X-linked adrenoleukodystrophy (X-ALD), also known as “Lorenzo’s Oil” Brain Disease. X-ALD is a devastating genetic disorder affecting the adrenal glands and nervous system. Identification of the gene defect and its biochemical consequences has opened up several approaches to therapy in recent years.

Following the report of successful gene therapy using an HIV-derived lentivirus vector in Science in 2010, we are collaborating with a French team and Children’s Hospital, Boston, in implementing a first gene therapy trial in the U.S. Research in our lab has supported the notion that microglial cells in the brain are the vulnerable cell population that brings about the devastating inflammatory demyelination in the brain. There is growing evidence that cell based therapies such as hematopoetic stem cell transplantation and gene therapy correct these aberrant microglia and stabilize disease.

Brain disease in X-ALD correlates closely with lesions seen on brain MRI. We collaborate with the Martinos Center for Biomedical Imaging and monitor children at risk with advanced imaging techniques. This allows us not only to identify the first signs of impending brain disease but also helps us understand the pathophysiology of this progressive disorder. Recently our team identified early metabolic brain changes in vivo using MR Spectroscopy on a 7 Tesla magnet.

Figure 1

Since more than 70% of male X-ALD patients have adrenocortical insufficiency, routine evaluation of the adrenopituitary axis is indicated, and adrenal replacement can be lifesaving. Ambiguous ACTH levels should be followed by an ACTH stimulation test. Families should be educated about the importance of stress-dose steroids with minor illnesses. We partner with the excellent endocrinology division at MGHfC in managing and guiding patients and families.

In the coming years the implementation of newborn screening will facilitate the assessment of new therapeutics in the early symptomatic stages of X-ALD. We are working with the New England Newborn Screening Program to implement screening in Massachusetts and other states in New England. This will open up enormous new opportunities for early intervention, and makes X-ALD one of the most exciting arenas for drug development in the field of neurogenetics in the years to come.

Publications on X-ALD