Genotype/phenotype of 6 Chinese cases with Niemann-Pick disease type C.
Niemann-Pick disease type C (NP-C), caused by mutations of either NPC1 or NPC2 gene, is an inherited lysosomal lipid storage disorder that is difficult to be diagnosed and treated. NP-C is rarely reported in China and so far very few literatures are available for Chinese clinical workers. To better characterize this disease in China and improve genetic counseling, mutational analyses of NPC1 gene were carried out in 6 unrelated Chinese patients.


METHODS
Clinical data of the probands from 2007 to 2010 were collected and analyzed. All exons of NPC1 were analyzed by direct sequencing.


RESULTS
The six cases, four males and two females, included three cases of late infantile subtype and three cases of juvenile subtype. Case one and case six had siblings who suffered from the same disease. The onset of clinical symptoms varied from three to ten years old, and they included progressive cognitive and language impairment, and motion retrogradation. All were caught by focal or generalized seizures from one to four years after the onset. Vertical supranuclear gaze palsy, dysarthria, dysphagia, internal rotation and adduction of bilateral hands and splenomegaly occurred gradually during the disease progression. Five patients had laughter-cataplexy. MRI indicated mild brain atrophy. Sea blue cells and Niemann-Pick cells were presented in bone marrow smears. Activity of acid sphingomyelinase was normal or only slightly lower than controls. Supporting and symptomatic treatments could improve some of the clinical signs. We identified 10 different NPC1 mutations were identified in 12/12 alleles, 3 of which are described for the first time. All mutations were missense mutations, which located throughout the gene with five clustering in the cysteine-rich luminal domain. Homozygous mutation of S865L correlated with a relatively severe juvenile neurological form.


CONCLUSIONS
NP-C is a rare autosomal recessive lysosomal storage disease that affects intellectual development of children, causing dementia, vegetative state and eventual death. The awareness of NP-C should be raised in the Chinese population. The typical clinical features of this disease include vertical supranuclear gaze palsy, seizures and cataplexy. Laboratory features include the presence of sea blue cells and Niemann-Pick cells in bone marrow smears. NPC1 mutation can be identified in most of these patients and most of them are missense mutations.
Department of Pediatric, Peking University First Hospital, Beijing 100034, China.
Hui
H
Xiong
Katsumi
K
Higaki
Cui-Jie
CJ
Wei
Xin-Hua
XH
Bao
Yue-Hua
YH
Zhang
Na
N
Fu
Jiong
J
Qin
Kaori
K
Adachi
Yumiko
Y
Kumura
Haruaki
H
Ninomiya
Eiji
E
Nanba
Xi-Ru
XR
Wu
D044466:Asian People / Q000235:genetics; D001854:Bone Marrow Cells / Q000473:pathology; D001921:Brain / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D002385:Cataplexy / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005091:Exons; D005260:Female; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D020125:Mutation, Missense; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000209:etiology / Q000235:genetics*; D010641:Phenotype
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein