This is a rare lysosomal storage disorder, also known as Anderson-Fabry disease. It is an autosomal recessive inheritance caused by a deficiency of alpha-galactosidase.
| DISEASE ASSOCIATIONS |
CHARACTERIZATION |
| HYPOTHYROIDISM |
|
-
Fucosidosis with hypothyroidism: a case report.
Onenli-Mungan N, Ozer G, Altunbasak S, Besley G, Yuksel B, Topaloglu AK, Soyupak S.
Department of Pediatric Endocrinology and Metabolism, Cukurova University, Faculty of Medicine, Adana, Turkey.
|
-
| Turk J Pediatr. 2004 Apr-Jun;46(2):170-3. Abstract quote |
|
Fucosidosis is a rare, autosomal recessive lysosomal storage disorder caused by a severe deficiency of alpha-L-fucosidase.
Here we present a 27-month-old male who was referred to us for evaluation of developmental delay, which was first detected at age six months. His past medical history was also remarkable for recurrent pulmonary infections and myoclonic seiures. His family history revealed that he was the first living child from a consanguineous marriage. He had a younger sister who died at five months of age from pneumonia who had facial resemblance to the proband, developmental delay and a congenital heart defect.
Physical examination revealed length: 81 cm (25-50p), weight: 10.2 kg (25-50p), and head circumference: 49 cm (50-75p). He had a coarse face, hepatomegaly and generalized spasticity. His initial laboratory examination revealed negative urine screening column chromatography for mucopolysaccharidosis. His X-ray findings were consistent with mild form of dysostosis multiplex.
Based on clinical and laboratory features, fucosidosis was suspected. Fucosidase enzyme activity was zero. In addition to fucosidosis, thyroid function tests indicated primary hypothyroidism. This is, to the best of our knowledge, the fourth case of fucosidosis diagnosed in Turkey.
|
| PATHOGENESIS |
CHARACTERIZATION |
| GENERAL |
|
-
Spectrum of mutations in fucosidosis.
Willems PJ, Seo HC, Coucke P, Tonlorenzi R, O'Brien JS.
Department of Medical Genetics, University of Antwerp, Belgium.
|
-
| Eur J Hum Genet. 1999 Jan;7(1):60-7. Abstract quote |
|
Fucosidosis is a lysosomal storage disorder characterised by progressive psychomotor deterioration, angiokeratoma and growth retardation. It is due to deficient alpha-l-fucosidase activity leading to accumulation of fucose-containing glycolipids and glycoproteins in various tissues.
Fucosidosis is extremely rare with less than 100 patients reported worldwide, although the disease occurs at a higher rate in Italy, in the Hispanic-American population of New Mexico and Colorado, and in Cuba.
We present here a review study of the mutational spectrum of fucosidosis. Exon by exon mutation analysis of FUCA1, the structural gene of alpha-l-fucosidase, has identified the mutation(s) in nearly all fucosidosis patients investigated. The spectrum of the 22 mutations detected to date includes four missense mutations, 17 nonsense mutations consisting of seven stop codon mutations, six small deletions, two large deletions, one duplication, one small insertion and one splice site mutation.
All these mutations lead to nearly absent enzymatic activity and severely reduced cross-reacting immunomaterial. The observed clinical variability is, therefore, not due to the nature of the fucosidosis mutation, but to secondary unknown factors.
|
-
Pedigree analysis of alpha-L-fucosidase gene mutations in a fucosidosis family.
Yang M, Allen H, DiCioccio RA.
Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263.
|
-
| Biochim Biophys Acta. 1993 Oct 20;1182(3):245-9. Abstract quote |
|
Fucosidosis is an autosomal recessive lysosomal storage disease resulting from absence of alpha-L-fucosidase activity. Lymphoid cell lines from two siblings with fucosidosis and a healthy individual (control) had alpha-L-fucosidase mRNA of normal size (2.3 kb) but the level of alpha-L-fucosidase mRNA in the patients' cells was reduced. cDNA was prepared and amplified from alpha-L-fucosidase mRNA of lymphoid cells of the patients, their carrier parents, and the control.
