Deciphering the modifiers for phenotypic variability of X-linked adrenoleukodystrophy

X-linked adrenoleukodystrophy(X-ALD),an inborn error of peroxisomalβ-oxidation,is caused by defects in the ATP Binding Cassette Subfamily D Member 1(ABCD1)gene.X-ALD patients may be asymptomatic or present with several clinical phenotypes varying from severe to mild,severe cerebral adrenoleukodystrophy to mild adrenomyeloneuropathy(AMN).Although most female heterozygotes present with AMN-like symptoms after 60 years of age,occasional cases of females with the cerebral form have been reported.Phenotypic variability has been described within the same kindreds and even among monozygotic twins.There is no association between the nature of ABCD1 mutation and the clinical phenotypes,and the molecular basis of phenotypic variability in X-ALD is yet to be resolved.Various genetic,epigenetic,and environmental influences are speculated to modify the disease onset and severity.In this review,we summarize the observations made in various studies investigating the potential modifying factors regulating the clinical manifestation of X-ALD,which could help understand the pathogenesis of the disease and develop suitable therapeutic strategies.

Traditional Chinese medicine for gait disturbance in adrenoleukodystrophy:A case report and review of literature

BACKGROUND Adrenoleukodystrophy(ALD)is caused by a deficit in the ABCD1 gene,which leads to demyelination of neurons and dysfunction of the adrenal cortices and testicles.Of the three known phenotypes,30%-50%of male ALD patients present with the adrenomyeloneuropathy phenotype,characterized by gait disturbance as the initial symptom.CASE SUMMARY A 46-year-old man with a prior diagnosis of ALD was admitted to a Korean medicine hospital for the treatment of gait disturbance.His ability to walk was severely impaired at admission,significantly affecting the patient’s quality of life.He was treated with acupuncture,pharmacopuncture,electroacupuncture,and herbal medicine for 23 d.The 25-Foot Walk test(25FW),timed up and go(TUG),comfortable gait speed(CGS),numeric rating scale(NRS),Berg Balance Scale(BBS),Tinetti test,manual muscle test(MMT),and 3-level version of EuroQol-5 dimension(EQ-5D-3L)were used to evaluate the patient.The outcomes of the 25FW,TUG,and CGS improved during hospitalization.From the time of admission to discharge we observed:A decrease in NRS scores in the lower extremities and the lower back;an increase of 3 points in the BBS;a 1-point increase in the balancing part of the Tinetti Test;MMT and EQ-5D-3L performances remained unchanged.CONCLUSION Traditional Chinese medicine treatments could be a therapeutic option to alleviate issues related to gait disturbance in ALD.

Adult-Onset Adrenoleukodystrophy with Frontal Lobe Symptoms: A Case Report

ALD, which is the X-linked adrenoleukodystrophy (X-ALD), is a rare inherited metabolic disease caused by an enzyme deficiency leading to accumulation of saturated very long chain fatty acid (VLCFA), especially in brain and adrenal cortex. Its prevalence is currently estimated at 1:30,000 to 50,000 in males in Japan. We report a 34-year-old man, who acts of theft, peep and obscenity with adult onset cerebral adrenoleukodystrophy (ALD). An elevated VLCFA and a point mutation in the ABCD1 gene confirmed the diagnosis of ALD. Diffusion-weighted MRI revealed a high intensity area in the white matter of the frontal lobes. T2-weighted image revealed diffuse high signal intensity in the deep white matter. MR diffusion-weighted image revealed high signal intensity area in the white matter of the frontal lobes.?Proton magnetic resonance spectroscopy?(H-MRS) of the white matter of the frontal lobes revealed an extreme decrease of?N-acetylaspartate (NAA) and an increase of the choline (Cho)/creatinine (Cr) ratio. The mild?hypoperfusion was detected in the both cerebral hemispheres by the single photon emission CT (SPECT). The genetic phenotype was detected and he was diagnosed adult onset ALD. The only neurological sign was deviant behaviors as frontal lobe symptoms;despite a diffuse high signal intensity was detected in the deep white matter in the MRI examination. Psychiatric symptomatology is presented and may be one of the earliest manifestations of ALD. Psychiatrists as well as and physicians may encounter ALD.

Mutation pattern in human adrenoleukodystrophy protein in terms of amino-acid pair predictability

The mutation pattern in protein is a very important feature and is studied through various approaches including the study on mutation pattern in domains where amino acids are converted into numbers from letters. In this study, we converted the amino acids in human adrenoleukodystrophy protein with its 128 missense mutations into random domain using the amino-acid pair predictability, and then we studied their mutation patterns. The results show 1) the mutations are more likely to target the amino-acid pairs whose actual frequency is larger than their predicted one, 2) the mutations are more likely to form the amino-acid pairs whose actual frequency is smaller than their predicted frequency, 3) mutations are more likely to occur at unpredictable amino-acid pairs, and 4) mutations have the trend to narrow the difference between predicted and actual frequencies of amino-acid pairs.

