Adrenoleukodystrophy is a hereditary pathology from the group of peroxisomal diseases associated with the accumulation of fatty acids with a very long carbon chain in the body. The disease is characterized by clinical polymorphism – various forms are characterized by damage to the brain tissue and adrenal glands, manifested by a combination of neurological disorders (sensorimotor, emotional-cognitive, behavioral) and hypocorticism. Pathology is diagnosed according to clinical data, confirmed by biochemical, molecular genetic tests, MRI and CT brain. Complex treatment involves diet, pharmacotherapy, hematopoietic cell transplantation.
E71.3 Disorders of fatty acid metabolism
Adrenoleukodistophia (Simmerling-Creutzfeldt’s disease, Addison-Schilder’s disease) was first described by German neurologists Ernst Simmerling and Hans-Gerhard Creutzfeldt in 1923. It is not as rare a disease as previously thought – it occurs everywhere, surpassing the prevalence of other peroxisomal diseases. According to various studies, the frequency of this variant of leukodystrophy varies from 1:100,000 to 1:15,000, the pathology affects representatives of all age groups (children, adolescents, adults). Usually, men are ill, women are carriers of a mutant gene, but with a heterozygous genotype in 20% of cases, symptoms are also found in them.
The occurrence of pathology is associated with mutations of the ABCD1 gene, which occupies the terminal section of the long arm of the X chromosome (locus Xq28). It encodes the synthesis of a transmembrane transporter protein called adrenoleukodistofic protein (ALDP). The latter is located on specific cellular organelles involved in oxidation reactions – peroxisomes, responsible for the transport and further cleavage of very long-chain fatty acids.
The structural defect of the peroxisomal transport protein makes it functionally incapable, which leads to the accumulation of toxic compounds in the tissues. More than 2,600 ABCD1 mutations associated with DNA nucleotide replacement, loss of loci have already been identified, and many of them cause structural changes in ALDP. Adrenoleukodistofii develop in the presence of only one recessive gene in the genotype (in men-hemizygotes) or two of its varieties (in heterozygous women).
Due to the structural anomaly of the carrier protein, the transport of very long-chain fatty acids into the peroxisome suffers, where they must undergo β-oxidation. Normally, saturated fatty acids with a long chain are present in lipids of nervous tissue (cerebrosides, sulfatides), erythrocytes, but with adrenoleukodystrophy their content can increase a thousand times. Ordinary cholesterol esters are replaced by abnormal ones with a chain length of 24-30 or more carbon atoms. When their concentration in the sheath of nerve fibers reaches 10%, myelin is destabilized and destroyed.
The accumulation of acyl-CoA-derived fatty acids violates the physico-chemical properties of cell membranes: the permeability of mitochondria increases, the concentration of cytosolic calcium increases. In turn, this leads to atrophy of the adrenal neuroendocrine tissue. Activation of neuroglial structures, stimulation of inflammatory processes involving cytokines (tumor necrosis factor) is considered an important mechanism of demyelination.
Histological changes in cerebral variants of adrenoleukodystopia are characterized by a sharp decrease in myelin content, perivascular lymphocytic-macrophage infiltration. Basically, the demyelinating process begins with the corpus callosum, gradually passing to the white matter of the occipital-parietal regions. Involvement of the frontal lobes, the pyramidal tract is less common.
Adrenoleukodistophy is characterized by a pronounced phenotypic polymorphism due to differences in the penetrance and expressiveness of the abnormal gene. Taking into account the time of the debut, the main manifestations, the rate of increase of symptoms, in modern neurology there are several forms of the disease:
- Cerebral. Neurological disorders prevail among the symptoms. Based on the age at which the disease began, there are children’s, juvenile, adult forms. The first one is more common than the others (48%).
- Adrenomyeloneuropathy. The most common option is for adult patients (26% of cases). It is characterized by a combination of corticoid insufficiency and cerebrospinal disorders.
- Isolated adrenal insufficiency. It usually proceeds without damage to the nervous system. In the general structure of adrenoleukodistophy, isolated hypocorticism is assigned a tenth part.
- Asymptomatic. Having no clinical manifestation, it is manifested only by a biochemical defect in the cleavage of molecules of very long-chain fatty acids. It is usually found among relatives of patients, but can be considered as a preclinical stage.
- Symptomatic in heterozygous carriers. The simultaneous presence of a dominant and recessive allele of a mutant gene in the genotype is accompanied by the disease in middle-aged women. It accounts for less than 1%.
- Atypical. It is characterized by cerebellar disorders – isolated or combined with adrenal insufficiency. It is extremely rare.
