Biomedical subjects

Edward H Schuchman

Publications and source records attributed to Edward H Schuchman.

At least 19 recordsLinked to original sources

PubMed2026

Targeting CD44 reverses sphingomyelin-induced oligodendrocyte maturation arrest in acid sphingomyelinase deficiency.

Loss-of-function mutations in the smpd1 gene cause acid sphingomyelinase deficiency (ASMD). Early neurodegeneration and lethality characterize its infantile neurovisceral form (type A). While neuronal dysfunction was traditionally considered the primary driver of the pathology, recent evidence suggests that dysmyelination and microgliosis are not merely secondary features. Specifically, myelin debris undermines the protective role of microglia, contributing to neuroinflammation and neuronal death. Herein, we examined central myelin and oligodendrocyte lineage progression in ASM knockout mice. We show that early-onset dysmyelination results from compromised oligodendrocyte maturation driven by aberrant sphingomyelin-mediated signaling. Transcriptomic profiling revealed that mature oligodendrocytes in these mice retain a gene expression signature similar to oligodendrocyte precursor cells, indicating a differentiation arrest. The cell adhesion molecule CD44 remained significantly upregulated in mature ASMko oligodendrocytes. Pharmacological inhibition of CD44 with verbascoside rescued oligodendroglial maturation in primary culture. Verbascoside administration in vivo restored myelin integrity and improved motor behavior. These findings establish that sphingomyelin homeostasis is critical for oligodendrocyte maturation and identify myelin defects as both primary pathological triggers and therapeutic targets for ASMD with neurologic symptoms.

Animals↗

PubMed2006

Acid ceramidase and human disease.

Acid ceramidase (N-acylsphingosine deacylase, EC 3.5.1.23; AC) is the lipid hydrolase responsible for the degradation of ceramide into sphingosine and free fatty acids within lysosomes. The enzymatic activity was first identified over four decades ago, and is deficient in the inherited lipid storage disorder, Farber Lipogranulomatosis (Farber disease). Importantly, AC not only hydrolyzes ceramide into sphingosine, but also can synthesize ceramide from sphingosine and free fatty acids in vitro and in situ. This "reverse" enzymatic activity occurs at a distinct pH from the hydrolysis ("forward") reaction (6.0 vs. 4.5, respectively), suggesting that the enzyme may have diverse functions within cells dependent on its subcellular location and the local pH. Most information concerning the role of AC in human disease stems from work on Farber disease. This lipid storage disease is caused by mutations in the gene encoding AC, leading to a profound reduction in enzymatic activity. Recent studies have also shown that AC activity is aberrantly expressed in several human cancers, and that the enzyme may be a useful cancer drug target. For example, AC inhibitors have been used to slow the growth of cancer cells, alone or in combination with other established, anti-oncogenic treatments. Aberrant AC activity also has been described in Alzheimer's disease, and overexpression of AC may prevent insulin resistant (Type II) diabetes induced by free fatty acids. Current information concerning the biology of this enzyme and its role in human disease is reviewed within.

Animals↗

PubMed2006

Imprinting at the SMPD1 locus: implications for acid sphingomyelinase-deficient Niemann-Pick disease.

Acid sphingomyelinase (ASM) is the lipid hydrolase that is deficient in types A and B Niemann-Pick disease (NPD). Here, we demonstrate that the gene encoding ASM (SMPD1) is paternally imprinted and that differential expression of the mutant alleles in patients with ASM-deficient NPD and in carriers influences the disease phenotype. Comparison of the results of genomic sequencing versus reverse-transcriptase polymerase chain reaction sequencing for several patients with NPD revealed preferential expression of one mutant allele. Further analysis of one family showed that the expressed allele was maternally inherited and that the distinct clinical presentations of the individual patients were correlated with the amount of residual ASM activity expressed from the maternal mutation. Treatment of NPD cell lines with 5-aza-2'-deoxycytidine enhanced the expression of the paternal SMPD1 allele, and bisulfite genomic sequencing identified which CpG dinucleotides within the SMPD1 promoter were methylated. In a related set of studies, we identified a carrier individual who had approximately 15% of normal ASM activity and clinical features of ASM-deficient NPD. DNA sequencing confirmed that this individual carried a single SMPD1 mutation and that this mutant allele was preferentially expressed. These data thus demonstrate, for the first time, imprinting at the SMPD1 gene and reveal the influence of this epigenetic modification on the presentation of ASM-deficient NPD.

