Search PubMed⌕ Search

Biomedical subjects

R J Desnick

Publications and source records attributed to R J Desnick.

At least 19 recordsLinked to original sources
PubMed2006

Natural history of Type A Niemann-Pick disease: possible endpoints for therapeutic trials.

OBJECTIVE: To describe the disease course and natural history of Type A Niemann-Pick disease (NPD). METHODS: Ten patients with NPD-A (six male, four female; age range at entry: 3 to 6 months) were serially evaluated including clinical neurologic, ophthalmologic, and physical examinations, and assessment of development. Laboratory analyses, abdominal and brain ultrasounds, and chest radiographs also were obtained and information on intercurrent illnesses and cause of mortality was collected. RESULTS: All affected infants had a normal neonatal course and early development. The first symptom detected in all patients was hepatosplenomegaly. Developmental age did not progress beyond 10 months for adaptive behavior, 12 months for expressive language, 9 months for gross motor skills, and 10 months for fine motor skills. Non-neurologic symptoms included frequent vomiting, failure to thrive, respiratory infections, irritability, and sleep disturbance. Neurologic examination at the time of presentation was normal in most patients. Later neurologic examinations revealed progressive hypotonia with loss of the deep tendon reflexes. All patients had cherry red spots by 12 months. The median time from diagnosis to death was 21 months. The cause of death was respiratory failure in nine patients and complications from bleeding in the tenth. CONCLUSIONS: The clinical course in Type A Niemann-Pick disease is similar among affected patients and is characterized by a relentless neurodegenerative course that leads to death, usually within 3 years.

Child Development↗
PubMed2006

Mucopolysaccharidosis type IV: N-acetylgalactosamine-6-sulfatase mutations in Tunisian patients.

Mucopolysaccharidosis type IVA (MPS IVA; OMIM #253000) or Morquio A syndrome is an autosomal recessive inborn error resulting from the deficient activity of the lysosomal enzyme, N-acetylgalactosamine-6-sulfatase (GALNS), and the progressive lysosomal accumulation of sulfated glycosaminoglycans. Clinically, the severe form of this lysosomal storage disease is characterized by a characteristic severe bone dysplasia and normal intelligence. To date, a variety of mutations have been associated with the severe MPS IVA phenotype. Here, we report the GALNS mutations in six severe MPS IVA patients from four unrelated Tunisian families. For mutation detection, each of the 14 exons and adjacent intron-exon junctions of the GALNS gene were sequenced after PCR-amplification from genomic DNA. Two novel mutations were identified: a G to A transition in the conserved 5' donor splice site of intron 1 (GACgt-->GACat: designated IVS1(+1g-->a)) and a G to C transversion in codon 66 of exon 2 predicting a glycine to arginine substitution (G66R). The IVS1(+1g-->a) mutation was homozygous in five similarly affected patients from three presumably unrelated families, but haplotype analysis suggested a common ancestor. The affected patient in the fourth family was homozygous for the G66R mutation. These are the first GALNS mutations causing severe MPS IVA disease identified in Tunisia. These molecular findings provide genotype/phenotype correlations, and permit accurate carrier detection, prenatal diagnosis, and counseling for MPS IVA disease in Tunisia where first cousin consanguineous mating remains frequent.

Adolescent↗
PubMed2005

Mucopolysaccharidosis I: Alpha-L-Iduronidase mutations in three Tunisian families.

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease resulting from the defective activity of the enzyme alpha-L-iduronidase (IDUA). The disease has severe and milder phenotypic subtypes. The IDUA mutations in five MPS I patients from three unrelated families from central and southern Tunisia were determined by amplifying and sequencing each of the IDUA exons and intron-exon junctions. Two novel IDUA mutations, c.1805delTinsGAACA in exon 13 and I270S in exon 7, and two previously reported mutations, P533R and R628X, were detected. The two patients in family 1 who had the Hurler phenotype were homoallelic for the novel deletion-insertion mutation. The patient in family 2 who also had the Hurler phenotype was heteroallelic for the novel missense mutation I270S and the previously reported nonsense mutation R628X. The two patients in family 3 who had the Hurler-Scheie phenotype were homoallelic for P533R. In addition, six known IDUA polymorphisms were identified. These are the first Tunisian MPS I patients to be genotyped. The identification of these mutations and their genotype-phenotype correlations should facilitate prenatal diagnosis and counselling for MPS I in Tunisia, where a very high rate of consanguinity exists.

Alleles↗
PubMed2005

A new syndrome, congenital extraocular muscle fibrosis with ulnar hand anomalies, maps to chromosome 21qter.