Direct DNA sequencing demonstrated three mutations in the fucosidosis family. One mutation, C1282-->T, changed the codon (CAA) for Gln-422 to a stop codon (UAA). This mutation was heterozygous (C and T) in the patients and their father and independently confirms an earlier report (J. Mol. Neurosci. (1989) 1, 177). Another mutation, C247-->T, changed the codon (CAG) for Gln-77 to a stop codon (UAG) and was heterozygous (C and T) in the patients and their mother. The third mutation, A860-->G, changed the codon CAG for Gln-281 to the codon (CGG) for Arg and was heterozygous (A and G) in the patients but homozygous in their father. alpha-L-Fucosidase activity in cells of the father was 37% of controls indicating that homozygosity of the A860-->G mutation did not cause an absence of alpha-L-fucosidase activity and fucosidosis.
This mutation probably results in a normal polymorphic variant of alpha-L-fucosidase. It is proposed that the combination of the C247-->T mutation on the maternal allele of the alpha-L-fucosidase gene and the C1282-->T mutation on the paternal allele caused fucosidosis in the patients.
|
LABORATORY/
RADIOLOGIC/
OTHER TESTS |
CHARACTERIZATION |
| RADIOLOGIC |
|
| BRAIN |
|
-
MR brain imaging of fucosidosis type I.
Galluzzi P, Rufa A, Balestri P, Cerase A, Federico A.
Unit of Diagnostic and Therapeutic Neuroradiology, Azienda Ospedaliera Senese, Italy.
|
-
| AJNR Am J Neuroradiol. 2001 Apr;22(4):777-80. Abstract quote |
|
SUMMARY: Fucosidosis is a rare autosomal recessive lysosomal storage disease with the main clinical findings of progressive neuromotor deterioration, seizures, coarse facial features, dysostosis multiplex, angiokeratoma corporis diffusum, visceromegaly, recurrent respiratory infections, and growth retardation. Fucosidosis type I rapidly evolves toward a progressive neurologic deterioration and death.
We report MR imaging findings of the brain of three patients with fucosidosis type I, including previously unreported findings, to expand the knowledge of the neuroradiologic spectrum of the disease.
|
-
Evolution of the neuroimaging changes in fucosidosis type II.
Terespolsky D, Clarke JT, Blaser SI.
Department of Pediatrics and Genetics, Hospital for Sick Children, Toronto, Ontario, Canada.
|
-
| J Inherit Metab Dis. 1996;19(6):775-81. Abstract quote |
|
We report on clinical and neuroradiological findings in two patients with fucosidosis type II; a 7-year-old Jordanian boy and a 3 1/2-year-old Anglo-Canadian girl.
This rare, autosomal recessive disorder is caused by deficiency of lysosomal alpha-fucosidase and is manifested clinically by progressive mental and motor deterioration, coarse facies, growth retardation, recurrent infections, dysostosis multiplex, angiokeratoma corporis diffusum, visceromegaly and seizures.
Cranial CT and magnetic resonance imaging showed density and signal abnormalities in the thalamus, globus pallidus and internal capsules bilaterally, as well as progressive CT density alterations in supratentorial white matter including the internal medullary laminae of the thalami and the internal capsules.
|
-
Neuroradiologic findings in fucosidosis, a rare lysosomal storage disease.
Provenzale JM, Barboriak DP, Sims K.
Department of Radiology, Duke University Medical Center, Durham, NC 27710, USA.
|
-
| AJNR Am J Neuroradiol. 1995 Apr;16(4 Suppl):809-13. Abstract quote |
|
Fucosidosis is a rare lysosomal storage disorder with the clinical features of mental retardation, cardiomegaly, dysostosis multiplex, progressive neurologic deterioration, and early death.
The neuroradiologic findings in two patients are reported, and include abnormalities within the globus pallidus (both patients) and periventricular white matter (one patient).
|
| LABORATORY MARKERS |
|
GROSS APPEARANCE/
CLINICAL VARIANTS |
CHARACTERIZATION |
| GENERAL |
|
-
Fucosidosis revisited: a review of 77 patients.
