In Gaucher disease (GD), inherited deficiency in lysosomal acid beta-glucocerebrosidase leads to the widespread accumulation of glycolipid-laden macrophages in tissues and consequent multisystemic ...disease. The presenting symptoms of type 1 (non neuronopathic) Gaucher disease commonly reflect the haematologic components of the disease, i.e., splenomegaly, thrombocytopenia, anaemia, and bleeding tendency. Consequently the majority of patients are referred to haematologists for diagnosis and management. However, the remarkable heterogeneity of the disease compounded by its rarity presents a diagnostic challenge. Only around 20% of haematologists consider GD in differential diagnosis even though all classic manifestations of the disease may be present. Haematologic malignancy is the most often considered diagnosis in such patients. Lack of awareness of GD and its protean manifestations renders individuals with Gaucher disease vulnerable to misdiagnosis, diagnostic delays and risk of irreversible complications that are otherwise preventable by timely therapy. Missed diagnosis may place individuals at risk of bleeding even in the presence of mild thrombocytopenia, irreversible skeletal complications leading to disability and impaired growth, and an increased risk of malignancy, especially multiple myeloma. Imiglucerase (Cerezyme) enzyme replacement therapy is effective in reversing haematological, visceral and some skeletal manifestations of the disease. In a minority of patients in whom imiglucerase is not suitable, Miglustat substrate reduction therapy (Zavesca) is an alternative. An international group of physicians met to harness their respective experience of managing the diverse phenotypes of Gaucher disease in order to raise awareness of GD and to determine under which circumstances GD should be given greater priority in differential diagnosis. As a result of their discussions, simple diagnostic algorithms have been devised, which focus on splenomegaly as the most prevalent presenting manifestation of GD in individuals of both Ashkenazi Jewish and non Ashkenazi Jewish background. Given the prevalence of GD in Ashkenazim, a possible diagnosis of GD is prioritised in the presence of splenomegaly in this population. When challenged by differential diagnosis of splenomegaly, GD can be confirmed or eliminated by a straightforward assay for beta glucocerebrosidase activity. Diagnostic algorithms are accompanied by disease management algorithms, which reflect published therapeutic goals and monitoring guidelines, to simplify decision making in the evaluation, treatment and ongoing monitoring of GD in response to therapy.
Molecular Diagnosis of Wilson Disease Butler, Patrice; McIntyre, Neil; Mistry, Pramod K.
Molecular genetics and metabolism,
03/2001, Letnik:
72, Številka:
3
Journal Article
Recenzirano
Wilson disease (WD) is caused by mutations in the ATP7B gene. The diagnosis is based on clinical and biochemical criteria but these are increasingly recognized to have low sensitivity. Genetic ...diagnosis is considered impractical due to the large coding region of the ATP7B gene and extreme diversity of mutations. We assessed the feasibility and utility of genetic diagnosis in WD. The coding region of the ATP7B gene was scanned by single-stranded conformation polymorphism (SSCP) analysis in 6 cases in whom the diagnosis of WD was uncertain. In addition, we attempted molecular diagnosis in 26 WD patients of similar ethnicity but variable disease manifestations. In 6 individuals in whom the biochemical/clinical diagnosis was uncertain, DNA analyses were useful for assigning their status with respect to WD. Molecular diagnosis identified presymptomatic individuals in families affected by WD and assigned heterozygote carrier or wild-type status to individuals previously diagnosed as affected. In 26 WD patients, 92% of disease alleles were identified. The most common mutations were H1069Q, L936X, and 2532delA representing 48, 10, and 8% of disease alleles, respectively. Three novel mutations were identified: Q898R, 3061(−1)g → a, and 3972insC. Genetic diagnosis is feasible for WD. Greater application of molecular diagnosis should enable an appreciation of the full spectrum of WD phenotype that is not possible with currently available diagnostic criteria.
Cyclosporine is the most common maintenance immunosuppressant in liver transplants patients, but it is often associated with nephrotoxicity.
We evaluated the safety and efficacy of monotherapy with ...mycophenolate mofetil (1 g twice daily) in five stable liver transplant patients with cyclosporine-induced renal impairment despite reduction of cyclosporine to subtherapeutic levels. Follow-up was 8.4+/-2.4 (range: 6-12) months.
No major side effects have been observed to date. Serum creatinine levels were significantly reduced from a median of 201 micromol/L before to 142 micromol/L at 3 months after mycophenolate (P=0.04) and remained low at 6 months. New onset cellular rejection occurred in only one patient after 3 months on mycophenolate monotherapy, and it responded completely to an intravenous course of methylprednisolone.
Monotherapy with mycophenolate mofetil in a dose of 1 g twice daily seems to significantly improve cyclosporine-induced renal impairment in stable liver transplant patients without major side effects or significant risk of rejection.
BACKGROUND The Gaucher Registry, the largest database of patients with Gaucher disease (GD) worldwide, was initiated to better delineate the progressive nature of the disorder and determine optimal ...therapy. This report describes the demographic and clinical characteristics of 1698 patients with GD before they received enzyme replacement therapy. METHODS Physicians worldwide who treat patients with GD were invited to submit prospective and retrospective data for an ongoing registry, using standardized data collection forms, for central processing and review. RESULTS Most patients were from the United States (45%) and Israel (17%), but patients are from 38 countries. Most (94%) had type 1 GD, fewer than 1% had type 2, and 5% had type 3. Mutant allele frequency data, available for 45% of patients, showed the most common alleles to be N370S (53%), L444P (18%), 84GG (7%), and IVS2+1 (2%). Twenty-five percent of L444P homozygotes (13 of 52 patients) had type 1 GD phenotype. Mean age at diagnosis in patients with the N370S/N370S genotype was 27.2 years (SD, 19.7 years); in L444P/L444P patients, 2.3 years (SD, 3.2 years). Histories of bone pain and radiological bone disease were reported by 63% and 94% of patients, respectively; both were more likely in asplenic patients than in patients with spleens. Mean spleen and liver volumes were 19.8 and 2.0 multiples of normal, respectively. Anemia and thrombocytopenia were present in 64% and 56%, respectively. Thrombocytopenia was present in 13% of asplenic patients. CONCLUSIONS The Gaucher Registry permits a comprehensive understanding of the clinical spectrum of GD because of the uniquely large sample size. The Registry will be useful in evaluating the effects of specific therapies in GD and the possible influences of environment, ethnicity, and genotype on the natural history of the disorder.Arch Intern Med. 2000;160:2835-2843-->
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