X-linked adrenoleukodystrophy: Clinical Guidelines

List of Abbreviations

AMN — adrenomyeloneuropathy

APS-1 — autoimmune polyglandular syndrome type 1

X-ALD — X-linked adrenoleukodystrophy

Asymptomatic X-ALD — asymptomatic form of X-linked adrenoleukodystrophy

CC X-ALD — childhood cerebral form of X-linked adrenoleukodystrophy

AdC X-ALD — adolescent cerebral form of X-linked adrenoleukodystrophy

AC X-ALD — adult cerebral form of X-linked adrenoleukodystrophy

(I)AI — (isolated) chronic adrenal insufficiency

GTO — glyceryl trioleate

GTE — glyceryl trierucate

CT — computed tomography

lysoPC — lysophosphatidylcholines

MGC — medical genetic counseling

MRI — magnetic resonance imaging

AI — adrenal insufficiency

VLCFA — very long-chain fatty acids

C22 — docosanoic acid

C24 — tetracosanoic acid

C26 — hexacosanoic acid

C27 — heptacosanoic acid

HSCT — hematopoietic stem cell transplantation

US — ultrasound

ENMG — electroneuromyography

CAI — chronic adrenal insufficiency

Terms and Definitions

Peroxisomal disorders — a group of inherited monogenic diseases associated with impaired peroxisomal functions.

X-linked adrenoleukodystrophy — an inherited peroxisomal disorder characterized by nervous system involvement combined with chronic adrenal insufficiency.

VLCFA — very long-chain fatty acids, which accumulate in various tissues in X-ALD.

Hematopoietic stem cell transplantation — a method of treatment in which healthy stem cells are administered to a patient, replacing damaged cells with donor or autologous cells.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

X-linked adrenoleukodystrophy (X-ALD) — an inherited X-linked recessive metabolic disorder belonging to the group of peroxisomal diseases, characterized by a combination of peripheral and central nervous system involvement and endocrine pathology (primarily adrenal insufficiency), developing as a result of impaired oxidation and subsequent accumulation of saturated very long-chain fatty acids in organs and tissues [1], [2].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

X-ALD is caused by pathogenic variants in the ABCD1 gene, which encodes the ALDP transmembrane transporter protein. The ABCD1 gene is mapped to the terminal segment of the long arm of the X chromosome at locus Xq28 [1].

The ALDP protein belongs to the superfamily of ATP-binding cassette transmembrane transporter proteins. Alterations in the ALDP protein disrupt the transport of very long-chain saturated fatty acids (VLCFA) into peroxisomes. The primary triggering mechanism of pathogenesis at the molecular level is the impairment of peroxisomal degradation of saturated VLCFAs ingested in the diet, as well as those synthesized de novo in the body. The result is a 2-10-fold increase in VLCFA concentration in the plasma, erythrocytes, leukocytes, fibroblasts of patients, and heterozygous carriers. A consequence of these changes and simultaneously an important pathogenetic mechanism is the alteration of the physicochemical properties of cell membranes due to the accumulation of VLCFA acyl derivatives within them. The molecular mechanisms of the pathogenesis of adrenal insufficiency include the toxic effect of structurally altered cholesterol esters on adrenal cortex cells, the incorporation of VLCFAs into the membranes of steroid-producing cells, and the reduction of steroidogenesis due to the binding of free cholesterol by VLCFAs [3], [4].

A correlation between clinical and pathological data is observed in rapidly progressing cerebral forms, both childhood and adult. Pathological changes are represented by perivascular lymphocytic infiltration of the white matter in areas where blood-brain barrier dysfunction is detected by contrast enhancement on brain CT. The involvement of tumor necrosis factor alpha (TNFα) in the inflammatory reaction has been established, with high levels found in macrophages and astrocytes in areas of active demyelination [5]. This led to the hypothesis that excess VLCFAs stimulate a TNFα cytokine cascade in astrocytes, perivascular cells, and macrophages, leading to primarily cytokine-mediated demyelination followed by myelin destruction predominantly by T cells [5], [6].

Furthermore, it was found that the activation of spinal cord microglia in adrenomyeloneuropathy is a leading factor in the development of clinical symptoms, and neuronal damage occurs due to increased phagocytic activity of microglia and overexpression of phagocytosis factors in the altered chemical environment caused by the elevated VLCFA concentration [7].

1.3 Epidemiology of the Disease or Condition

X-ALD is a relatively frequent disease occurring worldwide across all races and ethnic groups. The minimum frequency of X-ALD in France is 1:100,000 newborn males [8]. In Australia and Southeast Asia, this figure is 1.6:100,000, and in Japan, 2.0-3.3:100,000 [9], [10]. According to a large-scale population study in the USA utilizing extensive biochemical and DNA diagnostics, the minimum frequency of hemizygous carriers is 1:42,000, and the total frequency of hemi- and heterozygous carriers reaches 1:16,800 [11].

Following the introduction of newborn screening in the USA, it was shown that the frequency of X-ALD is 1:17,000 newborn males [12]. The range of figures reflects detection completeness rather than interpopulation differences: there is no compelling data for territorial or ethnic clustering of ALD (except for a rare ataxia phenotype more frequent in Japan) [13].

1.4 Features of Coding the Disease or Condition

ICD-10 code: E71.3 Disorders of fatty acid metabolism.

1.5 Classification of the disease or condition

According to the clinical classification based on the age of onset and nervous system involvement, the following forms of X-ALD are distinguished:

1. Childhood cerebral form (CC X-ALD);

2. Adolescent cerebral form (AdC X-ALD);

3. Adult cerebral form (AC X-ALD);

4. Adrenomyeloneuropathy (AMN);

5. Isolated adrenal insufficiency (IAI);

6. Asymptomatic form (Asymptomatic X-ALD) (in the presence of a biochemical defect and/or pathogenic variant);

7. Atypical forms;

8. X-ALD in heterozygous female carriers.

The classification presented is somewhat arbitrary, as some of its constituent forms overlap and in reality represent a clinical continuum of phenotypes differing in severity and time of manifestation [13], [14], [15].

1.6 Clinical presentation of the disease or condition

Childhood cerebral ALD (CCALD) is the most studied phenotype of the disease. According to large case series, disease onset occurs between the ages of 3 and 10 years (most commonly 4–8 years), with a peak at around 7 years; the mean age of onset is 7.1 ± 1.7 years [13], [15]. In some cases, neurological manifestations are preceded by subclinical attention and learning impairments, but children are most frequently considered somatically and mentally healthy prior to manifestation [13].

Initial symptoms are variable, but behavioral and cognitive disturbances (attention deficit, hyperactivity, emotional lability, academic decline) are the most typical and are frequently misdiagnosed as school maladaptation [13]. Frequent early signs include visual impairment and strabismus; cerebellar disorders, seizures, and headaches are less common. Very rarely, CCALD manifests as urinary and/or fecal incontinence, or tics. According to cohort studies, an acute onset of the disease (seizures, adrenal crisis, impaired consciousness) is possible in 9% of cases [16]. Atypical asymmetric involvement at the onset of CCALD has been reported (a case of onset in a 10-year-old boy with cognitive impairment and left-sided spastic hemiparesis, with predominantly right-sided lesion localization on brain MRI) [17].

The disease typically progresses rapidly with the development of severe encephalopathy: dysarthria and anarthria, dysphagia, spasticity, ataxia, and extrapyramidal disorders develop; in late stages, almost all patients develop epilepsy and profound dementia. Visual impairments progress to complete blindness. The terminal stage is characterized by immobility, loss of contact with the environment, decortication, and cerebral cachexia. The mean interval between the onset of neurological symptoms and decortication is about 2 years; the mean age of death is 9–11 years [18], [19].

Adolescent cerebral ALD is characterized by onset after 10 years of age (more commonly before 14–15 years, with an upper limit of 21 years). In its clinical picture and course, it is largely similar to the childhood cerebral form, which makes the differentiation between these phenotypes conditional; a number of authors consider them part of a single spectrum [8], [9], [20], [21]. In individual cases, the disease runs a slower course, but the overall prognosis remains unfavorable.

Adult cerebral ALD manifests after 21 years of age, sometimes up to 40–50 years [22]. It is characterized by pronounced psychiatric and cognitive disorders (psychoses, frontal lobe dementia), which frequently leads to diagnostic errors [23], [24], [25]. Focal neurological symptoms, including visual field defects, are possible; for instance, hemianopia has been described [26]. The disease usually progresses rapidly, leading to severe disability and decortication within 3–4 years, although rare cases of stabilization have been described.