The clinical picture of pathology is very variable, which is determined by a specific phenotypic variant. Clinicians most often have to deal with signs of cerebral form, adrenomyeloneuropathy, isolated adrenal insufficiency.
All types of cerebral adrenoleukodystrophy are characterized by rapid progression. The peak of the manifestation of the child form falls on the period between 5 and 10 years of life. In most patients, neuropsychiatric disorders precede signs of adrenal insufficiency. Disorders of behavior, thinking, and the motor sphere are characteristic. Children become hyperactive or autistic, occasionally show aggression. There is an attention deficit, progressive dementia, gait is disturbed.
Less often, the symptoms of adrenoleukodystrophy include visual (hemianopia, agnosia, acute vision loss), auditory disorders, convulsive syndrome. Hypocorticism is manifested by skin pigmentation, muscle weakness, periodic nausea and vomiting. The progression of the pathological process is accompanied by spastic tetraparesis, blindness and deafness, seizures resistant to drug therapy occur. Death occurs within a period of one to 15 years from the onset of the disease.
Juvenile adrenoleukodystrophy manifests at the age of 10-21 years. According to the symptoms, it resembles a child’s form. In adults 30-50 years of age, the pathology begins with a schizophrenic syndrome, increasing dementia. Among the cerebral symptoms there are dysphagia, visual disturbances (scotomas). Pathology can progress rapidly, but so-called chronic variants are also described, when the process is suspended for many years, and after remission there is a sudden deterioration with an increase in neurological deficit.
The disease begins in a wide age range – from 12 to 50 years (more often between the second and fourth decades of life). In many cases, symptoms of chronic hypocorticism precede or accompany neurological disorders. Sometimes the very first sign that occurs long before the deployment of the entire clinical picture (even in early childhood) becomes isolated hyperpigmentation of the skin.
The initial neurological signs are represented by myelopathy with a decrease in deep sensitivity, lower paraparesis. Further development of such adrenoleukodystrophy is manifested by tetraparesis with impaired pelvic organ function (urination, defecation, erection). Over time, mental disorders (depression), hypogonadism, alopecia join. The pathological condition is characterized by a slow course, but it is steadily progressing.
Isolated adrenal insufficiency
The defeat of the adrenal cortex is manifested first by glucocorticoid, and then by mineralocorticoid insufficiency, debuts at various times, starting at the age of two. The most common symptoms are loss of appetite, muscle weakness, vomiting. Patients lose weight, suffer from abdominal pain, hypotension. Skin hyperpigmentation does not always occur. Neurological research indicates a decrease in vibration sensitivity, hyperreflexia, intellectual disorders that occur after several years.
Some female carriers have the appearance of neurological symptoms without concomitant endocrine shifts. The disease debuts later than in men with spinal lesions – by the age of 50-60. In severe cases, the symptoms are similar to the cerebral form, moderate disorders resemble adrenomyeloneuropathy. Sensory ataxia, moderate spastic paraparesis and pain in the lower extremities, pelvic organ dysfunction are most often detected. Insufficiency of the adrenal cortex occurs rarely.
The progression of cerebral forms and adrenomyeloneuropathy is accompanied by a pronounced neurological deficit with disability. A dangerous complication of hypocorticism is acute decompensation with the development of an addisonic crisis, manifested by dehydration, cardiovascular, and renal insufficiency. Rapidly progressing variants without active correction end in a comatose state and death.
It is possible to assume the disease with a careful assessment of anamnestic information (the presence of family cases, the time of manifestation, the nature of the course), clinical data. But the etiopathogenetic features of adrenoleukodystrophy are established by a comprehensive laboratory and instrumental study. The diagnostic program includes the following methods:
- Blood test. Detection by mass spectrometry in plasma or cells (erythrocytes, leukocytes, skin fibroblasts) of very long-chain fatty acids – docosan (C22), tetracosan (C24), hexacosan (C26) and their ratios – is considered as a method of early diagnosis (screening). From other biochemical indicators, cortisol levels, ACTH, and electrolytes are necessarily examined.
- Molecular genetic tests. Direct sequencing is used to identify gene mutations. Pathology is characterized by a high frequency of unique mutations (point, shift of the reading frame). The correlation of the results of the molecular genetic study with the severity of the disease cannot be established.
- Tomography of the central nervous system. In individuals with cerebral forms, MRI reveals a symmetrical decrease in signal intensity in areas of the corpus callosum, corticospinal tract with a transition to the occipital-parietal zone. The progression of adrenoleukodystrophy is accompanied by the accumulation of contrast agent in the foci of demyelination. CT scans show a weakening of the intensity of the white medulla, calcifications.
