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Introduction: Rare endocrine diseases-diagnosis and treatment of X-linked adrenal leukodystrophy
.
X-linked adrenoleukodystrophy (ALD) is an abnormal lipid metabolism disease caused by abnormal peroxisome function
.
The main clinical manifestations are progressive demyelination of the white matter of the brain and adrenal insufficiency
.
There are two ways of inheritance of the disease: ① the often chromatic inheritance of the onset in the neonatal period is relatively rare; ② the X-linked recessive inheritance of the onset in the childhood or adolescence
.
This disease is relatively rare and has a poor prognosis
.
The main manifestations are hearing and visual impairment, loss of intelligence, abnormal behavior, and dyskinesia .
Treatment is mainly based on alternative treatments.
Early diagnosis should be made for ALD patients, and active intervention should be made to improve the quality of life of the patients and prolong their lives as much as possible
.
Etiology and epidemiology The disease is caused by mutations in the ABCD1 (adenosine triphosphate-binding cassette D1) gene on the X chromosome (Xq28), resulting in loss of peroxisome function, long-chain fatty acids cannot be oxidized by β, and a large number of very long-chain fatty acids ( Very long chain fatty (VLCFA) is deposited in the white matter of the brain and adrenal glands, causing abnormal nervous system function and hypofunction of the adrenal cortex
.
Ninety-five percent of patients are males, while females are mostly heterozygous and are carriers of disease gene mutations
.
The incidence of male ALD is 1/21 000～1/15500, while the common incidence of male ALD and female heterozygous carriers is 1/17000
.
Clinical manifestations The clinical manifestations of ALD are diverse
.
Typical ALD patients have two types of symptoms: central nervous system damage and low adrenal cortex function
.
Nervous system symptoms and symptoms of adrenal cortex dysfunction can occur simultaneously or one after another
.
A small number of patients can appear alone
.
The manifestations of adrenal insufficiency vary
.
According to differences in clinical phenotypes such as age of onset, site of involvement, and rate of progression, ALD is divided into 7 types, including childhood brain type, adolescent brain type, adult brain type, adrenomyeloneuropathy (adrenomyeloneuropathy, AMN), Addison type, and none.
Symptomatic and heterozygous
.
1.
Children's brain type is the most common type, accounting for 35% of all ALD patients
.
The onset usually occurs at the age of 4 to 8 years
.
The initial manifestations are inattention, memory loss, learning difficulties, gait instability, and abnormal behavior.
Later, symptoms such as decreased vision and hearing, dysarthria, seizures, ataxia, paralysis, and dementia appear
.
The clinical manifestations gradually worsened, eventually blindness or deafness, and complete paralysis
.
Some manifested as decerebral rigidity, and eventually died of central respiratory failure, brain herniation, and infection
.
Most patients have the performance of impaired adrenal cortex function when they first appear with neurological symptoms
.
2.
Juvenile brain type, which accounts for 4% to 7% of all ALD patients.
The disease is more than 10-20 years old.
The clinical manifestations are similar to children's brain type, and the progress of this type is slow
.
3.
Adult brain type accounted for 2% to 4% of all ALD patients, onset after 20 years of age, intracranial lesions progressed rapidly, and no AMN manifestations
.
4.
AMN type accounts for about 27% of ALD, onset after the age of 20 or middle-aged, mainly involving the white matter of the spinal cord, peripheral neuropathy is mild, and no inflammatory injury
.
It manifests as progressive spastic paralysis of the lower limbs, sphincter dysfunction and sexual dysfunction
.
AMN progresses slowly
.
5.
Addison type accounts for 10% to 14% of ALD patients, and the age of onset is 2 years old to adulthood
.
The main manifestations are primary adrenal insufficiency, including skin pigmentation, weakness, hyperhidrosis, halophilia, accompanied by vomiting, diarrhea, and even hypotension and syncope
.
The abnormalities of the nervous system mostly appear after middle age
.
6.
Asymptomatic type The examination found that the blood very long-chain fatty acid (VLCFA) was elevated or the ABCD1 gene was mutated, but the patient had no corresponding clinical symptoms
.
7.
Female carriers of heterozygous ABCD1 gene mutations may have mild symptoms of AMN
.
As the age increases, the clinical manifestations become more obvious
.
After 60 years of age, 65% of heterozygous patients will have clinical manifestations of AMN, but the symptoms are mild
.
Few brain symptoms, peripheral neuropathy, and adrenal cortex function decline
.
Auxiliary examination 1.
Primary adrenal cortex dysfunction plasma adrenocorticotropic hormone (ACTH) increased by more than 2 times; blood cortisol, 24-hour urine cortisol, 24-hour urine 17-hydroxycortisol levels decreased, suggesting the original Primary adrenal hypofunction
.
