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Spectrum of clinical disease in X-linked adrenoleukodystrophy (X-ALD)

Phenotype	Age at presentation	Symptoms and signs	Diagnostic tests	Follow-up tests	Usual therapy
Males
Childhood cerebral ALD
Asymptomatic with normal MRI	Variable; most commonly <4 years	None	Usually comes to light through newborn screening or testing family member of a patient with X-ALD Confirm with DNA testing	Adrenal function tests Monitor MRI Family screening	Glucocorticoid replacement therapy, if indicated
Asymptomatic with abnormal MRI	2 to ≥10 years	None	VLCFA levels Brain MRI Confirm diagnosis with DNA testing	Adrenal function tests Neurologic and neuropsychological testing Family screening	HCT Gene therapy is an experimental alternative treatment Glucocorticoid replacement therapy, if indicated
Early cerebral ALD	3 to 10 years; rarely presents at age >15 years	Behavior changes School difficulties Cognitive deficits Audiovisual changes	VLCFA levels Brain MRI Confirm diagnosis with DNA testing	Adrenal function tests Neurologic and neuropsychological testing Family screening	HCT Gene therapy is an experimental alternative treatment Glucocorticoid replacement therapy, if indicated
Spontaneously arrested ALD	3 years to adulthood	None or stable symptoms as with early cerebral ALD	VLCFA levels Brain MRI Confirm diagnosis with DNA testing	Adrenal function tests Neurologic and neuropsychological testing Family screening	Glucocorticoid replacement therapy, if indicated Important not to pursue HCT or GT
Advanced cerebral ALD	5 years to adulthood	Dementia Psychoses Paralysis Epilepsy Loss of vision Loss of speech Bulbar palsy	VLCFA levels Brain MRI Confirm diagnosis with DNA testing	Adrenal function tests Neurologic and neuropsychologic testing Family screening	Glucocorticoid replacement therapy, if indicated Supportive care
Pure cerebral ALD in adulthood
Cerebral ALD without preceding AMN	Adolescence to adulthood	Similar symptoms as in childhood cerebral ALD	VLCFA levels Brain MRI Confirm diagnosis with DNA testing	Adrenal function tests Neurologic and neuropsychological testing Family screening	Glucocorticoid replacement therapy, if indicated Supportive care Possibly HCT*
Adrenomyeloneuropathy (AMN)
Pure AMN	20 to 40 years	Paraparesis Sphincter disturbances Sensory changes Incoordination Erectile dysfunction Numbness and pain from polyneuropathy	VLCFA levels Confirm with DNA testing	Adrenal function tests Brain MRI MTS SSEP Family screening	Glucocorticoid replacement therapy, if indicated Physical therapy
AMN with cerebral involvement	20 to 40 years	Like pure AMN plus: Dementia Behavioral disturbances Psychosis Epilepsy Aphasia Visual loss Bulbar palsy	VLCFA levels Brain MRI Confirm with DNA testing	As in pure AMN plus: Neurologic and neuropsychological testing EEG Psychiatry evaluation	Glucocorticoid replacement therapy, if indicated Physical therapy for AMN symptoms Supportive care Possibly HCT*
Cerebellar
Olivo-ponto-cerebellar	Childhood; adolescence	Ataxia Brainstem signs	VLCFA levels Brain MRI Confirm with DNA testing	Adrenal function tests Neurologic testing Family screening	Glucocorticoid replacement therapy, if indicated Physical therapy
Adrenal insufficiency only
Adrenal insufficiency with normal MRI	0 to ≥10 years	Primary adrenocortical insufficiency	Adrenal function tests VLCFA levels Confirm with DNA testing	Monitor MRI Neurologic and neuropsychological testing Family screening	Glucocorticoid replacement therapy
Adrenal insufficiency with abnormal MRI	0 to ≥10 years	Primary adrenocortical insufficiency	Adrenal function tests VLCFA levels Brain MRI Confirm with DNA testing	Neurologic and neuropsychological testing Family screening	HCT Glucocorticoid replacement therapy
Female carriers
Asymptomatic	Younger women tend to be asymptomatic^¶	None	DNA testing is required for diagnosis False negatives can occur with VLCFA testing	Neurologic examination Adrenal function tests Monitor MRI Family screening	Genetic counseling General support
Symptomatic	Rare in women <30 years old; frequency rises sharply with age^¶	Paraparesis Sphincter disturbances Numbness and pain from polyneuropathy Incoordination Fatigue	DNA testing is required for diagnosis False negatives can occur with VLCFA testing	Adrenal function tests MTS SSEP Family screening	Genetic counseling Physical therapy Supportive care Glucocorticoid replacement therapy, if indicated (adrenal insufficiency is rare)

Percentages listed above vary by age group. The asymptomatic and adrenal insufficiency only groups decline with age while the ALD and AMN groups increase.

ALD: adrenoleukodystrophy; MRI: magnetic resonance imaging; VLCFA: very long chain fatty acids assay in plasma; AMN: adrenomyeloneuropathy; ADHD: attention deficit hyperactivity disorder; HCT: hematopoietic stem cell transplant; ALS: amyotrophic lateral sclerosis; N/A: not applicable; MTS: magnetization transfer MRI cervical cord; SSEP: somatosensory evoked potential; EEG: electroencephalogram.
* HCT may be an option for some adult patients with AMN who have mild cerebral involvement. Refer to UpToDate topic on adrenoleukodystrophy for additional details.
¶ The frequency of symptoms rises from <20% in women under 40 years of age, to almost 90% in women older than 60 years.

Adapted from: Moser HW, Raymond GV, Dubey P. Adrenoleukodystrophy: New approaches to a neurodegenerative disease. JAMA 2005; 294:3131.

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