Publications by authors named "Nobuyuki Shimozawa"

78 Publications

Stem cell transplantation for pediatric patients with adrenoleukodystrophy: A nationwide retrospective analysis in Japan.

Pediatr Transplant 2021 Oct 18:e14125. Epub 2021 Oct 18.

Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.

Background: Adrenoleukodystrophy (ALD) is an X-linked recessive disorder and 30-40% of patients develop progressive cerebral neurodegeneration. For symptomatic ALD patients, allogeneic stem cell transplantation (SCT) is considered the standard treatment modality to stabilize or prevent the progression of neurological symptoms.

Methods: We retrospectively analyzed the transplant outcomes of 99 pediatric patients with cerebral ALD in Japan. The conditioning regimens included Regimen A: fludarabine/melphalan/low-dose total body irradiation (TBI) with brain sparing (n = 39), Regimen B; busulfan/cyclophosphamide ± others (n = 23), Regimen C: melphalan/total lymphoid irradiation/thoracoabdominal irradiation ± anti-T lymphocyte globulin ± fludarabine (n = 27), and Regimen D: others (n = 10).

Results: The 5-year overall survival (OS) and event-free survival (EFS) of all patients were 90.0% and 72.9%, respectively. The 5-year OS was 100.0% for Regimen A, 91.1% for Regimen B, 84.4% for Regimen C, and 67.5% for Regimen D (p = 0.028). The 5-year EFS was 78.3% for Regimen A, 78.0% for Regimen B, 70.4% for Regimen C, and 48.0% for Regimen D (p = 0.304). The OS marginally improved after 2007 compared with before 2006 (95.3% vs. 85.2%, p = 0.066), due to the improvement of cord blood transplantation (CBT) outcomes after 2007 compared with before 2006 (96.6% vs. 68.4%, p = 0.005). On magnetic resonance imaging of the brain, a reduced Loes score after SCT was only observed in one of the 15 bone marrow transplantation (BMT) patients, but in 5 of the 15 CBT patients (p = 0.173).

Conclusions: Our study revealed that a reduced conditioning regimen with fludarabine/melphalan/low-dose TBI provides better outcomes, and the results of CBT significantly improved after 2007.
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http://dx.doi.org/10.1111/petr.14125DOI Listing
October 2021

Novel Variants Cause Progressive Leukodystrophy in Childhood: Case Report and Literature Review.

Child Neurol Open 2021 Jan-Dec;8:2329048X211048613. Epub 2021 Oct 11.

Hamamatsu University School of Medicine, Hamamatsu, Japan.

D-bifunctional protein (DBP) deficiency is a peroxisomal disorder with a high degree of phenotypic heterogeneity. Some patients with DBP deficiency develop progressive leukodystrophy in childhood. We report a 6-year-old boy with moderate hearing loss who presented with developmental regression. Brain magnetic resonance imaging demonstrated progressive leukodystrophy. However, very long chain fatty acids (VLCFAs) in the plasma were at normal levels. Whole-exome sequencing revealed compound heterozygous variants in (NM_000414.3:c.[350A > T];[394C > T], p.[[Asp117Val]];[[Arg132Trp]]). The c.394C > T variant has been identified in patients with DBP deficiency and is classified as likely pathogenic, while the c.350A > T variant was novel and classified as uncertain significance. Although one of the two variants was classified as uncertain significance, an accumulation of phytanic and pristanic acids was identified in the patient, confirming type III DBP deficiency. DBP deficiency should be considered as a diagnosis in children with progressive leukodystrophy and hearing loss even if VLCFAs are within normal levels.
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http://dx.doi.org/10.1177/2329048X211048613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8512218PMC
October 2021

Advanced Diagnostic System and Introduction of Newborn Screening of Adrenoleukodystrophy and Peroxisomal Disorders in Japan.

Int J Neonatal Screen 2021 Aug 25;7(3). Epub 2021 Aug 25.

Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.

We established a diagnostic system for adrenoleukodystrophy (ALD) and peroxisomal disorders (PD) over 35 years ago in Japan, and have diagnosed 237 families with ALD and more than 100 cases of PD other than ALD using biochemical and molecular analyses. In particular, since the only treatment for the cerebral form of ALD is hematopoietic stem cell transplantation at an early stage of onset, we have developed a protocol for the rapid diagnosis of ALD that can provide the measurements of the levels of very-long-chain fatty acids in the serum and genetic analysis within a few days. In addition, to improve the prognosis of patients with ALD, we are working on the detection of pre-symptomatic patients by familial analysis from the proband, and the introduction of newborn screening. In this review, we introduce the diagnostic and newborn screening approaches for ALD and PD in Japan.
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http://dx.doi.org/10.3390/ijns7030058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395936PMC
August 2021

Glycosphingolipids with Very Long-Chain Fatty Acids Accumulate in Fibroblasts from Adrenoleukodystrophy Patients.

Int J Mol Sci 2021 Aug 11;22(16). Epub 2021 Aug 11.

Faculty of Pharma-Science, Teikyo University, Itabashi-ku, Tokyo 173-8605, Japan.

Adrenoleukodystrophy (X-ALD) is an X-linked genetic disorder caused by mutation of the ATP-binding cassette subfamily D member 1 gene, which encodes the peroxisomal membrane protein, adrenoleukodystrophy protein (ALDP). ALDP is associated with the transport of very-long-chain fatty acids (VLCFAs; carbon chain length ≥ 24) into peroxisomes. Defective ALDP leads to the accumulation of saturated VLCFAs in plasma and tissues, which results in damage to myelin and the adrenal glands. Here, we profiled the glycosphingolipid (GSL) species in fibroblasts from X-ALD patients. Quantitative analysis was performed using liquid chromatography-electrospray ionization-tandem mass spectrometry with a chiral column in multiple reaction monitoring (MRM) mode. MRM transitions were designed to scan for precursor ions of long-chain bases to detect GSLs, neutral loss of hexose to detect hexosylceramide (HexCer), and precursor ions of phosphorylcholine to detect sphingomyelin (SM). Our results reveal that levels of C25 and C26-containing HexCer, Hex2Cer, NeuAc-Hex2Cer, NeuAc-HexNAc-Hex2Cer, Hex3Cer, HexNAc-Hex3Cer, and SM were elevated in fibroblasts from X-ALD patients. In conclusion, we precisely quantified SM and various GSLs in fibroblasts from X-ALD patients and determined structural information of the elevated VLCFA-containing GSLs.
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http://dx.doi.org/10.3390/ijms22168645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395492PMC
August 2021

Prevalence of patients with lysosomal storage disorders and peroxisomal disorders: A nationwide survey in Japan.

