = -0.65, p = 0.02) and NAA/Cr in centrum semiovale(r = -0.73, p = 0.006) and in parieto-occipital white matter (r= -0.64, p = 0.02). Cho/Cr was not significantly elevated.Conclusions: 1H-MR spectroscopic imaging is able to detect biochemical abnormalities sugge stive of axonal damage even in the brains of patients with pure adrenomyeloneuro pathy. The axonopathy is most prominent in internal capsule and parietooccipital white matter and may contribute to clinical disability.