Adrenomyeloneuropathy (AMN) is the most frequent phenotype in adult men. The age of onset varies from adolescence to adulthood, but in most cases, symptoms appear in the 3rd to 4th decade of life, with only about 8% of cases manifesting before 21 years of age [15], [27]. The leading manifestations are a slowly progressive lower spastic paraparesis, urinary disturbances, sexual dysfunction, and frequently early alopecia. Demyelinating polyneuropathy, autonomic and pelvic disorders are also characteristic [28], [29].

The progression of AMN is slow; loss of independent ambulation usually occurs 10–15 years after disease onset, and urinary and fecal incontinence appear over time. In approximately half of the patients, brain involvement is detected as the disease progresses, most often subclinically; 10–20% develop marked cognitive and behavioral impairments defined as "cerebral AMN" (in contrast to "pure AMN" without brain involvement), which is associated with an unfavorable prognosis [3], [16], [23], [30], [31].

Life expectancy in AMN varies widely and may be close to normal. In some cases, patients with adrenocortical insufficiency who lack neurological complaints and symptoms may be found to have polyneuropathy upon electroneuromyography (ENMG), representing the preclinical stage of AMN [13].

Adrenal insufficiency (AI) is one of the main components of X-ALD and occurs in 70–80% of cases as part of any form (except for the asymptomatic form of ALD) [32], [33].

According to Russian studies, AI mainly manifests in the first decade of the patient's life, with a peak at 6–7 years of age and a lifetime risk of development [34]. AI develops independently of nervous system involvement—depending on age, the diagnosis can be established either before or after the appearance of neurological symptoms.

The symptoms of AI are nonspecific and can often be masked by symptoms of nervous system involvement. A typical and pathognomonic sign is skin hyperpigmentation, found in the vast majority of patients with X-ALD. Hyperpigmentation is diffuse in nature, with accentuation in joint areas, skin folds, and the skin of the external genitalia. The second most frequent sign is asthenic syndrome—weakness, lethargy, and increased fatigue [34], [35], [36], [37]. Patients may also be troubled by hypotension, weight loss, and hypoglycemia. Based on the pathogenesis of adrenal insufficiency in X-ALD, mineralocorticoid deficiency and its associated symptoms develop in approximately half of the cases. The main symptoms of mineralocorticoid deficiency are increased salt craving, abdominal pain, and recurrent vomiting. If assistance is not provided, the patient's condition worsens, leading to a severe life-threatening condition—a salt-wasting crisis accompanied by characteristic electrolyte disturbances: hyponatremia and hyperkalemia [4], [33], [34]. An interruption in replacement therapy, or an increased demand for adrenocortical hormones due to illness and stress against the background of standard replacement doses, can also lead to acute adrenal insufficiency.

AI may represent a distinct clinical form of X-ALD—isolated adrenal insufficiency (IAI). IAI in X-ALD is a conventional phenotype, since most patients eventually develop neurological symptoms. The interval between the onset of adrenal insufficiency and the appearance of neurological manifestations can reach several decades (the longest known case reached 32 years) [15]. Even in the absence of overt neurological symptoms, subclinical neurological (hyperreflexia, decreased vibratory sensation in the legs) and/or cognitive impairments are frequently detected.

Asymptomatic ALD (A-ALD) in clinically healthy carriers of pathogenic variants in the ABCD1 gene is considered the presymptomatic stage of the disease. The age of manifestation is extremely variable; both very late-onset cases and the absence of clinical manifestations in the presence of MRI abnormalities have been described [15], [21], [38], [39].

Atypical phenotypes of X-ALD include rare variants with predominant cerebellar involvement and a clinical picture of olivopontocerebellar degeneration, as well as with other clinical manifestations (e.g., onset with hearing loss has been described, where further examination revealed involvement of the central auditory pathways correlating with the MRI picture) [13], [40], [41], [42], [43], [44], [45], [46]. Their proportion is small, but with the development of molecular diagnostics, the number of such observations is increasing.

Manifest forms in heterozygous female carriers are detected much more frequently than previously assumed. Clinical manifestations are noted in 15–20% of carriers, and in more than half after the age of 40 [15], [47]. Symptoms similar to AMN are most typical; cerebral forms are much rarer. Adrenal insufficiency in female carriers is observed extremely rarely [14], [28], [48], [49], [50].

Noting the high frequency of clinical manifestations of carrier state in X-ALD and a number of other X-linked diseases, Dobyns et al. (2004) propose abandoning their division into recessive and dominant and calling them "simply" X-linked [51]. In rare cases, severe manifestation in females is associated with X chromosome abnormalities, which requires karyotyping [52].

A characteristic feature of X-ALD is pronounced intrafamilial phenotypic variability: different forms of the disease can be combined within a single family, including cerebral forms, AMN, IAI, and manifest forms in heterozygous female carriers [13], [15], [21], [43], [53], [54]. The detection rate of de novo causative variants is low (about 1.7%), which explains the predominance of familial cases [11]. These observations point to the role of additional modifying factors in phenotype formation, the nature of which remains unclear [55]. A number of studies have analyzed the ratio of phenotypes in patient cohorts from different countries. These data are summarized in Appendix A3.1.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Please note that in accordance with the requirements for the development of clinical guidelines, each recommendation statement must indicate the strength of recommendations and the evidence base in accordance with the grading scales for the levels of evidentiary certainty (LEC) and the levels of recommendation persuasiveness (LRP). For many statements, the LRP and LEC will be low due to the lack of high-design clinical trials dedicated to them. Despite this, they are necessary elements of patient examination to establish a diagnosis and choose treatment tactics.

Criteria for establishing a diagnosis/condition: The diagnosis of X-ALD is established based on a combination of clinical and anamestic data, laboratory test results, and molecular genetic analysis. The main laboratory methods for confirming the diagnosis of X-ALD include biochemical (determination of VLCFA in blood plasma) and molecular genetic studies of the ABCD1 gene. The diagnosis is established by detecting an elevated level of VLCFA (C26:0, C24:0, C22:0) in blood serum or plasma and by identifying a hemizygous pathogenic (likely pathogenic) variant in the ABCD1 gene in males, or a heterozygous pathogenic (likely pathogenic) variant in the ABCD1 gene in females. Variants of uncertain clinical significance do not allow for confirming the diagnosis or making clinically significant decisions [2].

Differential diagnosis. Differential diagnosis is carried out with a wide range of conditions, depending on the X-ALD phenotype [56].

Childhood and juvenile cerebral ALD are differentiated from attention deficit hyperactivity disorder, epilepsy, brain tumors, other leukodystrophies, subacute sclerosing panencephalitis, early multiple sclerosis, and Lyme disease. The AMN phenotype must be differentiated from multiple sclerosis, hereditary spastic paraplegia (Strümpell disease), amyotrophic lateral sclerosis, vitamin B12 deficiency (funicular myelosis), and spinal cord tumors; the adult cerebral form—from endogenous mental illnesses, Alzheimer's disease, toxic and alcoholic encephalopathy; the olivopontocerebellar degeneration phenotype—from other ataxias.

More than 20 hereditary syndromes are known in which adrenal insufficiency develops. For differential diagnosis, it is important to assess the patient's age at the onset of adrenal insufficiency, concomitant pathology, and to analyze the family history. Cases of AI manifestation in X-ALD from birth have not been described. AI, as a rule, develops at a later age. Concomitant diseases can serve as a clue for determining the etiology of AI (for example, chronic mucocutaneous candidiasis combined with hypoparathyroidism suggests autoimmune polyglandular syndrome type 1 (APS-1)).

Information about relatives with multiple sclerosis among close family members of a boy or man with adrenal insufficiency may suggest the diagnosis of X-ALD, since MRI changes and the clinical presentation of X-ALD are often mistakenly regarded as manifestations of multiple sclerosis. The diagnosis of a hereditary disease with a known etiology must in any case be confirmed by genetic analysis.

The most common cause of adrenal insufficiency in adolescents and adults is autoimmune AI [36], [57]. However, even if a male patient tests positive for antibodies against 21-hydroxylase (a marker of autoimmune adrenal insufficiency), a VLCFA test is necessary to rule out X-ALD. Subsequently, the need for genetic diagnostics can be considered. Cases of X-ALD are known where a positive 21-hydroxylase antibody titer was also detected.

Family history can serve as a key to diagnosis, but sometimes pedigree analysis can be misleading. For example, the presence of clinical manifestations in females can mimic an autosomal dominant inheritance pattern.