Mol Genet Metab 2021 07 12;133(3):277-288. Epub 2021 May 12.

Advanced Clinical Research Center, Southern Tohoku Research Center for Neuroscience, Kanagawa, Japan.

Introduction: Lysosomal storage disorders and peroxisomal disorders are rare diseases caused by the accumulation of substrates of the metabolic pathway within lysosomes and peroxisomes, respectively. Owing to the rarity of these diseases, the prevalence of lysosomal storage disorders and peroxisomal disorders in Japan is unknown. Therefore, we conducted a nationwide survey to estimate the number of patients with lysosomal storage disorders and peroxisomal disorders in Japan.

Methods: A nationwide survey was conducted following the "Manual of nationwide epidemiological survey for understanding patient number and clinical epidemiology of rare diseases (3rd version)". A questionnaire asking for detailed information, such as disease phenotypes and medical history, was created and sent to 504 institutions with doctors who have experience in treating patients with lysosomal storage disorders and peroxisomal disorders. Result A total of 303 completed questionnaires were collected from 504 institutions (response rate: 60.1%). The number of patients was estimated by calculating the rate/frequency of overlap. The estimated number of patients was 1658 (±264.8) for Fabry disease, 72 (±11.3) for mucopolysaccharidosis I, 275 (±49.9) for mucopolysaccharidosis II, 211 (±31.3) for Gaucher disease, 124 (±25.8) for Pompe disease, 83 (±44.3) for metachromatic leukodystrophy, 57 (±9.4) for Niemann-Pick type C, and 262 (±42.3) for adrenoleukodystrophy. In addition the birth prevalence was calculated using the estimated number of patients and birth year data for each disease, and was 1.25 for Fabry disease, 0.09 for mucopolysaccharidosis I, 0.38 for mucopolysaccharidosis II, 0.19 for Gaucher disease, 0.14 for Pompe disease, 0.16 for metachromatic leukodystrophy, 0.16 for Niemann-Pick type C, and 0.20 for adrenoleukodystrophy.

Discussion: Among the diseases analyzed, the disease with the highest prevalence was Fabry disease, followed by mucopolysaccharidosis II, adrenoleukodystrophy, Gaucher disease and metachromatic leukodystrophy. In particular, the high prevalence of mucopolysaccharidosis II and Gaucher disease type II was a feature characteristic of Japan.

Conclusion: We estimated the number of patients with lysosomal storage disorders and peroxisomal disorders in Japan. The details of the age at diagnosis and treatment methods for each disease were clarified, and will be useful for the early diagnosis of these patients and to provide appropriate treatments. Furthermore, our results suggest that supportive care and the development of an environment that can provide optimal medical care is important in the future.
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http://dx.doi.org/10.1016/j.ymgme.2021.05.004DOI Listing
July 2021

Zebrafish model of human Zellweger syndrome reveals organ-specific accumulation of distinct fatty acid species and widespread gene expression changes.

Mol Genet Metab 2021 07 8;133(3):307-323. Epub 2021 May 8.

Division of Genomics Research, Life Science Research Center, Gifu University, Gifu, Japan; Institute for Glyco-core Research (iGCORE), Gifu University, Gifu, Japan; United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan.

In Zellweger syndrome (ZS), lack of peroxisome function causes physiological and developmental abnormalities in many organs such as the brain, liver, muscles, and kidneys, but little is known about the exact pathogenic mechanism. By disrupting the zebrafish pex2 gene, we established a disease model for ZS and found that it exhibits pathological features and metabolic changes similar to those observed in human patients. By comprehensive analysis of the fatty acid profile, we found organ-specific accumulation and reduction of distinct fatty acid species, such as an accumulation of ultra-very-long-chain polyunsaturated fatty acids (ultra-VLC-PUFAs) in the brains of pex2 mutant fish. Transcriptome analysis using microarray also revealed mutant-specific gene expression changes that might lead to the symptoms, including reduction of crystallin, troponin, parvalbumin, and fatty acid metabolic genes. Our data indicated that the loss of peroxisomes results in widespread metabolic and gene expression changes beyond the causative peroxisomal function. These results suggest the genetic and metabolic basis of the pathology of this devastating human disease.
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http://dx.doi.org/10.1016/j.ymgme.2021.05.002DOI Listing
July 2021

Bone marrow transplantation into Abcd1-deficient mice: Distribution of donor derived-cells and biological characterization of the brain of the recipient mice.

J Inherit Metab Dis 2021 05 4;44(3):718-727. Epub 2021 Jan 4.

Faculty of Pharmaceutical Sciences, Hiroshima International University, Hiroshima, Japan.

X-linked adrenoleukodystrophy (X-ALD) is a severe inherited metabolic disease with cerebral inflammatory demyelination and abnormal accumulation of very long chain fatty acid (VLCFA) in tissues, especially the brain. At present, bone marrow transplantation (BMT) at an early stage of the disease is the only effective treatment for halting disease progression, but the underlying mechanism of the treatment has remained unclear. Here, we transplanted GFP-expressing wild-type (WT) or Abcd1-deficient (KO) bone marrow cells into recipient KO mice, which enabled tracking of the donor GFP cells in the recipient mice. Both the WT and KO donor cells were equally distributed throughout the brain parenchyma, and displayed an Iba1-positive, GFAP- and Olig2-negative phenotype, indicating that most of the donor cells were engrafted as microglia-like cells. They constituted approximately 40% of the Iba1-positive cells. Unexpectedly, no decrease of VLCFA in the cerebrum was observed when WT bone marrow cells were transplanted into KO mice. Taken together, murine study suggests that bone marrow-derived microglia-like cells engrafted in the cerebrum of X-ALD patients suppress disease progression without evidently reducing the amount of VLCFA in the cerebrum.
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http://dx.doi.org/10.1002/jimd.12346DOI Listing
May 2021

Clinical evaluation of childhood cerebral adrenoleukodystrophy with balint's symptoms.

