Adult-onset X-linked adrenoleukodystrophy characterized by brainstem symptoms: a case report / 中华神经科杂志

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder. Adult-onset X-ALD characterized by brainstem symptoms is a rare phenotype of the disease. A male youth of adult-onset X-ALD characterized by brainstem symptoms in Tianjin Huanhu Hospital at April 12, 2021 is reported. The patient mainly presented with progressively gait disturbance, dysarthria and ataxia, which were consistent with the clinical diagnosis of X-ALD in combination with other ancillary tests. Genetic testing suggested the presence of a hemizygous mutation site in the ABCD1 gene. The clinical, imaging and genetic characteristics of X-ALD patients in the literature with brain stem lesion are also summarized, thereby improving the understanding of the rare clinical phenotype of X-ALD.

Genetic analysis of a pedigree affected with X-linked adrenoleukodystrophy / 中华医学遗传学杂志

Objective@#To explore the genetic basis for a pedigree affected with X-linked adrenoleukodystrophy presenting as spastic paraplegia of the lower limbs.@*Methods@#Genomic DNA was extracted from peripheral blood samples of the patient and his mother. Potential variant was detected with a panel for genes associated with spastic paraplegia. Candidate variant was verified by PCR and Sanger sequencing.@*Results@#Both the proband and his mother presented with walking difficulty. A previously known variant, c. 623T>A (p.V208E), was identified in the ABCD1 gene mapped on chromosome X in both.@*Conclusion@#X-link adrenoleukodystrophy should be taken into account as a possible diagnosis for this pedigree.

One case of adrenoleukodystrophy with initial Addison disease and identification of a novel ABCD1 gene mutation / 中华内分泌代谢杂志

Objective To identify the clinical manifestations, imaging findings, and genetic mutation characteristics in an uncommon case of adrenoleukodystrophy ( ALD) with adrenocortical dysfunction ( Addison's disease) as the first manifestation. Methods The clinical data of the proband and his family members were comprehensively collected, and ABCDl gene sequencing was meticulously performed for the proband and his mother using high-throughput sequencing method. Results The patient presented with systematical skin pigmentation accompanied by fatigue in early stage, arose stroke-like episodes manifested as a sudden loss of consciousness and incontinence induced by high fever, and followed by progressive unclear speech, unstable walking and worsening vision. Serum very long-chain fatty acid (VLCFA) concentration increased over normal range. The brain MRI showed an abnormal signal of the symmetric distribution of the bilateral corpus callosum. A new c. 874 876del GAG hemizygous variation in the patient's ABCD1 gene was detected, while his mother had a nucleotide heterozygous variation to this site . Conclusion The diagnosis of ALD requires a combination of clinical manifestations, imaging examination, and serum VLCFA levels, while the detection of ABCD1 gene mutations is considered to be the most reliable approach.

Research progress in diagnosis and treatment of female heterozygotes with X-linked adrenoleukodystrophy / 中华实用儿科临床杂志

X-linked adrenoleukodystrophy is the most common peroxisomal disorder,which belongs to single peroxidase enzyme deficiency disease.It is caused by mutations in the ABCDI gene and alterations in peroxisomal beta-oxidation of long chain fatty acid in plasma and tissues.It manifests a wide range of phenotypes in male and it has been frequently discussed,in which progressive myelopathy is the most common.For X-linked recessive inheritance,female heterozygotes are always thought to be nonpathogenic.There have been only limited studies specifically focused on the phenotype of female heterozygotes,while,these patients also need further study.This article discusses the clinical manifestations,diagnosis and treatment of female heterozygotes with X-linked adrenoleukodystrophy,to enhance people's understanding of clinical diagnosis and treatment,and provide the basis for accurate prognosis assess-ment and diagnosis.

Adrenoleucodistrofia ligada al X: presentación de tres casos. Importancia del diagnóstico precoz / X-linked adrenoleukodystrophy: a report of three cases. The importance of early diagnosis

La adrenoleucodistrofia ligada al X es el trastorno peroxisomal más común. Se debe a mutaciones en el gen ABCD1, lo que ocasiona un acúmulo de ácidos grasos saturados de cadena muy larga en el suero, la corteza adrenal y la sustancia blanca del sistema nervioso central. La clínica se caracteriza por deterioro neurològico e insuficiencia suprarrenal con un pronóstico devastador. Se presenta un primer caso clínico de adrenoleucodistrofia ligada al X con evolución fatal que permitió identificar a dos familiares asintomáticos e instaurar un tratamiento preventivo. Aunque, en la actualidad, no existe un tratamiento curativo definitivo, hay que destacar la importancia del estudio familiar de pacientes en situación de riesgo para poder instaurar un tratamiento preventivo precoz y dar un asesoramiento genético adecuado.

