What is Adrenoleukodystrophy?

ALD is a group of recessive hereditary lipid metabolism diseases. Due to the peroxisome's impaired oxidation of VLCFA in cells, VLCFA accumulates in organs and tissues such as blood, white matter, and adrenal cortex, causing the central nervous system. Demyelination and adrenal atrophy or dysplasia.

Liu Jianghong	(Attending physician)	Department of Neurology, Xuanwu Hospital, Capital Medical University
Dong Huiqing	(Chief physician)	Department of Neurology, Xuanwu Hospital, Capital Medical University

Adrenoleukodystrophy (ALD) is an X-linked recessive genetic disease. It is one of the most common peroxisomal diseases. It mainly affects the adrenal glands and white matter. More than half of the patients develop onset in children or adolescence. Main manifestations are progressive psychomotor disorders, decreased vision and hearing, and / or adrenal insufficiency. The incidence of this disease is about 0.5 / 100,000 to 1 / 100,000, 95% are male and 5% are heterozygous for women. No race or region specificity.

Western Medicine Name: Adrenal white matter malnutrition
English name: adrenoleukodystrophy, ALD

Affiliated Department: Internal Medicine-Neurology
Main cause: Heredity

Causes of adrenal white matter malnutrition

Pathogenesis of adrenal white matter malnutrition

The pathogenic gene ABCDl (ATP-binding Cassette, Sub-family D, Memberl) is located at Xq28. It consists of 10 exons and 9 introns. It encodes a protein containing 745 amino acid residues, which is called the adrenal brain. Adrenoleukodystrophy protein (ALDP) is located on the peroxisome membrane. ALDP binds to three other proteins located on the peroxisome membrane to form a dimer, which can transport saturated VLCFA into the peroxidase body for tritium oxidation. Due to the ABCD1 gene mutation, the ALDP function is abnormal, and the tritium oxidation of VLCFA is blocked, causing VLCFA aggregation. The accumulation of VLCFA in the nervous system can destroy the normal formation of myelin sheath and the stability of myelin sheath. The accumulation in adrenal cortex cells can cause the decline of ACTH receptor function on the surface of adrenal cortex cell membrane, the inhibition of intracellular steroid synthesis, and the adrenal function. Diminish.

Adrenal white matter dystrophy pathophysiology

The pathological characteristics of ALD are that the lesions of white matter in the brain are generally solid or rubbery, and the adrenal cortex atrophies, and the medulla is not affected. Microscopically, there are characteristic inclusions in the brain tissue, adrenal glands, peripheral nerves, and testes. Enriched with VLCFA esterified cholesterol. The most prominent feature of the brain is the demyelinating changes that develop from the occipital to the forehead along the anterior and posterior axis of the brain. Therefore, in any case, the white matter in the occipital region is always the most affected, and U-shaped fibers are retained; another feature is blood vessels Infiltration of surrounding inflammatory cells.

Clinical manifestations of adrenal white matter malnutrition

ALD is a hereditary metabolic disease with strong clinical heterogeneity. The same family may have different phenotypes, and the same patient has different performances at different times. According to the age and clinical manifestations of ALD, there are 7 types: pediatric brain type, adolescent brain type, adult brain type, adrenomyeloneuropathy (AMN), Addison type, asymptomatic type and heterozygous type.

Adrenal brain white matter malnutrition

It is the most common, accounting for about 35% of all ALD patients. It occurs at the age of 5-12 years. The initial manifestations are inattention, memory loss, learning difficulties, gait instability, and abnormal behavior. Gradually, vision and / or Hearing loss, dysarthria, ataxia, paralysis, seizures, dementia and other symptoms gradually progress, and eventually complete paralysis, blindness or deafness, convulsions, and even continuity. Some can maintain the state of de-brain rigidity for several years, and some die of central respiratory failure, cerebral hernia, infection, etc. Most have impaired adrenal function at the time of first neurological symptoms.

Adrenal cerebral white matter malnutrition

The adolescent brain type begins at the age of 10-21, and the clinical manifestations are similar to those of a child, but progress is slow. About 4-7% of all ALD patients.

Adrenal brain white matter malnutrition adult brain type

Onset after the age of 21, the brain quickly progresses, inflammatory reactive demyelination similar to children's brain type, no AMN manifestations. About 2-4% of all ALD patients

AMN Adrenal white matter dystrophy AMN type

It usually occurs in the age of 20-40 years old, and the lesions mainly involve the spinal cord. The peripheral nerves are less affected without inflammatory damage. Presented as progressive lower limb spastic paralysis, sphincter and sexual dysfunction, etc., paralysis progresses slowly, may be accompanied by peripheral nerve damage, adrenal insufficiency manifestations, and primary gonadal hypoplasia with reduced testosterone can be secondary Brain damage results in different degrees of cognitive and behavioral abnormalities. AMN progresses slowly without the characteristics of remission and recurrence of multiple sclerosis, accounting for about 27% of ALD.

Addison Adrenal white matter dystrophy Addison type

The age of onset is from 2 years to adulthood, manifested as primary adrenal insufficiency, clinically visible dark skin, salt, sweating, fatigue, often vomiting, diarrhea, syncope and so on. About 10-14% of ALD patients.

Adrenal white matter dystrophy asymptomatic

Refers to patients with elevated blood VLCFA or ABCD1 gene mutation without clinical symptoms.

Adrenal white matter dystrophy heterozygote

About 20% to 30% of female heterozygotes may have mild neurological symptoms, mostly manifested as AMN-like spastic paraplegia, but the symptoms are mild, and brain symptoms, peripheral neuropathy, and adrenal insufficiency are rare.