Willems PJ, Gatti R, Darby JK, Romeo G, Durand P, Dumon JE, O'Brien JS.
Department of Medical Genetics, University of Antwerp/U.I.A., Belgium.
|
-
| Am J Med Genet. 1991 Jan;38(1):111-31. Abstract quote |
|
Fucosidosis is a rare, autosomal recessive, lysosomal storage disorder caused by a severe deficiency of alpha-L-fucosidase in all tissues.
We have conducted a review of fucosidosis, compiling data from published reports and an international questionnaire survey. Seventy-seven patients affected with fucosidosis of which 19 had not been reported before have been identified. A major aim of the present study was to define the natural history of fucosidosis.
The clinical picture of fucosidosis consists of progressive mental (95%) and motor (87%) deterioration, coarse facies (79%), growth retardation (78%), recurrent infections (78%), dysostosis multiplex (58%), angiokeratoma corporis diffusum (52%), visceromegaly (44%), and seizures (38%). Whereas the original fucosidosis patients described by Durand et al. (J. Pediatr 75:665-674, 1969) were decerebrate and died before age 5 years, most fucosidosis patients have a slower course of degeneration. Mortality before age 5 years was observed in only 7 patients (9%), whereas 36 patients (64%) reached the second decade. We did not find evidence for the existence of clinical heterogeneity with a rapidly progressive type I and a slowly progressive type II fucosidosis as suggested in the literature. Instead, there seems to exist a wide continuous clinical spectrum.
At the biochemical level no heterogeneity in residual fucosidase enzyme activity or cross-reacting immunoreactive fucosidase protein was observed. At the DNA level at least 4 different mutations must be responsible for fucosidosis. These genotypic differences however do not explain the observed phenotypic differences.
|
| VARIANTS |
|
| ORAL |
|
-
Oral lesions in fucosidosis.
Prindiville DE, Stern D.
|
-
| J Oral Surg. 1976 Jul;34(7):603-8. Abstract quote |
|
The oral lesions in two previously reported cases of fucosidosis are discussed. The patients have coarse facies, severe mental retardation, spondyloepiphyseal dysplasia, deficiency of a-L-fucosidase, and red punctate lesions of the skin and oral mucosa.
Gingival biopsy specimens showed that these lesions were identical to the angiokeratoma corporis diffusum reported in Fabry's disease, but had different locations. Because of the slowly progressing psychomotor retardation and recurrent upper respiratory tract infections that the prognosis for patients with this disease is poor.
Treatment appears to be aimed at early diagnosis through amniocentesis.
|
| SKIN |
Angiokeratoma corporis diffusum |
-
Angiokeratoma corporis diffusum in a patient with normal enzyme activities.
Holmes RC, Fensom AH, McKee P, Cairns RJ, Black MM.
|
-
| J Am Acad Dermatol. 1984 Feb;10(2 Pt 2):384-7. Abstract quote |
|
A 34-year-old man is described with angiokeratoma corporis diffusum. This eruption was once thought to be diagnostic of Anderson-Fabry disease; however, recent studies have shown that it may also occur in the enzyme disorders fucosidosis and sialidosis.
In our patient with widespread angiokeratomas, the results of enzyme studies were normal, and there were no systemic problems or significant family history.
Our case demonstrates that angiokeratoma corporis diffusum can occur in a benign form without systemic features.
|
| HISTOLOGICAL TYPES |
CHARACTERIZATION |
| GENERAL |
|
| SKIN |
|
- Fucosidosis with angiokeratoma. Immunohistochemical & electronmicroscopic study of a new case and literature review.
Kanitakis J, Allombert C, Doebelin B, Deroo-Berger MC, Grande S, Blanc S, Claudy A.
Department of Dermatology (Pav. R), Ed. Herriot Hospital, Lyon, France.
|
-
| J Cutan Pathol. 2005 Aug;32(7):506-11. Abstract quote |
|
Fucosidosis is a rare lysosomal storage disease due to alpha-L-fucosidase deficiency.
