Original article
Acid sphingomyelinase deficiency: Prevalence and characterization of an intermediate phenotype of Niemann-Pick disease

https://doi.org/10.1016/j.jpeds.2006.06.034Get rights and content

Objective

To document the prevalence of neurologic disease in Niemann-Pick disease (NPD) NPD-B.

Study design

Sixty-four patients with NPD-B had detailed neurologic and ophthalmologic evaluations. The presence of neurologic abnormalities was compared with genotype.

Results

Nineteen of 64 patients (30%) had neurologic abnormalities, which were minor and nonprogressive in 14 (22%), and global and progressive in 5 (8%). In these five patients, the onset of neurologic difficulties occurred between 2 and 7 years of age and was associated with peripheral neuropathy, retinal abnormalities, and the Q292K mutation. No patients with at least one copy of ΔR608 had neurologic involvement.

Conclusions

The majority of patients with NPD-B have no neurologic abnormalities. In patients with neurologic abnormalities, the findings can be minor and static or severe and progressive. The latter phenotype follows a course distinct from that of classic NPD-A and is associated with the Q292K mutation and characteristic retinal findings. Thus, similar to other lysosomal storage disorders, there is a broad spectrum of neurologic abnormalities in acid sphingomyelinase deficiency, which makes the current classification scheme inaccurate.

Section snippets

Study Subjects

Sixty-four patients with NPD-B were admitted to the Mount Sinai General Clinical Research Center for medical and family histories and physical examinations. The diagnosis of each patient was confirmed by the demonstration of reduced ASM activity in isolated leukocytes and/or cultured skin fibroblasts and by the identification of two disease-causing ASM mutations. Detailed clinical neurologic examinations were carried out by a single examiner, including assessment of mental status, motor and

Results

The median age of the 64 patients was 20.9 years, with a range of 2 to 66 years at the time of the latest examination. Table I details the genotypes and ages of the 33 patients with retinal changes and/or neurologic involvement. The most common neurologic abnormalities were mild hypotonia and/or hyporeflexia, which were found in 10 patients. Three patients had one unusual neurologic abnormality: Patient 52 had a slight intention tremor, patient 54 had a terminal finger-nose tremor, and patient

Discussion

Acid sphingomelinase deficiency has traditionally been categorized as neuronopathic (NPD-A) or non-neuronopathic (NPD-B). Several reports have described patients with a subtle, intermediate form who satisfy criteria for NPD-B but who also have neurologic manifestations including cerebellar signs and nystagmus,3 extrapyramidal involvement,6 mental retardation,7 and psychiatric disorders.8 As in other lysosomal storage diseases,9 it is evident that neurologic manifestations in acid

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    Supported by a grant (5 MO1 RR00071) for the Mount Sinai General Clinical Research Center from the National Center for Research Resources, National Institutes of Health (NIH), and by NIH grant K24RR021991-02 (M.M.). M.W. is the recipient of a Mentored Patient-Oriented Research Career Development Award (K23 RR16052-01) from the NIH.

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