- EFI. Patients with adrenomyeloneuropathy may undergo electroneuromyography, which reveals a decrease in the amplitude of motor and sensory responses. The slowing down of the pulse rate is recorded in the analysis of stem evoked potentials (visual, auditory, somatosensory).
The neurologist has to differentiate the disease with many conditions. Cerebral disorders require the exclusion of other leukodystrophy, multiple sclerosis, subacute sclerosing encephalitis. Adrenomyeloneuropathy should be distinguished from amyotrophic lateral sclerosis, funicular myelosis, spinal tumors. It is necessary to differentiate isolated hypocorticism with Addison’s disease, Allgrove syndrome.
The choice of a reasonable pathogenetic therapy is the most acute problem facing the clinician in the treatment of a particular patient. Since it is possible to diagnose the disease even before the development of clinical signs, presymptomatic correction is of particular importance. When conducting therapy for adrenoleukodystrophy , conservative methods are used:
- Diet therapy. To normalize the level of very long-chain fatty acids in the blood, it is recommended to adhere to a low-fat diet, use Lorenzo oil. The latter is a mixture of triglycerides of oleic and erucic acids in a ratio of 4:1. Diet therapy has shown effectiveness only at the preclinical stage of the disease.
- Pharmacotherapy. With the phenomena of hypocorticism, replacement therapy with glucocorticoids and mineralocorticoids is clearly indicated, but these medications do not affect the pathological process in the central nervous system in any way. Symptomatic treatment of myelopathy is carried out with the help of neurometabolic agents, muscle relaxants, vitamins.
- Bone marrow transplantation. At the early stages of adrenoleukodystrophy in childhood and adolescence, allogeneic hematopoietic stem cell transplantation is able to stop the progression of demyelination, therefore it is recognized as the main method of treatment. The effectiveness of the procedure is explained by the renewal of the neuroglia with the cleavage of very long-chain fatty acids by perivascular macrophages.
- Physical rehabilitation. Methods of physical influence (acupuncture, transvertebral micropolarization) can be recommended for men suffering from adrenomyeloneuropathy. They are complemented by massage, therapeutic gymnastics.
Despite some successes, the disease does not respond well to treatment. But the increasing activity of researchers in the field of molecular genetics and a better understanding of the pathogenesis of adrenoleukodystrophy support attempts to develop new effective methods of correction. Among them, the following deserve special attention:
- Transplantation of genetically modified cells. Gene therapy is considered the most promising direction of pathogenetic correction. It involves the injection of autologous hematopoietic stem cells, in which the defective gene was restored with the help of a lentivirus (the drug Lenti-D). Studies show that this makes it possible to achieve stabilization of the condition in 88% of patients.
- Increased gene expression. Pharmacological gene correction was chosen as an alternative treatment strategy. By stimulating the synthesis of the ALDRP protein (66% identical to the mutant one), it is possible to compensate for the deficiency of the peroxisomal transporter in the fibroblast population.
- Immunotherapy. The severity of demyelination is assumed to correlate with an inflammatory reaction mediated by as yet unknown immune mechanisms. Therefore, the use of gamma-interferon, immunoglobulins, immunosuppressors (cyclophosphamide, cyclosporine) is considered a treatment option. But their effectiveness has not yet been confirmed.
- Hypolipidemic agents. Cholesterol-lowering drugs can normalize the content of long-chain molecules in fibroblasts. The use of lovastatin is promising, studies of the effectiveness of which are still ongoing. The drug sobetir is also undergoing clinical trials, which has already demonstrated the ability to reduce the concentration of very long-chain fatty acids in the brain, adrenal glands and blood of mice deprived of the ABCD1 gene.
Prognosis and prevention
The long-term prognosis for X-linked adrenoleukodystrophy depends on the specific phenotype. In children, the cerebral form takes on a particularly severe, rapidly progressing course with a five-year survival rate of 59%, many die within a few years after the onset of the disease. Other forms may not affect life expectancy, but reduce its quality due to disability. Given the high degree of polymorphism, even among members of the same family, the prognosis can vary significantly.
Primary prevention measures for adrenoleukodystrophy involve medical and genetic counseling of probable carriers, prenatal diagnostics (chorionic villi biopsy, amniotic fluid analysis). Early detection of biochemical changes in the blood is important to confirm the diagnosis at preclinical stages. In combination with active pathogenetic therapy, this will help to avoid progression, reducing the risk of further disability.