It presents clinically with neurological, skeletal, and cutaneous findings, including mainly angiokeratoma corporis diffusum. Electronmicroscopic examination reveals characteristic electron-lucent cytoplasmic vacuolization present in several cell types of the skin and other tissues.
We present here a new patient suffering from fucosidosis with angiokeratoma, whose normal and diseased skin was studied by lightmicroscopy and electronmicroscopy. The salient clinicopathological features of this disease are briefly reviewed.
|
-
Cutaneous manifestations of fucosidosis.
Fleming C, Rennie A, Fallowfield M, McHenry PM.
Royal Hospital for Sick Children, Western Infirmary, Glasgow, Scotland, U.K.
|
-
| Br J Dermatol. 1997 Apr;136(4):594-7. Abstract quote |
|
Angiokeratoma corporis diffusum (ACD) is still often thought to be synonymous with Anderson-Fabry disease, a deficiency of alpha-galactosidase. It is important, however, to consider other possible enzyme deficiencies in patients with ACD.
We report an 8-year-old boy with neurodevelopmental delay who was diagnosed as having fucosidosis following recognition of ACD in the dermatology department. Other cutaneous features in this patient included distal transverse purple nail bands, acrocyanosis and a naevus anaemicus. Histology and electron microscopy of skin papules was consistent with angiokeratoma. Skeletal survey demonstrated dysostosis multiplex.
The diagnosis was confirmed by leucocyte oligosaccharide enzyme analysis. There are only three previous reports of fucosidosis in the U.K.
|
-
Histology and electron microscopy of fucosidosis of the skin. Subtle clues to diagnosis by electron microscopy.
Breier F, Hobisch G, Fang-Kircher S, Braun F, Paschke E, Jurecka W.
Department of Dermatology/Division of General Dermatology, University of Vienna, Austria.
|
-
| Am J Dermatopathol. 1995 Aug;17(4):379-83. Abstract quote |
|
Fucosidosis is an autosomal recessive inborn error of metabolism in which fucose-containing glycolipids, glycoproteins, and oligo- and polysaccharides accumulate in tissues as a consequence of alpha-L-fucosidase deficiency.
Since the detection of this entity in 1966 several cases have been described, but until now investigations of clinically uninvolved skin have not been performed.
In this study we have investigated clinically normal skin obtained from a patient with fucosidosis and his healthy sister, by light and electron microscopy, to determine whether normal skin in this condition yields clues that may have prognostic relevance.
We found "empty"- appearing storage vesicles in melanocytes, endothelial cells, sweat glands, and fibroblasts in the skin.
|
-
Angiokeratoma corporis diffusum (Fabry's disease) with unusual features in a female patient. Light- and electron-microscopic investigation.
Voglino A, Paradisi M, Dompe G, Onetti Muda A, Faraggiana T.
Immacolata Dermatology Institute, Polyclinic Umberto I, Rome, Italy.
|
-
| Am J Dermatopathol. 1988 Aug;10(4):343-8. Abstract quote |
|
A case of clinically apparent angiokeratoma corporis diffusum (Fabry's disease) in an adult female carrier is presented. The patient had biochemical evidence of the disease, and showed multiple cutaneous lesions, in the absence of other major organ involvement.
Ultrastructural examination of tissue fragments obtained by skin biopsies demonstrated the presence of a few typical electron-dense lamellar structures in endothelial cells, but not in smooth muscle cells. Electron microscopy proved to be the only effective way of detecting the intracytoplasmic inclusions, since light-microscopic histochemistry failed to reveal small amounts of the stored glycolipid.
The exclusive involvement of endothelial cells suggests that they are more prone to store glycolipid than are all other types of cells usually involved in the disease. The abundance of intermediate filaments in the cytoplasm of endothelial cells is related exclusively to the high blood pressure in angiomatous arteriovenous shunts.
|
SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHER |
CHARACTERIZATION |
| SPECIAL STAINS |
|
| IMMUNOPEROXIDASE |
|
| ELECTRON MICROSCOPY |
|
-
Ultrastructural studies of type II fucosidosis.
