title: De novo mutation in a male patient with Fabry disease: a case report.
abstract: BACKGROUND
  Fabry disease is an X-linked inherited metabolic condition where the deficit of the α-galactosidase A enzyme, encoded by the GLA gene, leads to glycosphingolipid storage, mainly globotriaosylceramide. To date, more than 600 mutations have been identified in human GLA gene that are responsible for FD, including missense and nonsense mutations, small and large deletions. Such mutations are usually inherited, and cases of de novo onset occur rarely.
  
  
  METHODS
  In this article we report an interesting case of a 44-year-old male patient suffering from a severe form of Fabry disease, with negative family history. The patient showed signs such as cornea verticillata, angiokeratomas, cardiac and neurological manifestations, an end-stage renal disease and he had low α-galactosidase A activity. We detected, in this subject, the mutation c.493 G > C in the third exon of the GLA gene which causes the amino acid substitution D165H in the protein. This mutation affects the amino acid - belonging to the group of buried residues - involved, probably, in the preservation of the protein folding. Moreover, studies of multiple sequence alignment indicate that this amino acid is highly conserved, thus strengthening the hypothesis that it is a key amino acid to the enzyme functionality.The study of the relatives of the patient showed that, surprisingly, none of the members of his family of origin had this genetic alteration, suggesting a de novo mutation. Only his 11-year-old daughter - showing acroparaesthesias and heat intolerance with reduced enzymatic activity - had the same mutation.
  
  
  CONCLUSIONS
  We suggest that a non-inherited mutation of the α-galactosidase A gene is responsible for Fabry disease in the patient who had reduced enzyme activity and classical clinical manifestations of the disease. In a family, it is rare to find only one Fabry disease affected subject with a de novo mutation. These findings emphasize the importance of early diagnosis, genetic counselling, studying the genealogical tree of the patients and starting enzyme replacement therapy to prevent irreversible vital organ damage that occurs during the course of the disease.
authors.forename: Francesco
authors.initials: F
authors.lastname: Iemolo
authors.forename: Federica
authors.initials: F
authors.lastname: Pizzo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Albeggiani
authors.forename: Carmela
authors.initials: C
authors.lastname: Zizzo
authors.forename: Paolo
authors.initials: P
authors.lastname: Colomba
authors.forename: Simone
authors.initials: S
authors.lastname: Scalia
authors.forename: Caterina
authors.initials: C
authors.lastname: Bartolotta
authors.affiliation: CNR-IBIM: Institute of Biomedicine and Molecular Immunology "A, Monroy", Via Ugo la Malfa n,153, Palermo, Italy. duro@ibim.cnr.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Duro
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002648:Child; D017124:Conserved Sequence; D056947:Enzyme Replacement Therapy; D000795:Fabry Disease / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007676:Kidney Failure, Chronic / Q000209:etiology; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D017354:Point Mutation; D017510:Protein Folding; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D020521:Stroke / Q000209:etiology; D063189:Symptom Assessment; D019851:Thrombophilia / Q000235:genetics; D000519:alpha-Galactosidase / Q000737:chemistry / Q000235:genetics*
chemical_list: D000519:alpha-Galactosidase