X-linked adrenoleukodystrophy is the most common peroxisomal disorder. This disease is caused by a defect in the ABCD1 gen. Saturated very long chain fatty acids are accumulated in serum, adrenal cortex and central nervous system white matter. The clinical spectrum is characterized by progressive neurological dysfunction and adrenal insufficiency with a devastating prognosis. We report a first case of X-linked adrenoleukodystrophy with fatal evolution which identified two asymptomatic family members and established a preventive treatment. Although there is no definitive cure, we stress the importance of family study and evaluation of the individual in situation of risk to establish an early preventive treatment and to give in each particular situation suitable professional advice.

Diagnosis and managements of X-linked adrenoleukodystrophy / 中华实用儿科临床杂志

Adrenoleukodystrophy (ALD,OMIM# 300100) is one of the most common peroxisomal disease.It is a kind of X-linked genetic disorder.The disease is caused by mutations in the ABCD1 gene that encodes the peroxisomal membrane protein(ALDP).A defect in ALDP results in very long-chain fatty acids can not be transported from the cytosol into the peroxisome and impaired accumulation of very long chain fatty acid (VLCFA)-CoA esters in the white matter of the brain,the spinal cord and adrenal cortex.The clinical spectrum in males with X-ALD ranges from isolated adrenocortical insufficiency and slowly progressive myelopathy to devastating cerebral demyelination.Corticosteroid replacement therapy is essential and life saving treatment,bone marrow transplantation (BMT) is an option for boys and adolescents in early stages.This review focus on the genetic pathology,diagnosis and managements of patients with X-ALD and provides a guideline for clinicians.

Isolated Cerebellar Variant of Adrenoleukodystrophy with a de novo Adenosine Triphosphate-Binding Cassette D1 (ABCD1) Gene Mutation

X-linked adrenoleukodystrophy (X-ALD) shows a wide range of phenotypic expression, but clinical presentation as an isolated lesion of the cerebellar white matter and dentate nuclei has not been reported. We report an unusual presentation of X-ALD only with an isolated lesion of the cerebellar white matter and dentate nuclei. The proband, a 37-year-old man presented with bladder incontinence, slurred speech, dysmetria in all limbs, difficulties in balancing, and gait ataxia. Brain magnetic resonance imaging showed an isolated signal change of white matter around the dentate nucleus in cerebellum. With high level of very long chain fatty acid, gene study showed a de novo mutation in exon 1 at nucleotide position c.277_296dup20 (p.Ala100Cysfs*10) of the adenosine triphosphate-binding cassette D1 gene. It is advised to consider X-ALD as a differential diagnosis in patients with isolated cerebellar degeneration symptoms.

Construction and expression of lentiviral vector containing adrenoleukodystrophy gene / 第二军医大学学报

Objective To construct a lentiviral vector carrying the wild-type and mutant adrenoleukodystrophy gene(ABCD1) and to investigate the effects of ABCD1 mutation on the structure and function of adrenoleukodystrophy protein(ALDP). Methods Different computational algorithms were used to predict the pathogenicity and the structural stability of ALDP mutants: H283R and P534R. Lentiviral vectors carrying wild type and mutants ABCD1 gene were constructed with pLEX-MCS, namely, pLEX-ABCD1, pLEX-ABCD1-H283R and pLEX-ABCD1-P534R. The recombinant plasmids and two packaging vectors were co-transfected into 293T cells to obtain virus, and the latter was used to infect host cells. The expression of the wild type and mutant ABCD1 mRNA in lentivirus infected cells was detected by RT-PCR. The subcellular localization and expression of the wild type and mutant ALDP were detected by immunofluorescence and Western blotting analysis. Results Bioinformatic prediction results showed that both mutations in this study were at conserved codons, suggesting a pathogenic nature. Overexpression of the wild type and mutant ABCD1 mRNA was detected by RT-PCR in lentivirus infected cells. Immunofluorescence study and Western blotting analysis showed overexpression of the wild type ALDP and lower expression of the mutant ALDP, with no subcellular mislocalization of the mutant ALDP detected. Conclusion We have successfully constructed a recombinant lentiviral vector carrying the ABCD1 gene and assessed the effects of the ABCD1 mutations on the expression and localization of ALDP, providing evidence for understanding the pathogenic mechanism of ALD.