2.1 Complaints and Anamnesis

Comments: when collecting anamnesis and complaints, it is necessary to pay attention to the following complaints and anamnestic events:

• burdened family history (similar symptoms in brothers, as well as maternal male relatives; presence of such diseases as multiple sclerosis, schizophrenia, and early death of boys in the family);

• decreased or loss of appetite;

• memory impairment;

• behavioral changes, apathy, irritability;

• hearing loss;

• vision loss;

• gait changes;

• balance difficulties, coordination impairment (especially with eyes closed);

• muscle weakness of the upper and lower extremities (usually the patient first complains of weakness in the feet and hands, then of the entire limb);

• sensory loss (up to its complete disappearance);

• strange sensations in the extremities (tingling, burning);

• darkening of the skin;

• episodes of lethargy, drowsiness;

• repeated vomiting, nausea against the background of stress, intercurrent diseases;

• craving for salty foods;

• sweating that does not depend on temperature and physical exertion; breathing disorders, shortness of breath, palpitations, dizziness;

• impaired control of pelvic organ functions;

• erectile dysfunction in men.

2.2 Physical Examination

Comments: upon examination, it is necessary to pay attention to the main clinical manifestations of X-ALD indicating adrenal insufficiency, damage to the central and peripheral nervous system:

• skin hyperpigmentation;

• pallor or grayish skin tone;

• weight loss;

• episodes of lowered blood pressure;

• decreased skin turgor;

• alopecia (hair loss);

• signs of polyneuropathy (weakness or atrophy of distal lower extremity muscles, sensory disturbances, decreased or absent tendon reflexes).

2.3 Laboratory Diagnostics

Comments: as part of neonatal screening, the concentration of C26:0-LPC is determined in level 3A medical centers. As part of confirmatory diagnostics in the reference center of the federal expanded neonatal screening program, the concentration of the following LPCs is determined: C26:0-LPC, C24:0-LPC, C22:0-LPC, as well as the determination of LPC ratios: C24:0-LPC to C22:0-LPC (C24:0-LPC/C22:0-LPC) and C26:0-LPC to C22:0-LPC (C26:0-LPC/C22:0-LPC). Biochemical studies are reliable and main methods for verifying the diagnosis; false-positive or false-negative results are extremely rare [51], [52], [53], [54].

Comments: the concentration of the following VLCFA is determined: C26:0 (hexacosanoic acid), C24:0 (tetracosanoic acid), C22:0 (docosanoic acid), as well as the ratios of the following acids: C24 to C22 (C24/C22) and C26 to C22 (C26/C22). Biochemical testing is a reliable and primary method for confirming the diagnosis; false-positive or false-negative results are extremely rare. Elevated plasma VLCFA levels in patients can be observed in other peroxisomal disorders, although the clinical presentation in these conditions differs markedly from X-ALD. Additionally, elevated VLCFA levels may occur in children on a ketogenic diet or due to improper sample collection (blood hemolysis) [66], [67]. Data obtained from plasma VLCFA measurements in X-ALD patients and controls demonstrated that measuring all three parameters, as well as their ratios, reliably establishes the diagnosis of X-ALD in male patients. However, false-negative cases in X-ALD have been described in the literature [68], [69], [70]. Plasma VLCFA concentration is elevated in approximately 85% of heterozygous female carriers [56], whereas in 10-15% of definite heterozygous carriers, VLCFA testing yields false-negative results due to the compensatory function of the unaffected X chromosome [54], [56], [71], [72].

Comment: this test is primarily indicated for patients with elevated VLCFA levels and/or ratios. Ordering the test, selecting the DNA diagnostics strategy, and subsequently interpreting the results require an initial and follow-up diagnostic consultation with a geneticist. DNA analysis is a highly informative diagnostic method for X-ALD. Information on pathogenic variants of the ABCD1 gene is published in international databases (e.g., http://www.hgmd.cf.ac.uk/ac/index.php, http://www.x-ald.nl/, http://grenada.lumc.nl/LOVD2/MR/home.php?select_db=ABCD1). Missense variants predominate (nearly 2/3), about 1/4 are nonsense variants (with frameshift), while other types of nucleotide variants are quite rare. In virtually 100% of patients (both affected males and female carriers), direct automated sequencing and deletion/duplication analysis via quantitative assays lead to the identification of the causative variant. Due to the very high homology between the pseudogene and the ABCD1 gene, careful attention must be given to the selection of nucleotide primers for DNA diagnostics. Each laboratory may select and use its own oligonucleotide primer sequences; their design must account for the presence of the pseudogene, and patient sample testing should only begin after obtaining convincing results regarding the specificity of the assay. If direct Sanger sequencing fails to detect a causative variant, other molecular genetic testing methods should be applied.

Comment: the tests are performed in all patients to assess for both glucocorticoid and mineralocorticoid deficiency [64]. Ordering these tests requires an initial and (if necessary) follow-up diagnostic consultation with an endocrinologist (pediatric endocrinologist). Diagnosis and treatment are carried out in accordance with the clinical guidelines for "Primary Adrenal Insufficiency". It is preferable to collect biological samples in the early morning hours (7:00–9:00 AM), taking into account the circadian rhythms of hormone secretion. Screening for AI should begin in the first 6 months of life in male patients, and thereafter every 6 months up to 10 years of age, and annually thereafter [64]. Adrenal insufficiency is typically characterized by low cortisol levels (less than 140 nmol/L) in the presence of ACTH levels exceeding the upper laboratory reference limit twofold. Blood glucose testing will detect hypoglycemia, which is characteristic of glucocorticoid deficiency. To evaluate mineralocorticoid function under the age of 1 year, blood electrolyte testing is advised. Hyponatremia can be a sign of both glucocorticoid and mineralocorticoid deficiency. Hyperkalemia is more characteristic of mineralocorticoid deficiency. Starting from 1 year of age, it is advisable to assess electrolytes together with blood plasma renin (plasma renin activity). An elevated renin level (plasma renin activity) in the presence of hyponatremia and/or hyperkalemia allows for the diagnosis of mineralocorticoid deficiency [76].

2.4 Instrumental Diagnostics

Neuroimaging methods play a paramount role in the instrumental diagnosis of X-ALD. Currently, a substantial body of data has been accumulated regarding CT/MRI findings in cerebral forms of X-ALD [77].

Comments: general anesthesia is indicated when necessary (general anesthesia should be used until the patient is able to lie still during the procedure).

MRI changes typically precede neurological and neurophysiological changes; therefore, MRI is of exceptional importance for examining patients with X-ALD identified within affected families [79].

From 24 months to 3 years of age, it is advisable to perform annual imaging assessments, from 3 to 12 years every 6 months, and from 12 years of age annually.

The baseline brain MRI protocol for X-ALD must include at least the following sequences: 3D T1-weighted imaging, T2-weighted imaging (spin-echo), 3D FLAIR, and diffusion-weighted imaging (DWI). Contrast-enhanced T1-weighted imaging is performed according to clinical indications [80].

Occipital/occipitoparietal demyelinating lesions are characteristic of X-ALD. Such localization clearly distinguishes X-ALD from a number of other leukodystrophies [3], [77].

In 80% of patients with childhood cerebral ALD, extensive symmetric demyelinating lesions are found in the occipital and parietal lobes with involvement of periventricular areas: in the early stages of cerebral X-ALD, a hyperintense signal on T2-weighted imaging (T2W) is detected in the corpus callosum, corticospinal, and corticopontine tracts, which rapidly spreads into the occipital and posterior parietal regions as the disease progresses [81].

The presence of demyelination in the caudal brain regions correlates with cortical visual and hearing impairments. The signal intensity (T2W) indicates not only myelin breakdown but also the presence of an inflammatory response [82].

Although this onset of the demyelinating process is the most common, other lesion localizations at disease onset are also possible. Frontal localization of lesions was observed in 5 of 40 patients with cerebral forms and is most characteristic of the adult cerebral form, which is consistent with "frontal" psychiatric symptoms [83].

The initial foci of the demyelinating process were identified in the internal capsule, corpus callosum, corona radiata, and cerebral peduncles. Involvement may also begin in the cerebellum or pons [42].

Atypical localization has been described, for example, unilateral lesion localization in childhood cerebral ALD [17].

In patients with neurological symptoms, MRI shows a characteristic pattern of symmetric T2 hyperintensity in the corpus callosum and parieto-occipital region [53], [82].

Brain MRI is also used to assess the severity of X-ALD using the Loes scale (Appendix G1). Examples of lesions visualized on brain MRI are presented in Appendix A3.5.

Comments: the frequency is determined by the attending physician; it is advisable to determine the need for the study as part of the annual primary and follow-up (as needed) diagnostic consultation with a neurologist.

Comment: spinal cord MRI has limited diagnostic value for confirming the diagnosis and is primarily necessary to rule out other conditions being considered in the differential diagnosis.

Comment: the scope of the study is determined by the specialist. Signs of both axonal and demyelinating polyneuropathy are detected.

Comment: routine regular audiometry is generally not required in asymptomatic patients and patients without signs of cerebral adrenoleukodystrophy; periodic evaluation (e.g., once every 1–2 years) as part of multidisciplinary follow-up is acceptable.