Diagnosis and differential diagnosis of adrenal white matter malnutrition

Diagnosis of adrenal white matter malnutrition

Diagnosis depends on clinical manifestations and testing of the following indicators:

(1) Endocrine function test:

For patients with adrenal insufficiency, the excretion of 17-hydroxysteroids and 17-ketosteroids was decreased in 24 hours; plasma adrenocorticotropic hormones were elevated; and the adrenocortical hormone stimulation test showed low or no response.

(2) VLCFA measurement of plasma and skin fibroblasts: Increased VLCFA is the main biochemical indicator of diagnosis at present, and it is found in almost all male patients and 80% female carriers. VLCFA detection The use of gas chromatography to detect abnormal rises in VLCFA in plasma, red blood cells, and cultured skin fibroblasts is a specific method for diagnosing this disease. It is found in all male patients and 85% of female heterozygotes. The elevation of VLCFA has nothing to do with the severity of the disease. Detection of VLCFA in cultured amniotic cells and chorionic cells can be used as a prenatal diagnosis.

(3) Imaging performance

CT manifests as a low-density butterfly lesion confined to the white matter of the brain; MRI is superior to CT and can show lesions on the visual, auditory, and motor conduction pathways.

Craniocerebral MRI has characteristic changes. The performance of MRI can lead or appear simultaneously with ALD symptoms, and develop with the development of the disease.

The symmetry is located in the bilateral parietal occipital region with white matter long Tl and long T2, with digits in the periphery, early involvement of the corpus callosum, and "butterfly wings". It is unique to ALD, and is rare in other white matter diseases. The characteristic is that the lesion progresses from back to front, involving the occipital, parietal, temporal, and frontal lobe one by one; it can involve the spinal tract of the brain stem cortex, and the subcortical U-shaped fibers are free from involvement; enhanced scans around the lesion are enhanced, suggesting that it is active; There was no strengthening, and most of them were accompanied by brain atrophy. Different stages of ALD have different performances on the head MRI, which can be used as indicators of treatment outcome and prognosis.

1HMRS The MRS technology of the human brain has been used in the clinic for more than a decade. Because human body contains more hydrogen protons, and has higher sensitivity and spatial resolution, 1H-MRS is the most widely used. In ALD, 1HMRS showed that Cho peak increased significantly, NAA peak decreased or disappeared, and Lac peak increased. 1HMRS is of great help to the early diagnosis of ALD. The demyelinating lesions of the central nervous system can be found by MRI. Metabolites have changed in the normal area of MRI. MRI and 1HMRS can directly reflect the severity of the disease.

(4) Pathological examination

Pathological examination of brain tissue, peripheral nerves, adrenal glands, rectal mucosa, etc. found that cytoplasmic inclusions with lamellar structures in the cells can confirm the diagnosis of the disease. ^[1]

Differential diagnosis of adrenal white matter malnutrition

Differentiate from other types of white matter lesions.

Adrenal white matter malnutrition treatment

There are currently no specific treatments for ALD, and multiple methods are being explored. The main treatments of ALD are:

Adrenal white matter malnutrition diet treatment

At present, some people use diet therapy to limit the intake of VLCFA in the diet, while taking Lorenzo oil to reduce the synthesis of VLCFA, and return C26: C22 to normal. After the above treatment, the patient's peripheral nerve conduction velocity improved, fat accumulation decreased, and the condition eased. But most people think that diet therapy can neither change the progress of the disease nor improve the quality of life of patients. Although it can change the function of peripheral nerves, it still cannot change the clinical course. Asymptomatic ALD patients limit their fat intake while taking Lorenzo oil (fat intake should not exceed 30-34% of total calories), which can play a preventive role, and there is no clear effect for symptomatic patients. Therefore diet therapy is recommended for asymptomatic patients. ^[2]

Adrenal white matter dystrophy medication

A. Adrenocortical hormone replacement therapy: Most children have adrenocortical insufficiency, so corticosteroid replacement therapy is often necessary, but this treatment is not effective for neurological lesions, cannot improve symptoms, and cannot prevent the disease from worsening. It is mainly applicable to Addison patients, and no significant improvement is seen for patients with brain type.

B. Considering the inflammatory demyelinating reaction of cerebral ALD, some people have tried cyclophosphamide and immunoglobulin therapy, but no effect has been seen.

Adrenal white matter dystrophy and other medications

Lovastatin is a 3-HMG-CoA synthetase inhibitor, which can prevent the release of inflammatory mediators from astrocytes, microglia and macrophages, strengthen the -oxidation of VLCFA, and make ALD VLCFA levels were reduced in the patient's skin fibroblasts.

(3) Bone marrow transplantation: Bone marrow transplantation can correct the metabolic disorders of VLCFA, rebuild the activity of enzymes, improve clinical symptoms, prevent dementia, and have better effects in early treatment. With the improvement of bone marrow transplantation technology and the early detection of asymptomatic ALD, bone marrow transplantation has a certain therapeutic future. However, bone marrow transplantation itself has a certain mortality rate and is expensive. It is generally considered to be suitable for early childhood ALD in children.

(4) Gene therapy This is the most promising treatment method, but it needs further discussion due to technical issues.

(5) Hematopoietic stem cell therapy: Recently, hematopoietic stem cell therapy has also been used in patients with ALD and has achieved certain effects. It is currently considered suitable for early patients, and progressive patients can be used as candidate treatments. However, it is not recommended for asymptomatic patients with normal skull MRI and patients with pure AMN. ^[3]

Prognosis of adrenal white matter dystrophy

The prognosis of this disease is poor, and usually 1-3 years after the onset of neurological symptoms.

Prevention of adrenal white matter malnutrition

There are no effective preventive measures.

Adrenal white matter malnutrition care

Eat a diet rich in unsaturated fatty acids and avoid foods with long chain fatty acids.