Adrenoleukodystrophy (ALD), or Schilder-Addison’s disease, is a progressive genetic disease occurring at birth and eventually affects adrenal glands and myelin in central nervous system, which eventually leads to neurological degeneration. The disease occurs most commonly in the male population and heterozygote females, which occurs when a gene on the X-chromosome is either mutated/ defective such that proteins required to bind the Very Long Chain of Fatty Acids (VLCFA) are either not produced or are dysfunctional. The inability of the body to break down the stored fatty acids contributes to the deterioration of the myelin sheaths, hence weakening the nervous system of the body.
Although seven different presenting phenotypes have been reported, the two most common are the adult-onset adrenomyeloneuropathy (AMN; primarily affects adults) and the progressive neuroinflammatory Childhood Cerebral ALD (CCALD). Childhood ALD, the most severe, is said to occur in 35% of all ALD phenotypes and is considered fatal without treatment . First recorded in late 19th century , ALD is rarely detected in the first phase. Pediatricians, endocrinologists, neurologists and psychiatrists encounter X-ALD as a relatively common metabolic disorder in their practice .
Epidemiology and Statistics:
The average age of diagnosis is estimated to be 7.5 years, although childhood ALD manifests between the ages of 4 and 8 years . ALD affects 1 in every 17,000 newborns across the globe every year, usually passed on from the mother to the child . In Australasia and Canada, the incidence is 1.6 in 100,000 children born alive, in the USA 1.1 in 100,000 and in the Netherlands over 1 in 200,000 boys .
Various authors who had followed up cases in patients aged over 15 years, over wide geographical areas, reported the frequency of the disease . Kennedy Krieger Institute and Mayo Clinic Rochester estimated a frequency of X-linked ALD hemizygotes in the USA of 1:42,000 and hemizygotes plus heterozygotes of 1:16,800 .
The initial symptom in most of the cases is noted to be of seizures, hyperactivity and attention deficit behavioral problems. As the severity of the disease gradually increases, vision impairment, speech deterioration and lethargy begin to appear. Hypoglycemia and tanning of skin are also observed in some patients 6
Currently, the most efficient therapeutic opportunity for patients with the cerebral form of X-ALD is hematopoietic stem cell transplantation and possibly gene therapy of autologous hematopoietic stem cells . Although the most promising, stem-cell therapy is extremely dangerous since it accounts for a death rate of 10–20%, mainly because of the lack of markers that can predict the onset of cerebral demyelination . Scientists are looking into the results obtained from Gene Therapy, which involves inserting the corrected genetic sequence with the appropriate ‘blueprints’ into cells. The repaired cells will then produce the ALD protein that had been missing or defective prior to treatment, and the disease process will halt or moderately reverse.
Early trials are very preliminary, but they appear quite promising so far. Four boys with ALD have been treated with gene therapy in France; the first received his transplant in September 2006, and the second in early 2007. Oral intake of “Lorenzo’s oil,” a 4:1 mixture of glyceryl trioleate and glyceryl trierucate, combined with moderate reduction of fat in the diet, has shown to significantly lower the VLCFA levels in plasma within 4 weeks, hence reducing the deterioration of the myelin compound. Other new treatment options such as consumption of the drug Mucomyst (acetylcysteine), ALDR upregulation and myelin restoration are also being studied. These new techniques appear to provide protection from rapid neurological decline in the advanced form of ALD. The important laboratory findings are low serum sodium and chloride levels and elevated potassium levels reflecting the atrophy of the adrenal glands . Bone marrow transplantation has also been done in one case of X-linked ALD .
Important research institutes:
Although the rarity of the disease constrains researchers from performing at peak, StopALD Foundation, the Myelin Project and Moser Center for Leukodystrophies at the Kennedy Krieger Institute are known to conduct studies that have been very helpful in providing the correct treatment to the patients. Since symptoms such as ‘losing focus’ and nausea are very similar to general health problems, ALD is difficult to detect and is often misdiagnosed and subjected to misguided treatment.
1. Treatment of Adrenal and Gonadal Insufficiency
Approximately 70% of male X-ALD patients develop primary adrenocortical insufficiency, often before the onset of neurological symptoms. If the ACTH level is more than 1000 picogram/ml (normal <70), the affected patients, are subjected to adrenal hormone replacement therapy.
Males with clinical manifestation of hypogonadism that are associated with a low serum testosterone concentration should receive androgens.
2. Lorenzo’s Oil
Oral administration of “Lorenzo’s oil,” a 4:1 mixture of glyceryl trioleate and glyceryl trierucate, combined with moderate reduction of fat in the diet, normalizes or significantly lowers the VLCFA levels in plasma within 4 weeks . The use of Lorenzo’s oil is purely to break the VLCFA down in serum or cultured fibroblasts of X-ALD patients. Although the levels in the fatty acids in the patients undergoing this treatment appear indistinguishable, there is also growing evidence that oxidative stress contributes to the pathogenesis of X-ALD and that excess of VLCFAs plays a role in this process. Thus, there is a good rationale for therapies aiming at lowering VLCFAs in the central nervous system (CNS). The reduction of VLCFAs might be beneficial for all different clinical manifestations of X-ALD .
A study involving 89 asymptomatic X-ALD patients with normal brain MRI and a mean age of 4.7 years at enrollment and a follow-up period of 6.9 ± 2.8 years suggests that substantial and consistent reduction of plasma C26:0 (a type of VLCFA) levels led to a twofold or greater reduction in the risk of developing the childhood cerebral form of X-ALD .