Porfiri B, Ricci R, Seminara D, Segni G.
|
-
| Arch Dermatol Res. 1981;270(1):57-66. Abstract quote |
|
Type II fucosidosis in an autosomal recessive disease.
The paper presents a case of a patient with alpha-L-fucosidase of whom a skin specimen was examined under the electron microscope. Storage material was observed mainly in endothelial cells of blood capillaries and Schwann cells surrounding small peripheral nerves of papillary dermis.
Within both cells two different kinds of inclusions were revealed: (1) clear vacuoles and (2) dense bodies with an internal structure prevalently lamellar. All these ultrastructural alterations were observed long before the appearance of clinically defined angiokeratoma at cutaneous level.
Hence, they present the same alteration found in the absence of angiokeratoma in type I fucosidosis.
|
-
Fucosidosis with angiokeratoma. Electron microscopic changes in the skin.
Kornfeld M, Snyder RD, Wenger DA.
|
-
| Arch Pathol Lab Med. 1977 Sep;101(9):478-85. Abstract quote |
|
An electron microscopic investigation was performed on the skin from three patients suffering from fucosidosis accompanied by diffuse angiokeratoma. Storage of fucose containing substances was represented by the following two kinds of cytosomes: lamellated bodies, found in Schwann cells and myoepithelial cells of sweat glands and membrane-bound vacuoles, located in various other cellular elements of the skin.
Storage in endothelial cells caused narrowing or occlusion of some dermal blood vessels; in the papillary plexus, angiectasis was the result. Extensive vacuolation of the secretory cells of sweat glands could account for hypohydrosis.
The characteristic distribution of cytosomes in various kinds of cells is helpful in differentiating fucosidosis from some other storage diseases on the basis of skin biopsy.
|
| DIFFERENTIAL DIAGNOSIS |
KEY DIFFERENTIATING FEATURES |
| ALPHA-N-ACETLYGALACTO-SAMINIDASE DEFICIENCY |
|
-
Angiokeratoma corporis diffusum with glycopeptiduria due to deficient lysosomal alpha-N-acetylgalactosaminidase activity. Clinical, morphologic, and biochemical studies.
Kanzaki T, Yokota M, Irie F, Hirabayashi Y, Wang AM, Desnick RJ.
Department of Dermatology, Nagoya City University Medical School, Japan.
|
-
| Arch Dermatol. 1993 Apr;129(4):460-5. Abstract quote |
|
BACKGROUND--Angiokeratoma corporis diffusum is a prominent cutaneous feature of certain lysosomal storage diseases. In this article, the clinical, morphologic, and biochemical features of a new, adult-onset lysosomal disease with angiokeratoma are described.
OBSERVATIONS--A 46-year-old Japanese woman had diffuse angiokeratoma, mild intellectual impairment, and peripheral neuroaxonal degeneration. The angiokeratoma first appeared on her lower torso when she was 28 years old, and then it became diffusely distributed. Histopathologically, the telangiectasia had localized hyperkeratosis; ultrastructural examination revealed clear cytoplasmic vacuoles in all dermal cells, particularly in vascular and lymphatic endothelial cells and in eccrine sweat gland cells. The lysosomal pathologic features and increased urinary excretion of O-linked glycopeptides suggested the deficiency of a specific glycosidase. Enzyme analyses revealed less than 2% of normal alpha-N-acetylgalactosaminidase activity and the absence of immunodetectable enzyme protein. Her two unaffected children had half-normal alpha-N-acetylgalactosaminidase levels, consistent with the autosomal recessive inheritance of the enzymatic defect.
CONCLUSIONS--Since this enzyme deficiency was previously identified in patients with an infantile form of inherited neuroaxonal dystrophy, the occurrence of the enzymopathy in the 46-year-old proband described herein represents an adult-onset form of alpha-N-acetylgalactosaminidase deficiency. This newly recognized entity should be considered in the differential diagnosis of angiokeratoma corporis diffusum.
|
-
A new case of alpha-N-acetylgalactosaminidase deficiency with angiokeratoma corporis diffusum, with Meniere's syndrome and without mental retardation.
