Dataset Information

Misdiagnosis of Niemann-Pick disease type C as Gaucher disease.

ABSTRACT: Niemann-Pick disease type C (NPC) is a model for inborn errors of metabolism whose gene product mediates molecular trafficking rather than catabolizing macromolecules, as in classic lipidoses. We report the case of an infant who presented with hepatosplenomegaly without neurological abnormalities. Decreased activity of acid ?-glucosidase and elevated serum chitotriosidase and tartrate-resistant acid phosphatase on repeated measurements led to initial diagnosis of Gaucher disease (GD). Failure to respond to enzyme replacement therapy after one year, however, put the diagnosis in question. Cholesterol esterification assays in cultured skin fibroblasts and NPC gene analysis led to the correct diagnosis of NPC. The patient had markedly reduced cholesterol esterification and was a compound heterozygote for a known and a novel mutation in the NPC gene (395delC and 2068insTCCC), which are both predicted to lead to protein truncation. Although the full phenotype of NPC involves hepatosplenomegaly and neurodegenerative disease, the initial presentation in a pediatric patient may be restricted to visceral disease. Of interest, this patient had decreased activity of leukocyte acid ?-glucosidase activity and elevated serum chitotriosidase to levels often seen in GD. Although acid ?-glucosidase activity in leukocytes was low, it was in the normal range in skin fibroblasts. Therefore, diagnostic delay may occur in NPC due to false positive testing for GD. Diagnosis of NPC requires a high index of suspicion and should be considered in a patient with hepatosplenomegaly even in the absence of neurodevelopmental signs. Prompt diagnosis will become increasingly important as effective therapies are developed for NPC.

SUBMITTER: Lo SM

PROVIDER: S-EPMC3053412 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Misdiagnosis of Niemann-Pick disease type C as Gaucher disease.

Lo Sarah M SM McNamara Joseph J Seashore Margherita R MR Mistry Pramod K PK

Journal of inherited metabolic disease 20100930

Niemann-Pick disease type C (NPC) is a model for inborn errors of metabolism whose gene product mediates molecular trafficking rather than catabolizing macromolecules, as in classic lipidoses. We report the case of an infant who presented with hepatosplenomegaly without neurological abnormalities. Decreased activity of acid β-glucosidase and elevated serum chitotriosidase and tartrate-resistant acid phosphatase on repeated measurements led to initial diagnosis of Gaucher disease (GD). Failure to ...[more]

PMID: 20882348

Similar Datasets

Project description:OBJECTIVES:The aim of this study was to comprehensively evaluate the auditory phenotype in Niemann-Pick disease, type C1 (NPC1), to understand better the natural history of this complex, heterogeneous disorder, and to define further the baseline auditory deficits associated with NPC1 so that use of potentially ototoxic interventions (e.g., 2-hydroxypropyl-ß-cyclodextrin) may be more appropriately monitored and understood. DESIGN:Fifty patients with NPC1 ranging in age from 4 months to 21 years (mean = 9.3 years) enrolled in a natural history/observational study at the National Institutes of Health. The auditory test battery included, when possible, immittance audiometry, pure-tone and speech audiometry, otoacoustic emission testing, and a neurotologic auditory brainstem response study. Longitudinal data were collected on a subset of patients. RESULTS:Over half of the cohort exhibited hearing loss involving the high frequencies ranging from a slight to moderate degree, and 74% of patients presented with clinically significant hearing loss involving the frequencies most important to speech understanding (0.5, 1, 2, 4 kHz). Despite the heterogeneity of the sample, results among patients were sufficiently consistent to implicate retrocochlear dysfunction in the majority (66%) of individuals, with (22%) or without (44%) accompanying cochlear involvement. Some patients (10%) presented with a profile for auditory neuropathy spectrum disorder. The combination of cross-sectional and longitudinal data indicates these patients are at risk for a progressive decline in auditory function. CONCLUSIONS:This is the largest cohort of patients with NPC1 evaluated comprehensively for auditory dysfunction, and results implicate the pathological processes of NPC1 in the manifestation of hearing loss. Patients with NPC1 should be monitored audiologically throughout their lives, beginning at the time of diagnosis. Clinicians and researchers should be aware of this historically overlooked aspect of the phenotype.

Project description:Niemann-Pick disease type C (NP-C) is a rare, autosomal recessive, neurodegenerative disease associated with a wide variety of progressive neurological manifestations. Miglustat is indicated for the treatment of progressive neurological manifestations in both adults and children. Since approval in 2009 there has been a vast growth in clinical experience with miglustat. The effectiveness of miglustat has been assessed using a range of measures.Comprehensive review of published data from studies of cellular neuropathological markers and structural neurological indices in the brain, clinical impairment/disability, specific clinical neurological manifestations, and patient survival.Cranial diffusion tensor imaging and magnetic resonance spectroscopy studies have shown reduced levels of choline (a neurodegeneration marker), and choline/N-acetyl aspartate ratio (indicating increased neuronal viability) in the brain during up to 5 years of miglustat therapy, as well as a slowing of reductions in fractional anisotropy (an axonal/myelin integrity marker). A 2-year immunoassay study showed significant reductions in CSF-calbindin during treatment, indicating reduced cerebellar Purkinje cell loss. Magnetic resonance imaging studies have demonstrated a protective effect of miglustat on cerebellar and subcortical structure that correlated with clinical symptom severity. Numerous cohort studies assessing core neurological manifestations (impaired ambulation, manipulation, speech, swallowing, other) using NP-C disability scales indicate neurological stabilization over 2-8 years, with a trend for greater benefits in patients with older (non-infantile) age at neurological onset. A randomized controlled trial and several cohort studies have reported improvements or stabilization of saccadic eye movements during 1-5 years of therapy. Swallowing was also shown to improve/remain stable during the randomized trial (up to 2 years), as well as in long-term observational cohorts (up to 6 years). A meta-analysis of dysphagia - a potent risk factor for aspiration pneumonia and premature death in NP-C - demonstrated a survival benefit with miglustat due to improved/stabilized swallowing function.The effects of miglustat on neurological NP-C manifestations has been assessed using a range of approaches, with benefits ranging from cellular changes in the brain through to visible clinical improvements and improved survival.

Dataset Information

Misdiagnosis of Niemann-Pick disease type C as Gaucher disease.

Publications

Misdiagnosis of Niemann-Pick disease type C as Gaucher disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets