ACID SPHINGOMYELINASE DEFICIENCY (NIEMANN–PICK DISEASE)
Key features
An autosomal recessive disorder due to deficiency of acid sphingomyelinase
Rare skin involvement in type A consists of yellow–brown discolor- ation and facial papules
Failure to thrive, hepatosplenomegaly, and neurologic deterioration occur in type A
Minimal neurologic involvement and milder disease characterize type B
This is an autosomal recessive lysosomal storage disorder caused by acid sphingomyelinase deficiency, which results in the accumulation of sphingomyelin and other phospholipids. There are two classic forms: type A, with an incidence of 1 in 40 000 births in the Ashkenazi Jewish population; and type B, with a lower incidence and no specific ethnic predilection. Type A (infantile neurovisceral) is a severe disorder associated with failure to thrive, hepatosplenomegaly, thrombocytopenia, and rapid neurologic degeneration leading to death by 2–3 years of age; cherry-red retinal spots are evident in ~50% of patients. Type B (chronic visceral) is characterized by little or no neurologic involvement, later onset, and survival into adult life. Progressive pulmonary infiltration may occur in either subtype, and the disease spectrum includes a chronic neurovisceral phenotype with intermediate severity (type A/B). Type C, which has primarily neurologic findings, results from defects in other genes (NPC1>NPC2) and is associated with an accumulation of unesterified cholesterol.
Cutaneous manifestations are typically observed only in patients with type A disease. The skin may exhibit a generalized ochre or brownishyellow discoloration. Papular lesions, most commonly located on the face and upper extremities, may also be present. Histologically, these papules consist of foamy histiocytes, multinucleated cells, and a variable infiltrate of lymphocytes.
Diagnosis of type A or B disease is established by demonstration of deficient sphingomyelinase activity in leukocytes or cultured skin fibroblasts, or via molecular genetic analysis. Carrier detection for type A can also be performed via genetic testing, and prenatal diagnosis is available by CVS or amniocentesis. In recent clinical trials, recombinant enzyme-replacement therapy with olipudase-α has shown promising results for the non-neurologic manifestations of types A/B and B. Treatment approaches utilizing gene therapy, molecular chaperones, and anti-inflammatory agents are also under investigation. Lastly, hematopoietic stem cell transplantation may improve the non-neurologic features, but treatment-related complications limit its use.