Adrenoleukodystrophy: ALD

Adrenoleukodystrophy (ALD) is a dysfunction of one of the components of cells called peroxisome (mutation in ABCD1 gene). This rare X-linked disease is more common in men, which unfortunately cannot be predicted at birth.

In adrenoleukodystrophy, there are elevated levels of long-chain fatty acids (VLCFA) in plasma due to peroxisomes beta-oxidation defects, which results in VLCFA accumulation in various tissues.

This accumulation leads to disruption of mitochondrial function by increasing reactive oxygen species (ROS) and also causes cell death by increasing endoplasmic reticulum stress. Clinically, manifestations from adrenal insufficiency to rapid and fatal neurological dysfunction and chronic disability have been reported in adult patients. Adrenal insufficiency is the first manifestation in more than 80% of patients and is caused by the high tendency of VLCFA accumulation in the zona fasciculata and zona reticularis of brain.

Thus, glucocorticoid and androgen deficiency are common, while mineralocorticoid deficiency is rare. Subsequently, hyperpigmentation, fatigue, nausea, anorexia, weight loss and poor growth occur in patients with adrenoleukodystrophy. Glucocorticoid deficiency is associated with positive feedback with an increase in adrenocorticotropic hormone (ACTH), a decrease in morning cortisol, mild hyponatremia and hypoglycemia. Mineralocorticoid deficiency manifests with dizziness, hypotension and electrolyte imbalance.

Accumulation of VLCFA in Leydig and Sertoli cells leads to testicular failure in Adrenoleukodystrophy and increased gonadotropins (low testosterone level). Of course, androgen receptor resistance is also involved in these deficiencies.

Cerebral Adrenoleukodystrophy symptoms usually appear in the first decade of life and lead to rapid neurologicaldeterioration of cognitive, motor and sensory functions. Myeloneuropathy with walking problems, spastic paraparesis, sphincter control disorders and sexual dysfunction is more evident in affected men.

Thus, it can be concluded that the management of ALD requires a multidisciplinary team including neurology, genetics, endocrinology, ophthalmology, audiology, psychology, rehabilitation and palliative care.

Treatment of glucocorticoid and mineralocorticoid deficiency by prescribing hydrocortisone and fludrocortisone (with or without sodium chloride) is necessary for ALD patients with adrenal insufficiency to prevent complications and mortality associated with adrenal crisis.

Administeration of intradermal and intramuscular testosterone is also necessary to compensate for testicular failure in men. In addition to hormone replacement therapy, adrenomyloneuropathytreatment is primarily supportive and is performed with the aim of reducing pain (pregabalin and gabapentin), spasticity (baclofen), bladder dysfunction, sexual dysfunction, and rehabilitation treatment.

None of these are definitive treatments and they are considered helpful to patients only in a supportive way to compensate the deficiencies.
Despite advances in understanding the genetics and molecular pathogenesis of Adrenoleukodystrophy, allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment for early- stage disease (before the onset of irreversible brain manifestations). Replacing blood cells with natural peroxisome stops fatty acid accumulation to a large extent, especially in brain.

The effect of Adrenoleukodystrophy

of this treatment is to the point that according to the studies, if hematopoietic stem cell transplantation is not done for the patients, the survival rate of the patients in 10 and 20 years has been reported as 50 and 25 percent, respectively, but in the case of early treatment with HSCT, the survival rate in 5 year improves to 94%. However, it should be noted that this treatment does not restore neurological changes or prevent adrenal involvement or myeloneuropathy.

Moreover,HSCT transplantation is considered only a supportive treatment that prevents deterioration to some extent for Adrenoleukodystrophy patients in advanced stages. Despite the fact that hematopoietic stem cell transplantation is currently the best option for patients with Adrenoleukodystrophy, this option is also associated with challenges.

These include difficulties in rapid identification of highly matched allogeneic donors to ensure timely treatment before the occurrence of brain injuries, risks associated with HSCT and the need for continuous monitoring of patients; conditions after transplantation.

Therefore, new diagnostic and therapeutic options such as gene editing should be investigated in order to overcome the lack of genotype-phenotype correlation, the large number of ABCD1 variants, the absence of markers related to early diagnosis and prognostic assessments and also the lack of treatment options for advanced disease.