Kodama K, Kobayashi H, Abe R, Ohkawara A, Yoshii N, Yotsumoto S, Fukushige T, Nagatsuka Y, Hirabayashi Y, Kanzaki T.
Department of Dermatology, Hokkaido University School of Medicine, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan.
|
-
| Br J Dermatol. 2001 Feb;144(2):363-8. Abstract quote |
|
alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency is a rare hereditary lysosomal storage disease, and only three alpha-NAGA-deficient patients with angiokeratoma corporis diffusum (Kanzaki) have been described.
We report a further case in a 47-year-old Japanese woman, the product of a consanguineous marriage. The remarkable findings in this patient were her normal intelligence, Meniere's syndrome, disturbance of peripheral sensory nerves, hearing loss and cardiac hypertrophy. alpha-NAGA enzyme activity in her plasma was 0.77% of the normal value. Other enzyme activities, such as alpha-galactosidase, beta-galactosidase, alpha-L-fucosidase, beta-mannosidase and aspartylglucosaminidase, were within normal limits. A large quantity of amino acid O-glycans was detected in her urine.
Gene analysis revealed a novel point mutation (G-->A transition) at nucleotide 11018 (986 in the cDNA) resulting in an Arg-329-Gln substitution. Kanzaki disease has the same enzyme defect as Schindler disease, but the manifestations are quite different.
|
-
Lysosomal alpha-N-acetylgalactosaminidase deficiency, the enzymatic defect in angiokeratoma corporis diffusum with glycopeptiduria.
Kanzaki T, Wang AM, Desnick RJ.
Department of Dermatology, Nagoya City University Medical School, Japan.
|
-
| J Clin Invest. 1991 Aug;88(2):707-11. Abstract quote |
|
Recently a novel case of angiokeratoma corporis diffusum with glycoaminoaciduria was described in a 46-yr-old Japanese woman.
Known causes of the cutaneous manifestation were eliminated by enzyme analyses, and further characterization of the accumulated urinary O-linked sialopeptides revealed identity to those excreted by patients with an infantile neuroaxonal dystrophy due to lysosomal alpha-N-acetylgalactosaminidase deficiency. Investigation of the alpha-N-acetylgalactosaminidase activity and protein in the proband revealed less than 2% of normal activity and the absence of detectable immunoreactive enzyme protein, findings comparable to those in the patients with infantile neuroaxonal dystrophy and alpha-N-acetylgalactosaminidase deficiency. In addition, the proband's unaffected offspring had half-normal levels of alpha-N-acetylgalactosaminidase activity, consistent with this enzymatic deficiency being the primary metabolic defect in this autosomal recessive trait.
Ultrastructural examination of skin and blood cells from the adult proband revealed the presence of prominent lysosomal inclusions containing diffuse amorphous and filamentous material. In contrast, these morphologic findings were not observed in the nonneural tissues from patients with infantile neuroaxonal dystrophy and alpha-N-acetylgalactosaminidase deficiency.
These studies document the occurrence of two forms of alpha-N-acetylgalactosaminidase deficiency and sialopeptiduria, a severe infantile-onset form of neuroaxonal dystrophy without angiokeratoma or visceral lysosomal inclusions and an adult-onset form characterized by angiokeratoma, extensive lysosomal accumulation of sialoglycopeptides and the absence of detectable neurologic involvement.
|
| BETA-MANNOSIDOSIS |
|
-
Beta-mannosidosis with angiokeratoma corporis diffusum.
Suzuki N, Konohana I, Fukushige T, Kanzaki T.
Division of Dermatology, Hiratsuka City Hospital, Kanagawa, Japan.
|
-
| J Dermatol. 2004 Nov;31(11):931-5. Abstract quote |
|
Beta-mannosidosis is a lysosomal disorder which is caused by a deficiency of beta-mannosidase. This disorder was first described in goats. Twelve human cases have already been reported.