Brain Dev 2021 Mar 11;43(3):396-401. Epub 2020 Dec 11.

Division of Clinical Genetics, Gifu University Hospital, Gifu, Japan; Division of Genomics Research, Life Science Research Center, Gifu University, Gifu, Japan.

Background: Childhood cerebral adrenoleukodystrophy (CCALD) is the most common phenotype of adrenoleukodystrophy (ALD) and is characterized by the progression of intellectual, psychic, visual, and gait disturbances. Progression of this intractable disease can only be prevented by hematopoietic stem cell transplantation during the early stages of the disease. The aim of this study was to clinically evaluate children with CCALD who have visual symptoms to enable early diagnosis.

Methods: We enrolled 41 Japanese children with CCALD who had visual symptoms. We retrospectively analyzed age of onset, past medical history, initial symptoms, visual symptoms and findings on brain magnetic resonance imaging.

Results: The median age of disease onset was 7 years (range 5-10 years). The most common visual symptom was strabismus (n = 22). There was only one patient with the triad of symptoms of Balint's syndrome. Seventeen patients had incomplete Balint's syndrome and showed one or two of the triad of symptoms. Almost all patients with complete or incomplete Balint's syndrome showed bilateral parieto-occipital white matter lesions.

Conclusions: CCALD could develop into Balint's syndrome, especially the incomplete form. Therefore, CCALD should be considered when boys show new symptoms, including lack of eye contact or bumping into objects.
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http://dx.doi.org/10.1016/j.braindev.2020.11.010DOI Listing
March 2021

Novel ACOX1 mutations in two siblings with peroxisomal acyl-CoA oxidase deficiency.

Brain Dev 2021 Mar 21;43(3):475-481. Epub 2020 Nov 21.

Department of Pediatrics, University of Tsukuba Hospital, Japan; Department of Child Health, Faculty of Medicine, University of Tsukuba, Japan.

Peroxisomal acyl-CoA oxidase (ACOX1) deficiency is a rare autosomal recessive single enzyme deficiency characterized by hypotonia, seizures, failure to thrive, developmental delay, and neurological regression starting from approximately 3 years of age. Here, we report two siblings with ACOX1 deficiency born to non-consanguineous Japanese parents. They showed mild global developmental delay from infancy and began to regress at 5 years 10 months and 5 years 6 months of age respectively. They gradually manifested with cerebellar ataxia, dysarthria, pyramidal signs, and dysphasia. Brain MRI revealed T2 high-intensity areas in the cerebellar white matter, bilateral middle cerebellar peduncle, and transverse tracts of the pons, followed by progressive atrophy of these areas. Intriguingly, the ratios of C24:0, C25:0, and C26:0 to C22:0 in plasma, which usually increase in ACOX1 deficiency were within normal ranges in both patients. On the other hand, whole exome sequencing revealed novel compound heterozygous variants in ACOX1: a frameshift variant (c.160delC:p.Leu54Serfs*18) and a missense variant (c.1259 T > C:p.Phe420Ser). The plasma concentration of individual very long chain fatty acids (C24:0, C25:0, and C26:0) was elevated, and we found that peroxisomes in fibroblasts of the patients were larger in size and fewer in number as previously reported in patients with ACOX1 deficiency. Furthermore, the C24:0 β-oxidation activity was dramatically reduced. Our findings suggest that the elevation of individual plasma very long chain fatty acids concentration, genetic analysis including whole exome analysis, and biochemical studies on the patient's fibroblasts should be considered for the correct diagnosis of ACOX1 deficiency.
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http://dx.doi.org/10.1016/j.braindev.2020.10.011DOI Listing
March 2021

A case of female adrenoleukodystrophy carrier with insidious neurogenic bladder.

J Gen Fam Med 2020 Jul 18;21(4):146-147. Epub 2020 Mar 18.

Department of Neurology National Hospital Organization Akita National Hospital Yurihonjo Japan.

A 65-year-old woman with mutation of the ABCD1 gene for adrenoleukodystrophy (ALD) was admitted to our hospital with a urinary tract infection. Abdominal computed tomography showed dilation of the urinary tract. Although she had noticed pollakisuria since her forties, she had not been followed up by any medical institutions until we diagnosed her as a female carrier with ALD. ALD is an X-linked pattern of inheritance that typically affects males, but many female carriers actually present slowly progressive myelopathy and neuropathy. Therefore, it is important to identify female carriers with ALD and treat them at the earliest stage possible.
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http://dx.doi.org/10.1002/jgf2.314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388670PMC
July 2020

Positional determination of the carbon-carbon double bonds in unsaturated fatty acids mediated by solvent plasmatization using LC-MS.

Sci Rep 2020 07 31;10(1):12988. Epub 2020 Jul 31.

Division of Genomics Research, Life Science Research Center, Gifu University, 1-1 Yanagido, Gifu City, Gifu, 501-1193, Japan.

Fatty acids (FAs) are the central components of life: they constitute biological membranes in the form of lipid, act as signaling molecules, and are used as energy sources. FAs are classified according to their chain lengths and the number and position of carbon-carbon double bond, and their physiological character is largely defined by these structural properties. Determination of the precise structural properties is crucial for characterizing FAs, but pinpointing the exact position of carbon-carbon double bond in FA molecules is challenging. Herein, a new analytical method is reported for determining the double bond position of mono- and poly-unsaturated FAs using liquid chromatography-mass spectrometry (LC-MS) coupled with solvent plasmatization. With the aid of plasma on ESI capillary, epoxidation or peroxidation of carbon-carbon double bond in FAs is facilitated. Subsequently, molecular fragmentation occurs at or beside the epoxidized or peroxidized double bond via collision-induced dissociation (CID), and the position of the double bond is elucidated. In this method, FAs are separated by LC, modified by plasma, fragmented via CID, and detected using a time-of-flight mass spectrometer in a seamless manner such that the FA composition in a mixture can be determined. Our method enables thorough characterization of FA species by distinguishing multiple isomers, and therefore can uncover the true diversity of FAs for their application in food, health, and medical sciences.
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http://dx.doi.org/10.1038/s41598-020-69833-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395107PMC
July 2020

A 29-year-old patient with adrenoleukodystrophy presenting with Addison's disease.