Adult↗

PubMed2006

KLF6 is one transcription factor involved in regulating acid ceramidase gene expression.

Acid ceramidase (AC; E.C.3.5.1.23) activity is required to hydrolyze ceramide into sphingosine. An inherited deficiency of this enzymatic activity leads to the lipid storage disorder, Farber Lipogranulomatosis. Aberrant AC activity also has been demonstrated in several human cancers. We have characterized a 1931-bp putative promoter region of the murine AC gene by Luciferase reporter assays, electrophoretic mobility shift assays, and mutational analysis. A 143-bp sequence essential for AC promoter activity was found, and mobility shift and super-shift experiments using nuclear extracts of NIH3T3 cells demonstrated that a 34-bp, GC-rich sub-region could bind the transcription factors KLF6, Sp1, and AP2. Transient over-expression of KLF6 in NIH3T3 cells significantly increased the activity of a co-transfected Luciferase reporter construct containing the wild-type AC promoter, and a positive correlation was observed between AC and KFL6 RNA and protein expression in two different human cancer cell lines in which KLF6 expression was either "knocked-down" by RNAi or increased by retroviral-mediated gene transfer. Northern blot analysis also revealed a correlation of KLF6 and AC gene expression in various human tissues. These results provide the first characterization of the AC promoter from any species and demonstrate that KLF6 is one transcription factor involved in the regulation of AC gene expression.

Animals↗

PubMed2005

Gene transfer of human acid sphingomyelinase corrects neuropathology and motor deficits in a mouse model of Niemann-Pick type A disease.

Niemann-Pick type A disease is a lysosomal storage disorder caused by a deficiency in acid sphingomyelinase (ASM) activity. Previously we showed that storage pathology in the ASM knockout (ASMKO) mouse brain can be corrected by adeno-associated virus serotype 2 (AAV2)-mediated gene transfer. The present experiment compared the relative therapeutic efficacy of different recombinant AAV serotype vectors (1, 2, 5, 7, and 8) using histological, biochemical, and behavioral endpoints. In addition, we evaluated the use of the deep cerebellar nuclei (DCN) as a site for injection to facilitate global distribution of the viral vector and enzyme. Seven-week-old ASM knockout mice were injected within the DCN with different AAV serotype vectors encoding human ASM (hASM) and then killed at either 14 or 20 weeks of age. Results showed that AAV1 was superior to serotypes 2, 5, 7, and 8 in its relative ability to express hASM, alleviate storage accumulation, and correct behavioral deficits. Expression of hASM was found not only within the DCN, but also throughout the cerebellum, brainstem, midbrain, and spinal cord. This finding demonstrates that targeting the DCN is an effective approach for achieving widespread enzyme distribution throughout the CNS. Our results support the continued development of AAV based vectors for gene therapy of the CNS manifestations in Niemann-Pick type A disease.

Animals↗

PubMed2005

Identification of novel biomarkers for Niemann-Pick disease using gene expression analysis of acid sphingomyelinase knockout mice.

Although several therapies are available or being developed for lysosomal storage disorders (LSDs), assessment of therapeutic efficacy is challenged by the lack of markers to assess disease progression and severity. This is particularly true for rare diseases such as LSDs, since natural history data from human populations are often lacking. Herein we describe the use of gene expression analysis in the acid sphingomyelinase-deficient mouse model (ASMKO) of Types A and B Niemann-Pick disease (NPD) to identify novel serum biomarkers. We used microarray and real-time PCR analyses to compare mRNA expression in ASMKO and normal mice in two important sites of pathology, lung and brain, and from these data identified and validated several potential biomarkers. The cytokine MIP-1alpha was markedly elevated in ASMKO mouse serum, and following enzyme replacement therapy (ERT) it was reduced to normal levels. Total iron levels were similarly elevated in ASMKO mice, reflective of the elevated ferritin light chain transcript, and decreased to normal after ERT. Serum growth hormone levels were also elevated in ASMKO mice and were reduced to normal after brain-directed gene therapy, but not ERT. These studies illustrate the value of gene expression analysis for the identification of biomarkers, and provide new insight into the pathobiology of NPD.

Animals↗

PubMed2005

Lysosomal enzyme delivery by ICAM-1-targeted nanocarriers bypassing glycosylation- and clathrin-dependent endocytosis.

