Introduction
X-linked adrenal leukodystrophy(ALD) is a refractory neurodegenerative disease associated with the accumulation of very long-chain saturated fatty acids (VLCFA) in tissues and body fluids. We have established a Japanese ALD diagnostic center using VLCFA measurement and mutation analysis. ABCD 1 identified 60 mutations in 69 Japanese ALD families, including 38 missense mutations, 6 nonsense mutations, 8 frame translocation mutations, 3 amino acid deletions, 2 exon mutations, and large deletions. 3 types. By reference to the current worldwide ALD mutation database, 24 mutations (40%) were found in Japanese patients. In these 69 families, there was no significant correlation between these mutations and phenotype in 81 male patients. About 12% of ALD patients Drewo performed mutation analysis on male probands and their mothers, providing useful data for genetic counseling. The only effective treatment for brain-type ALD is early hematopoietic stem cell transplantation. Therefore, we conducted extensive family screening of probands and conducted pre-tympanic diagnosis of ALD through genetic counseling, and established long-term for these patients. Follow-up system to prevent progression of brain involvement and to monitor adrenal insufficiency. Further elucidation of the pathology of ALD, especially the mechanism of brain involvement, is worth looking forward to.
preface
X-linked adrenal leukodystrophy is one of the most common peroxisomal diseases involving impaired oxidation of saturated long-chain fatty acids (β), leading to accumulation of fatty acids in tissues and plasma. The pathogenic gene of ALD, ABCD 1 has been mapped to Xq 28, a gene of the peroxisome membrane protein homologous to the ATP-binding cassette transporter family, which acts as a VLCF- on the peroxisome membrane. The transporter of CoA. Clinical manifestations include childhood brain type (CCALD), adolescent brain type, adult brain type, adrenal myelinopathy (AMN), Olivo-P-cerebellar type and Addison's disease. 1CCALD is the most common phenotype characterized by progression of intellectual, psychological, visual, and gait disorders between the ages of 3 and 10. The prognosis of CCALD is generally poor, and patients are thought to die within a few years, but good comprehensive care improves the prognosis of these days. Hematopoietic stem cell transplantation (HSCT) is currently the only treatment that can prevent brain-type ALD brain involvement, but HSCT is only effective in patients with early brain symptoms. 2 Therefore, we established a rapid diagnostic system for ALD patients, combined with the detection and mutation analysis of VLCFA in serum, established a rapid diagnosis system for ALD patients. ABCD 1 gene. Even so, even now, only about one-third of CCALD patients have received HSCT in Japan (data not shown), so pre-tympanic diagnosis and early intervention are important to overcome this thorny disease.
Diagnostic system and mutation range of Japanese ALD patients
In this paper, VLCFA in serum or plasma of suspected ALD patients with clinical and brain magnetic resonance imaging (MRI) was analyzed by gas chromatography/mass spectrometry. 3 These patients were diagnosed with an increase in VLCFA, and then we performed molecular analysis. ABCD 1 gene. The ratio of C24:0/C22:0, C25:0/C22:0 and C26:0/C22:0 in male ALD patients was significantly higher than that in the control group, but some female carriers had C24:0/C22:0, C25 The ratio of :0/C22:0 and C26:0/C22:0 overlaps with the control value (Figure 1). Moser et al. 4 also reported that 85% of obligate heterozygotes have abnormally high VLCFA levels, but normal results do not preclude carrying status. Therefore, male ALD patients can only be diagnosed by an increase in VLCFA, but female carriers should conduct molecular analysis. ABCD 1 in order to get an accurate diagnosis.
In addition, our data showed that mutations in male probands and their mothers were analyzed in 33 families, 4 of whom found no mutations in the proband, which means approximately 12% of ALD patients There may be mutations. Drevo mutation. In the ALD database, approximately 93% of index cases are mutations that are inherited from one of the parents. Both data indicate that a significant number of male probands may not inherit mutations that cause disease from their mothers, and accurate carrier testing is necessary not only for further family analysis, but also for genetic counseling. .