Endocr J 2020 Jun 26;67(6):655-658. Epub 2020 Feb 26.

Department of Internal Medicine, Tokyo Saiseikai Central Hospital, Minato-ku, Tokyo 108-0073, Japan.

Adrenoleukodystrophy (ALD) is an X-linked disorder caused by a hemizygous mutation of the ABCD1 gene. Patients with ALD show progressive central nervous system demyelination and primary adrenal insufficiency. In Japan, most reported ALD cases were childhood-onset, and only one case of an adult patient with Addison's disease form of ALD has ever been reported. Herein, we present a case of a 29-year-old man with Addison's disease form of ALD. The patient had anorexia, weight loss, and skin pigmentation from 18 years of age. At first visit, his weight had decreased by 12 kg from 57 kg when he was 15 years old. Endocrinological examination showed low serum cortisol (1.2 μg/dL) with high plasma ACTH (4,750 pg/mL), and abdominal computed tomography showed normal adrenal glands. Very-long-chain fatty acid (VLCFA) levels were elevated, and the ABCD1 mutation, p.Gly116Arg, was identified in hemizygous state. He had no significant neurological findings on physical examination and no white matter lesions on brain magnetic resonance imaging (MRI). He was diagnosed with ALD presenting as Addison's disease, and glucocorticoid replacement therapy was initiated. Four years after the diagnosis, he still did not show any neurological findings and any white matter lesions on brain MRI. Evaluating VLCFA levels for ALD diagnosis is important in young adult men with idiopathic primary adrenal insufficiency as well as in children. Early diagnosis enables more rational approaches including the early detection of neurological complications and might improve the prognosis of patients.
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http://dx.doi.org/10.1507/endocrj.EJ19-0576DOI Listing
June 2020

Hexacosenoyl-CoA is the most abundant very long-chain acyl-CoA in ATP binding cassette transporter D1-deficient cells.

J Lipid Res 2020 04 19;61(4):523-536. Epub 2020 Feb 19.

Faculty of Pharma-Science, Teikyo University, Itabashi-ku, Tokyo 173-8605, Japan.

X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder caused by deleterious mutations in the gene. The ABCD1 protein transports very long-chain FAs (VLCFAs) from the cytosol into the peroxisome where the VLCFAs are degraded through β-oxidation. ABCD1 dysfunction leads to VLCFA accumulation in individuals with X-ALD. FAs are activated by esterification to CoA before metabolic utilization. However, the intracellular pools and metabolic profiles of individual acyl-CoA esters have not been fully analyzed. In this study, we profiled the acyl-CoA species in fibroblasts from X-ALD patients and in ABCD1-deficient HeLa cells. We found that hexacosenoyl (26:1)-CoA, but not hexacosanoyl (26:0)-CoA, was the most abundantly concentrated among the VLCFA-CoA species in these cells. We also show that 26:1-CoA is mainly synthesized from oleoyl-CoA, and the metabolic turnover rate of 26:1-CoA was almost identical to that of oleoyl-CoA in both WT and ABCD1-deficient HeLa cells. The findings of our study provide precise quantitative and metabolic information of each acyl-CoA species in living cells. Our results suggest that VLCFA is endogenously synthesized as VLCFA-CoA through a FA elongation pathway and is then efficiently converted to other metabolites, such as phospholipids, in the absence of ABCD1.
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http://dx.doi.org/10.1194/jlr.P119000325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112142PMC
April 2020

Biallelic mutation of induces middle age-onset spinocerebellar ataxia.

Neurol Genet 2020 Feb 16;6(1):e396. Epub 2020 Jan 16.

Department of Epidemiology (Y.M., H. Morino, K.K., Y.K., Y.T., R.O., H.K.), Research Institute for Radiation Biology and Medicine, Hiroshima University; Japan Society for the Promotion of Science (Y.M.), Tokyo; the Department of Clinical Neuroscience (R.M.), Institute for Biomedical Science, Tokushima University; the Department of Neurology (T.K.), National Hospital Organization Kure Medical Center and Chugoku Cancer Center; the Department of Periodontal Medicine (N.M.), Graduate School of Biomedical and Sciences, Hiroshima University; the Department of Plastic Surgery (K.Y.), Hiroshima University Hospital; the Division of Genomics Research (N.S.), Life Science Research Center, Gifu University; the Department of Clinical Neuroscience and Therapeutics (H. Maruyama), Hiroshima University, Japan.

Objective: To determine the genetic underpinnings of slowly progressive spinocerebellar ataxia, autosomal recessive (SCAR), we performed exome analysis and examined the relationship between clinical severity and functional change induced by the mutation.

Methods: Homozygosity fingerprinting and exome sequencing were performed to identify causative mutations in 2 consanguineous families. We assessed the expression of D-bifunctional protein (DBP) and the amount of dimerized DBP in fibroblasts by immunoblot and quantitative reverse transcription PCR. The pathogenicity of the mutation was evaluated using the Combined Annotation-Dependent Depletion (CADD) scores; these results were compared with the scores of previously reported mutations.

Results: We identified a homozygous mutation as causative of middle age-onset SCAR: p.Ala175Thr, which is located in that encodes peroxisomal DBP. The patients developed cerebellar ataxia, and the subsequent progression was slow. The symptoms presented were milder than those in previously reported cases. The messenger RNA expression levels were normal, but protein levels were diminished. Dimerization of DBP was also reduced. The CADD score of the identified mutation was lower than those of previously reported mutations.

Conclusions: This is the report of middle age-onset DBP deficiency. Residual functional DBP caused relatively mild symptoms in the affected patients, i.e., slowly progressive ataxia and hearing loss. This study broadens the scope of DBP deficiency phenotypes and indicates that CADD scores may be used to estimate the severity of DBP deficiencies.
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http://dx.doi.org/10.1212/NXG.0000000000000396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975179PMC
February 2020

POLR3A variants in striatal involvement without diffuse hypomyelination.

Brain Dev 2020 Apr 10;42(4):363-368. Epub 2020 Jan 10.

Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan. Electronic address:

Background: Biallelic variants in POLR3A encoding the largest subunit of RNA polymerase III cause POLR3-related (or 4H) leukodystrophy characterized by neurologic dysfunction, abnormal dentition, endocrine abnormalities and ocular abnormality. Recently, whole-exome sequencing enabled the discovery of POLR3A variants in cases lacking diffuse hypomyelination, the principal MRI phenotype of POLR3-related leukodystrophy. Homozygous c.1771-6C > G variants in POLR3A were recently suggested to cause striatal and red nucleus involvement without white matter involvement.

Case Report: Here, we report three cases in two families with biallelic POLR3A variants. We identified two sets of compound heterozygous variants in POLR3A, c.1771-6C > G and c.791C > T, p.(Pro264Leu) for family 1 and c.1771-6C > G and c.2671C > T, p.(Arg891*) for family 2. Both families had the c.1771-6C > G variant, which led to aberrant mRNA splicing. Neuropsychiatric regression and severe intellectual disability were identified in three patients. Two cases showed dystonia and oligodontia. Notably, characteristic bilateral symmetric atrophy and abnormal signal of the striatum without diffuse white matter signal change were observed in brain MRI of all three individuals.

Conclusions: Striatum abnormalities may be another distinctive MRI finding associated with POLR3A variants, especially in cases including c.1771-6C > G variants and our cases can expand the phenotypic spectrum of POLR3A-related disorders.
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http://dx.doi.org/10.1016/j.braindev.2019.12.012DOI Listing
April 2020

Allogeneic stem cell transplantation with reduced intensity conditioning for patients with adrenoleukodystrophy.

Mol Genet Metab Rep 2019 Mar 20;18:1-6. Epub 2018 Nov 20.

Department of Hematology and Oncology, Children' Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan.

Objective: The prognosis of adrenoleukodystrophy (ALD)with neurological involvement is generally dismal; however, allogeneic stem cell transplantation (SCT) is recognized as effective to stabilize or improve the clinical symptoms of ALD. Herein, we report the clinical outcomes of patients with ALD who consecutively underwent allogeneic stem cell transplantation with reduced intensity conditioning at our institution.

Patients: Sixteen patients with ALD, who were symptomatic (n = 14) or presymptomatic (n = 2), received SCT from 2010 to 2016. The stem cell source was cord blood (n = 14), or bone marrow from a human leukocyte antigen identical sibling (n = 2). The conditioning regimen prior to transplantation was reduced intensity and consisted of fludarabine (125 mg/m), melphalan (140 mg/m) and low dose total body irradiation (TBI) of 4Gy (n = 15) or 3Gy (n = 1).

Results: Primary engraftment was obtained in 11 patients, and 4 of the 5 patients who lost the primary graft received a second cord blood transplantation and were engrafted. Five years overall and event-free survival were 90.9% and 61.1% respectively, with a median of 45 months (range 16-91). Loes score stabilized or improved by 18 months after transplantation except for patients with internal capsule involvement.

Conclusion: Allogeneic SCT with reduced intensity conditioning for patients with ALD was safely performed without major transplant-related complications even in symptomatic patients and neurological symptoms were stabilized after SCT in patients without internal capsule involvement.
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http://dx.doi.org/10.1016/j.ymgmr.2018.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260425PMC
March 2019

Expanding the concept of peroxisomal diseases and efficient diagnostic system in Japan.

J Hum Genet 2019 Feb 20;64(2):145-152. Epub 2018 Sep 20.

Division of Genomics Research, Life Science Research Center, Gifu University, Gifu, Japan.

The concept of peroxisomal diseases is expanding because of improvements in diagnostic technology based on advanced biochemical analysis and development of next-generation sequencing. For quicker and more accurate diagnosis of as many patients as possible, we developed a new diagnostic system combining the conventional diagnostic system and comprehensive mutational analysis by whole-exome sequencing in Japan. Adrenoleukodystrophy (ALD) is the most common peroxisomal disease. In the cerebral type of ALD, hematopoietic stem cell transplantation is the only treatment in the early stage, and thus prompt diagnosis will improve the prognosis of affected patients. Furthermore, it is also important to identify pre-symptomatic patients by family analysis of probands by providing appropriate disease information and genetic counseling, which will also lead to early intervention. Here, we summarize current information related to peroxisomal diseases and ALD and introduce our efficient diagnostic system for use in Japan, which resulted in the diagnosis of 73 Japanese patients with peroxisome biogenesis disorders, 16 with impaired β-oxidation of fatty acids, three with impaired etherphospholipid biosynthesis, and 191 Japanese families with ALD so far.
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http://dx.doi.org/10.1038/s10038-018-0512-1DOI Listing
February 2019

Atypical PEX16 peroxisome biogenesis disorder with mild biochemical disruptions and long survival.

Brain Dev 2019 Jan 2;41(1):57-65. Epub 2018 Aug 2.

Departments of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates; Research Institute, Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H 5B2, Canada. Electronic address:

Background: Mutations in PEX16 cause peroxisome biogenesis disorder (PBD). Zellweger syndrome characterized by neurological dysfunction, dysmorphic features, liver disease and early death represents the severe end of this clinical spectrum. Here we discuss the diagnostic challenge of atypical PEX16 related PBD in 3 patients from highly inbred kindred and describe the role of specific metabolites analyses, fibroblasts studies, whole-exome sequencing (WES) and metabolomics profiling to establish the diagnosis.

Methods And Patients: The proband is a 12-year-old male born to consanguineous parents. Despite normal development in the first year, regression and progressive spastic diplegia, poor coordination and dysarthria occurred thereafter. Patient 2 (3-year old female) and Patient 3 (19-month old female) shared similar clinical course with the proband. Biochemical studies on plasma and fibroblasts, WES and global metabolomics analyses were performed.

Results: Very-long-chain fatty acids analysis showed subtle elevations in C26 and C26/C22. Global Metabolomics-Assisted Pathway profiling was not remarkable. Immunocytochemical investigations on fibroblasts revealed fewer catalase and PMP70-containing particles indicating aberrant peroxisomal assembly. Complementation studies were inconclusive. WES revealed a novel homozygous variant in PEX16 (c.859C>T). The biochemical profiles of Patient 2 and Patient 3 were similar to the proband and the same genotype was confirmed.