CT examination of the adrenal glands, except for adrenal tuberculosis or hypoadrenal cortex dysfunction caused by autoimmunity
.
2.
Determination of Very Long Chain Fatty Acids (VLCFA) Increased VLCFA is the main biochemical indicator for the diagnosis of diseases, which is seen in almost all male patients and 85% of female carriers
.
The elevated level of VLCFA has nothing to do with the severity of the disease
.
Detection of VLCFA in amniotic cells and chorionic cells can be used for prenatal diagnosis; it should be noted that 10% to 15% of female heterozygous carriers have low VLCFA levels, so genetic testing is the gold standard for female heterozygous diagnosis
.
3.
Genetic diagnosis Research has shown that ABCD1 gene mutations in ALD patients
.
Genetic diagnosis can provide reliable genetic counseling for asymptomatic and female heterozygous carriers
.
4.
Imaging manifestations.
Magnetic resonance imaging (MRI) of the head can detect the manifestations of ALD lesions at different stages, providing a reliable basis for early diagnosis
.
The characteristic imaging change is the butterfly-shaped long T1 and T2 signals symmetrically distributed in the white matter of the bilateral parieto-occipital area.
The enhanced examination shows that there is a band-like enhancement around the lesion; if the lesion progresses further, the extent of the lesion can be affected by the brain tissue The rear is extended to the front
.
5.
Pathological examination.
Pathological biopsy of brain tissue, adrenal glands, peripheral nerves, rectal mucosa, etc.
The cells contain lamellar cytoplasmic inclusions, which can confirm the diagnosis of the disease
.
Diagnosis If the patient has both central or peripheral nervous system disease and adrenal hypofunction, it is highly indicative of the diagnosis of this disease
.
The characteristic demyelinating lesions on MRI of the head further support this diagnosis
.
Elevated levels of very long-chain fatty acids and mutations in the ABCD1 gene help the diagnosis of the disease
.
Differential diagnosis When the patient only presents with white matter lesions, it is necessary to make a differential diagnosis with a variety of neurological diseases
.
When the patient only presents with primary adrenal insufficiency, addison's disease caused by a variety of etiologies should be considered, including tuberculosis, tumors, hemorrhage, viruses, drugs, and autoimmune-induced adrenal insufficiency
.
Treatment 1.
Principles of treatment There is currently no effective treatment for this disease
.
For ALD patients, early diagnosis and active intervention should be adopted, and comprehensive treatment methods should be adopted to improve the quality of life of the patients and prolong the life of the patients
.
2.
Diet therapy reduces the intake of diets rich in VLCFA.
Supplementing foods composed of long-chain monounsaturated fatty acids has been shown to reduce the level of very long-chain fatty acids (VLCA) in ALD patients.
Patients may try to take Lorenzo oil (Lorenzo's).
Oil) to reduce the synthesis of VLCFA and restore the ratio of C26 in plasma to normal
.
Diet therapy can relieve the condition of some patients, but cannot reverse the progress of the condition, and does not significantly improve the quality of life
.
3.
Replacement therapy of adrenal corticosteroids Give oral glucocorticoid therapy
.
Child patients should be given hydrocortisone 10-15mg/(m^2·d) 2 to 3 times a day, if the patient is an adult, prednisone 2.
5-5mg/d, but blood electrolyte and renin levels need to be evaluated.
If hyponatremia is present, fludrocortisone is also needed for treatment
.
During stress, the dose of glucocorticoid is doubled
.
The specific usage is the same as that of primary adrenal hypofunction
.
4.
Statins, such as simvastatin and lovastatin, belong to hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which can reduce the level of VLCFA in skin fibroblasts of ALD patients, but the effect is not For sure
.
5.
Allogeneic hematopoietic stem cell transplantation Allogeneic hematopoietic stem cell transplantation is currently an effective method for the treatment of early childhood brain-type ALD, but the final efficacy is affected by the success of the transplantation and the complications after the transplantation
.
Existing clinical studies have confirmed that the efficacy of early patients is better than that of progressive patients
.
However, the current number of patients receiving this treatment is relatively small, and the efficacy of allogeneic hematopoietic stem cell transplantation needs to be observed for a longer period of time
.
6.
Symptomatic support and rehabilitation treatment
.
Symptomatic treatment can be given to patients with symptoms such as epilepsy and limb dysfunction .
Rehabilitation treatment for existing abnormalities of motor function
.
Figure 1 X-chain adrenal leukodystrophy The above content is extracted from: The National Health Commission of the People's Republic of China.
Guidelines for the diagnosis and treatment of rare diseases (2019 edition) [J].