2.5 Other Procedures

Comments: differential diagnosis for X-ALD can also be performed in familial cases of multiple sclerosis and isolated adrenal insufficiency. Signs of adrenal involvement may precede neurological symptoms; therefore, it is advisable to perform X-ALD diagnostics (determination of very long-chain fatty acid levels) in all male patients older than 1 year with adrenal insufficiency of unclear etiology. An accurate diagnosis in cases of isolated adrenal insufficiency is essential for predicting further disease progression, determining follow-up tactics, and providing genetic counseling to the family.

Comments: during the initial consultation, the geneticist performs a differential diagnosis of the condition and determines the strategy for DNA diagnostics. A follow-up consultation is necessary upon receiving DNA diagnostic results to interpret the findings and determine indications for additional studies (if required). The diagnosis is confirmed by the detection of hemizygous pathogenic/likely pathogenic variants in males, or heterozygous pathogenic/likely pathogenic variants in females, in the ABCD1 gene. It is important to remember that no DNA diagnostic method can rule out the hereditary nature of the disease.

Comments: the neurologist determines the schedule for procedures including brain MRI, followed by an assessment of severity based on neuroimaging data, which is subsequently used in treatment decision-making [2]. Adult patients with the adrenomyeloneuropathy phenotype may exhibit symptoms of spastic paraplegia, ataxia, cognitive impairment, and sleep disorders.

Comments: it is advisable to conduct monitoring every 6 months up to the age of 10 years, and annually thereafter [2]. Signs of adrenal involvement may precede neurological symptoms; therefore, it is advisable to perform diagnostics to rule out/confirm X-ALD (determination of very long-chain fatty acid levels) in all male patients older than 1 year with adrenal insufficiency of unclear etiology. An accurate diagnosis in cases of isolated adrenal insufficiency is essential for predicting further disease progression, determining follow-up tactics, and providing genetic counseling to the family.

Comment: testing blood levels of total testosterone, luteinizing hormone, and follicle-stimulating hormone is performed according to indications. Signs of hypogonadism may be detected in patients with X-ALD, though their clinical significance remains unclear. For instance, erectile dysfunction may be a manifestation of primary hypogonadism or caused by spinal cord lesions.

Comments: this is most relevant for adult patients with the adrenomyeloneuropathy phenotype. Complications such as neurogenic bladder, urinary incontinence, and erectile dysfunction in men may be observed [2].

Comments: gastrointestinal disorders may occur, and some patients may require nutritional support [2].

Comments: behavioral disturbances may be observed in both pediatric and adult patients [2].

Comments: some patients may require orthopedic support; prevention of joint contractures and falls is essential [2].

Comment: the frequency is determined by the specialist depending on the severity and progression of motor impairments and may range from scheduled assessments 1–2 times a year in patients without pronounced spasticity to regular monthly or every 2–3 months visits in patients with severe motor impairments [57].

Comments: assessment of development and cognitive impairments, and rehabilitation measures as needed. Families need a consultation (examination) with a medical psychologist, since the disease is progressive in nature; it is necessary to help the patient "accept" the diagnosis and adapt to life with it in order to maximize their learning abilities and capacity for independent living in the future.

Comments: initial and follow-up therapeutic and diagnostic consultations (examinations) are indicated with a geneticist, neurologist, endocrinologist/pediatric endocrinologist, gastroenterologist, dietitian, trauma surgeon/orthopedic surgeon, pediatrician, general practitioner, family physician, ophthalmologist, audiologist-otorhinolaryngologist, physical therapist, and palliative care physician, as well as initial and follow-up consultations with a medical psychologist.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

The two main therapeutic approaches are most accessible: medical nutrition therapy and hormone replacement therapy for adrenal insufficiency.

The principles of hormone replacement therapy for adrenal insufficiency in X-ALD do not differ from other forms of adrenal insufficiency. Mineralocorticoid deficiency in X-ALD develops in approximately half of patients, in some cases later than glucocorticoid deficiency.

Comments: the principles of diet therapy are presented in Appendix A3.3. Diet therapy for X-ALD has three main directions: restriction of VLCFA with an emphasis on excluding C26:0 (hexacosanoic acid), inhibition of fatty acid elongation, and enhancement of peroxisomal beta-oxidation by introducing a mixture of Lorenzo's oil (LO) [a 4:1 mixture of glyceryl trioleate (GTO) (C18:1 n-9) and glyceryl trierucate (GTE) (C22:1 n-9)], conjugated linoleic acid (CLA), and antioxidant compounds. Given the crucial role of dietary lipids for growth and neurodevelopment in early life, fat intake should not be restricted in patients under 2 years of age, but it is advisable to consume foods naturally low in VLCFA (see Appendix A3.3). During this period of life, the patient is provided a balanced diet in accordance with intake norms. Restriction of dietary fat intake begins after two years of age, and the goal of the diet is to reduce C26:0 intake to < 2–3 mg/day. Thus, dietary fat intake amounts to < 15% of total caloric intake. Families are given instructions regarding the main foods to avoid or choose based on their C26:0 content. Particular attention should be paid to fatty foods and the composition of the outer rind/peel of plants, fruits, vegetables, and nuts (see Appendix A3.4).

Comments: the principles of nutrition therapy and dosages of Lorenzo's oil are specified in Appendix A3.3. Administration is advisable no earlier than 2 years of age. The use of Lorenzo's oil is indicated for patients without neurological symptoms, preferably under 10 years of age with normal MRI findings. In older patients, prophylactic use of GTO/GTE is limited, since the probability of developing the cerebral form of the disease is significantly lower in them. In the event of adverse events (e.g., thrombocytopenia), consider adjusting the dosage or discontinuing medical nutrition. Lorenzo's oil does not reverse neurological disorders; if neurological symptoms or even just MRI changes are already present, Lorenzo's oil is not indicated, nor is it advisable to use Lorenzo's oil in patients with severe neurological symptoms, or newly diagnosed adrenomyeloneuropathy, or in female heterozygous carriers [92].

In children under one year of age, Lorenzo's oil is usually not used due to the potential decrease in essential fatty acid levels, particularly docosahexaenoic acid. The duration of treatment should be individualized. Treatment generally can be continued indefinitely, as its efficacy disappears after discontinuation, and may be stopped if the disease progresses and serious adverse events occur.

3.2 Surgical Treatment

Not applicable.

3.3 Other Treatment

Symptomatic treatment requires consultations with relevant specialists within a multidisciplinary approach.

Comments: HLA typing and donor search are performed only if the cerebral form of the disease is identified. First, HLA typing of first-degree family members (non-carriers of the disease) is performed; if no compatible related donor is found, an unrelated search is initiated. To determine the indications for hematopoietic stem cell transplantation (HSCT), an initial and follow-up diagnostic consultation by a neurologist is required. The physician evaluates the severity of X-ALD using the X-ALD functional neurologic disability scale and the Loes scale (Appendix G1, G2) [49], [96], [97]. HSCT is indicated for patients with early-stage cerebral X-ALD. Optimal selection criteria for HSCT are: an X-ALD functional neurologic disability score of < 2 and a Loes score of no more than 10 points [98]. Patients with the cerebral form of X-ALD who lack an HLA-compatible donor and exhibit rapid progression of neurological symptoms are indicated for haploidentical bone marrow transplantation (in which the donor is a partially compatible donor, such as one of the parents) [94]. The best effect is achieved in the early stage of the disease, in patients with an IQ > 80 and moderate MRI changes [99]. At the stage of severe neurological disorders and pronounced dementia (IQ < 80), HSCT is inadvisable [56]. HSCT does not correct adrenal insufficiency, so patients will require lifelong hormone replacement therapy [103].

Comments: it is advisable to perform follow-up every 6 months up to 10 years of age, and annually thereafter [2]. If indicated, testing for total testosterone, luteinizing hormone, and follicle-stimulating hormone in the blood may be performed to confirm/exclude hypogonadism.

Comment: the prescription of diet therapy and the specialized medical nutrition product Lorenzo's oil is considered for patients starting from 2 years of age with the asymptomatic form of X-ALD or in the early stages of cerebral forms of X-ALD; efficacy and safety are monitored, and indications for adjusting the dose of the specialized medical nutrition product Lorenzo's oil or discontinuing it are determined.

Comments: most relevant for adult patients with the adrenomyeloneuropathy phenotype. Complications such as neurogenic bladder, urinary incontinence, and erectile dysfunction in men may be observed.

Comments: gastrointestinal disorders may occur, and some patients may require nutritional support.

Comments: behavioral disturbances, aggressiveness, emotional lability, and cognitive impairment may be observed in both pediatric and adult patients.

Comments: some patients may require orthopedic support.