We present the first case in Japan in whom the diagnosis was reached from angiokeratoma corporis diffusum. Futhermore, mental retardation, hearing loss, and renal failure were also detected. Pseudoxanthoma elasticum was also present, but whether it is a complication of beta-mannosidosis or not remains unknown. The activity level of beta-mannosidase in the patient's plasma was only 2% of the normal range, while that in the patient's mother was 40%.
We suggest that beta-mannosidosis should be one of the differential diagnoses when lysosomal enzyme disorders are suspected in cases of angiokeratoma corporis diffusum.
|
| TREATMENT |
CHARACTERIZATION |
| GENERAL |
|
-
Fabry disease: recognition and management of cutaneous manifestations.
Mohrenschlager M, Braun-Falco M, Ring J, Abeck D.
Department of Dermatology and Allergy Biederstein, Technical University of Munich, Munich, Germany.
|
-
| Am J Clin Dermatol. 2003;4(3):189-96. Abstract quote |
|
Fabry disease (angiokeratoma corporis diffusum universale) is a rare, X chromosome-linked lysosomal storage disease. The deficient enzyme, alpha-galactosidase A (alpha-gal A), is responsible for the accumulation of neutral glycosphingolipids within vascular endothelial lysosomes of various organs, including skin, kidneys, heart, and brain.
The disease manifests primarily in affected hemizygous men and to some extent in heterozygous women ('carriers'). The diagnosis of Fabry disease is made in hemizygous males after the detection of the presence of angiokeratomas, irregularities in sweating, edema, scant body hair, painful sensations, and of cardiovascular, gastrointestinal, renal, ophthalmologic, phlebologic, and respiratory involvement. A deficiency of alpha-gal A in serum, leukocytes, tears, tissue specimens, or cultured skin fibroblasts further supports the diagnosis in male patients. Since heterozygous women show angiokeratomas in only about 30% of cases and may have alpha-gal A levels within normal range, genetic analysis is recommended.
Current treatment of angiokeratomas of Fabry disease is based mainly on the use of laser systems, including variable pulse width 532nm Neodymium:Yttrium-Aluminum-Garnet (Nd:YAG) laser, 578nm copper vapor laser, and flashlamp-pumped dye laser. When cutaneous and mucous glands are affected, restrictions may be required with regard to the time spent in a warm climate and the amount time spent working or on sporting activities, and may necessitate the use of topical and systemic antiperspirant agents, and topical application of artificial lacrimal fluid and saliva, respectively.
-
For the future, new treatment modalities, including enzyme replacement therapy, substrate deprivation strategies, and gene therapy offer extraordinary options for the cutaneous and visceral lesions in patients with Fabry disease. |
| GENE THERAPY |
|
-
Correction of alpha-L-fucosidase deficiency in fucosidosis fibroblasts by retroviral vector-mediated gene transfer.
Occhiodoro T, Hopwood JJ, Morris CP, Anson DS.
Department of Chemical Pathology, Adelaide Children's Hospital, South Australia.
|
-
| Hum Gene Ther. 1992 Aug;3(4):365-9. Abstract quote |
|
A full-length cDNA clone encoding the lysosomal hydrolase alpha-L-fucosidase was cloned into two retroviral vectors, one using the human cytomegalovirus immediate-early promoter for expression, and the other, the retroviral long terminal repeat (LTR).
High-titer amphotropic virus was produced for both constructs by infection of PA317 cells, and used to efficiently transduce the alpha-L-fucosidase gene into both human and canine fucosidosis fibroblasts. This resulted in correction of the alpha-L-fucosidase enzyme deficiency characteristic of these fibroblasts. The high levels of recombinant enzyme produced corrected the degradative defect normally seen in these cells, enabling them to catabolize efficiently the accumulated storage product present in lysosomes.
Therefore, these retroviral constructs should allow us to start evaluating the value of gene therapy in treating the central nervous system pathology associated with fucosidosis and other lysosomal storage disorders in humans, using a canine model of fucosidosis.
|