BACKGROUND: Congenital fibrosis of the extraocular muscles (CFEOM) is a heterogeneous group of disorders that may be associated with other anomalies. The association of a CFEOM syndrome with ulnar hand abnormalities (CFEOM/U) has not been reported to date. OBJECTIVE: To describe a new autosomal recessive syndrome of CFEOM and ulnar hand abnormalities, and localise the disease causing gene. METHODS: Clinical evaluation of the affected members and positional mapping. RESULTS: Six affected patients with CFEOM/U (aged 2 to 29 years) from a large consanguineous Turkish family were studied. Ophthalmological involvement was characterised by non-progressive restrictive ophthalmoplegia with blepharoptosis of the right eye. The postaxial oligodactyly/oligosyndactyly of the hands was more severe on the right side. A genome-wide scan established linkage of this new autosomal recessive syndrome to a locus on chromosome 21qter. The multipoint LOD score was 4.53 at microsatellite marker D21S1259, and fine mapping defined a approximately 1.5 Mb critical region between microsatellite marker D21S1897 and the telomere of the long arm. CONCLUSIONS: CFEOM/U maps to a 1.5 Mb region at chromosome 21qter. Future identification of the disease causing gene may provide insights into the development of the extraocular muscles and brain stem alpha motor neurones, as well as anteroposterior limb development.

Adult↗
PubMed2004

Enzyme replacement and enhancement therapies for lysosomal diseases.

Although first suggested by de Duve in 1964, enzyme replacement therapy (ERT) for lysosomal storage diseases did not become a reality until the early 1990s when its safety and effectiveness were demonstrated in type 1 Gaucher disease. Today, ERT is a reality for Gaucher disease, Fabry disease and mucopolysaccharidosis type I (MPS I), and clinical trials with recombinant human enzymes are ongoing in Pompe disease, MPS II and MPS VI, and are about to begin in Neimann-Pick B disease. In addition to ERT, enzyme enhancement therapy (EET) offers a novel therapeutic strategy to increase the residual function of mutant proteins. EET employs small molecules as 'pharmacological chaperones' to rescue misfolded and/or unstable mutant enzymes or proteins that have residual function. EET also offers the possibility of treating neurodegenerative lysosomal disorders since these small therapeutic molecules may cross the blood-brain barrier. The current status of ERT and the prospects for EET for lysosomal storage diseases are reviewed.

Enzyme Therapy↗
PubMed2003

Niemann-Pick disease: sixteen-year follow-up of allogeneic bone marrow transplantation in a type B variant.

Allogenic bone marrow transplantation (BMT) was carried out on a 3-year-old white caucasian girl with Niemann-Pick disease (NPD) type B. The donor was her unaffected brother. The patient was neurologically normal at the time of transplantation. Engraftment was based on cytogenetic studies and increased leukocyte acid sphingomyelinase (ASM) activity. However, liver biopsies taken up to 33 months post transplantation showed only a moderate reduction in stored sphingomyelin and no significant increase in ASM activity. The post-transplantation period was complicated by severe graft-versus-host disease and a respiratory arrest. By 6 years of age, neurological involvement was observed, including bilateral cherry red spots. The proband is now severely mentally and physically disabled. Liver cirrhosis has continued to progress despite the BMT, and haematemesis due to portal hypertension occurred at 17 years of age. However, pulmonary infiltration regressed after BMT and there has been no clinical evidence of pulmonary insufficiency.

Adolescent↗
PubMed2003

Pulmonary involvement in type 1 Gaucher disease: functional and exercise findings in patients with and without clinical interstitial lung disease.

Pulmonary disease is a well-known complication of Type 1 Gaucher disease (GD), although its incidence is not well established and its severity varies. The purpose of this study was to determine the frequency and extent of pulmonary involvement in patients with GD. Pulmonary involvement was assessed by history, physical examination and chest radiograph in 150 consecutive patients with Type 1 GD presenting at a specialized center for genetic diseases. Five patients were noted to have clinical evidence of pulmonary involvement. Full pulmonary function tests were performed in these five patients and in an additional 13 patients randomly selected from the remaining 145. Many of the 18 patients also underwent radionuclide body imaging with 67 Gallium citrate and 111Indium-tagged leucocyte scans, as well as incremental cardiorespiratory exercise tests. Lung biopsies were available in two patients with lung disease, and a second examination of lung tissue was performed in one of these two patients post-mortem. Clinical lung disease was detected in five patients. All five had dyspnea, diffuse infiltrates, restrictive impairment and low single breath CO diffusing capacity (DLCOSB). Two of these patients underwent exercise testing and showed abnormalities consistent with lung disease (ventilatory limitation, excessive ventilation and increased dead space) as well as decreased VO2 max. and anaerobic threshold (AT). In contrast, in the other 13 patients, physical examination, chest radiographs and pulmonary function were normal (except for a low DLCOSB in one patient). Responses on exercise testing (performed in six of the 13 patients) were consistent with a circulatory impairment (decreased VO2 max. and AT). Our study found that <5% of patients with Type 1 GD have clinical interstitial lung disease. In addition, we found that some patients, without evident lung involvement, may experience limitations in physical exertion and are easily fatigued; this is attributable to impaired circulation.

