Niemann-Pick disease

1.Historical aspects of Niemann-Pick disease12
2.Biochemistry of Niemann-Pick disease18
2.1.Introduction and definitions18
2.2.Missing or pathological products of “Niemann-Pick genes“19
2.3.Biochemical foundations of diagnosing Niemann-Pick diseases 19
2.3.1.Niemann-Pick disease, SMPD1-associated19
2.3.2.Niemann-Pick disease, transport protein deficiency-associated (NPC1, NPC2)19
2.3.3.Chitotriosidase activity in plasma20
2.3.4.Determination of oxysterols20
2.3.5.Determination of lyso-sphingomyelin-509 (lyso-SM-509)21
2.3.6.Determination of bile acids21
2.4.Biochemistry of Niemann-Pick diseases that is pathogenetically relevant or suspected
to be significant21
2.4.1.Niemann-Pick disease, SMPD1-associated21
2.4.2.Niemann-Pick disease, transport protein deficiency-associated (NPC1, NPC2) in general22
2.4.3.Niemann-Pick disease, transport protein deficiency-associated (NPC1, NPC2), central nervous
system24
2.5.Animal models25
2.5.1.Niemann-Pick disease, SMPD1-associated25
2.5.2.Niemann-Pick disease, transport protein deficiency-associated (NPC1, NPC2)25
2.6.Therapeutic concepts for the possible influence of pathogenetically significant
metabolic changes26
2.6.1.Niemann-Pick disease, SMPD1-associated26
2.6.2.Niemann-Pick disease, transport protein deficiency-associated (NPC1)26
3.Genetics of Niemann-Pick disease34
3.1.Niemann-Pick disease type A/B (NPA/B) [MIM: 257200/607616]34
3.1.1.SMPD1 gene and ASM protein [HGNC Gene-ID: 11120]34
3.1.2.SMPD1 variants34
3.2.Niemann-Pick disease type C (NPC) [MIM: 257220/607625]35
3.2.1.NPC1 gene and protein [HGNC Gene-ID: 7897]36
3.2.2.NPC1 variants37
3.2.3.NPC2 gene and protein [HGNC Gene-ID: 14537]38
3.2.4.NPC2 variants38
3.3.Challenges of genetic testing in Niemann-Pick disease and outlook38
3.4.Genetic databases for Niemann-Pick diseases39
4.Diagnosis of Niemann-Pick disease type C (NPC) 44
4.1.Recommendations for differential diagnosis and initial diagnosis44
4.2.Clinical diagnosis and key findings in NPC46
4.2.1.Neuropsychological diagnosis and key findings46
4.2.2.Laboratory diagnostics and biomarkers47
4.3.Significance of genetic testing in NPC50
4.3.1.Next-generation sequencing (NGS) and gene panels52
4.3.2.Differentiation from acid sphingomyelinase deficiency (ASMD)52
4.4.Differential diagnosis of similar lysosomal diseases54
5.Clinical manifestation58
5.1.Niemann-Pick disease type A and type B58
5.2.Niemann-Pick type C disease62
5.2.1.Perinatal type63
5.2.2.Infantile type64
5.2.3.Late-infantile type64
5.2.4.Juvenile classic type67
5.2.5.Adult type70
5.2.6.Psychiatric manifestations in Niemann-Pick type C disease71
6.Management and treatment of Niemann-Pick diseases80
6.1.Management and treatment of Niemann-Pick type A/B disease80
6.1.1.Supportive care80
6.1.2.Causal therapeutic approaches81
6.1.3.Future therapy options82
6.2.Management and treatment of Niemann-Pick type C disease83
6.2.1.Miglustat84
6.2.2.Bone marrow and liver transplantations85
6.2.3.Treatment of extrapyramidal symptoms, spasticity, cataplexy and epilepsy85
6.2.4.Substances in preclinical and experimental studies86
Index87