A prospective, cross-sectional survey study of the natural history of Niemann-Pick disease type B.
OBJECTIVE
The objective of this study was to characterize the clinical features of patients with Niemann-Pick disease type B and to identify efficacy end points for future clinical trials of enzyme-replacement therapy.


METHODS
Fifty-nine patients who had Niemann-Pick disease type B, were at least 6 years of age, and manifested at least 2 disease symptoms participated in this multicenter, multinational, cross-sectional survey study. Medical histories; physical examinations; assessments of cardiorespiratory function, clinical laboratory data, and liver and spleen volumes; radiographic evaluation of the lungs and bone age; and quality-of-life assessments were obtained during a 2- to 3-day period.


RESULTS
Fifty-three percent of the patients were male, 92% were white, and the median age was 17.6 years. The R608del mutation accounted for 25% of all disease alleles. Most patients initially presented with splenomegaly (78%) or hepatomegaly (73%). Frequent symptoms included bleeding (49%), pulmonary infections and shortness of breath (42% each), and joint/limb pain (39%). Growth was markedly delayed during adolescence. Patients commonly had low levels of platelets and high-density lipoprotein, elevated levels of low-density lipoprotein, very-low-density lipoprotein, triglycerides, leukocyte sphingomyelin, and serum chitotriosidase, and abnormal liver function test results. Nearly all patients had documented splenomegaly and hepatomegaly and interstitial lung disease. Patients commonly showed restrictive lung disease physiology with impaired pulmonary gas exchange and decreased maximal exercise tolerance. Quality of life was only mildly decreased by standardized questionnaires. The degree of splenomegaly correlated with most aspects of disease, including hepatomegaly, growth, lipid profile, hematologic parameters, and pulmonary function.


CONCLUSIONS
This study documents the multisystem involvement and clinical variability of Niemann-Pick B disease. Several efficacy end points were identified for future clinical treatment studies. Because of its correlation with disease severity, spleen volume may be a useful surrogate end point in treatment trials, whereas biomarkers such as chitotriosidase also may play a role in monitoring patient treatment responses.
McGovern
Margaret M
MM
Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, New York, USA. margaret.mcgovern@mssm.edu
Wasserstein
Melissa P
MP
Giugliani
Roberto
R
Bembi
Bruno
B
Vanier
Marie T
MT
Mengel
Eugen
E
Brodie
Scott E
SE
Mendelson
David
D
Skloot
Gwen
G
Desnick
Robert J
RJ
Kuriyama
Noriko
N
Cox
Gerald F
GF
D000293:Adolescent; D000328:Adult; D000368:Aged; D002318:Cardiovascular Diseases / Q000209:etiology / Q000503:physiopathology; D002648:Child; D003430:Cross-Sectional Studies; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D006130:Growth Disorders / Q000209:etiology / Q000503:physiopathology; D006529:Hepatomegaly / Q000209:etiology / Q000503:physiopathology; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D020125:Mutation, Missense; D052537:Niemann-Pick Disease, Type B / Q000150:complications* / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D011336:Probability; D011379:Prognosis; D011446:Prospective Studies; D011788:Quality of Life; D018570:Risk Assessment; D012720:Severity of Illness Index; D013163:Splenomegaly / Q000209:etiology / Q000503:physiopathology; D016019:Survival Analysis