Comments: families are in need of a consultation with a medical psychologist because the disease is progressive in nature; it is necessary to help the patient "accept" the diagnosis and adapt to life so that their learning potential and independent living skills can be maximized in the future.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

The main challenge in the rehabilitation of patients with X-ALD is the presence of symptoms affecting the nervous system. Rehabilitation implies creating optimal conditions for palliative care in patients with severe functional impairments, as well as a comprehensive set of measures for adaptation in mild impairments that only slightly affect the patient's ability to study, work, and live a full life.

5. Prevention and Dispensary Observation

The severity of clinical manifestations and the prognosis of the disease can vary significantly even within the same family. Current therapeutic options for X-ALD are very limited; therefore, genetic counseling of families burdened with this disease is the best means of prevention, reducing the likelihood of new cases. Once a diagnosis is established, it is advisable for the patient or their legal representatives to consult a geneticist to discuss genetic risks within the family, options for family screening, and prenatal and preimplantation diagnostics. Dispensary follow-up and management of comorbidities and disease complications are carried out in accordance with relevant clinical guidelines.

Comments: as part of genetic counseling for patients with a confirmed diagnosis, the following topics should be discussed: the inheritance pattern of the disease, options for family screening (including the identification of heterozygous female carriers), options for prenatal diagnostics and prevention of further transmission of the disease within the family, in order to enable the family to make informed medical and personal decisions. Family screening and early genetic testing of boys will allow the disease to be identified at the preclinical or early clinical stage and guide the selection of the most effective therapy. Prenatal diagnostics can only be performed for pathogenic/likely pathogenic variants recognized as causative in the specific patient. Clinically significant decisions (including prenatal diagnostics) must not be based on variants of uncertain significance. Given the X-linked inheritance pattern, testing the patient's biological father is not advisable. Approximately 93–95% of patients inherit the disease from one of the parents, and only about 5% have de novo variants. Probability of maternal transmission of the disease to children: 50% of boys will have the disease, and 50% of girls will be heterozygous carriers. In men with X-ALD, 100% of girls will be heterozygous carriers, and all boys will be healthy. It is advisable to test the mother of the affected patient to detect carrier status. If no causative variants are detected in the patient's parents, the possibility of parental gonadal mosaicism must be taken into account when planning subsequent pregnancies. For X-ALD, the probability of maternal somatic/gonadal mosaicism is approximately 13%. It must be kept in mind that heterozygous female carriers may manifest symptoms of the disease in adulthood, and plasma VLCFA concentrations may be normal in 20% of them.

Comment: the prescription of diet therapy and the specialized medical nutrition product Lorenzo's oil is considered for patients starting from 2 years of age with the asymptomatic form of X-ALD or in the early stages of cerebral forms of X-ALD; efficacy and safety are monitored, and indications for adjusting the dose of the specialized medical nutrition product Lorenzo's oil or discontinuing it are determined.

Comments: anesthesia is indicated as needed (general anesthesia should be used until the patient can remain still during the procedure). MRI changes typically precede neurological and neurophysiological changes, making MRI extremely important for examining patients with childhood cerebral ALD identified in affected families [79]. From 12 months to 3 years of age, scans should be evaluated annually; from 3 to 12 years, every 6 months; and from 12 years onward, annually.

Comments: monitoring should be carried out every 6 months up to the age of 10, and annually thereafter [2]. Signs of adrenal involvement may precede neurological symptoms; therefore, all male patients with adrenal insufficiency of unclear etiology should undergo diagnostic testing to rule out/confirm X-ALD (determination of very long-chain fatty acid levels). An accurate diagnosis in cases of isolated or concurrent adrenal insufficiency is essential for predicting further disease progression, determining monitoring tactics, and providing genetic counseling to the family.

Comment: testing for total testosterone, luteinizing hormone, and follicle-stimulating hormone in the blood is performed according to clinical indications.

Comments: most relevant for adult patients with the adrenomyeloneuropathy phenotype. Complications such as neurogenic bladder, urinary incontinence, and erectile dysfunction in men may be observed.

Comments: gastrointestinal disorders may occur, and some patients may require nutritional support.

Comments: behavioral disturbances, aggressiveness, emotional lability, and cognitive impairment may be observed in both pediatric and adult patients.

Comments: some patients may require orthopedic support.

Comments: families are in need of a consultation with a medical psychologist because the disease is progressive in nature; it is necessary to help the patient "accept" the diagnosis and adapt to life so that their learning potential and independent living skills can be maximized in the future.

Comments: palliative care should begin after diagnosis and continue regardless of whether the patient is receiving disease-specific treatment. The primary goal of palliative services is to create all necessary conditions to ensure that patients can remain at home rather than in a medical institution, which improves the quality of life for patients and their families and significantly reduces government expenditures on continuous inpatient care.

6. Organization of Medical Care

Patients with X-ALD may receive any type, conditions, and forms of medical care provided for by the legislation of the Russian Federation, as clinically indicated.

Indications for planned hospitalization in a medical organization:

1) When diagnostic procedures and treatment requiring round-the-clock medical supervision are necessary;

2) When various types of expert evaluations or examinations in a medical organization are required and cannot be performed on an outpatient basis, requiring dynamic monitoring (including issuing a federal medical board conclusion);

3) Assessment of indications for hematopoietic stem cell transplantation (HSCT).

Indications for discharging a patient after elective hospitalization:

1) completion of the patient's examination plan;

2) delivery of rehabilitation measures;

3) provision of recommendations for further monitoring and treatment.

Indications for emergency hospitalization to a medical organization:

1) acute diseases, exacerbations of chronic illnesses, poisoning and injuries, conditions requiring intensive care and transfer to intensive care units or critical care units, and other life-threatening acute conditions, as well as round-the-clock medical supervision and special diagnostic and treatment modalities;

2) adrenal crisis.

Indications for discharging a patient after emergency hospitalization:

1) absence of a threat to the patient's life;

2) absence of a threat of complications requiring urgent treatment;

3) stabilization of the patient's condition and main clinical and laboratory parameters of the pathological process regarding the underlying disease;

4) absence of the need for continuous medical and round-the-clock clinical observation regarding the underlying disease;

5) necessity of transferring the patient to another medical organization or a palliative care unit.

7. Additional Information

Many researchers note the importance of MRI not only in diagnosis but also in predicting the course of X-ALD [49]. Loes et al. (2003) studied 206 patients with cerebral forms (mean age 18.5 years, range 1.7–73.8 years), 140 of whom had serial MRI follow-up data (MRI scans performed after HSCT were excluded). They identified 5 variants of initial white matter lesion localization: 1) parieto-occipital; 2) frontal; 3) corticospinal tract involvement; 4) cerebellar; 5) combined parieto-occipito-frontal. The severity of involvement was assessed using a scoring scale. The first and fifth variants were observed exclusively in childhood, the second and fourth in adolescence, and the third in adult patients. Based on the localization and severity of MRI changes, the authors developed formulas for predicting X-ALD. The most rapid progression was observed in a small number of patients in group 5. In group 1, rapid progression occurred in cases with particularly early MRI changes and contrast enhancement of demyelinating lesions. The latter feature correlated with the rate of progression in group 2 patients as well. The slowest progression was noted in patients of groups 3 and 4. Thus, the progression of MRI changes depends on the patient's age, baseline severity of involvement (on a point scale), and its localization. The authors suggest using these findings in selecting patients for HSCT.

Brain MRI changes are also present in patients with "cerebral adrenomyeloneuropathy (AMN)", although their pattern differs from that of cerebral forms [23], [30], [77].

Brain MRI changes in heterozygous female carriers are possible but rare, even in the presence of clinical symptoms. Of 76 carriers evaluated by Fatemi et al. (2003), MRI changes were present in 11, but only 3 of them were considered related to X-ALD: two women showed demyelinating lesions similar to those in patients with cerebral forms, while a third woman with mild AMN symptoms had MRI changes restricted to the corticospinal tracts.

Acute adrenal insufficiency ("adrenal crisis") can develop both at disease onset (i.e., before the patient is diagnosed) and during ongoing treatment. The cause of a crisis during treatment may be interruption of medication intake (intentional or unintentional omission) or a sharp increase in the demand for adrenal hormones due to physiological stress or illness.

7.1 Outcomes and prognosis

To date, the overall outcomes and prognosis of X-ALD remain unfavorable. Research into novel treatment modalities continues, which may fundamentally alter the prognosis for patients with X-ALD.

The prognosis of the disease depends on the clinical form. Cerebral forms unfortunately lead to patient death often within a few years, although in many cases ten or more years pass from the first brain MRI changes to death.

Quality and duration of life depend primarily on neurological impairments.

With proper treatment, adrenal insufficiency does not affect the disease outcome since hormone replacement therapy compensates for lost adrenal function. Nevertheless, cases of death from acute adrenal insufficiency do occur due to failure to provide emergency medical care. For example, if a crisis develops in a patient with severe neurological impairments and the clinical symptoms of the crisis are not promptly recognized by their caregivers, or in case of sudden loss of consciousness on the street or in a public place.

Patients leading an active lifestyle are advised to wear bracelets or carry information cards indicating their personal details and information about the disease. Information that should be included on the card: name, surname, diagnosis, contact phone number for family or physician.

Criteria for Evaluating the Quality of Medical Care

Criteria for evaluating the quality of primary health care

Criteria for evaluating the quality of specialized medical care

References

Appendix A1. Working Group Composition

1. Daria Yu. Alexandrova — Researcher, Center for Collective Use "Metabolom", Research Centre for Medical Genetics.

2. Inga V. Anisimova — Cand. Sc. (Med.), Medical Geneticist, Head of the Department of Medical Care Organization, Research Centre for Medical Genetics, Member of the Association of Medical Geneticists (AMG).

3. Galina V. Baydakova — Head of the Center for Collective Use "Metabolom", Research Centre for Medical Genetics.

4. Aleksandr A. Baranov — Academician of the Russian Academy of Sciences, Professor, Dr. Sc. (Med.), Chief freelance pediatric specialist of the Russian Ministry of Health.

5. Polina V. Baranova — Researcher, Center for Collective Use "Metabolom", Research Centre for Medical Genetics.

6. Nato D. Vashakmadze — Dr. Sc. (Med.), Professor at the Department of Faculty Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health, Head of the Department of Orphan Diseases and Prevention of Disabling Conditions, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery.

7. Victoria Yu. Voinova — Dr. Sc. (Med.), Head of the Department of General and Medical Genetics, Faculty of Biomedical Sciences, Head of the Department of Clinical Genetics, Geneticist at the Laboratory of Molecular and Biochemical Diagnostics, Veltischev Research and Clinical Institute of Pediatrics of the Pirogov Russian National Research Medical University of the Russian Ministry of Health.

8. Sergey V. Voronin — Cand. Sc. (Med.), Chief Medical Officer, Research Centre for Medical Genetics, Chief freelance medical geneticist of the Russian Ministry of Health in the Far Eastern Federal District.

9. Sofya R. Enikeeva — Cand. Sc. (Med.), Pediatric Endocrinologist at the Pediatric Department of Endocrine Tumors, Analyst at the Department of Endinocrinopathy Epidemiology, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

10. Ekaterina Yu. Zakharova — Dr. Sc. (Med.), Head of the Department of Molecular Mechanisms of Hereditary Metabolic Disorders, Research Centre for Medical Genetics, Member of the Russian Society of Medical Geneticists, Member of the Society for the Study of Inborn Errors of Metabolism (SSIEM).

11. Alexey V. Kiyaev — Dr. Sc. (Med.), Professor at the Department of Endocrinology, Ural State Medical University of the Russian Ministry of Health; Head of the Regional Center of Pediatric Endocrinology, Regional Children's Clinical Hospital; Chief freelance pediatric endocrinologist of the Russian Ministry of Health in the Ural Federal District; Chief freelance pediatric endocrinologist of the Sverdlovsk Region.

12. Lyudmila M. Kuzenkova — Dr. Sc. (Med.), Professor, Head of the Center of Child Psychoneurology, National Medical Research Center for Children's Health of the Russian Ministry of Health.

13. Sergey I. Kutsev — Academician of the Russian Academy of Sciences, Professor, Dr. Sc. (Med.), Director of the Research Centre for Medical Genetics, President of the Association of Medical Geneticists (AMG).

14. Anastasia A. Lyalina — Neurologist, Junior Researcher at the Center of Child Psychoneurology, National Medical Research Center for Children's Health of the Russian Ministry of Health.

15. Natalia G. Mokrysheva — Academician of the Russian Academy of Sciences, Dr. Sc. (Med.), Professor, Scientific Director of the Department of Parathyroid Pathology and Mineral Metabolism Disorders, Director of the National Medical Research Center for Endocrinology.

16. Svetlana V. Mikhailova — Dr. Sc. (Med.), Professor at the Badalyan Department of Neurology, Neurosurgery and Medical Genetics, Pediatric Faculty, and the Department of General and Medical Genetics, Faculty of Biomedical Sciences, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health; Head of the Department of Medical Genetics, Russian Children's Clinical Hospital, a branch of the Pirogov Russian National Research Medical University of the Russian Ministry of Health.

17. Leyla S. Namazova-Baranova — Academician of the Russian Academy of Sciences, Dr. Sc. (Med.), Professor, Head of the Department of Faculty Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Head of the Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery, Chief freelance pediatric specialist in preventive medicine of the Russian Ministry of Health, President of the Union of Pediatrists of Russia, Professor at MSU-PPI Joint University in Shenzhen (China).

18. Maria D. Orlova — Medical Laboratory Geneticist, Laboratory of Molecular Genetic Diagnostics 3, Research Centre for Medical Genetics.

19. Valentina A. Peterkova — Academician of the Russian Academy of Sciences, Dr. Sc. (Med.), Professor, Chief freelance pediatric endocrinologist of the Russian Ministry of Health, Scientific Director of the Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

20. Tatiana V. Podkletnova — Cand. Sc. (Med.), Neurologist at the Department of Psychoneurology and Neurorehabilitation, Senior Researcher, National Medical Research Center for Children's Health of the Russian Ministry of Health.

21. Svetlana A. Repina — Cand. Sc. (Med.), Geneticist at the Department of Medical Care Organization, Research Centre for Medical Genetics, Member of the Association of Medical Geneticists (AMG).

22. Galina E. Rudenskaya — Dr. Sc. (Med.), Chief Researcher at the Scientific Advisory Department, Research Centre for Medical Genetics.

23. Valeria V. Sviridova — Geneticist at the Department of Medical Care Organization, Research Centre for Medical Genetics.

24. Alla N. Semyachkina — Dr. Sc. (Med.), Chief Researcher at the Department of Clinical Genetics, Moscow Research Institute of Pediatrics and Pediatric Surgery of the Russian Ministry of Health, Member of the Association of Medical Geneticists (AMG).

25. Elena V. Skorobogatova — Dr. Sc. (Med.), Anesthesiologist-Resuscitator, Head of the Bone Marrow Transplantation Department, Head of the Interdisciplinary Center of Oncology, Hematology and Transplantology, Russian Children's Clinical Hospital, a branch of the Pirogov Russian National Research Medical University of the Russian Ministry of Health.

26. Leyla S. Sozaeva — Cand. Sc. (Med.), Pediatrician, Pediatric Endocrinologist, Senior Researcher at the Pediatric Department of Endocrine Tumors, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

27. Dmitry M. Subbotin — Geneticist, Researcher at the Laboratory of Neurogenetics, Specialist at the Department of Medical Care Organization, Research Centre for Medical Genetics, Member of the Association of Medical Geneticists (AMG).

28. Maria G. Sumina — Geneticist, Head of the Department of Medical Genetic Counseling, Clinical and Diagnostic Center "Maternal and Child Health Protection".

29. Evgenia V. Uvakina — Cand. Sc. (Med.), Head of the Department of Psychoneurology and Neurorehabilitation, National Medical Research Center for Children's Health of the Russian Ministry of Health.

30. Igor S. Chugunov — Cand. Sc. (Med.), Head of the Pediatric Department of Endocrine Tumors, Associate Professor at the Department of Pediatric Endocrinology and Diabetology, National Medical Research Center for Endocrinology.

    Conflict of interest:

    The authors declare no financial support or conflicts of interest that need to be disclosed.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Medical geneticists, neurologists, pediatric endocrinologists, endocrinologists, neurosurgeons, anesthesiologists-resuscitators, gastroenterologists, dietitians, psychiatrists, pediatric psychiatrists, orthopedic trauma surgeons, cardiologists, general practitioners, pediatricians, general family practitioners, exercise therapy doctors, physical and rehabilitation medicine physicians.

2. Medical students, residents, postgraduate students.

Methods used for evidence collection/selection: electronic database search.

Description of methods used to assess the quality and strength of evidence: the evidence base for the guidelines includes publications from the Cochrane Library, MEDLINE, and PubMed databases.

Search depth: 40 years.

Methods used for assessing the quality and strength of evidence:

− expert consensus;

− significance assessment according to the rating scheme (scheme attached).

Methods used for analyzing evidence:

− reviews of published meta-analyses;

− systematic reviews with evidence tables.