Enzyme replacement therapy, a state-of-the-art treatment for many lysosomal storage disorders, relies on carbohydrate-mediated binding of recombinant enzymes to receptors that mediate lysosomal delivery via clathrin-dependent endocytosis. Suboptimal glycosylation of recombinant enzymes and deficiency of clathrin-mediated endocytosis in some lysosomal enzyme-deficient cells limit delivery and efficacy of enzyme replacement therapy for lysosomal disorders. We explored a novel delivery strategy utilizing nanocarriers targeted to a glycosylation- and clathrin-independent receptor, intercellular adhesion molecule (ICAM)-1, a glycoprotein expressed on diverse cell types, up-regulated and functionally involved in inflammation, a hallmark of many lysosomal disorders. We targeted recombinant human acid sphingomyelinase (ASM), deficient in types A and B Niemann-Pick disease, to ICAM-1 by loading this enzyme to nanocarriers coated with anti-ICAM. Anti-ICAM/ASM nanocarriers, but not control ASM or ASM nanocarriers, bound to ICAM-1-positive cells (activated endothelial cells and Niemann-Pick disease patient fibroblasts) via ICAM-1, in a glycosylation-independent manner. Anti-ICAM/ASM nanocarriers entered cells via CAM-mediated endocytosis, bypassing the clathrin-dependent pathway, and trafficked to lysosomes, where delivered ASM displayed stable activity and alleviated lysosomal lipid accumulation. Therefore, lysosomal enzyme targeting using nanocarriers targeted to ICAM-1 bypasses defunct pathways and may improve the efficacy of enzyme replacement therapy for lysosomal disorders, such as Niemann-Pick disease.

Antibodies, Monoclonal↗

PubMed2005

A lipid analogue that inhibits sphingomyelin hydrolysis and synthesis, increases ceramide, and leads to cell death.

We report the synthesis and characterization of a novel thiourea derivative of sphingomyelin (AD2765). In vitro assays using pure enzyme and/or cell extracts revealed that this compound inhibited the hydrolysis of BODIPY-conjugated or 14C-labeled sphingomyelin by acid sphingomyelinase and Mg2+-dependent neutral sphingomyelinase. Studies in normal human skin fibroblasts further revealed that AD2765 was taken up by cells and inhibited the hydrolysis of BODIPY-conjugated sphingomyelin in situ. In situ and in vitro studies also showed that this compound inhibited the synthesis of sphingomyelin from BODIPY-conjugated ceramide. The specificity of AD2765 for enzymes involved in sphingomyelin metabolism was demonstrated by the fact that it had no effect on the hydrolysis of BODIPY-conjugated ceramide by acid ceramidase or on the synthesis of BODIPY-conjugated glucosylceramide from BODIPY-conjugated ceramide. The overall effect of AD2765 on sphingomyelin metabolism was concentration-dependent, and treatment of normal human skin fibroblasts or cancer cells with this compound at concentrations > 10 microM led to an increase in cellular ceramide and cell death. Thus, AD2765 might be used to manipulate sphingomyelin metabolism in various ways, potentially to reduce substrate accumulation in cells from types A and B Niemann-Pick disease patients, and/or to affect the growth of human cancer cells.

Boron Compounds↗

PubMed2005

Simultaneous quantitative analysis of ceramide and sphingosine in mouse blood by naphthalene-2,3-dicarboxyaldehyde derivatization after hydrolysis with ceramidase.

Ceramide and sphingosine are sphingolipids with important functional and structural roles in cells. In this paper we report a new enzyme-based method to simultaneously quantify the levels of ceramide and sphingosine in biological samples. This method utilizes purified human recombinant acid ceramidase to completely hydrolyze ceramide to sphingosine, followed by derivatization of the latter with naphthalene-2,3-dialdehyde (NDA) and quantification by reverse-phase high-performance liquid chromatography. The limits of detection for sphingosine-NDA and ceramidase-derived sphingosine-NDA were 9.6 and 12.3 fmol, respectively, and the limits of quantification were 34.2 and 45.7 fmol, respectively. The recovery of sphingosine and ceramide standards quantified by this assay were between 95.6 and 104.6%. The relative standard deviations for the intra- and interday sphingosine assay were 2.1 and 4.5%, respectively, and those for the ceramide assay were 3.3 and 4.1%, respectively. To validate this procedure, we quantified ceramide and sphingosine in mouse plasma, white blood cells, and hemoglobin, the first reported time that the amounts of these lipids have been documented in individual blood components. We also used this technique to evaluate the ability of a novel ceramide analog, AD2646, to inhibit the hydrolytic activity of acid ceramidase. The results demonstrate that this new procedure can provide sensitive, reproducible, and simultaneous ceramide and sphingosine quantification. The technique also may be used for determining the activity and inhibition of ceramidases and may be adapted for quantifying sphingomyelin and sphingosine-1-phosphate levels. In the future it could be an important tool for investigators studying the role of ceramide/sphingosine metabolism in signal transduction, cell growth and differentiation, and cancer pathogenesis and treatment.

