Clinical Guidance

NPC1. The following phenotype correlations have been observed for homozygous pathogenic variants and the more common pathogenic variants in the compound heterozygous state:

• No individuals with had early-infantile NPC in an international study that included the Hispanic population in the upper Rio Grande Valley of the southwestern United States, as well as the United Kingdom and France .

• Premature-termination-codon variants, variants involving the sterol-sensing domain, and in the cysteine-rich luminal loop of NPC1 are associated with early-infantile NPC .

• In 40 unrelated individuals of Spanish descent homozygous for the pathogenic variant had early-infantile NPC, and those homozygous for the pathogenic variant had late-infantile NPC .

NPC2

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

Diagnostic Criteria

Consensus clinical management guidelines for Niemann-Pick disease type C (NPC) developed under the auspices of the International Niemann-Pick Disease Alliance include recommendations for clinical and laboratory diagnosis of NPC.

Suggestive Findings

NPC should be suspected in individuals with the following clinical findings (full text) and preliminary laboratory findings.

Clinical findings

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"

Management Guidelines

Clinical management guidelines for Niemann-Pick disease type C (NPC) have been published (full text). Note: Revised clinical management guidelines for NPC are being developed to incorporate the recently approved targeted therapies arimoclomol/miglustat and levacetylleucine. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with NPC, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 5. Niemann-Pick Disease Type C: Recommended Evaluations Following Initial Diagnosis

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"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 8. Niemann-Pick Disease Type C: Recommended Surveillance

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