Clinical characteristics: Niemann-Pick disease type C (NPC) is a lipid storage disease that can present in infants, children, or adults. Neonates can present with ascites and severe liver disease from infiltration of the liver and/or respiratory failure from infiltration of the lungs. Other infants, without liver or pulmonary disease, have hypotonia and developmental delay. The classic presentation occurs in mid-to-late childhood with the insidious onset of ataxia, vertical supranuclear gaze palsy (VSGP), and dementia. Dystonia and seizures are common. Dysarthria and dysphagia eventually become disabling, making oral feeding impossible; death usually occurs in the late second or third decade from aspiration pneumonia. Adults are more likely to present with dementia or psychiatric symptoms.
Diagnosis/testing: The diagnosis of NPC is confirmed by biochemical testing that demonstrates impaired cholesterol esterification and positive filipin staining in cultured fibroblasts. Biochemical testing for carrier status is unreliable. Most individuals with NPC have NPC1, caused by pathogenic variants in NPC1; fewer than 20 individuals have been diagnosed with NPC2, caused by pathogenic variants in NPC2. Molecular genetic testing of NPC1 and NPC2 detects pathogenic variants in approximately 94% of individuals with NPC.
Management: Treatment of manifestations: Symptomatic therapy for seizures, dystonia, and cataplexy; a nocturnal sedative to help disordered sleep; physical therapy to maintain mobility as long as possible. Prevention of secondary complications: Chest physical therapy with aggressive bronchodilation and antibiotic therapy of intercurrent infection; regular bowel program for mobility-impaired individuals to prevent severe constipation and resulting increased seizure frequency and/or increased spasticity. Surveillance: Swallowing is monitored to allow placement of a gastrostomy tube when aspiration or nutritional compromise is imminent. Agents/circumstances to avoid: Drugs that cause excessive salivation or that may exacerbate seizures by interacting with antiepileptic drugs; alcohol and other drugs that may exacerbate ataxia.
Genetic counseling: NPC is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. The phenotype (i.e., age of onset and severity of symptoms) usually runs true in families. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants have been identified in the family.
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