International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy

Abstract

Pathogenic variants in the ABCD1 gene cause adrenoleukodystrophy (ALD), a progressive metabolic disorder characterized by three core clinical syndromes: a slowly progressive myeloneuropathy, a rapidly progressive inflammatory leukodystrophy (cerebral ALD), and primary adrenal insufficiency. These syndromes are not present in all individuals, and are not related to genotype. Cerebral ALD and adrenal insufficiency require early detection and intervention and warrant clinical surveillance because of variable penetrance and age of onset. Newborn screening has increased the number of presymptomatic individuals under observation, but clinical surveillance protocols vary.We used a consensus-based modified Delphi approach among 28 international ALD experts to develop best-practice recommendations for diagnosis, clinical surveillance, and treatment of ALD patients. We identified 39 discrete areas of consensus. Regular monitoring to detect the onset of adrenal failure and conversion to cerebral ALD is recommended in all male patients. Hematopoeitic cell transplant (HCT) is the treatment of choice for cerebral ALD. This guideline addresses a clinical need in the ALD community worldwide as the number of overall diagnoses as well as presymptomatic individuals is increasing due to newborn screening and greater availability of next generation sequencing. The poor ability to predict the disease course informs current monitoring intervals but remains subject to change as more data emerges. This knowledge gap should direct future research and illustrates once again that international collaboration amongst physicians, researchers and patients is essential to improving care.

An update on the diagnosis and treatment of adrenoleukodystrophy

“…Cerebral ALD is the most common phenotype accounting for 30–40% of all patients [22]. Symptoms usually begin in the first decade of life and result in rapid neurological deterioration of cognitive, motor, and sensory functions [3 ▪▪ ,22]. MRI with T1, T2, and FLAIR imaging +/− gadolinium is required for the diagnosis of cerebral ALD.…”

“…In males it usually occurs between the ages of 20–40 years. Although females are carriers, a subset of them can be affected in adulthood by myeloneuropathy [3 ▪▪ ,22].…”

“…Adrenoleukodystrophy is an X-linked progressive neurodegenerative disorder (OMIM#300100) caused by pathogenic mutations in the ATP-binding cassette sub-family D member 1( ABCD1 ) gene located on the X chromosome. It is characterized by defective β-oxidation and resultant accumulation of peroxisomal saturated very long chain fatty acids (VLCFA) in the cerebral white matter, spinal cord, adrenal glands, and testes [1,2,3 ▪▪ ]. The prevalence of adrenoleukodystrophy (ALD) is estimated to be 1 in 17 000 to 1 in 21 000 in the United States [4].…”

“…Because this disorder is X-linked, it affects only males in its severe forms. The phenotype is highly variable in its presentation and has three distinct presentations – rapidly progressive cerebral leukodystrophy, slowly progressive adrenomyeloneuropathy (AMN), and primary adrenal insufficiency (AI) [3 ▪▪ ]. Early identification and surveillance of ALD are critical given the high mortality and morbidity rates and the ability to prevent neurological progression with hematopoietic stem cell transplant (HSCT).…”

Can We Generalize Key Principles in the Care of Rare Diseases?

“…The article in the current issue of Neurology ® entitled "International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy: A Consensus-Based Approach" by Marc Engelen et al 7 is both a timely and much needed compilation of a rapidly evolving and complex body of expertise for the diagnosis, clinical surveillance, and treatment/ management consensus guidelines for ALD from a multidisciplinary group of international experts. The authors provide a distinctive and elegant model for a collaborative approach to the care of this phenotypically diverse neurometabolic disorder.…”