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Genome sequencing in a case of Niemann–Pick type C
- Source :
- Cold Spring Harbor Molecular Case Studies
- Publication Year :
- 2016
- Publisher :
- Cold Spring Harbor Laboratory, 2016.
-
Abstract
- Adult-onset Niemann–Pick disease type C (NPC) is an infrequent presentation of a rare neurovisceral lysosomal lipid storage disorder caused by autosomal recessive mutations in NPC1 (∼95%) or NPC2 (∼5%). Our patient was diagnosed at age 33 when he presented with a 10-yr history of difficulties in judgment, concentration, speech, and coordination. A history of transient neonatal jaundice and splenomegaly with bone marrow biopsy suggesting a lipid storage disorder pointed to NPC; biochemical (“variant” level cholesterol esterification) and ultrastructural studies in adulthood confirmed the diagnosis. Genetic testing revealed two different missense mutations in the NPC1 gene—V950M and N1156S. Symptoms progressed over >20 yr to severe ataxia and spasticity, dementia, and dysphagia with aspiration leading to death. Brain autopsy revealed mild atrophy of the cerebrum and cerebellum. Microscopic examination showed diffuse gray matter deposition of balloon neurons, mild white matter loss, extensive cerebellar Purkinje cell loss with numerous “empty baskets,” and neurofibrillary tangles predominantly in the hippocampal formation and transentorhinal cortex. We performed whole-genome sequencing to examine whether the patient harbored variants outside of the NPC1 locus that could have contributed to his late-onset phenotype. We focused analysis on genetic modifiers in pathways related to lipid metabolism, longevity, and neurodegenerative disease. We identified no rare coding variants in any of the pathways examined nor was the patient enriched for genome-wide association study (GWAS) single-nucleotide polymorphisms (SNPs) associated with longevity or altered lipid metabolism. In light of these findings, this case provides support for the V950M variant being sufficient for adult-onset NPC disease.
- Subjects :
- Research Report
Male
0301 basic medicine
Pathology
Hepatosplenomegaly
progressive encephalopathy
Genome-wide association study
0302 clinical medicine
falls
progressive psychomotor deterioration
Niemann-Pick Diseases
central nervous system degeneration
Membrane Glycoproteins
neurodegeneration
Intracellular Signaling Peptides and Proteins
atrophy/degeneration affecting the cerebrum
Brain
Neurodegenerative Diseases
Neurofibrillary Tangles
Niemann-Pick Disease, Type C
General Medicine
3. Good health
progressive language deterioration
medicine.symptom
medicine.medical_specialty
Ataxia
Lipid storage disorder
Mutation, Missense
Cerebellar Purkinje cell
03 medical and health sciences
Atrophy
Niemann-Pick C1 Protein
medicine
Humans
progressive forgetfulness
Genetic Testing
Base Sequence
Whole Genome Sequencing
business.industry
slowed slurred speech
Lipid metabolism
medicine.disease
neuronal loss in central nervous system
030104 developmental biology
social and occupational deterioration
Mutation
Dementia
hepatosplenomegaly
NPC1
Carrier Proteins
business
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 23732873 and 23732865
- Volume :
- 2
- Database :
- OpenAIRE
- Journal :
- Molecular Case Studies
- Accession number :
- edsair.doi.dedup.....311b56761b18634466e92e040b6437ad