Physician/Scientist

Clinical Manifestations of
Types A and B Niemann-Pick Disease

Type B Phenotype

In contrast to the stereotyped Type A phenotype, the clinical presentation and course of patients with Type B disease are more variable. Most patients are diagnosed in infancy or childhood when enlargement of the liver and/or spleen is detected during a routine physical examination. At diagnosis, Type B NPD patients usually have evidence of mild pulmonary involvement, usually detected as a diffuse reticular or finely nodular infiltration on the chest roentgenogram. In most patients, hepatosplenomegaly is particularly prominent in childhood, but with increasing linear growth, the abdominal protuberance decreases and becomes less conspicuous. In mildly affected patients, the splenomegaly may not be noted until adulthood, and there may be minimal disease manifestations.

In most Type B patients, decreased pulmonary diffusion resulting from alveolar infiltration becomes evident in childhood and progresses with age. Severely affected individuals may experience significant pulmonary compromise by 15 to 20 years of age. Such patients have low PO2 values and dyspnea on exertion. Life-threatening bronchopneumonias may occur, and cor pulmonale has been described. Severely affected patients also may have liver involvement leading to life-threatening cirrhosis, portal hypertension, and ascites. Clinically significant pancytopenia resulting from secondary hypersplenism may require partial or complete splenectomy, but is rare.

In general, Type B patients do not have neurologic involvement and are intellectually intact. However, there are Type B NPD patients who have cherry-red maculae or a gray, granular pigmentation around the fovea; notably, these patients have apparently normal intelligence and minimal to no neurologic findings. In addition, Sogawa et al. have reported two unrelated patients of 9 and 18 years of age who had mental retardation, and Takada et al. have reported two Type B NPD sisters aged 9 and 13 who had vacuolated macrophages in their cerebrospinal fluid and inclusion bodies in the axons and Schwann cells of rectal biopsies, but no signs of mental retardation. Several cases of Type B NPD with cerebellar ataxia also have been reported. It is likely that these patients represent the expected clinical spectrum between the typical Type A and B NPD phenotypes. Presumably, they have ASM activities that are sufficient to preclude the development of the severe Type A disease, but accumulate sufficient neuronal substrate to cause mild to moderate neurologic complications. It is also possible that some of the Type B patients with neurologic involvement (particularly those with cerebellar ataxia) may have been misdiagnosed and had Type C NPD.