Clinical and Genetic Aspects in Twelve Korean Patients with Adrenomyeloneuropathy

PURPOSE: This study was designed to investigate the characteristics of Korean adrenomyeloneuropathy (AMN) patients. MATERIALS AND METHODS: We retrospectively selected 12 Korean AMN patients diagnosed by clinical analysis and increased plasma content of very long chain fatty acids. RESULTS: All 12 patients were men. Patient ages at symptom onset ranged from 18 to 55 years. Family history was positive in two patients. The phenotype distributions consisted of AMN without cerebral involvement in seven patients, AMN with cerebral involvement in two patients, and the spinocerebellar phenotype in three patients. Nerve conduction studies revealed abnormalities in four patients and visual evoked tests revealed abnormalities in three patients. Somatosensory evoked potential tests revealed central conduction defects in all of the tested patients. Spinal MRI showed diffuse cord atrophy or subtle signal changes in all 12 patients. Brain MRI findings were abnormal in six of the nine tested patients. These brain abnormalities reflected the clinical phenotypes. Mutational analysis identified nine different ABCD1 mutations in 10 of 11 tested patients. Among them, nine have been previously reported and shown to be associated with various phenotypes; one was a novel mutation. CONCLUSION: In conclusion, the present study is the first to report on the clinical and mutational spectrum of Korean AMN patients, and confirms various clinical presentations and the usefulness of brain MRI scan.

A Korean boy with atypical X-linked adrenoleukodystrophy confirmed by an unpublished mutation of ABCD1 / 소아과

X-linked adrenoleukodystrophy (X-ALD) is a rare peroxisomal disorder, that is rapidly progressive, neurodegenerative, and recessive, and characteristically primary affects the central nervous system white matter and the adrenal cortex. X-ALD is diagnosed basaed on clinical, radiological, and serological parameters, including elevated plasma levels of very long chain fatty acids (VLCFA), such as C24:0 and C26:0, and high C24:0/C22:0 and C26:0/C22:0 ratios. These tests are complemented with genetic analyses. A 7.5-year-old boy was admitted to Department of Pediatrics, Chungnam National University Hospital with progressive weakness of the bilateral lower extremities. Brain magnetic resonance imaging confirmed clinically suspected ALD. A low dose adrenocorticotropic hormone stimulation test revealed parital adrenal insufficiency. His fasting plasma levels of VLCFA showed that his C24:0/C22:0 and C26:0/C22:0 ratios were significantly elevated to 1.609 (normal, 0-1.390) and 0.075 (normal, 0-0.023), respectively. Genomic DNA was extracted from peripheral whole blood samples collected from the patient and his family. All exons of ABCD1 gene were amplified by polymerase chain reaction (PCR) using specific primers. Amplified PCR products were sequenced using the same primer pairs according to the manufacturer's instructions. We identified a missense mutation (p.Arg163Leu) in the ABCD1 gene of the proband caused by the nucleotide change 488G>T in exon 1. His asymptomatic mother carried the same mutation. We have reported an unpublished mutation in the ABCD1 gene in a patient with X-ALD, who showed increased ratio of C24:0/C22:0 and C26:0/C22:0, despite a normal VLCFA concentrations.

An Incidentally Identified Sporadic Case with Adrenoleukodystrophy with the ABCD1 Mutation

Adrenoleukodystrophy (ALD) is an X-linked disorder which has diverse constellation of clinical pictures, ranging from the severe childhood cerebral form to adrenocortical insufficiency without neurological manifestations. This disorder is caused by the mutations in the ABCD1 gene encoding the adrenoleukodystrophy protein (ALDP), a transporter in the peroxisome membrane. ALD in most cases is inherited from one parent. Here, we report an incidentally identified sporadic case with ALD after traffic accident. He had adrenocortical insufficiency as well as abnormal findings in brain image. Genetic testing of ABCD1 gene revealed a previously reported mutation. With the description of clinical features of ALD in this patient, we discussed the difficulty in determining an appropriate therapeutic option for ALD patients with minimal neurological manifestation.

Cerebral Adrenomyeloneuropathy with Trp77-Leu82del Mutation in ABCD1 Gene

Cerebral adrenomyeloneuropathy is a subtype of X-linked adrenoleukodystrophy with a mutation of ABCD1; however, there have been no reported cases of cerebral adrenomyeloneuropathy with myelopathy. Here we report a 20-year-old male cerebral adrenomyeloneuropathy patient with myelopathy harboring a deletion mutation of c.225-242 (Trp77-Leu82del) from exon 1 of ABCD1. His spinal cord MRI revealed high signal intensities in the cervical spinal cord. Electrophysiological and histopathologic studies revealed mixed axonal and demyelinating neuropathy.

A new method avoids interference of ABCD1 pseudogenes in molecular diagnosis of X-linked adrenoleukodystrophy / 第二军医大学学报

Objective: To introduce a new method which can avoid the interference of ABCD1 pseudogenes in the molecular diagnosis of X-linked adrenoleukodystrophy. Methods: The coding regions of ABCD1 gene of 3 unrelated Chinese patients with X-linked adrenoleukodystrophy were amplified from the total RNA of peripheral blood by long distance RT-PCR; the product was further amplified in 4 segments in a second round PCR; and the PCR products were purified and directly sequenced. To confirm the mutations, the genomic DNA from peripheral blood cells of the patients was analyzed by direct sequencing after amplification of the ABCD1 genes by nested PCR, in which the product of the first round PCR covered the fragment starting from exon 6 and ending at 3′UTR of the ABCD1 gene. Results: The 3 Chinese patients with X-linked adrenoleukodystrophy had 3 different base substitutions(2235C>T,2065C>T and 2190A>T)in the ABCD1 genes of the 3 probands and their mothers, which resulted in 2 missense mutations (R617C and P560L) and one nonsense mutation (K602X). Conclusion: Nested PCR can rapidly and efficiently avoid the interference of ABCD1 pseudogenes in the molecular diagnosis of X-ALD.

