Fabry's disease Zarate, Yuri A, MD; Hopkin, Robert J, Dr
The Lancet (British edition),
2008-Oct-18, Letnik:
372, Številka:
9647
Journal Article
Recenzirano
Summary Fabry's disease is an X-linked lysosomal storage disorder caused by abnormalities in the GLA gene, which leads to a deficiency in α-galactosidase A. The consequent abnormal accumulation of ...glycosphingolipids results in several clinical signs and symptoms and substantial morbidity and mortality. This review covers all basic aspects of the disease such as epidemiology, pathophysiology, clinical presentation by systems, diagnosis, management, prevention, and repercussions on quality of life. With the development of enzyme replacement therapy in the past few years, early initiation of treatment is key for improvement in major affected organs with decreased cardiac mass and stabilisation of kidney function, and improvement in neuropathic pain, sweating, gastrointestinal symptoms, hearing loss, and pulmonary symptoms. However, treatment of individual symptoms in addition to enzyme replacement therapy seems to be needed for many patients, especially those who have had some degree of organ dysfunction. Additional data are needed to document long-term treatment outcomes.
Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene leading to deficient α-galactosidase A activity, glycosphingolipid accumulation, and life-threatening ...complications. Phenotypes vary from the “classic” phenotype, with pediatric onset and multi-organ involvement, to later-onset, a predominantly cardiac phenotype. Manifestations are diverse in female patients in part due to variations in residual enzyme activity and X chromosome inactivation patterns. Enzyme replacement therapy (ERT) and adjunctive treatments can provide significant clinical benefit. However, much of the current literature reports outcomes after late initiation of ERT, once substantial organ damage has already occurred. Updated monitoring and treatment guidelines for pediatric patients with Fabry disease have recently been published. Expert physician panels were convened to develop updated, specific guidelines for adult patients. Management of adult patients depends on 1) a personalized approach to care, reflecting the natural history of the specific disease phenotype; 2) comprehensive evaluation of disease involvement prior to ERT initiation; 3) early ERT initiation; 4) thorough routine monitoring for evidence of organ involvement in non-classic asymptomatic patients and response to therapy in treated patients; 5) use of adjuvant treatments for specific disease manifestations; and 6) management by an experienced multidisciplinary team.
Fabry's disease is an X-linked lysosomal storage disorder caused by abnormalities in the GLA gene, which leads to a deficiency in α-galactosidase A. The consequent abnormal accumulation of ...glycosphingolipids results in several clinical signs and symptoms and substantial morbidity and mortality. This review covers all basic aspects of the disease such as epidemiology, pathophysiology, clinical presentation by systems, diagnosis, management, prevention, and repercussions on quality of life. With the development of enzyme replacement therapy in the past few years, early initiation of treatment is key for improvement in major affected organs with decreased cardiac mass and stabilisation of kidney function, and improvement in neuropathic pain, sweating, gastrointestinal symptoms, hearing loss, and pulmonary symptoms. However, treatment of individual symptoms in addition to enzyme replacement therapy seems to be needed for many patients, especially those who have had some degree of organ dysfunction. Additional data are needed to document long-term treatment outcomes. PUBLICATION ABSTRACT
Curry-Jones syndrome (CJS) is a multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, ...and intestinal malrotation with myofibromas or hamartomas. Cerebellar medulloblastoma has been described in a single affected individual; in another, biopsy of skin lesions showed features of trichoblastoma. The combination of asymmetric clinical features, patchy skin manifestations, and neoplastic association previously led to the suggestion that this could be a mosaic condition, possibly involving hedgehog (Hh) signaling. Here, we show that CJS is caused by recurrent somatic mosaicism for a nonsynonymous variant in SMO (c.1234C>T p.Leu412Phe), encoding smoothened (SMO), a G-protein-coupled receptor that transduces Hh signaling. We identified eight mutation-positive individuals (two of whom had not been reported previously) with highly similar phenotypes and demonstrated varying amounts of the mutant allele in different tissues. We present detailed findings from brain MRI in three mutation-positive individuals. Somatic SMO mutations that result in constitutive activation have been described in several tumors, including medulloblastoma, ameloblastoma, and basal cell carcinoma. Strikingly, the most common of these mutations is the identical nonsynonymous variant encoding p.Leu412Phe. Furthermore, this substitution has been shown to activate SMO in the absence of Hh signaling, providing an explanation for tumor development in CJS. This raises therapeutic possibilities for using recently generated Hh-pathway inhibitors. In summary, our work uncovers the major genetic cause of CJS and illustrates strategies for gene discovery in the context of low-level tissue-specific somatic mosaicism.
