In 1984, there was a young boy named Lorenzo Odone. He was a gifted child who was fluent in not only English, but French and Italian as well. Unfortunately, shortly after his 6th birthday, he experienced several unusual symptoms, such as speech problems, worsening hand-eye coordination, and decreased hearing. His mother recalls the day during which she was reading him a story, and as he snuggled up to her, Lorenzo complained that he could not hear well. Shortly after that, Lorenzo was diagnosed with X-linked Adrenoleukodystrophy (X-ALD).
X-ALD is a rare and irreversible disease, which progressively degrades the brain and nervous system. Doctors had given him 2 years left to live. However, his father, Augusto, was not ready to give up. Regardless of having no prior medical knowledge, Augusto devoted his life to finding a cure for X-ALD. Even though he was unable to cure Lorenzo (and X-ALD for that matter), he managed to prolong his life for two decades, thanks to a medicine he invented, named “Lorenzo’s oil”, in memory of his son. This story is an example of how one man’s love for his son sparked scientific research in the treatment of a debilitating disorder. Even though there is no strong scientific proof that Lorenzo’s oil helps decrease the effects of X-ALD, it undoubtedly increased the quality of Lorenzo’s life.
This scientific literature review will address X-ALD through case studies that demonstrate the clinical features of the disorder. It will also discuss the genetic, metabolic and biochemical aspects, and treatment options of X-ALD, and areas of future research.
In this section, we will explore several case studies, as well as the symptoms of X-ALD. The first two case studies reviewed here are those of a seven-year-old male child (Case 1) and a six-year-old male child (Case 2).
Case 1 presented primarily with decreased hearing. The child seemed to have had relatively normal motor dexterity in all four limbs but abnormal tendon reflexes. Magnetic Resonance Imaging (MRI) produced the following image (Figure 1) (Rai, 2013). In this image, abnormal brain signal activity has been noted in the cerebral white matter, in forms of patchy and/or bilaterally symmetrical spots. This description is similar to that of X-ALD patients.
Case 2 presented with more severe symptoms. The child was born to a non-consanguineous couple (parents were not related). He had delayed developmental milestones, compared to that of an average child. Additionally, he presented with approximately five instances of non-projectile vomiting in a period of six months. Hyperpigmentation was evident in his oral cavities, skin, and nails. Similarly to Case 1, he had relatively normal motor dexterity in all four limbs, but had abnormal tendon reflexes. The MRI of Case 2 (Figure 2) was similar to that of Case 1. It showed abnormalities in the cerebral white matter, in forms of patchy and/or bilaterally symmetrical spots (Rai, 2013). Additionally, another key symptom depicted by Case 2 was the abnormally high level of Very Long Chain Fatty Acids (VLCFAs), which were observed on his blood test results (Figure 3) (Rai, 2013).
Our last case study is that of a 37-year-old Korean man (Case 3) (Kang, 2014). Unlike the other two cases, he had bladder incontinence, difficulty speaking, and motor-dexterity problems. Additionally, Case 3 is different from the other two cases in that the symptoms arose much later in the patient’s life. Additional research showed a de novo mutation (a mutation that was not inherited from his parents) located on exon 1 at nucleotide position c.277_296dup20 (p.Ala100Cysfs*10) of the adenosine triphosphate-binding cassette D1 (ABCD1) gene (Kang, 2014). The MRI of Case 3 (Figure 4) was very similar to that of the other two cases, however the brainstem seemed to be relatively unaffected (Kang, 2014).
To summarize the clinical aspects of X-ALD, this disorder does not have one set of symptoms, but rather a unique set for each of its phenotypes. If diagnosed from 3 to 10 years of age, it will classify as the “childhood cerebral form”, which is the progressive degeneration of neurons and white matter, resulting in a comatose state if left untreated. The “adolescent form” is from 11-21 years of age, and has a less severe phenotype than that of the “childhood cerebral form”. “Adrenomyeloneuropathy” (AMN) occurs in patients aged 21-37 years, and results in progressive neuropathy and paraparesis. The “adult cerebral form” is from 38 years onwards, and results in dementia and behavioural abnormalities. However, one must note that these are not perfectly discrete forms of the disorder, as symptoms can differ from case to case. For example in Case 2, the non-projectile vomiting was not an expected symptom.
In this section, we will be discussing the location of the gene responsible for X-ALD on the chromosome, as well as its function. X-ALD is caused by a mutation in the ATP-binding cassette sub-family D member 1 (ABCD1) gene (“Genetics Home Reference”, 2014). X-ALD is an X-linked variant of ALD, meaning that the affected gene causing the disorder is located on the X chromosome. The normal function of this gene is to produce the Adrenoleukodystrophy Protein (ALDP). The purpose of this protein is to bring VLCFAs in through the peroxisome membrane, in order for the peroxisomes to break them up. However, due to a mutation, ALDP is unable to bind to the VLCFAs, therefore they cannot be brought into the peroxisomes and begin to accumulate in the body. Due to this accumulation, they damage the nervous system in ways that will be further discussed in the “Biochemical Aspects” section.