Acid Ceramidase↗

PubMed2005

Joint and bone disease in mucopolysaccharidoses VI and VII: identification of new therapeutic targets and biomarkers using animal models.

The mucopolysaccharidoses (MPS) are inherited metabolic disorders resulting from the defective catabolism of glycosaminoglycans. In this report, we find that the stimulation of MPS connective tissue cells by the inflammatory cytokines causes enhanced secretion of several matrix-degrading metalloproteinases (MMPs). In addition, expression of tissue inhibitor of metalloproteinase-1 was elevated, consistent with the enhanced MMP activity. These findings were not restricted to one particular MPS disorder or species, and are consistent with previous observations in animal models with chemically induced arthritis. Bromodeoxyuridine incorporation studies also revealed that MPS chondrocytes proliferated up to 5-fold faster than normal chondrocytes, and released elevated levels of transforming growth factor-beta, presumably to counteract the marked chondrocyte apoptosis and matrix degradation associated with MMP expression. Despite this compensatory mechanism, studies of endochondral ossification revealed a reduction in chondro-differentiation in the growth plates. Thus, although MPS chondrocytes grew faster, most of the newly formed cells were immature and could not mineralize into bone. Our studies suggest that altered MMP expression, most likely stimulated by inflammatory cytokines and nitric oxide, is an important feature of the MPS disorders. These data also identify several proinflammatory cytokines, nitric oxide, and MMPs as novel therapeutic targets and/or biomarkers of MPS joint and bone disease. This information should aid in the evaluation of existing therapies for these disorders, such as enzyme replacement therapy and bone marrow transplantation, and may lead to the development of new therapeutic approaches.

Animals↗

PubMed2005

AAV vector-mediated correction of brain pathology in a mouse model of Niemann-Pick A disease.

Niemann-Pick A disease (NPA) is a fatal lysosomal storage disorder caused by a deficiency in acid sphingomyelinase (ASM) activity. The lack of functional ASM results in cellular accumulation of sphingomyelin and cholesterol within distended lysosomes throughout the brain. In this study, we investigated the potential of AAV-mediated expression of ASM to correct the brain pathology in an ASM knockout (ASMKO) mouse model of NPA. An AAV serotype 2 vector encoding human ASM (AAV2-hASM) was injected directly into the adult ASMKO hippocampus of one hemisphere. This resulted in expression of human ASM in all major cell layers of the ipsilateral hippocampus for at least 15 weeks postinjection. Transduced cells were also present in the entorhinal cortex, medial septum, and contralateral hippocampus in a pattern consistent with retrograde axonal transport of AAV2. There was a substantial reduction of distended lysosomes and an almost complete reversal of cholesterol accumulation in all areas of the brain that were targeted by AAV2-hASM. These findings show that the ASMKO brain is responsive to ASM replacement and that retrograde transport of AAV2 functions as a platform for widespread gene delivery and reversal of pathology in affected brain.

Animals↗

PubMed2005

AAV8-mediated hepatic expression of acid sphingomyelinase corrects the metabolic defect in the visceral organs of a mouse model of Niemann-Pick disease.

Acid sphingomyelinase deficiency is a lysosomal storage disorder in which the defective lysosomal hydrolase fails to degrade sphingomyelin. The resulting accumulation of substrate in the lysosomes of histiocytic cells leads to hepatosplenomegaly and severe pulmonary inflammation. Administration of a recombinant AAV1 vector encoding human acid sphingomyelinase to acid sphingomyelinase knockout (ASMKO) mice effectively reduced the accumulated substrate in all of the affected visceral organs. However, more complete and rapid clearance of sphingomyelin was observed when an AAV8-based serotype vector was used in lieu of AAV1. Importantly, AAV8-mediated hepatic expression of higher and sustained levels of the enzyme also corrected the abnormal cellularity, cell differentials, and levels of the chemokine MIP-1alpha in the bronchoalveolar lavage fluids of the ASMKO mice. Treatment also reversed the morphological aberrations associated with the alveolar macrophages of ASMKO mice and restored their phagocytic activity. No antibodies to the expressed enzyme were detected when the viral vectors were used in conjunction with a transcription cassette harboring a liver-restricted enhancer/promoter. Together, these data support the continued development of AAV8-mediated hepatic gene transfer as an approach to treat the visceral manifestations observed in individuals with acid sphingomyelinase deficiency.