Historically, medical geneticists and genetic counselors have provided the majority of genetic services. Advances in technology, reduction in testing costs, and increased public awareness have led to ...a growing demand for genetic services in both clinical and direct-to-consumer spaces. Recent and anticipated changes in the workforce of genetic counselors and medical geneticists require a reexamination of the way we educate health-care providers and the means by which we provide access to genetic services. The time is ripe for rapid growth of genetic and genomic services, but to capitalize on these opportunities, we need to consider a variety of educational mechanisms to reach providers both within and beyond the traditional genetic counseling and medical genetics sectors, including nurses, physician assistants, and nongenetics physicians. This article summarizes the educational efforts underway in each of these professions.
BackgroundFabry disease (α-galactosidase deficiency) is an X-linked genetic disease caused by a variety of pathogenic GLA variants. The phenotypic heterogeneity is considerable, with two major forms, ...classic and later-onset disease, but adjudication of clinical phenotype is currently lacking for many variants. We aimed to determine consensus phenotypic classification for previously unclassified GLA variants from the GLA-specific fabry-database.org database.MethodsA Fabry disease genotype–phenotype workgroup developed a five-stage iterative system based on expert clinical assessment, published literature and clinical evidence of pathogenicity using a 2-point scoring system based on clinical hallmarks of classic disease. Kaplan–Meier (KM) analysis of severe clinical event-free survival was used as final validation. Results were compared with those from web-based disease databases and in silico pathogenicity prediction programmes.ResultsFinal consensus on classifications of ‘pathogenic’ was achieved for 32 of 33 GLA variants (26 ‘classic’ phenotype, 171 males; 6 ‘later-onset’ phenotype, 57 males). One variant remained of uncertain significance. KM curves were similar for the known fabry-database.org database phenotypes and when workgroup consensus classifications were added, and the curves retained the same separation between ‘classic’ and ‘later-onset’ phenotypes.ConclusionThe iterative system implemented by a Fabry disease genotype–phenotype workgroup achieved phenotypic classifications for variants that were previously unclassified. Clinical pathogenicity associated with a particular GLA variant defined in affected males appears to have predictive value and also generally correlates with risk for affected females. The newly established classifications can be of benefit to the clinical care of Fabry patients harbouring these variants.
Objective To characterize morbidity, mortality, and surgical outcomes in pediatric patients with symptomatic plexiform neurofibromas (PNFs). Study design We conducted retrospective analysis of data ...from clinical records of surgical history and other neurofibromatosis type 1 (NF1)-related complications in children with PNFs seen at Cincinnati Children’s Hospital Medical Center between 1997 and 2007. Results A total of 154 children with NF1 and PNFs were identified. Children with symptomatic PNFs had increased incidence of other NF1-related tumors ( P < .05). Patients with NF1 and PNFs had a higher mortality rate (5/154, 3.2%) when compared with patients without or with asymptomatic PNFs (2/366, 0.5%; P = .024). The most common morbidities leading to surgeries were neurologic, disfigurement, orthopedic, and airway complaints. Less extensive resection predicted a shorter interval to second surgery ( P < .0019). The highest recurrence was seen in tumors located in the head, neck, and thorax ( P < .001). Conclusions These findings quantify the increased risk for additional tumors and mortality associated with symptomatic PNFs. Surgical interventions were required in many cases and resulted in added morbidity in some cases. Patients with PNFs were more likely to benefit from surgery when the indications were airway compression or disfigurement.