Adolescent↗
PubMed2002

Enzyme replacement therapy for Fabry disease, an inherited nephropathy.

Fabry disease, an X-linked lysosomal storage disease, results from the deficient activity of the enzyme alpha-galactosidase A (alpha-Gal A) and the progressive accumulation of globotriaosylceramide (GL-3) and related glycosphingolipids. In classically affected males with this inherited nephropathy, early and marked GL-3 deposition in the podocytes leads to proteinuria in childhood or adolescence. With increasing age, GL-3 deposition in renal microvascular endothelial cells, and to a lesser extent in interstitial and mesangial cells, leads to renal insufficiency in the third to fifth decades of life. Recently identified "renal variants" who lack the classical disease manifestations of acroparesthesias, angiokeratoma, hypohidrosis, and characteristic corneal/lenticular opacities also develop renal failure. In contrast, "cardiac variants" who also lack the classical phenotype, develop proteinuria in adulthood, but survive a normal lifespan without developing renal failure. Here, we review the renal involvement and pathology in the classical, renal and cardiac variant phenotypes, and present highlights of the preclinical studies and clinical trials that demonstrated the safety and effectiveness of recombinant alpha-Gal A replacement for this inherited nephropathy.

Adult↗
PubMed2001

Safety and efficacy of recombinant human alpha-galactosidase A replacement therapy in Fabry's disease.

BACKGROUND: Fabry's disease, lysosomal alpha-galactosidase A deficiency, results from the progressive accumulation of globotriaosylceramide and related glycosphingolipids. Affected patients have microvascular disease of the kidneys, heart, and brain. METHODS: We evaluated the safety and effectiveness of recombinant alpha-galactosidase A in a multicenter, randomized, placebo-controlled, double-blind study of 58 patients who were treated every 2 weeks for 20 weeks. Thereafter, all patients received recombinant alpha-galactosidase A in an open-label extension study. The primary efficacy end point was the percentage of patients in whom renal microvascular endothelial deposits of globotriaosylceramide were cleared (reduced to normal or near-normal levels). We also evaluated the histologic clearance of microvascular endothelial deposits of globotriaosylceramide in the endomyocardium and skin, as well as changes in the level of pain and the quality of life. RESULTS: In the double-blind study, 20 of the 29 patients in the recombinant alpha-galactosidase A group (69 percent) had no microvascular endothelial deposits of globotriaosylceramide after 20 weeks, as compared with none of the 29 patients in the placebo group (P<0.001). Patients in the recombinant alpha-galactosidase A group also had decreased microvascular endothelial deposits of globotriaosylceramide in the skin (P<0.001) and heart (P<0.001). Plasma levels of globotriaosylceramide were directly correlated with clearance of the microvascular deposits. After six months of open-label therapy, all patients in the former placebo group and 98 percent of patients in the former recombinant alpha-galactosidase A group who had biopsies had clearance of microvascular endothelial deposits of globotriaosylceramide. The incidence of most treatment-related adverse events was similar in the two groups, with the exception of mild-to-moderate infusion reactions (i.e., rigors and fever), which were more common in the recombinant alpha-galactosidase A group. IgG seroconversion occurred in 88 percent of patients who received recombinant alpha-galactosidase A. CONCLUSIONS: Recombinant alpha-galactosidase A replacement therapy cleared microvascular endothelial deposits of globotriaosylceramide from the kidneys, heart, and skin in patients with Fabry's disease, reversing the pathogenesis of the chief clinical manifestations of this disease.

Adolescent↗
PubMed2001

A phase 1/2 clinical trial of enzyme replacement in fabry disease: pharmacokinetic, substrate clearance, and safety studies.