Animals↗

PubMed2005

Neurodegeneration augments the ability of bone marrow-derived mesenchymal stem cells to fuse with Purkinje neurons in Niemann-Pick type C mice.

After transplantation, adult bone marrow-derived mesenchymal stem cells (BM-MSCs) may undergo transdifferentiation and/or cell fusion in response to new environments. However, the mechanism(s) that govern these cell fate switches remain unknown. Here we demonstrate that the pathology associated with murine Niemann-Pick disease type C (NP-C) cerebellum augments the ability of BM-MSCs to fuse with Purkinje neurons. The results suggest that the degenerative microenvironment of Purkinje neurons in the NP-C cerebellum modulates the cell fate switch of BM-MSCs via cell fusion.

Animals↗

PubMed2005

Acid sphingomyelinase: relation of 93lysine residue on the ratio of intracellular to secreted enzyme activity.

Acid sphingomyelinase (ASM) is the lysosomal enzyme responsible for the hydrolysis of sphingomyelin to ceramide and phosphocholine. An inherited deficiency of this enzymatic activity results in the Type A and B forms of Niemann-Pick disease (NPD). ASM is also readily secreted from cultured cells and can rapidly move from lysosomes to the cell surface upon stimulation by cytokines and other factors. Recent interest has focused on the role of this secreted/cell surface enzyme in ceramide-mediated signal transduction. We therefore sought to understand the mechanism(s) that might regulate intracellular targeting and secretion of this important hydrolase. Most lysosomal proteins are targeted to lysosomes in mammalian cells via the mannose 6-phosphate recognition system. Using cultured skin fibroblasts from I-cell disease patients, in which one of the enzymes responsible for mannose phosphorylation, GlcNAc-phosphotransferase, is deficient, we determined ASM activities in cell homogenates and media. The ratio of secreted to intracellular activity was approximately 8-fold greater in I-cell than in normal cells, indicating that mannose phosphorylation is important in the trafficking of this hydrolase. Most of the secreted activity required Zn+2 for full activity, supporting the concept that intracellular exposure of ASM to zinc within lysosomes is required for enzymatic activation. The recognition of lysosomal proteins by GlcNAc-phosphotransferase is mediated by protein structure, and a specific three-dimensional arrangement of lysine residues exposed on the surface of several enzymes has been shown to be critical for mannose phosphorylation. Alanine scanning mutagenesis of thirteen lysine residues in ASM demonstrated that 93lysine residue plays a critical role in ASM targeting since the K93A mutant had reduced intracellular activity, but enhanced secreted activity that was zinc responsive.

Animals↗

PubMed2004

Preimplantation genetic diagnosis for Niemann-Pick disease type B.

BACKGROUND: Acid sphingomyelinase (ASM) deficient Niemann-Pick disease (NPD) is an autosomal recessive disorder caused by mutations in the ASM gene (SMPD1). More than 70 different mutations have been reported in this gene. NPD type B is the most common type in Saudi Arabia with a frequency of 1:40 000 to 1:100 000. The phenotype of Saudi Type B patients is more severe than patients reported from the West. Two mutations specific to Saudi patients have been inherited in the SMPD1 gene. Given the difficult management of the disease, we opted for a preventive approach to the suffering families by screening the whole SMPD1 gene for mutations followed by Preimplantation Genetic Diagnosis (PGD). METHODS: The family suffering from NPD-B underwent mutation screening for the entire SMPD1 gene followed by PGD using nested PCR and sequencing. RESULTS: A novel mutation in a family suffering from the same severe NPD-B phenotype is described in this report (W533R). After PGD, a singleton pregnancy ensued after transfer of one heterozygous and one normal embryo. Postnatal DNA testing of the newborn showed a normal homozygous genotype. CONCLUSIONS: This report reveals a new SMPD1 mutation responsible for similar Saudi severe phenotype, and the prevention of this disorder by PGD.

Adult↗

PubMed2004

The natural history of type B Niemann-Pick disease: results from a 10-year longitudinal study.