Conclusion: This paper highlights the diagnostic challenge of PEX16 patients due to the widely variable clinical and biochemical phenotypes. It also emphasizes the important roles of combined biochemical assays with next generation sequencing techniques in reaching diagnosis in the context of atypical clinical presentations, subtle biomarker abnormalities and consanguinity.
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http://dx.doi.org/10.1016/j.braindev.2018.07.015DOI Listing
January 2019

Characteristics of Japanese patients with X-linked adrenoleukodystrophy and concerns of their families from the 1st registry system.

Brain Dev 2019 Jan 1;41(1):50-56. Epub 2018 Aug 1.

Department of Pediatrics, The Jikei University School of Medicine, Tokyo, Japan.

Objective: Early diagnosis is critical in achieving the best outcome following hematopoietic stem cell transplantation (HSCT) for X-linked adrenoleukodystrophy (X-ALD). We used a questionnaire to gather detailed clinical information and information regarding the anxieties of patients' families using the registry system for X-ALD.

Methods: We and the patients' families established the registry system for X-ALD in Japan. We created a questionnaire and distributed it to the patients' families.

Results: Questionnaire data from 28 patients were collected. The median age at enrollment was 14.5 years. The most common type of X-ALD was the childhood cerebral form (22 patients, 78.6%). The median age at symptom onset was 7.4 years. Frequently reported initial observations were behavior or character changes (46.4%), gait disturbances (42.9%), strabismus (39.3%), reduced academic ability (32.1%), failing vision (21.4%), a positive family history (21.4%), clumsiness (17.9%), hearing disturbances (17.9%), convulsions (10.7%), and suspected psychiatric disorders (10.7%). The median duration from symptom onset to diagnosis was 12 months. The families of 12 patients (42.9%) with X-ALD who received HSCT were satisfied regardless of its effectiveness. Common concerns of patients' families were worries regarding heritability of X-ALD (78.6%), present symptoms (57.1%), frequent hospital visits (42.9%), problems at school or work (42.9%), economic issues (35.7%), and limited information regarding X-ALD (32.1%).

Conclusion: This is the first study clarifying the clinical characteristics of X-ALD and the concerns of patients' families using the registry system. Investigation of rare diseases using registry systems is very valuable for the understanding of such conditions.
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http://dx.doi.org/10.1016/j.braindev.2018.07.007DOI Listing
January 2019

Stability of the ABCD1 Protein with a Missense Mutation: A Novel Approach to Finding Therapeutic Compounds for X-Linked Adrenoleukodystrophy.

JIMD Rep 2019 21;44:23-31. Epub 2018 Jun 21.

Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.

Mutations in the ABCD1 gene that encodes peroxisomal ABCD1 protein cause X-linked adrenoleukodystrophy (X-ALD), a rare neurodegenerative disorder. More than 70% of the patient fibroblasts with this missense mutation display either a lack or reduction of the ABCD1 protein because of posttranslational degradation. In this study, we analyzed the stability of the missense mutant ABCD1 proteins (p.A616T, p.R617H, and p.R660W) in X-ALD fibroblasts and found that the mutant ABCD1 protein p.A616T has the capacity to recover its function by incubating at low temperature. In the case of such a mutation, chemical compounds that stabilize mutant ABCD1 proteins could be therapeutic candidates. Here, we prepared CHO cell lines stably expressing ABCD1 proteins with a missense mutation in fusion with green fluorescent protein (GFP) at the C-terminal. The stability of each mutant ABCD1-GFP in CHO cells was similar to the corresponding mutant ABCD1 protein in X-ALD fibroblasts. Furthermore, it is of interest that the GFP at the C-terminal was degraded together with the mutant ABCD1 protein. These findings prompted us to use CHO cells expressing mutant ABCD1-GFP for a screening of chemical compounds that can stabilize the mutant ABCD1 protein. We established a fluorescence-based assay method for the screening of chemical libraries in an effort to find compounds that stabilize mutant ABCD1 proteins. The work presented here provides a novel approach to finding therapeutic compounds for X-ALD patients with missense mutations.
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http://dx.doi.org/10.1007/8904_2018_118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323035PMC
June 2018

Profiling and Imaging of Phospholipids in Brains of Abcd1-Deficient Mice.

Lipids 2018 01 22;53(1):85-102. Epub 2018 Feb 22.

Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan.

ABCD1 is a gene responsible for X-linked adrenoleukodystrophy (X-ALD), and is critical for the transport of very long-chain fatty acids (VLCFA) into peroxisomes and subsequent β-oxidation. VLCFA-containing lipids accumulate in X-ALD patients, although the effect of ABCD1-deficiency on each lipid species in the central nervous system has not been fully characterized. In this study, each phospholipid and lysophospholipid species in Abcd1-deficient mice brains were profiled by liquid chromatography-mass spectrometry. Among the phospholipid and lysophospholipid species that are significantly more enriched in Abcd1-deficient mice brains, VLCFA were present in 75, 15, 5, 4, and 1 species of phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, lysophosphatidylcholine, and lysophosphatidylethanolamine, respectively. Most VLCFA were incorporated at the sn-1 position of phosphatidylcholine and phosphatidylethanolamine. Among the phospholipid species that are significantly less enriched in Abcd1-deficient mice brains, odd-numbered saturated or mono-unsaturated fatty acyl moieties are contained in all phosphatidylcholine species. In addition, a number of phosphatidylglycerol, phosphatidylinositol, and phosphatidylserine species contained highly unsaturated fatty acyl moieties. Intriguingly, 44:1 phosphatidylcholine with VLCFA was mainly distributed in the gray matter, such as the cortex, but not in the white matter in the cerebrum and cerebellum. These results show that ABCD1-deficiency causes metabolic alternation of long-chain fatty acids and VLCFA. Moreover, our results imply a molecular mechanism for the incorporation of saturated or monounsaturated VLCFA into the sn-1 position of phospholipids, and also indicate that the distribution of phospholipids with VLCFA may correlate with the development of X-ALD.
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http://dx.doi.org/10.1002/lipd.12022DOI Listing
January 2018

Highly asymmetric and subacutely progressive motor weakness with unilateral T2-weighted high intensities along the pyramidal tract in the brainstem in adrenomyeloneuropathy.