Analysis of ABCD1 Gene Mutation in Patients with X-Linked Adrenoleukodystrophy / 实用儿科临床杂志

Objective To analyze the ABCD1 gene mutations in 5 cases of X-linked adrenoleukodystrophy(X-ALD) patients and 2 cases of their mothers.Methods Of 5 patients with X-ALD,10 exons and flanking intronic sequences of ABCD1 gene were amplified by polyme-rase chain reaction,and then sequenced directly.The outcomes were compared with normal ABCD1 sequencings to identify the mutation type and site.Thirty normal men were examined in the mean time as control for the confirmation of mutations and gene polymorphisms.Results Three patients showed ABCD1 gene mutations,1 had a point mutation in exon 6,Arg518Gly(CGG→GGG);2 patients showed the same novel mutation in exon 1 with 8 bases deletion(134del8).Four gene polymorphisms were identified in exon 7.They were Gly551X(GGC→GGT),Arg554His(CGT→CAT),Gln567Arg(CAA→CGA) and Val582Ile(GTC→ATC).ABCD1 gene mutation was not found in 2 mothers from 2 unrelated fa-milies with X-ALD.Conclusions Three cases of 5 were detected for ABCD1 gene mutations.Between them,the 134del8 mutation is a novel one.Four new gene polymorphisms were detected in exon 7 in normal Chinese people,which were Gly551X,Arg554His,Gln567Arg and Val582Ile.

Adrenoleukodystrophy: a case report and pedigree study associated with genetic research / 中华内分泌代谢杂志

Objective To analyse the clinical manifestations of adrenoleukodystrophy (ALD) pedigree and the background of the associated genes. Methods The clinical data of an ALD pedigree were collected and PCR productsequencingwereperformedtoresearch into the change of ALD gene. Results Diagnosis of ALD was determined by the clinical manifestations and brain MRI. The homozygote mutation GGG(Gly)→AGG(Arg) at codon 266 in exon 1 was found in the ALD patient and the heterozygote mutation at the same loci was found in his mother,butwasnotfoundin other members of the family and 2 normal subjects. Conclusions The ALD patient′s mother is the first person taking this point mutation and the mutation causes severe clinical manifestations. The gene research could be regarded as the molecular base of the antenatal diagnosis.

Application of DHPLC in molecular diagnosis of X-linked adrenoleukodystrophy(report of 12 cases) / 解放军医学杂志

T),one dinucleotide deletion(1801-02 del AG) and one base insertion(1125 ins GCCATCG),which resulted in eight missense mutations,two nonsense mutations and two frame shift mutations,namely P534R,G343V,R259W,A141T,R401Q,K276E,Y174C,A314P,S108X,Q177X,fs E471 and fs A247.Conclusion The combined DHPLC and sequencing approach may act as a rapid and efficient method for ABCD1 gene mutation analysis in patients and carriers of X-linked adrenoleukodystrophy families.There exist different ABCD1 gene mutations in different pedigrees,and no obvious correlation between the genotype and phenotype has been found.

Mutational analysis of seven Chinese pedigrees with X-linked adrenoleukodystrophy / 解放军医学杂志

Objective To identify the mutational genotype in seven Chinese families with X-linked adrenoleukodystrophy (X-ALD). Methods The coding region of ABCD1 gene of seven patients was amplified in 4 segments by PCR after reverse transcription using RT-PCR technology. The PCR products were purified and directly sequenced. To confirm the mutations, the genomic DNA was analyzed by PCR-restrictive digestion or direct sequencing of purified PCR products. Results Six base substitutions (709CA, 807GA, 1161CT, 2065CT, 2113TC and 2235CT), one base deletion (1801delAG) and one base insertion (1126 ins GCCATCG) were identified in seven X-linked adrenoleukodystrophy pedigrees, resulting in five missense mutations (A141T, R259W, P560L, L576P and R617C), two frame shift mutations (fs I246 and fs E471) and one nonsense mutation (S108X), respectively. Conclusion Four novel ABCD1 mutations, namely S108X, fs I246, R259W and L576P, were detected in Chinese X-linked adenoleukodystrophy patients. There was different ABCD1 gene mutation in different pedigree and no obvious correlation between the type of mutation and phenotype was found.