Lorenzo’s oil remains a bit of mystery as efficacy of a therapy is still unknown even after 20 years of use in probably more than 500 patients.
3. 4-phenylbutyrate (4-PBA)
Initial studies with cultured cells showed that small organic acids, such as phenylacetate , or its prodrug 4-PBA could reduce the level of VLCFA in X-ALD fibroblasts, which was attributed to increased peroxisomal β-oxidation rates. Studies reported that long-term continuous administration of 4-PBA in Abcd1-deficient mice leads to a reduced drug response (tachyphylaxis) and a return to pretreatment levels of VLCFA .
To circumvent the problems associated with the large amount of medication needed with oral 4-PBA, an intermittent pulsed regime of intravenous arginine butyrate was developed for treatment of hemoglobinopathies. A case report describes an open trial of intravenous infusion of arginine butyrate during 4 months, with intermittent days off medication, in one patient with childhood cerebral X-ALD . The treatment was well tolerated and quickly led to a substantial decrease in plasma VLCFA, showing that this class of compounds can reduce VLCFA levels also in human patients . However, in this patient, the neurological deterioration progressed during treatment, possibly related to the fact that the inflammatory process in the CNS was already underway at the start of the trial .
Although researchers and scientists have been involved with the disease for almost a century (the first recorded case was in 1923 by Siemerling and Creutzfeldt ), the pretty high mortality rate and rarity of the disease make research difficult. Doctors and patients usually fail to recognize the disease since the symptoms are very common to those of general health. Although recent case studies prove that the Addison’s disease can be treated if detected at an early stage, it often spreads very fast and can be difficult to treat if subjected to incorrect or unsuitable treatment option. Institutes such as StopALD, the Myelin Project (started by Lorenzo’s family) and Moser Center for Leukodystrophies at the Kennedy Krieger Institute offer treatment for both ccALD and AMN, and accept patients from all around the world. Among the many other challenges faced by patients include signing up for the study and research in order to benefit from certain like medication like Lorenzo’s oil, since it is not approved by the associated authorities yet.
 Gale Encyclopedia of Neurological Disorders, The Gale Group, Inc. Web. <http://www.encyclopedia.com/medicine/diseases-and-conditions/pathology/adrenoleukodystrophy>
 “24 Notable Adrenoleukodystrophy Statistics. Medical Articles and Infographics. .” Health Research Funding.org. Web. <http://healthresearchfunding.org/24-notable-adrenoleukodystrophy-statistics/>.
 Engelen et al. (2012). “X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management”. Orphanet Journal of Rare Diseases. Web. <http://ojrd.biomedcentral.com/articles/10.1186/1750-1172-7-51>
 “Current Treatment Research.” The Stop ALD Foundation. Web. <http://www.stopald.org/current-treatment-research/>.
 Berger, Johannes et al. “Current and Future Pharmacological Treatment Strategies in X-Linked Adrenoleukodystrophy.” Brain pathology (Zurich, Switzerland) 20.4 (2010): 845–856. PMC. Web. 2 May 2017. url: “https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2967711/”
 Galesanu, Corina, Natalia Lisnic, D. Branisteanu, Liliana Moisii, Cristina Tache, Geogeta Diaconu, and Cristina Rusu. “Adrenoleukodystrophy — Case Report.” Diss. U of Medicine and Pharmacy, Iassy, Romania, 2005. Acta Endocrinologica (Buc) 1.3 (2005): 359–68. Print. Department of Endocrinology, Radiology, Pediatrics, Pediatric Neurology, Human Genetics.
 Raja, Uma, and K.A. Krishnamurthy. Adrenoleukodystrophy. Diss. Department of Pediatrics, Meenakshi Mission Hospital and Research Centre, 1993.
 Aubourg, Patrick, MD, Stephane Blanch, MD, Isabelle Jambaque, PhD, Francis Rocchiccioli, PhD, Gabriel Kalifa, MD, Catherine Naud-Saudreau, MD, Marie-Odile Rolland, PhD, Mariane Debre, MD, Jean-Louis Chaussain, MD, Claude Griscelli, MD, Alain Fischer, MD, and Pierre-Francois Bougneres, MD. Reversal of Early Neurologic and Neuroradiologic Manifestations of X-Linked Adrenoleukodystrophy by Bone Marrow Transplantation. Diss. 1990. N Engl J Med 1990; 322:1860–1866. Print. DOI: 10.1056/NEJM199006283222607
 Bamiou, Doris-Eva, Rosalyn Davies, Steve Jones, Frank E. Musiek, Peter Rudge, John Stevens, and Linda M. Luxon. “An Unusual Case of X-Linked Adrenoleukodystrophy with Auditory Processing Difficulties as the First and Sole Clinical Manifestation.” Diss. 2004. J Am Acad Audiol 15 (2004): 152–160. Print.
Dr. Sukant Khurana runs an academic research lab and several tech companies. He is also a known artist, author, and speaker. You can learn more about Sukant at www.brainnart.com or www.dataisnotjustdata.com and if you wish to work on biomedical research, neuroscience, sustainable development, artificial intelligence or data science projects for public good, you can contact him at firstname.lastname@example.org or by reaching out to him on linkedin https://www.linkedin.com/in/sukant-khurana-755a2343/.