Physician/Scientist

Clinical Manifestations of
Types A and B Niemann-Pick Disease

Type A Phenotype

The clinical presentation and course of Type A NPD are relatively uniform. Pregnancy, labor, and delivery are typically unremarkable, and affected newborns appear normal at birth. Occasionally, the newborn period will be complicated by prolonged jaundice. Typically, in the first few months of life, or less frequently by 4 to 6 months, the abdomen will become protuberant and hepatosplenomegaly will be noted on physical examination. Moderate lymphadenopathy also is usually present. Bone marrow examination reveals the histochemically characteristic Niemann-Pick "foam cells." A moderate microcytic anemia, which may be responsive to iron supplementation, and a decreased platelet count occur later in the disease. Early neurologic manifestations include hypotonia and muscular weakness that are clinically manifested by feeding difficulties. Recurrent vomiting and chronic constipation are frequent complications. As a result of feeding difficulties and the splenomegaly, affected infants will eventually have decreased linear growth and body weight. Cardiac function is typically normal. Most infants with Type A NPD have minimal respiratory difficulties in the first year of life, with the exception of repeated bronchitis and intercurrent or aspiration pneumonias. However, chest X-ray films demonstrate infiltration of the alveoli as a uniform, diffuse reticular or finely nodular pattern in the lungs.

By the time the patient is six months old, the psychomotor retardation becomes evident. As the infant becomes progressively weaker and hypotonic, retrogression of developmental milestones is noted (e.g., the child can no longer sit). Ophthalmologic examination reveals cherry-red maculae in about half of affected infants in the first or second year of life. Occasionally, gray granular-appearing maculae are observed (the "macular halo syndrome"). The electroretinogram is abnormal; however, impairment of vision is rare. Deep-tendon reflexes are diminished or absent, and the cerebrospinal fluid pressure and electroencephalograms are generally normal.

With advancing age, the loss of motor function and the deterioration of intellectual capabilities are progressively debilitating. In addition, affected infants exhibit striking emaciation with a protuberant abdomen and thin extremities. In the late stages, spasticity and rigidity are evident, and affected infants experience complete loss of contact with their environment. Seizures are rare. Hyperacusis and macrocephaly, features of Tay-Sachs disease, do not occur.

The skin of Type A NPD patients may have an ochre or brownish-yellow color. Xanthomas also have been observed in some Type A NPD patients, often occurring on the face and upper extremities. Bony involvement is minimal, considering the extensive infiltration of the Niemann-Pick macrophages in the marrow. The Erlenmeyer flask deformities seen in Gaucher disease resulting from marrow expansion are rarely observed. However, osteoporosis is common, presumably because of infiltration and poor nutrition. Bone age, as well as serum calcium and phosphorus levels, are normal.