The official website of the National Health Commission of the People's Republic of China.
.
X-linked adrenoleukodystrophy (ALD) is an abnormal lipid metabolism disease caused by abnormal peroxisome function
.
The main clinical manifestations are progressive demyelination of the white matter of the brain and adrenal insufficiency
.
There are two ways of inheritance of the disease: ① the often chromatic inheritance of the onset in the neonatal period is relatively rare; ② the X-linked recessive inheritance of the onset in the childhood or adolescence
.
This disease is relatively rare and has a poor prognosis
.
The main manifestations are hearing and visual impairment, loss of intelligence, abnormal behavior, and dyskinesia .
Treatment is mainly based on alternative treatments.
Early diagnosis should be made for ALD patients, and active intervention should be made to improve the quality of life of the patients and prolong their lives as much as possible
.
Etiology and epidemiology The disease is caused by mutations in the ABCD1 (adenosine triphosphate-binding cassette D1) gene on the X chromosome (Xq28), resulting in loss of peroxisome function, long-chain fatty acids cannot be oxidized by β, and a large number of very long-chain fatty acids ( Very long chain fatty (VLCFA) is deposited in the white matter of the brain and adrenal glands, causing abnormal nervous system function and hypofunction of the adrenal cortex
.
Ninety-five percent of patients are males, while females are mostly heterozygous and are carriers of disease gene mutations
.
The incidence of male ALD is 1/21 000～1/15500, while the common incidence of male ALD and female heterozygous carriers is 1/17000
.
Clinical manifestations The clinical manifestations of ALD are diverse
.
Typical ALD patients have two types of symptoms: central nervous system damage and low adrenal cortex function
.
Nervous system symptoms and symptoms of adrenal cortex dysfunction can occur simultaneously or one after another
.
A small number of patients can appear alone
.
The manifestations of adrenal insufficiency vary
.
According to differences in clinical phenotypes such as age of onset, site of involvement, and rate of progression, ALD is divided into 7 types, including childhood brain type, adolescent brain type, adult brain type, adrenomyeloneuropathy (adrenomyeloneuropathy, AMN), Addison type, and none.
Symptomatic and heterozygous
.
1.
Children's brain type is the most common type, accounting for 35% of all ALD patients
.
The onset usually occurs at the age of 4 to 8 years
.
The initial manifestations are inattention, memory loss, learning difficulties, gait instability, and abnormal behavior.
Later, symptoms such as decreased vision and hearing, dysarthria, seizures, ataxia, paralysis, and dementia appear
.
The clinical manifestations gradually worsened, eventually blindness or deafness, and complete paralysis
.
Some manifested as decerebral rigidity, and eventually died of central respiratory failure, brain herniation, and infection
.
Most patients have the performance of impaired adrenal cortex function when they first appear with neurological symptoms
.
2.
Juvenile brain type, which accounts for 4% to 7% of all ALD patients.
The disease is more than 10-20 years old.
The clinical manifestations are similar to children's brain type, and the progress of this type is slow
.
3.
Adult brain type accounted for 2% to 4% of all ALD patients, onset after 20 years of age, intracranial lesions progressed rapidly, and no AMN manifestations
.
4.
AMN type accounts for about 27% of ALD, onset after the age of 20 or middle-aged, mainly involving the white matter of the spinal cord, peripheral neuropathy is mild, and no inflammatory injury
.
It manifests as progressive spastic paralysis of the lower limbs, sphincter dysfunction and sexual dysfunction
.
AMN progresses slowly
.
5.
Addison type accounts for 10% to 14% of ALD patients, and the age of onset is 2 years old to adulthood
.
The main manifestations are primary adrenal insufficiency, including skin pigmentation, weakness, hyperhidrosis, halophilia, accompanied by vomiting, diarrhea, and even hypotension and syncope
.
The abnormalities of the nervous system mostly appear after middle age
.
6.
Asymptomatic type The examination found that the blood very long-chain fatty acid (VLCFA) was elevated or the ABCD1 gene was mutated, but the patient had no corresponding clinical symptoms
.
7.
Female carriers of heterozygous ABCD1 gene mutations may have mild symptoms of AMN
.
As the age increases, the clinical manifestations become more obvious
.
After 60 years of age, 65% of heterozygous patients will have clinical manifestations of AMN, but the symptoms are mild
.
Few brain symptoms, peripheral neuropathy, and adrenal cortex function decline
.
Auxiliary examination 1.
Primary adrenal cortex dysfunction plasma adrenocorticotropic hormone (ACTH) increased by more than 2 times; blood cortisol, 24-hour urine cortisol, 24-hour urine 17-hydroxycortisol levels decreased, suggesting the original Primary adrenal hypofunction
.
