Metabolic Diseases
Stephan Strobel, Lewis Spitz, Stephen D. Marks in Great Ormond Street Handbook of Paediatrics, 2019
Fabry disease is a multi-system disease that is extremely heterogeneous. Presentations include painful burning extremities in late childhood that are typically exacerbated by exercise or extremes of temperature. Gastrointestinal complaints, e.g. diarrhoea and abdominal pain, as well as signs of vestibular dysfunction and tinnitus are also common. Presentation with severe renal impairment, heart failure, stroke and/or psychiatric disease in adulthood is also well recognised and make up the classical, severe, life-threatening pathology of the disease. Many patients are asymptomatic with the diagnosis following family screening. Physical findings include angiokeratoma and cornea verticillata on slit-lamp examination.
Fabry disease
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop in Atlas of Inherited Metabolic Diseases, 2020
X-linked inheritance was first established by pedigree analysis (Figure 87.6). Two populations of cells – one with normal galactosidase activity and the other defective – were shown by cloning of cultured fibroblasts [54]. The cDNA for the gene for α-galactosidase has been cloned and sequenced [12], and this has permitted delineation of the nature of a number of mutations. The gene has seven exons. Major gene rearrangement detected by Southern hybridization included five deletions and duplication [55]. A number of smaller deletions and insertions have been identified, many of which led to frameshifts and premature termination. Most mutations in Fabry hemizygotes are not detected in this way. Mutations altering the processing of the mRNA transcript have been observed. Single nucleotide missense mutations have been identified in a majority of families [55–57], and most have been found only in one single family. However, a high frequency of mutation was observed at 14 CpG dinucleotides in the coding sequence. More than 300 mutations have been found in patients with Fabry disease [58]. Among them two novel mutations, 1277delAA (del2) and 1284delACTT(del4) in the 3ʹ terminus, obliterated the termination codon and generated multiple transcripts, most of them inactive [58]. Among 110 patients [50] the mutations were 76 percent missense 16 nonsenses and 3 percent each frameshift and splice site. Fabry disease is the most common lysosomal storage disease after Gaucher disease. The prevalence of heterozygous carriers in the United Kingdom was estimated at 1 in 339,000 females [41]. Heterozygote detection has been carried out by enzyme assay of cultured fibroblasts after cloning [52] and cell sorting, but these methods are not practical for clinical use. The assay of the enzyme in individual hair roots [59] is more convenient but still labor intensive. In a family in which the mutation has been identified, targeted analysis can be employed for precise identification of heterozygosity. Prenatal diagnosis has been accomplished by the demonstration of deficient α-galactosidase activity in cultured amniotic fluid cells [60]. A microtechnique for α-galactosidase has been developed for prenatal diagnosis, which requires small numbers of cultured amniocytes [61]. Diagnosis has also been made prenatally by chorionic villus sampling [62].
Renal and urinary tract diseases
Angus Clarke, Alex Murray, Julian Sampson in Harper's Practical Genetic Counselling, 2019
Fabry disease is X-linked with partial manifestation in some females. Cardiac involvement, characteristic skin lesions and painful neuropathy are other predominant features, in addition to nephropathy and also ocular involvement. Diagnosis of the affected hemizygous male can employ enzyme assay (α-galactosidase), but the detection of heterozygous carrier females (whether or not they manifest clinical features of the disorder) is often best achieved by molecular methods. Prenatal diagnosis is also available by molecular diagnostics or by enzyme assay (for a male fetus). Enzyme replacement therapy is available (and useful) for affected males and for females who manifest complications of the condition.
Agalsidase alfa for the treatment of Fabry disease: new data on clinical efficacy and safety
Published in Expert Opinion on Biological Therapy, 2009
Background: Fabry disease is an X-linked disease caused by the deficiency of the lysosomal enzyme α-galactosidase A. The lack of enzyme activity leads to progressive depositions of undegraded glycolipids in a great number of organs, resulting in a multisystemic disorder. Objectives: Enzyme replacement therapy is available for patients with Fabry disease. Two enzyme preparations have been approved in the European Union by the European Agency for the Evaluation of Medicinal Products (EMEA): agalsidase beta (Fabrazyme®, Genzyme Corporation), produced in Chinese hamster ovary cells; and agalsidase alfa (Replagal®, Shire Human Genetic Therapies, Inc.), produced in human cell lines. Methods: This review details the latest reports regarding the clinical efficacy and tolerability of agalsidase alfa in patients with Fabry disease. Results: Agalsidase alfa was shown to be effective in treating pain and in reducing heart size in patients with Fabry disease, to stabilize kidney function and to improve hearing, sweating and quality of life. It is able slow down progression of renal failure in patients with end-stage renal disease.
Cognitive and speech perception outcomes after cochlear implantation in Fabry disease
Published in Hearing, Balance and Communication, 2020
Filiz Aslan, Mehtap Yıldırım, Gonca Sennaroğlu
Purpose: To study the audiological, rehabilitative and cognitive outcomes of cochlear implantation in patients with Fabry disease (FD). Method: This is a retrospective case study. Two adults with progressive hearing loss were followed up for over 3 years. Results: The patients had progressive hearing loss from the first decade of life. Preoperative evaluations indicated delays in speech perception and cognitive skills due to hearing loss. There was a significant increase in hearing thresholds and speech perception in both patients after the cochlear implantation. The cognitive skills and memory skills of the patient who started using the cochlear implant later in life continued to lag. Conclusion: In FD, hearing loss should be closely monitored and appropriate interventions should be selected early. Two patients from the same family showed the strong impact of early intervention on speech perception and cognitive skills. The study aimed to emphasize the necessity of speech perception and cognitive skills assessment during the follow-up of patients with FD.
Improved hearing with cochlear implantation in Fabry's disease
Published in Cochlear Implants International, 2011
David J Clinkard, Hosam Amoodi, Vincent Y W Lin, Joseph M Chen, Julian M Nedzelski
Objective To describe our center's experience with cochlear implantation in patients suffering from Fabry's disease, an inherited mutation resulting in an alpha-galactosidase A enzyme deficiency. Clinical Presentation Case report of two patients aged 49 and 59 at implant, with genetically confirmed Fabry's disease and progressive hearing loss. Intervention Surgical implantation of Clarion (Advanced Bionics) and Nucleus Freedom (Cochlear) cochlear implants. Conclusion Cochlear implantation improves hearing discrimination by 60 points on the HINT scale. This suggests that cochlear implantation is a safe and effective intervention that improves hearing discrimination in patients suffering from Fabry's disease.
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