Description of methods used for evidence analysis: when selecting publications as potential sources of evidence, the methodology used in each study is examined to ensure its validity. The result of this assessment influences the level of evidence assigned to the publication, which in turn affects the strength of the recommendations. To minimize potential errors, each study was evaluated independently. Any discrepancies in evaluations were discussed by the full panel of authors. If consensus could not be reached, an independent expert was involved.

In these clinical guidelines, all information is ranked by the level of reliability (evidence) or LRE, depending on the quantity and quality of studies on the issue, in accordance with the tables:

Table 1. Scale for assessing levels of reliability of evidence (LRE) for diagnostic methods (diagnostic interventions).

Table 2. Scale for assessing levels of reliability of evidence (LRE) for methods of prevention, treatment, and medical rehabilitation, including those based on the use of natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions).

Table 3. Scale for assessing levels of recommendation strength (LRS) for methods of prevention, diagnosis, treatment, and medical rehabilitation, including those based on the use of natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions).

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Appendix A3.1 X-ALD Classification

Appendix A3.2 Frequency of Examination in Patients with X-ALD

Appendix A3.3 Principles of diet therapy and dosages of the specialized medical nutrition product Lorenzo's oil

1. Lorenzo's oil

2. Daily fat requirement

3. Low-fat diet:

Appendix A3.4 VLCFA Content in Foods

Note: Table adapted from Van Duyn et al. [106]

Appendix A3.5 Examples of Brain MRIs in Patients with X-ALD (Different Lesion Zones)

Appendix B. Physician Action Algorithms

Appendix B1. Expanded Newborn Screening Algorithm for X-ALD

FIA-MS/MS — flow injection analysis tandem mass spectrometry, LC-MS/MS — liquid chromatography-tandem mass spectrometry, cut-off — threshold value.

Objective: to ensure full integration of the patient into the medical, genetic, and psychological care system, and to organize dispensary monitoring and family member screening.

Documentation and Registration (Organizational Unit)

• Entering data into the regional segment of the Federal Register of Persons with Life-Threatening and Chronic Progressive Rare (Orphan) Diseases Leading to Reduced Life Expectancy or Disability in accordance with Decree of the Government of the Russian Federation No. 403 dated April 26, 2012 with a confirmed diagnosis.

• Registration at the regional medical genetic center (MGC) or specialized orphan disease center.

• Preparation of relevant medical documentation.

Care Coordination

• Conducting a telemedicine consultation (TMC) with the federal expert center for

  ○ developing an individualized treatment and monitoring plan (including the question of allogeneic hematopoietic stem cell transplantation).

Family Information

• Issuing an information sheet to parents/legal representatives containing:

  ○ Brief explanation of the diagnosis.

  ○ Plan of mandatory scheduled examinations (frequency of MRI, consultations with a neurologist and endocrinologist, adrenal function assessment, audiometry, and other tests).

  ○ Contact details of responsible physicians (regional MGC, federal center).

  ○ Information on dietary therapy (Lorenzo's oil) and its initiation.

  ○ Recommendations for home health monitoring.

  ○ Contact details of psychological support organizations.

• Sending an official notification/discharge summary to the local pediatric clinic with recommendations for monitoring and emergency actions in case of adrenal crises.

Family Screening

• Genetic counseling for the family.

• Screening of the proband's siblings (brothers and sisters).

• Screening of the mother for carrier status and providing recommendations for maternal relatives.

Appendix C. Patient Information

What is X-linked adrenoleukodystrophy?

X-linked adrenoleukodystrophy (X-ALD) is a hereditary disease caused by alterations in the nucleotide sequence of the ABCD1 gene.

Our body's cells contain specialized structures called peroxisomes. They house enzymes required for the breakdown of fatty acids. Normally, these fatty acids (known as very long-chain fatty acids) enter peroxisomes via a protein that acts as a channel. In X-linked adrenoleukodystrophy, this protein ceases to function properly, causing very long-chain fatty acids to accumulate inside the cell rather than entering peroxisomes.

Very long-chain fatty acids are highly toxic to nerve cells; their accumulation triggers neuronal cell death.

Furthermore, the highest accumulation of very long-chain fatty acids occurs in organs involved in steroid hormone synthesis. In our body, these organs include the adrenal glands and testes.

Starting in 2026, X-ALD is included in the neonatal screening program in the Russian Federation.

Upon diagnosing the disease, patient data is entered into the Federal Register of Persons with Life-Threatening and Chronic Progressive Rare (Orphan) Diseases Leading to Reduced Life Expectancy or Disability (Decree of the Government of the Russian Federation No. 403 dated April 26, 2012). Legally, this means the state assumes the obligation to provide patients with the necessary therapy.

How is X-ALD inherited?

This condition is transmitted via the X chromosome, which is why it is called X-linked. A male has two different sex chromosomes, X and Y (XY), whereas a female has two copies of the X chromosome (XX). Due to the presence of the second X chromosome, which carries no genetic alterations, clinical manifestations in females are milder or absent. Males have only a single altered X chromosome, and therefore will exhibit prominent clinical symptoms of the disease.

If a woman is a carrier of a pathogenic variant in the ABCD1 gene, the following genotypes are possible in the family: a 50% probability that a daughter will also be a carrier of the 'altered' gene, and a 50% probability that the pathogenic variant will not be transmitted to her. If the child is a male, there is a 50% chance he will have X-ALD.

If the father is affected, all male children born into the family will be healthy, since they only inherit the Y chromosome from the father (which is not affected by this condition). However, all daughters will be carriers of this altered gene and may pass it on to the next generation.

Clinical manifestations of X-ALD.

Currently, several main forms of the disease are distinguished: cerebral, adrenomyeloneuropathy, and isolated chronic primary adrenal insufficiency. Cases of manifestation in female carriers also occur, but they are less severe than in males.

The initial symptoms of adrenoleukodystrophy in a boy may include uncorrectable vision impairment, hearing loss, sudden onset of speech and gait disturbances, and episodes of memory loss. Seizures may also develop.

In adrenomyeloneuropathy, sensory disturbances in the limbs, especially the legs, may occur.

Adrenal insufficiency is characterized by skin darkening, particularly pronounced in skin folds and over large joints. Unexplained lethargy, weakness, and drowsiness also develop.

An increased craving for salty foods may be noted (the child eats salt straight from the salt shaker). Intractable vomiting and seizures are symptoms of acute adrenal crisis.

Symptoms usually worsen sharply in the presence of concurrent illnesses, high fever, or stressful situations.

If the diagnosis is confirmed by newborn screening before the child shows any clinical manifestations, it is practically impossible to determine the form of X-ALD based on metabolite levels or the mutation variant. Therefore, an individualized follow-up plan is created for the child. The main goal is to prevent severe complications and detect the very earliest signs of cerebral white matter involvement on MRI. This exact "window of opportunity" is the optimal time for hematopoietic stem cell transplantation (HSCT).

What needs to be done to confirm the diagnosis?

If symptoms are present, you should consult a specialist (geneticist, neurologist, endocrinologist/pediatric endocrinologist). In addition to a clinical examination including height, weight, skin color assessment, and blood pressure measurement, the doctor will order blood hormone tests and very long-chain fatty acid levels if adrenoleukodystrophy is suspected. The geneticist determines the optimal DNA diagnostic method, interprets the results, and confirms the diagnosis.

Adrenal insufficiency presents with high levels of ACTH, potassium, and renin, alongside low blood cortisol and sodium levels, which requires a consultation with a pediatric endocrinologist/endocrinologist.

It will also be necessary to perform a brain MRI and electroneuromyography — these diagnostic methods help assess the extent of nervous system involvement.

What to do if the diagnosis is established?

You need to consult a geneticist to ensure the diagnosis is confirmed. The diagnosis is confirmed based on a comprehensive evaluation: determining very long-chain fatty acid (VLCFA) levels and analyzing the ABCD1 gene.

It must be remembered that adrenal insufficiency requires mandatory hormone replacement therapy, without which the child may die. Missing or delaying prescribed hormone doses is unacceptable. Parents must learn to respond to acute situations in the child's life and be able to increase the dose of glucocorticoid medications during viral infections, injuries, or severe stress.

It is essential to keep an emergency kit at home and while traveling, containing injectable hormone medications (for IM or IV administration). The injection must be given in emergency situations (seizures, vomiting, loss of consciousness) before the ambulance crew arrives.

Unfortunately, there is currently no medical therapy for neurological manifestations. However, numerous clinical trials are underway and experimental treatments are being developed. A multidisciplinary approach to follow-up and treatment (a team of physicians who will monitor the patient from the moment of diagnosis) is extremely important.