J Neurol Sci 2017 10 12;381:107-109. Epub 2017 Aug 12.

Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2017.08.018DOI Listing
October 2017

Effect of Lorenzo's Oil on Hepatic Gene Expression and the Serum Fatty Acid Level in abcd1-Deficient Mice.

JIMD Rep 2018 31;38:67-74. Epub 2017 May 31.

Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.

Lorenzo's oil is known to decrease the saturated very long chain fatty acid (VLCFA) level in the plasma and skin fibroblasts of X-linked adrenoleukodystrophy (ALD) patients. However, the involvement of Lorenzo's oil in in vivo fatty acid metabolism has not been well elucidated. To investigate the effect of Lorenzo's oil on fatty acid metabolism, we analyzed the hepatic gene expression together with the serum fatty acid level in Lorenzo's oil-treated wild-type and abcd1-deficient mice. The change in the serum fatty acid level in Lorenzo's oil-treated abcd1-defcient mice was quite similar to that in the plasma fatty acid level in ALD patients supplemented with Lorenzo's oil. In addition, we found that the hepatic gene expression of two peroxisomal enzymes, Dbp and Scp2, and three microsomal enzymes, Elovl1, 2, and 3, were significantly stimulated by Lorenzo's oil. Our findings indicate that Lorenzo's oil activates hepatic peroxisomal fatty acid β-oxidation at the transcriptional level. In contrast, the transcriptional stimulation of Elovl1, 2, and 3 by Lorenzo's oil does not cause changes in the serum fatty acid level. It seems likely that the inhibition of these elongation activities by Lorenzo's oil results in a decrease in saturated VLCFA. Thus, these results not only contribute to a clarification of the mechanism by which the saturated VLCFA level is reduced in the serum of ALD patients by Lorenzo's oil-treatment, but also suggest the development of a new therapeutic approach to peroxisomal β-oxidation enzyme deficiency, especially mild phenotype of DBP deficiency.
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http://dx.doi.org/10.1007/8904_2017_32DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874209PMC
May 2017

A first case of adrenomyeloneuropathy with mutation Y174S of the adrenoleukodystrophy gene.

Neuro Endocrinol Lett 2017 Feb;38(1):13-18

Department of Diabetes and Endocrinology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Japan.

The patient first noticed spasticity and weakness in his legs. He was diagnosed with chronic myelogenous leukemia (CML); the symptoms were attributed to neuropathy associated with CML. By treatment with dasatinib, he achieved complete hematological remission, but his difficulty in walking was not improved. His neurological symptom worsened together with an increase in body temperature and then disappeared together with a normalized body temperature, which may be attributed to the Uhthoff's phenomenon often observed in multiple sclerosis. He later developed acute fever, vomiting and a high adrenocorticotropic hormone (ACTH) level, which was diagnosed as adrenal insufficiency. Eventually, he was diagnosed with a milder form of adrenoleukodystrophy (ALD), adrenomyeloneuropathy (AMN) by increased levels of Very Long Chain Fatty Acids (VLCFAs) and genetic testing of the ATP binding cassette subfamily D member 1 (ABCD1) gene. A missense mutation (c.521A>C, p.Tyr174Ser), previously reported to induce severe cerebral ALD, was detected in exon1. Thus, clinical manifestation of ALD is determined by interaction between the primary ABCD1 mutation and modifying genetic and environmental factors. Physicians should be aware of the differing symptoms of AMN and determine the level of VLCFAs in patients having primary adrenal insufficiency, especially those complicated with neurological dysfunction. This is the first report of an AMN patient complicated with CML.
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February 2017

Ataxic form of autosomal recessive PEX10-related peroxisome biogenesis disorders with a novel compound heterozygous gene mutation and characteristic clinical phenotype.

J Neurol Sci 2017 Apr 27;375:424-429. Epub 2017 Feb 27.

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikatacho, Okayama 700-8558, Japan.. Electronic address:

Peroxisome biogenesis factor 10 (PEX10) is involved in the import of peroxisomal matrix proteins, and the mutation of this gene causes 3 subtypes of peroxisome biogenesis disorders, namely Zellweger syndrome (severe), neonatal adrenoleukodystrophy (moderate) and an ataxic form (mild). Here, we report 3 siblings of the ataxic form with cerebellar ataxia, mild mental retardation, and 3 additional characteristic features: mydriasis, hyperreflexia and involuntary head movement. All 3 siblings are compound heterozygous for a previously reported mutation, c.2T>C (p.M1T), and a novel mutation, c.920G>A, causing a missense change (p.C307Y) located in the RING finger domain of PEX10. The present cases suggest that these PEX10 mutations involve not only cerebellar but also more multiple nervous systems including pupillary autonomic, pyramidal and extrapyramidal systems.
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http://dx.doi.org/10.1016/j.jns.2017.02.058DOI Listing
April 2017

Detection of unusual very-long-chain fatty acid and ether lipid derivatives in the fibroblasts and plasma of patients with peroxisomal diseases using liquid chromatography-mass spectrometry.

Mol Genet Metab 2017 03 7;120(3):255-268. Epub 2017 Jan 7.

Division of Genomics Research, Life Science Research Center, Gifu University, Japan.

Metabolic changes occur in patients with peroxisomal diseases owing to impairments in the genes involved in peroxisome function. For diagnostic purposes, saturated very-long-chain fatty acids (VLCFAs) such as C24:0 and C26:0, phytanic acid, pristanic acid, and plasmalogens are often measured as metabolic hallmarks. As the direct pathology of peroxisomal disease is yet to be fully elucidated, we sought to explore the fatty acid species that accumulate in patients with peroxisomal diseases. We developed a method for detecting a range of fatty acids implicated in peroxisomal diseases such as Zellweger syndrome (ZS) and X-linked adrenoleukodystrophy (X-ALD). To this end, we employed an ultra-performance liquid chromatography-mass spectrometry (LC-MS) coupled with negatively charged electrospray ionization. Fatty acids from patients and control subjects were extracted from total lipids by acid-hydrolysis and compared. In accordance with previous results, the amounts of VLCFAs, phytanic acid, and pristanic acid differed between the two groups. We identified extremely long and highly polyunsaturated VLCFAs (ultra-VLC-PUFAs) such as C44:12 in ZS samples. Moreover, three unknown molecules were prominent in control samples but scarcely detectable in ZS samples. LC-MS/MS analysis identified these as 1-alkyl-sn-glycerol 3-phosphates derived from ether lipids containing fatty alcohols such as C16:0, C18:0, or C18:1. Our method provides an approach to observing a wide range of lipid-derived fatty acids and related molecules in order to understand the metabolic changes involved in peroxisomal diseases. This technique can therefore be used in identifying metabolic markers and potential clinical targets for future treatment.
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http://dx.doi.org/10.1016/j.ymgme.2016.12.013DOI Listing
March 2017

Serial Monitoring of Plasma Levetiracetam Levels in a Child With Epilepsy Undergoing Cord Blood Transplantation.