Adrenal Insufficiency by Adrenoleukodystrophy

The X-linked adrenoleukodystrophy (ALD) is a severe neurodegenerative disorder due to mutations in the ABCD1 gene. Objective: To report a case of a 19-year-old man with adrenal insufficiency due to adrenoleukodystrophy. Method: Case report and literature review. Result: A previously healthy 19-year-old male patient was admitted to the emergency room with nausea and vomiting for 5 days, who progressed to abdominal pain, severe asthenia, and fever (38.5°C). He referred progressive darkening of the skin, oral mucosa, tongue and nail bed of the hands and feet, observed in the last 6 years. Emergency laboratory evaluation showed severe hyponatremia and hyperkalemia, which, together with decreased plasma cortisol, directed the investigation to causes of adrenal insufficiency. High ACTH (Adrenocorticotropic hormone) and very long chain fatty acid levels closed the diagnosis. Discussion: ALD is characterized by progressive demyelination in the central and peripheral nervous system and adrenal insufficiency consequence to the accumulation of very long chain fatty acids (VLCFA) in the adrenal. The overall incidence of ALD is 1:17,000. Adrenal insufficiency may be the first symptom of ALD in boys and adults. The diagnosis is based on the measurement of VLCFA plasma levels. Allogeneic bone marrow transplantation is the only treatment that provides a permanent cure when the procedure is performed at an early stage of brain demyelination, i.e. when patients are asymptomatic, although brain magnetic resonance imaging (MRI) is abnormal. Treatment of Addison’s disease is obligatory, but does not change the course of neurological symptoms.

Eight novel mutations in the ABCD1 gene and clinical characteristics of 25 Chinese patients with X-linked adrenoleukodystrophy

Background:X-linked adrenoleukodystrophy(X-ALD)is a fatal neurodegenerative disease caused by mutations in the adenosine triphosphate-binding cassette D1(ABCD1)gene.This study aimed to retrospectively investigate the clinical characteristics of 25 patients with X-ALD including members of large pedigrees,to analyze ABCD1 gene mutations,the effect of gene novel variants on ALD protein(ALDP)structure and function,and to expand gene mutation spectrum of Chinese patients.Methods:Twenty-five male patients diagnosed with X-ALD were enrolled in this study.The clinical characteristics of the patients were retrospectively summarized by reviewing medical records or telephone consultation.ABCD1 gene mutations were analyzed.The pathogenicity of novel missense variants was analyzed using cobalt constraint-based multiple protein alignment tool,polymorphism phenotyping,sorting intolerant from tolerant,Align-Grantham variation and Grantham deviation,and Swiss-Program Database Viewer 4.04 software,respectively.Results:Childhood cerebral form ALD(CCALD)is the most common phenotype(64%)in the 25 patients with X-ALD.The progressive deterioration of neurological and cognitive functions is the main clinical feature.The demyelination of the brain white matter and elevated plasma very long chain fatty acids(VLCFAs)were found in all patients.Different phenotypes were also presented within family members of the patients.Twenty-two different mutations including 8 novel mutations in the ABCD1 gene were identifi ed in the 25 patients.Of the mutations,63.6%were missense mutations and 34.8%located in exon 1.The amino acid residues of three novel missense mutations in eight species were highly conserved,and were predicted to be"probably"damaging to ALDP function.The other five novel mutations were splice,nonsense,deletion or duplication mutations.Conclusions:CCALD is the most common phenotype(64%)in our patients with X-ALD.Eight novel mutations in the ABCD1 gene identifi ed are disease-causing mutations.Brain magnetic resonance imaging and plasma VLCFA determination should be performed for the patients who present with progressive deterioration of neurological development.

Adult Onset Cerebral X-Linked Adrenoleuokodystrophy in 18 Cases

Adrenoleukodystrophy (ALD) is an X-linked inherited metabolic disease associated with the accumulation of very long chain fatty acids (VLCFA) in the nervous system, adrenal cortex, and testes. At least seven phenotypes can be distinguished, which are Addison only, childhood, adolescent and adult cerebral ALD, adrenomyeloneuropathy (AMN), and symptomatic or asymptomatic carriers. Children most often develop rapidly a progressive cerebral disease, whereas adults rarely develop a cerebral disease. The majority of adult-onset ALD patients are AMN. The prognosis of ALD remains unpredictable in individual patients. Family history can be very informative. The plasma VLCFA assay permits precise diagnosis. Specific changes on brain Magnetic Resonance Imaging (MRI) can have diagnostic utility. However, there is considerable overlap among adult-onset leukodystrophies. Adult onset form of cerebral X-linked ALD (AOCALD) is a rare disease. The disease progresses rapidly with widespread demyelination of the cerebral hemispheres. AOCALD is an important differential diagnosis for adults with psychiatric symptoms and progressive cognitive changes. In this article, we review on case reports of AOCALD.