The only way to slow down or halt the progression of neurological symptoms in the cerebral form of the disease is hematopoietic stem cell transplantation (bone marrow transplantation). Indications for this major procedure are determined by the treating neurologist based on brain MRI and clinical examination data. It is important to provide hormone replacement therapy for confirmed adrenal insufficiency, other symptomatic therapy, rehabilitation measures, and regular brain MRI monitoring if the cerebral form is suspected. Following a low-fat diet is advisable.

The hereditary nature of this disease must also be kept in mind. Warn all family members about this diagnosis. Since the altered gene can be passed down through generations, genetic counseling is necessary when planning a pregnancy, and early diagnosis among asymptomatic boys allows timely identification of a bone marrow donor. Female carriers may also develop clinical symptoms. If a pathogenic variant in the ABCD1 gene is detected in the mother, attention must be paid to the presence of neurological symptoms. Mothers of X-ALD patients may develop symptoms after the age of 40. Symptoms can be overt or concealed. The most common complaints include: leg fatigue, impaired sensation in the legs, leg buckling, and urinary and fecal incontinence. Adrenal insufficiency in female carriers is rare but can occur; if weakness, lethargy, decreased performance, or skin discoloration appear, diagnostic workup for adrenal insufficiency should be performed. If neurological symptoms are present, a neurologist should be consulted for evaluation and treatment.

How to prevent an adrenal crisis?

In established adrenal insufficiency, a salt-wasting crisis can occur if a hormone dose is missed, so it is important to take the prescribed therapy regularly.

During illnesses and stressful situations, the adrenal glands normally produce higher amounts of cortisol. Accordingly, to prevent a salt-wasting crisis, it is necessary to respond promptly to changes in the child's condition by increasing the prescribed doses according to the doctor's recommendations.

Parent Guide.

What to do if the diagnosis is established via newborn screening?

If X-linked adrenoleukodystrophy is detected in an infant via newborn screening, they will be referred to a geneticist who will explain all newborn screening and confirmatory diagnostic results, discuss the risk of the disease for close relatives, and schedule testing for them. The geneticist will also draw up a plan for the child's ongoing follow-up by specialist physicians.

Boys with an X-ALD diagnosis confirmed by newborn screening typically have no clinical symptoms of the disease in the first months of life. However, over the course of their lives, the majority of boys develop one or another form of the disease. According to literature data, adrenal insufficiency occurs in 86% of boys, the childhood cerebral form in 35–40% of affected boys under 18 years of age, while the rest remain at risk for the adult cerebral form and adrenomyeloneuropathy.

Girls identified as X-ALD carriers through newborn screening overwhelmingly lack clinical manifestations in childhood, but according to literature data, 80% of women develop symptoms of adrenomyeloneuropathy in adulthood.

Based on diagnostic results obtained in a newborn, it is impossible to predict which specific form of the disease will develop or when it will manifest. Even members of the same family can have different clinical symptoms and age of onset.

At the time of X-ALD diagnosis via newborn screening, the child does not require any treatment, but boys need continuous monitoring by physicians—primarily an endocrinologist and a neurologist—along with regular laboratory and instrumental check-ups, even in the absence of complaints and clinical symptoms.

An endocrinologist should regularly monitor the boy starting from the first 6 months of life and perform hormonal testing when necessary for the timely detection and treatment of adrenal insufficiency. The frequency of examinations depends on the child's age and will be prescribed by the endocrinologist.

Parents need to know that adrenal insufficiency can present as an acute condition, a so-called adrenal crisis, even if recent hormone assays were normal. If the child's condition worsens and drowsiness, lethargy, refusal to eat, or vomiting appears, medical assistance must be sought immediately; if impaired consciousness or seizures develop, call an ambulance. Immediately inform medical staff that your child is at high risk for acute adrenal insufficiency and present the endocrinologist's evaluation with recommendations for management in the event of a life-threatening condition.

A neurologist will monitor the boy from the first months of life. Starting from the age of 2 years, regular brain MRI is necessary — this will allow the detection of the first signs of cerebral white matter involvement characteristic of the cerebral form of the disease, long before symptoms appear. The frequency of examinations depends on the child's age and will be scheduled by the neurologist.

Starting from the age of two, a fat-restricted diet will be recommended for the boy, and in some cases, a specialized medical nutrition product — Lorenzo's oil — will be prescribed to slow down disease progression.

Upon diagnosing the disease, patient data is entered into the Federal Register of Persons with Life-Threatening and Chronic Progressive Rare (Orphan) Diseases Leading to Reduced Life Expectancy or Disability (Decree of the Government of the Russian Federation No. 403 dated April 26, 2012). Legally, this means the state assumes the obligation to provide patients with the necessary therapy.

If the boy shows initial laboratory signs of adrenal insufficiency and/or early X-ALD-specific brain MRI changes, physicians will prescribe therapy even in the absence of clinical manifestations. For adrenal insufficiency, this is hormone replacement therapy; for the cerebral form, it is hematopoietic stem cell transplantation.

It is very important for parents to follow medical recommendations, not refuse treatment, and not interrupt it on their own. Only early initiation of therapy will reduce the risk of life-threatening manifestations of the disease.

Men who were diagnosed with X-ALD in the neonatal period but remained asymptomatic throughout childhood need to continue follow-up with an endocrinologist and neurologist in adulthood, as the risk of developing adrenal insufficiency, the cerebral form, and adrenomyeloneuropathy persists throughout life.

Girls identified as X-ALD carriers through neonatal screening generally do not require special evaluation, monitoring, or treatment. However, in rare cases, adrenal insufficiency may develop in girls; therefore, if symptoms characteristic of adrenal insufficiency appear (severe weakness, lethargy, skin hyperpigmentation, recurrent vomiting), it is advisable to consult an endocrinologist. If life-threatening conditions develop, present the same recommendations from the endocrinologist as for boys.

In the future, the girl needs to be informed about the high risk of having a son with X-ALD, as well as the risk of developing symptoms of adrenomyeloneuropathy of varying severity herself in adulthood. To this end, a consultation with a medical geneticist is indicated during adolescence, upon marriage, or when planning pregnancy.

If X-ALD is diagnosed in a newborn, the medical geneticist will schedule an examination of family members — the mother, sisters and/or brothers, and sometimes more distant maternal relatives. The purpose of this examination is to identify relatives in the pre-symptomatic stage of the disease and prescribe timely therapy, as well as to identify potential disease carriers and prevent the birth of affected children in the family.

Follow-up schedule for X-ALD patients identified by neonatal screening

Adrenal Crisis Fact Sheet

A patient diagnosed with X-linked adrenoleukodystrophy is at risk for developing a severe, life-threatening condition — an adrenal crisis!

An adrenal crisis may develop during acute illnesses with fever, intestinal infections, trauma, or increased emotional stress. A crisis can also develop in a previously stable state due to the gradual onset of mineralocorticoid deficiency.

Symptoms:

• Acute weakness, drowsiness, altered consciousness (loss of consciousness)

• Nausea, vomiting, regurgitation

• Refusal to eat

• Diarrhea, abdominal pain

• Seizures

Parental actions:

Call an ambulance or independently bring the child to the emergency department of a medical facility.

Physician actions:

1. Emergency hospitalization to an inpatient facility.

2. Determine blood sodium, potassium, and glucose. If the patient has not been previously diagnosed with adrenal insufficiency, a blood sample must be drawn to measure adrenocorticotropic hormone and total cortisol levels in the blood before administering glucocorticoids. If prompt blood sampling is not feasible, therapy must be initiated immediately (if the patient is not yet in a medical facility).

3. Initiate therapy immediately.

4. Emergency consultation with an endocrinologist (pediatric endocrinologist) in person or via telemedicine.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Loes Severity Assessment of X-ALD [49]

Source: Loes DJ, Fatemi A, Melhem ER, et al. Analysis of MRI patterns aids prediction of progression in X-linked adrenoleukodystrophy. Neurology. 2003;61(3):369-374. doi:10.1212/01.wnl.0000079050.91337.83

Type: rating scale.

Purpose: assessment of X-ALD severity.

Assessment tool: scale.

Content and scoring: the physician evaluates the patient's brain MRI and assigns points according to each feature. The points are summed up.

Each region is scored as 0 if unremarkable; 0.5 if unilateral involvement is present; 1 if the involvement or atrophy is bilateral. The maximum severity score is 34; a score ≥ 1 is considered pathological.

Appendix G2. X-ALD Neurological Functional Severity Scale [15]

Source: Moser HW, Loes DJ, Melhem ER, et al. X-Linked adrenoleukodystrophy: overview and prognosis as a function of age and brain magnetic resonance imaging abnormality. A study involving 372 patients. Neuropediatrics. 2000;31(5):227-239. doi:10.1055/s-2000-9236

Type: rating scale.

Purpose: functional neurological rating scale for X-ALD severity.

Assessment tool: scale.

Content and scoring: