Niemann-Pick Disease

Incidence in live births: 1:100,000-120,000

Affects equally males and females of all ethnic groups

NP-D type A frequent in the Ashkenazi-Jewish population

No curative therapy, although several symptomatic manifestations are treatable

Associated with a decrease in life expectancy, although many pts survive until late adulthood

NP-D pts require a multitude of diagnostic and therapeutic procedures (e.g., medical imaging, lumbar puncture, intrathecal chemotherapy injection, auditory brainstem response measurements, and skin biopsies). General anesthesia with endotracheal intubation is often required.

Pts at increased risk of aspiration, especially those with severe lung involvement, recurrent aspiration, and chronic cough.

Perianesthetic morbidity includes need for tracheal reintubation; pneumonitis, hypothermia, and seizures.

Severe visceral, pulmonary, and neurologic involvement

Hepatomegaly, ascites, coagulation disorders, and hypersplenism with thrombocytopenia

Alterations of liver function and in some cases, liver cirrhosis and liver failure

Rarely causes spontaneous splenic rupture

Recurrent respiratory infections are common; prior episodes of aspiration

It is classified into the neurovisceral lysosomal lipid-storage disease group (types A–D).

Two distinct entities exist: acid sphingomyelinase deficiency (type A and B) and loss-of-function mutations in either the NPC1 or NPC2 genes (C and D).

Age of clinical onset varies widely.

Broad clinical spectrum ranges from a rapidly fatal disorder in neonates to an adult onset chronic neurodegenerative disease, a mix of visceral and neurologic deficits including vertical gaze palsy, ataxia, dystonia, dysphagia, seizures, and progressive dementia.

With systemic disease, hepatosplenomegaly can be severe.

Lung involvement can be present and results from severe neurologic impairment and associated dysphagia, recurrent aspirations, and thoracic muscle weakness.

Autosomal recessive lysosomal storage disorders

Mutations in the SMPD1 gene (types A and B) resulting in sphingomyelinase deficiency with progressive accumulation of sphingomyelin in systemic organs and brain, and secondary accumulation of other lipids

Historically, categorized into a severe, acute neuronopathic form (A), and a nonneuronopathic form (B), also intermediate cases

Extremely variable degree of systemic involvement depending on age of discovery; retarded body growth (common); often delayed skeletal age and puberty

Vomiting and diarrhea in first months of life; failure to thrive often motivating a first consultation, leading to the discovery of a usually prominent hepatosplenomegaly (80% of pts); additionally, hypotrophy, dysmorphia, brownish skin pigmentation, macular halo, and cherry-red spots, which are typical

Further hypotonia, progressive loss of acquired motor skills, increasing spasticity, abolished deep-tendon reflexes, joint/limb pain, bruising, headache, abdominal pain, and diarrhea

NP-D type C, which involves alterations in the intracellular transport of endocytosed cholesterol and accumulation of unesterified cholesterol in lysosomes and endosomes due to mutations in either the NPC1 (95% of families) or NPC2 genes

Hypercholesterolemia with marked decrease of HDL cholesterol (common); complex lipid storage observed in extra neural tissues

Pulmonary involvement:

• Common at all ages, with widely variable impairment of respiratory function ranging from dyspnea on exertion (frequent) to oxygen dependency

• CXR: Reticulonodular pattern, interlobular septal thickening, ground-glass density; in adults with a long follow-up, pulm involvement (often the main complaint)