CT examination of the adrenal glands, except for adrenal tuberculosis or hypoadrenal cortex dysfunction caused by autoimmunity
.
2.
Determination of Very Long Chain Fatty Acids (VLCFA) Increased VLCFA is the main biochemical indicator for the diagnosis of diseases, which is seen in almost all male patients and 85% of female carriers
.
The elevated level of VLCFA has nothing to do with the severity of the disease
.
Detection of VLCFA in amniotic cells and chorionic cells can be used for prenatal diagnosis; it should be noted that 10% to 15% of female heterozygous carriers have low VLCFA levels, so genetic testing is the gold standard for female heterozygous diagnosis
.
3.
Genetic diagnosis Research has shown that ABCD1 gene mutations in ALD patients
.
Genetic diagnosis can provide reliable genetic counseling for asymptomatic and female heterozygous carriers
.
4.
Imaging manifestations.
Magnetic resonance imaging (MRI) of the head can detect the manifestations of ALD lesions at different stages, providing a reliable basis for early diagnosis
.
The characteristic imaging change is the butterfly-shaped long T1 and T2 signals symmetrically distributed in the white matter of the bilateral parieto-occipital area.
The enhanced examination shows that there is a band-like enhancement around the lesion; if the lesion progresses further, the extent of the lesion can be affected by the brain tissue The rear is extended to the front
.
5.
Pathological examination.
Pathological biopsy of brain tissue, adrenal glands, peripheral nerves, rectal mucosa, etc.
The cells contain lamellar cytoplasmic inclusions, which can confirm the diagnosis of the disease
.
Diagnosis If the patient has both central or peripheral nervous system disease and adrenal hypofunction, it is highly indicative of the diagnosis of this disease
.
The characteristic demyelinating lesions on MRI of the head further support this diagnosis
.
Elevated levels of very long-chain fatty acids and mutations in the ABCD1 gene help the diagnosis of the disease
.
Differential diagnosis When the patient only presents with white matter lesions, it is necessary to make a differential diagnosis with a variety of neurological diseases
.
When the patient only presents with primary adrenal insufficiency, addison's disease caused by a variety of etiologies should be considered, including tuberculosis, tumors, hemorrhage, viruses, drugs, and autoimmune-induced adrenal insufficiency
.
Treatment 1.
Principles of treatment There is currently no effective treatment for this disease
.
For ALD patients, early diagnosis and active intervention should be adopted, and comprehensive treatment methods should be adopted to improve the quality of life of the patients and prolong the life of the patients
.
2.
Diet therapy reduces the intake of diets rich in VLCFA.
Supplementing foods composed of long-chain monounsaturated fatty acids has been shown to reduce the level of very long-chain fatty acids (VLCA) in ALD patients.
Patients may try to take Lorenzo oil (Lorenzo's).
Oil) to reduce the synthesis of VLCFA and restore the ratio of C26 in plasma to normal
.
Diet therapy can relieve the condition of some patients, but cannot reverse the progress of the condition, and does not significantly improve the quality of life
.
3.
Replacement therapy of adrenal corticosteroids Give oral glucocorticoid therapy
.
Child patients should be given hydrocortisone 10-15mg/(m^2·d) 2 to 3 times a day, if the patient is an adult, prednisone 2.
5-5mg/d, but blood electrolyte and renin levels need to be evaluated.
If hyponatremia is present, fludrocortisone is also needed for treatment
.
During stress, the dose of glucocorticoid is doubled
.
The specific usage is the same as that of primary adrenal hypofunction
.
4.
Statins, such as simvastatin and lovastatin, belong to hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which can reduce the level of VLCFA in skin fibroblasts of ALD patients, but the effect is not For sure
.
5.
Allogeneic hematopoietic stem cell transplantation Allogeneic hematopoietic stem cell transplantation is currently an effective method for the treatment of early childhood brain-type ALD, but the final efficacy is affected by the success of the transplantation and the complications after the transplantation
.
Existing clinical studies have confirmed that the efficacy of early patients is better than that of progressive patients
.
However, the current number of patients receiving this treatment is relatively small, and the efficacy of allogeneic hematopoietic stem cell transplantation needs to be observed for a longer period of time
.
6.
Symptomatic support and rehabilitation treatment
.
Symptomatic treatment can be given to patients with symptoms such as epilepsy and limb dysfunction .
Rehabilitation treatment for existing abnormalities of motor function
.
Figure 1 X-chain adrenal leukodystrophy The above content is extracted from: The National Health Commission of the People's Republic of China.
Guidelines for the diagnosis and treatment of rare diseases (2019 edition) [J].
The official website of the National Health Commission of the People's Republic of China.