Pediatr Neurol 2016 11 25;64:e5-e6. Epub 2016 Jul 25.

Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.

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http://dx.doi.org/10.1016/j.pediatrneurol.2016.07.009DOI Listing
November 2016

A novel method for determining peroxisomal fatty acid β-oxidation.

J Inherit Metab Dis 2016 09 20;39(5):725-731. Epub 2016 Jun 20.

Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.

The purpose of this study is to establish an assay method to screen for chemical compounds that stimulate peroxisomal fatty acid β-oxidation activity in X-linked adrenoleukodystropy (X-ALD) fibroblasts. In this investigation, we used 12-(1-pyrene)dodecanoic acid (pyrene-C12:0), a fluorescent fatty acid analog, as a substrate for fatty acid β-oxidation. When human skin fibroblasts were incubated with pyrene-C12:0, β-oxidation products such as pyrene-C10:0 and pyrene-C8:0 were generated time-dependently. These β-oxidation products were scarcely detected in the fibroblasts from patients with Zellweger syndrome, a peroxisomal biogenesis disorder. In contrast, in fibroblasts with mitochondrial carnitine-acylcarnitine translocase deficiency, the β-oxidation products were detected at a level similar to control fibroblasts. These results indicate that the β-oxidation of pyrene-C12:0 takes place in peroxisomes, but not mitochondria, so pyrene-C12:0 is useful for measuring peroxisomal fatty acid β-oxidation activity. In X-ALD fibroblasts, the β-oxidation activity for pyrene-C12:0 was approximately 40 % of control fibroblasts, which is consistent with previous results using [1-(14)C]lignoceric acid as the substrate. The present study provides a convenient procedure for screening chemical compounds that stimulate the peroxisomal fatty acid β-oxidation in X-ALD fibroblasts.
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http://dx.doi.org/10.1007/s10545-016-9952-yDOI Listing
September 2016

Living-Donor Liver Transplantation From a Heterozygous Parent for Infantile Refsum Disease.

Pediatrics 2016 06;137(6)

Organ Transplantation Center, and.

Infantile Refsum disease (IRD) is a rare autosomal recessive disorder of peroxisome biogenesis characterized by generalized peroxisomal metabolic dysfunction, including accumulation of very long-chain fatty acids (VLCFAs) and phytanic acid (PA), as well as decreased plasmalogen contents (PL). An effective therapy for this intractable disease has not been established, and only supportive management with docosahexaenoic acid supplementation and low PA diet has been reported so far. A boy of 3 years and 8 months presented with facial dysmorphism, transaminitis, and psychomotor retardation. Biochemical analysis showed elevated PA and VLCFAs, with reduced PL in the serum. Immunofluorescence study of fibroblasts from the patient indicated a mosaic pattern of catalase-positive and -negative particles, and molecular analysis revealed compound heterozygous mutations of PEX6 The failure of medical management to prevent the progression of clinical symptoms and abnormal biochemistry prompted us to consider liver transplantation (LT). With the chances of receiving a deceased donor liver being poor, we performed a living-donor LT from the patient's heterozygous mother. At 6-month follow-up, the patient's serum PA levels had normalized. VLCFAs and PL levels had declined and increased, respectively. To the best of our knowledge, this is the second reported case in which IRD was treated by living-donor LT by using a heterozygous donor. Only long-term follow-up will reveal if there is any clinical improvement in the present case. With the liver being a major site for peroxisomal pathways, its replacement by LT may work as a form of partial enzyme therapy for patients with IRD.
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http://dx.doi.org/10.1542/peds.2015-3102DOI Listing
June 2016

Successive MRI Findings of Reversible Cerebral White Matter Lesions in a Patient with Cystathionine β-Synthase Deficiency.

Tohoku J Exp Med 2015 12;237(4):323-7

Department of Pediatrics, Graduate School of Medicine, Gifu University.

Cystathionine β-synthase (CBS) deficiency, well known as classical homocystinuria, is a rare autosomal recessive inborn error of homocysteine and sulfur metabolism. CBS converts homocysteine to cystathionine. The clinical features of untreated CBS deficiency include myopia, ectopia lentis, mental retardation, skeletal anomalies resembling Marfan syndrome, and thromboembolic events. Cerebral white matter lesions (CWMLs), identified in magnetic resonance imaging (MRI), are related to various clinical conditions including ischemia, inflammation, demyelination, infection, a tumor, and metabolic disorders such as phenylketonuria. The presence of CWMLs is, however, believed to be a very rare condition in CBS-deficient patients. Herein, we report reversible CWMLs associated with hypermethioninemia caused by poor protein restriction and betaine therapy in a 21-year-old male with pyridoxine-nonresponsive CBS deficiency. T2-weighted images (T2WI) and fluid-attenuated inversion-recovery (FLAIR) images showed diffuse high signal intensity in subcortical areas extending to the deep white matter. Diffusion-weighted images (DWI) showed high signal intensity, while apparent diffusion coefficient (ADC) map demonstrated decreased ADC value in the lesions. The course of improvement after correct methionine restriction was successively followed by brain MRI. The CWMLs had regressed at 1 month after restriction, and disappeared after 5 months. ADC values were very low before proper methionine restriction, but normalized after 2 months. Use of betaine in the presence of elevated plasma methionine may increase the risk of reversible CWMLs in some CBS-deficient patients.
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http://dx.doi.org/10.1620/tjem.237.323DOI Listing
December 2015
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