title: The severe clinical phenotype for a heterozygous Fabry female patient correlates to the methylation of non-mutated allele associated with chromosome 10q26 deletion syndrome.
abstract: Heterozygous Fabry females usually have an attenuated form of Fabry disease, causing them to be symptomatic; however, in rare cases, they can present with a severe phenotype. In this study, we report on a 37-year-old woman with acroparesthesia, a dysmorphic face, left ventricular hypertrophy, and intellectual disability. Her father had Fabry disease and died due to chronic renal and congestive cardiac failure. Her paternal uncle had chronic renal failure and intellectual disability, and her paternal aunt was affected with congestive cardiac failure. The patient has two sisters with no significant medical illness. However, her nephew has acroparesthesia, anhidrosis, and school phobia, and her niece shows mild phenotypes. The patient's enzyme analysis showed very low α-galactosidase A (α-gal A) activity in dried blood spot (DBS), lymphocytes, and skin fibroblasts with massive excretion of Gb3 and Gb2 in urine and lyso-Gb3 in DBS and plasma. Electron microscopic examination showed a large accumulation of sphingolipids in vascular endothelial cells and keratinocytes. Chromosomal analysis and comparative genomic hybridization microarray showed 10q26 terminal deletion. Molecular data showed a novel heterozygous stop codon mutation in exon 1 of the GLA gene in her sisters and niece, and a hemizygous state in her nephew. When we checked the methylation status, we found her non-mutated allele in the GLA gene was methylated. However, the non-mutated alleles of her sisters were non-methylated, and those of her niece were partially methylated. The chromosomal and methylation study may speculate the severity of her clinical phenotypes.
authors.affiliation: Advanced Clinical Research Center, Institute of Neurological Disorders, Shin-Yurigaoka General Hospital, Kawasaki, Kanagawa, Japan. Electronic address: drarif_04@hotmail.com.
authors.forename: Mohammad Arif
authors.initials: MA
authors.lastname: Hossain
authors.affiliation: Advanced Clinical Research Center, Institute of Neurological Disorders, Shin-Yurigaoka General Hospital, Kawasaki, Kanagawa, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Yanagisawa
authors.affiliation: Advanced Clinical Research Center, Institute of Neurological Disorders, Shin-Yurigaoka General Hospital, Kawasaki, Kanagawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Miyajima
authors.affiliation: Advanced Clinical Research Center, Institute of Neurological Disorders, Shin-Yurigaoka General Hospital, Kawasaki, Kanagawa, Japan.
authors.forename: Chen
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Biological Regulation School of Health Science, Faculty of Medicine, Tottori University, Yonago, Tottori, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Takamura
authors.affiliation: Advanced Clinical Research Center, Institute of Neurological Disorders, Shin-Yurigaoka General Hospital, Kawasaki, Kanagawa, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Akiyama
authors.affiliation: Advanced Clinical Research Center, Institute of Neurological Disorders, Shin-Yurigaoka General Hospital, Kawasaki, Kanagawa, Japan.
authors.forename: Rina
authors.initials: R
authors.lastname: Itagaki
authors.affiliation: Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Eto
authors.affiliation: Advanced Clinical Research Center, Institute of Neurological Disorders, Shin-Yurigaoka General Hospital, Kawasaki, Kanagawa, Japan; Core Research Facilities for Basic Science, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Iwamoto
authors.affiliation: Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Kanagawa, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yokoi
authors.affiliation: Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Kanagawa, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kurosawa
authors.affiliation: Department of Genetic Counselling, Natural Science Division, Faculty of Core Research, Ochanomizu University, Tokyo, Japan.
authors.forename: Hironao
authors.initials: H
authors.lastname: Numabe
authors.affiliation: Advanced Clinical Research Center, Institute of Neurological Disorders, Shin-Yurigaoka General Hospital, Kawasaki, Kanagawa, Japan; Department of Gene Therapy, Institute for DNA Medicine, The Jikei University School of Medicine, Tokyo, Japan. Electronic address: yosh@sepia.ocn.ne.jp.
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Eto
mesh_terms: D000328:Adult; D000483:Alleles; D002872:Chromosome Deletion; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics / Q000378:metabolism; D018389:Codon, Nonsense; D055028:Comparative Genomic Hybridization; D019175:DNA Methylation; D000795:Fabry Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019066:Facies; D005260:Female; D006579:Heterozygote; D006801:Humans; D007859:Learning Disabilities / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA; D000519:alpha-Galactosidase / Q000097:blood* / Q000235:genetics
chemical_list: D018389:Codon, Nonsense; C576330:GLA protein, human; D000519:alpha-Galactosidase
keywords: Globotriaosylceramide; Intellectual disability; Methylation; X-chromosomal inactivation; α-Galactosidase A