OBJECTIVES: Type B Niemann-Pick disease (NPD-B) caused by acid sphingomyelinase deficiency is a rare, autosomal recessive, lysosomal storage disorder with a broad range of disease severity. The objectives of this study were to document the natural history of the disease in a large, clinically heterogeneous patient population that was followed for a period of 10 years and to determine how genotype influences phenotype. METHODS: Twenty-nine patients with NPD-B had serial evaluations at least 9 months apart. Organ volumes, hematologic indices, lipid concentrations, pulmonary function, and hepatic activity were studied, and individual phenotypic severity was compared with genotype. RESULTS: All patients with intact spleens had splenomegaly (mean value: 12.7 multiples of normal [MN]; range: 4.5-27.3 MN), and all but 1 had hepatomegaly (mean volume: 1.91 MN; range: 0.93-3.21 MN). At initial visit, 39% had thrombocytopenia and 3% had leukopenia. At final visit, the percentages increased to 54% and 34%, respectively. Mean annual decreases in platelet count and leukocyte count were 7 x 10(3) and 0.2 x 10(3) per mm3, respectively. The typical atherogenic lipid profile was worse in older patients. A total of 69% of patients had low diffusion capacity for carbon monoxide, and more than one third had low forced expiratory volume in 1 second, forced vital capacity, and forced expiratory volume in 1 second/forced vital capacity at initial visit. All measurements of pulmonary function showed a gradual deterioration over time. Liver dysfunction was characterized by stable elevation of hepatic transaminases and bilirubin. Homozygotes for DeltaR608, P323A, and P330R had milder disease than patients with all other genotypes. CONCLUSIONS: The natural history of NPD-B is characterized by hepatosplenomegaly with progressive hypersplenism, worsening atherogenic lipid profile, gradual deterioration in pulmonary function, and stable liver dysfunction.

Adolescent↗

PubMed2004

Lipid abnormalities in children with types A and B Niemann Pick disease.

OBJECTIVE: To characterize the lipid profiles in patients with types A and B Niemann Pick disease (NPD) and determine if lipid abnormalities are associated with evidence of early cardiovascular disease or correlate with genotype. STUDY DESIGN: The study was a cross-sectional analysis of 10 patients with NPD type A and 30 patients with NPD type B that was carried out in the General Clinical Research Center. For each patient, fasting lipid profile and glucose, T4, height or length, weight, resting blood pressure, and acid sphingomyelinase deficiency genotype were measured. In type B patients, electrocardiograhic-gated helical computed tomography of the heart also was obtained. RESULTS: Lipid abnormalities included low (<35 mg/dL) high-density lipoprotein cholesterol in 100% of patients and hypertriglyceridemia and increased low-density lipoprotein cholesterol in 62% (25/40) and 67% (27/40) of patients, respectively. Coronary artery calcium scores were positive (>1.0) in 10 of 18 type B patients studied. There was no correlation of the Delta R608 genotype with a milder phenotype for the lipid abnormalities, as has been observed for a number of other NPD manifestations. CONCLUSIONS: Lipid abnormalities are part of the phenotype in types A and B NPD and may be associated with early atherosclerotic heart disease.

Calcium↗

PubMed2004

Ocular manifestations of Niemann-Pick disease type B.

PURPOSE: To investigate the ocular manifestations in Niemann-Pick disease type B (NPD-B). DESIGN: Observational case series. PARTICIPANTS: Forty-five patients (23 male and 22 female) with NPD-B from 37 unrelated families. METHODS: Serial clinical evaluations were carried out over a 2- to 14-year period, including a complete physical examination, neurologic assessment, and ophthalmologic examination. Genotyping of the specific mutations in the acid sphingomyelinase (ASM) gene was performed when possible for genotype-phenotype correlations. MAIN OUTCOME MEASURES: Fundus photographs to evaluate the retina, ASM genotype, and neurologic examination findings. RESULTS: Ophthalmoscopic examination revealed retinal stigmata in 15 of 45 patients, 3 with macular halos and 12 with cherry red maculae. Neurologic examinations did not reveal any evidence of neurodegeneration, and there was no consistent relationship between retinal findings and genotype. CONCLUSIONS: The presence of macular halos and/or cherry red maculae is not an absolute predictor of neurodegeneration, but should prompt a thorough evaluation to determine the underlying etiology and the precise diagnosis.

Adolescent↗