The systematic collection of disease-specific symptoms and impacts on the lives of patients with Fabry Disease (FD) can offer unique insights into the patient experience, yet no disease-specific tool ...to measure FD symptoms exists. This study describes the development of the Fabry Disease Patient-Reported Outcome (FD-PRO).
A targeted literature search, interviews with key opinion leaders (KOLs), and concept elicitation (CE) interviews with patients identified the most frequent signs and symptoms associated with FD and their impact on daily life. Cognitive interviews evaluated patients' ability to understand the FD-PRO instructions and respond to the items on the draft FD-PRO instrument.
The targeted literature search identified key signs and symptoms in domains that were confirmed in KOL interviews. In CE interviews with 37 treated and treatment-naïve patients, neuropathic pain symptoms (95% treated, 82% treatment-naïve), temperature intolerance (95% treated, 88% treatment-naïve), energy difficulties (95% treated, 94% treatment-naïve), hearing/vision impairment (95% treated, 71% treatment-naïve), and gastrointestinal symptoms (80% treated, 59% treatment-naïve) were most frequently mentioned. Results were similar for men and women in both treated and treatment-naïve groups. While treatment-naïve patients in general expressed fewer and milder symptoms compared to treated patients, the overall sets of symptoms expressed by the two groups were similar. The most severe symptoms were neuropathic pain, stomach pain, burning pain, and fatigue. The most bothersome symptoms were stomach pain, breathing difficulty, fatigue, neuropathic pain, and constipation. The most frequent impacts were in the work/school limitations domain for both treated and treatment-naïve patients. The impacts with the highest difficulty ratings were stress, limited outdoor activity, and guilt. Cognitive interviews with 14 treated and treatment-naïve patients resulted in the refinement of FD-PRO items and language.
The FD-PRO is a novel, disease-specific instrument that measures the patient experience in Fabry disease. Such tools are valuable in capturing the burden of disease in patients with FD and demonstrating the value of treatment in clinical trials.
Objective To evaluate the utility of screening brain/orbital magnetic resonance imaging (MRI) in a large population of children with neurofibromatosis type 1 (NF1) over a 20-year period. Study design ...A retrospective analysis of clinical and imaging data from children with NF1 seen at a single center between 1990 and 2010 was performed. Results During the 20-year study period, 826 individuals with NF1 (402 females, 424 males) ages 1-9 years were screened for optic pathway gliomas (OPGs) using brain/orbital MRI; 18% were identified with OPGs with a median age at detection of 3 years. Fifteen percent of patients with OPGs had radiologic or clinical progression requiring therapy. Children with chiasmatic and postchiasmatic tumors were more likely to require therapy compared with patients with prechiasmatic OPGs ( P < .0001). Patients with visual deficits at the time of diagnosis were more likely to experience visual decline despite therapy when compared with patients treated based on radiologic progression ( P < .012). Conclusions Our findings confirm that chiasmatic and postchiasmatic OPG in children with NF1 have the highest risk for progression and vision loss. Early identification of OPG by screening MRI prior to the development of vision loss may lead to improved visual outcomes. Children with negative brain and orbital MRI screening at age 15 months or later did not develop symptomatic OPGs.
Holoprosencephaly is the most common malformation of forebrain development and includes a wide spectrum of severity. The objective of this retrospective study was to evaluate fetal magnetic resonance ...imaging (MRI) associations with outcome. Of the 63 cases identified on antenatal ultrasonography, 28 cases were confirmed on fetal MRI. There were 17 live births; 9 patients died within the first month of life. There were 7 survivors. The vast majority were nonambulatory and required feeding support; none required respiratory support. We found that presence and number of non–holoprosencephaly-associated malformations was also associated with survival. Of 5 patients with 3 or more systemic anomalies, 4 died regardless of holoprosencephaly subtype and 1 was lost to follow-up. Patients with suspected holoprosencephaly on ultrasonography should have full body fetal MRI and echocardiogram to better evaluate systemic anomalies. Counseling should involve pediatric palliative care services to prepare families in caring for babies with limited life span.
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