We analyzed the phenotypes of 142 patients in 69 families, including 52 children with brain type, 5 with adolescent brain type, 2 with adult brain type, and 7 with adult brain type, and 3 cases with adolescent or adult brain type. Amn>Adoc or amn>ac), 1 case of cerebellum, 11 cases of tympanic membrane, 60 cases of female carrier. figure 2). There was no significant correlation between these mutations and phenotype in Japanese ALD patients, which was not reported in previous reports. 1 Even in the same family, there is the same mutation ABCD 1, and there is variation in phenotype. At present, we cannot predict the further clinical course of tympanic ALD patients by analyzing family, genotype, VLCFA values, and even their expression. ABCD 1 gene and ALDP protein.
Premature diagnosis of HSCT and ALD
HSCT is by far the only treatment that prevents brain-type ALD brain involvement, but is only effective in patients with early brain symptoms. 2 Although we have established a rapid diagnostic system for ALD in Japan, only one-third of patients with CCALD are able to receive HSCT after onset (data not shown) for the following reasons. First, for a significant number of CCALD patients, there was a gap between onset and brain MRI/VLCFA detection because they were initially diagnosed with attention deficit/hyperactivity disorder, learning disability, hearing impairment, exotropia, and vision loss. In addition, HSCT preparation will take a considerable amount of time, including finding matching donors, while HSCT surgery in advanced brain patients can accelerate neurological decline. Therefore, familial screening of probands has important clinical implications for early intervention and prevention of advanced brain symptoms. In addition, at least 70% of patients with CCALD and AMN have clinical and biochemical evidence of primary adrenal insufficiency (http://www.x-ald.nl). Therefore, pre-tympanic diagnosis is also useful for preparing adrenal hormone therapy. This is necessary to save the lives of all patients with ALD who have adrenal insufficiency.
The vector is detected by genetic counseling, which can be achieved by paying attention to the increase in VLCFA in plasma and mutation analysis. The ABCD 1 gene is an important gene for identifying pre-tympanic patients and other female carriers. Elevated VLCFA levels confirm the diagnosis of carriers, but there may be C24 between 0:0/C22:0, C25:0/C22:0, and C26:0/C22:0 between healthy controls and at least 10% of carriers. The overlap between them. In addition, our data and other data indicate that approximately 10% of the probands are identified by the ABCD 1 gene, which means that the mother of these patients should not be carriers. For these reasons, the ABCD 1 gene is not only necessary for vector detection, but also a necessary condition for confirming spontaneous mutation. In summary, 32%-48% of female carriers over the age of 20 have some symptoms, mainly due to abnormalities in the spinal cord and leg nerves, similar to AMN. It seems that as you get older, the frequency of carriers with symptoms increases. Http://www.x-ald.nl). Proper medications are often recommended for these carriers to reduce leg cramps and pain in the lower back and hips. Neonatal screening may be a potential method for the widespread discovery of pre-tympanic male patients and female carriers. Hubbard et al.6 used liquid chromatography-tandem mass spectrometry to conduct a preliminary study on the quality screening of 1-hexacosanoyl-2-lyso-sn-3-glycerophosphorylcholine (26:0-lyso-PC).
Early intervention and long-term follow-up system for anterior tympanic patients
Male patients in the tympanic cavity can develop into a variety of phenotypes between the ages of 3 and 50, and their phenotype may be different from those of the proband. Therefore, it is very important to provide information to patients and their families through genetic counseling. For HSCT diagnosis of anterior tympanic ALD patients under 3 years of age, follow-up every 6 months for subtle neuropsychological signs, brain MRI and electrophysiological examination is beneficial to such boys. When any abnormalities are found, the HSCT should be performed as soon as possible. Lorenzo's oil is one of the choices for these pretympanic patients, because Moser et al. reported that Lorenzo oil therapy for asymptomatic ALD boys reduced the risk of MRI abnormalities in the normal MRI of the brain. 7 However, further research confirms that this validity has not been reported. In addition, it is reported that approximately 80% of asymptomatic ALD boys have impaired adrenal function, 8 therefore, all male patients should be monitored for adrenal insufficiency. Adrenal hormone replacement therapy is necessary and effective in patients with morbid adrenal insufficiency.
Recently, HSC gene therapy with lentiviral vectors successfully prevented the progression of CCALD in two patients at an early stage. 11 However, the therapeutic mechanism of this therapy remains unclear, probably because of the replacement of ABCD 1 gene, normal stem cells or other factor. Further research on VLCFA regulation or prevention of brain damage in patients and their families should be expedited, and predictors of brain damage should be identified as the key to solving the problem.
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