Clinical Guidance

Niemann-Pick disease type C (NPC) is a slowly progressive lysosomal disorder whose principal manifestations are age dependent. The manifestations in the perinatal period and infancy are predominantly visceral, with hepatosplenomegaly, cholestatic jaundice, and (in some instances) pulmonary infiltrates. From late infancy onward, the presentation is dominated by neurologic manifestations. The youngest children may present with hypotonia and developmental delay, with the subsequent emergence of ataxia, dysarthria, dysphagia, and (in some individuals) epileptic seizures, dystonia, and gelastic cataplexy. Although cognitive impairment may be subtle at first, it eventually becomes apparent that affected individuals have progressive dementia. Older teenagers and young adults may present predominantly with apparent early-onset dementia or psychiatric manifestations; however, detailed examination usually identifies typical neurologic signs. Table 2. Niemann-Pick Disease Type C: Comparison of Age-Related Phenotypes by Select Features Feature | Phenotypes by Age of Onset

Source: GeneReviews — "Niemann-Pick Disease Type C"

Differential Diagnosis

The differential diagnosis of neonatal and infantile presentations of Niemann-Pick disease type C (NPC) includes:

• Acquired conditions such as biliary atresia*

• Congenital infections (e.g., TORCH)

• Malignancies (leukemia, lymphoma, histiocytosis)

• Other genetic disorders (See .)

*A study from Colorado found that 27% of infants initially diagnosed with idiopathic neonatal cholestasis (see Pediatric Genetic Cholestatic Liver Disease Overview) and 8% of all infants with cholestasis had NPC .

Table 3.

Niemann-Pick Disease Type C (Neonatal and Infantile Presentations): Differential Diagnosis

Gene | Disorder | MOI | Clinical Characteristics

Source: GeneReviews — "Niemann-Pick Disease Type C"

Clinical Guidance

Avoid the following:

• Drugs that cause excessive salivation or that may exacerbate seizures directly by interacting with anti-seizure medications

• Alcohol as well as many drugs that exacerbate ataxia

Source: GeneReviews — "Niemann-Pick Disease Type C"

Therapies Under Investigation

Electroconvulsive therapy (ECT) has been effective in an adult and in an adolescent with NPC manifesting as drug-resistant catatonia . ECT may be a preferred therapeutic option in such individuals with NPC who may be at increased risk of extrapyramidal manifestations (EPS), as described in a 28-year-old man with NPC and schizoaffective disorder, who experienced prolonged EPS after risperidone . Intrathecal 2-hydroxypropyl-beta-cyclodextrin. Based on results of studies of hydroxypropyl-beta-cyclodextrin in the murine model of NPC , uncontrolled clinical studies of intrathecal 2-hydroxypropyl--cyclodextrin suggested amelioration of disease progression . However, a controlled clinical trial of this therapy failed to show a difference between controls and the intervention group (NCT02534844).

Source: GeneReviews — "Niemann-Pick Disease Type C"