Fabry disease results from deficient alpha-galactosidase A (alpha-Gal A) activity and the pathologic accumulation of the globotriaosylceramide (GL-3) and related glycosphingolipids, primarily in vascular endothelial lysosomes. Treatment is currently palliative, and affected patients generally die in their 40s or 50s. Preclinical studies of recombinant human alpha-Gal A (r-halphaGalA) infusions in knockout mice demonstrated reduction of GL-3 in tissues and plasma, providing rationale for a phase 1/2 clinical trial. Here, we report a single-center, open-label, dose-ranging study of r-halphaGalA treatment in 15 patients, each of whom received five infusions at one of five dose regimens. Intravenously administered r-halphaGalA was cleared from the circulation in a dose-dependent manner, via both saturable and non-saturable pathways. Rapid and marked reductions in plasma and tissue GL-3 were observed biochemically, histologically, and/or ultrastructurally. Clearance of plasma GL-3 was dose-dependent. In patients with pre- and posttreatment biopsies, mean GL-3 content decreased 84% in liver (n=13), was markedly reduced in kidney in four of five patients, and after five doses was modestly lowered in the endomyocardium of four of seven patients. GL-3 deposits were cleared to near normal or were markedly reduced in the vascular endothelium of liver, skin, heart, and kidney, on the basis of light- and electron-microscopic evaluation. In addition, patients reported less pain, increased ability to sweat, and improved quality-of-life measures. Infusions were well tolerated; four patients experienced mild-to-moderate reactions, suggestive of hypersensitivity, that were managed conservatively. Of 15 patients, 8 (53%) developed IgG antibodies to r-halphaGalA; however, the antibodies were not neutralizing, as indicated by unchanged pharmacokinetic values for infusions 1 and 5. This study provides the basis for a phase 3 trial of enzyme-replacement therapy for Fabry disease.

Adolescent↗
PubMed2001

Nonradioactive detection of the common Connexin 26 167delT and 35delG mutations and frequencies among Ashkenazi Jews.

Mutations in the gap junction beta2 (GJB2) gene, Connexin 26 (Cx26), cause nonsyndromic sensorineural recessive deafness (NSRD). Two frameshift mutations, 167delT and 35delG, are the most frequent Cx26 lesions causing NSRD. The 35delG mutation is panethnic, while the 167delT lesion occurs almost exclusively in the Ashkenazi Jewish population at a carrier frequency of 2 to 4%. To facilitate carrier detection, a simple nonradioactive allele-specific oligonucleotide (ASO) hybridization assay was developed for the 167delT and 35delG mutations. Screening of 1012 anonymous Ashkenazi Jewish individuals from the New York Metropolitan area revealed carrier frequencies for 167delT and 35delG of 3.96% (95% CI: 2.75-5.15%) and 0.69% (95% CI: 0.18-1.20%), respectively. This sensitive, specific, and relatively inexpensive method can reliably identify affected newborns and patients with NSRD as well as facilitate carrier screening for Connexin 26 deafness in the Ashkenazi Jewish community.

Connexin 26↗
PubMed2001

Fabry disease: twenty novel alpha-galactosidase A mutations causing the classical phenotype.

Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from the deficient activity of the lysosomal exoglycohydrolase, alpha-galactosidase A (EC 3.2.1.22; alpha-Gal A). The nature of the molecular lesions in the alpha-Gal A gene in 40 unrelated families with the classical phenotype (absent alpha-Gal A activity) was determined in order to provide precise heterozygote detection and prenatal diagnosis, and to explore possible genotype/phenotype correlations. Genomic DNA was isolated from unrelated affected males, and the entire alpha-Gal A coding region and flanking intronic sequences were analyzed by polymerase chain reaction (PCR) amplification and automated sequencing. Twenty new mutations were identified: M51K, D92N, D136H, F169S, C172F, L191Q, S247P, Q250X, P259R, G261D, T282N, R301P, W349X, T410K, 124delAT, 842delTAA, 1033delTC, 82insG, 893insG, and 903insG. In the remaining 20 unrelated Fabry families, 17 previously reported mutations were detected. These studies further define the heterogeneity of mutations in the alpha-Gal A gene causing the classic Fabry disease phenotype, and permit precise heterozygote detection and prenatal diagnosis.

DNA Mutational Analysis↗
PubMed2001

Experiences in molecular-based prenatal screening for Ashkenazi Jewish genetic diseases.

Multiple-option prenatal carrier testing in the Ashkenazi Jewish community for three and now eight disorders has been readily accepted in this prenatal, health-oriented and knowledgeable population. Counseling of screenees concerning the nature (severity, treatability, etc.), inheritance, and frequencies of each disorder was essential for informed test choices and future reproductive decision making. The value of couple testing for a group of disorders when 1 in about 6 would be found to be a carrier of at least one disease was emphasized. These studies identified issues of education, confidentiality, posttest anxiety, and self-esteem that must be continuously addressed in the Ashkenazi population. However, an important value of these studies is that they provide a framework for the development of mass carrier screening programs in the general population or in specific segments of the population with similar demographic characteristics and in more diverse prenatal populations.

Genes, Recessive↗
PubMed2001

Prenatal genetic screening in the Ashkenazi Jewish population.

The Ashkenazi Jewish community is a unique and ideal population in which to provide multiple disease screening because detection rates are high (> 95%) by testing a limited number of mutations. The residual risk that remains is very low. In addition, the lessons learned from carrier screening in this community indicate that only through genetic counseling and education can screening in the general population gain wide acceptance and provide maximum benefit.

Counseling↗