Niemann-Pick Disease Type C

Clinical characteristics: 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, 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 a progressive dementia.

Older teenagers and young adults may present predominantly with apparent early-onset dementia or psychiatric manifestations; however, careful examination usually identifies typical neurologic signs.

Diagnosis/testing: The diagnosis of NPC is established in a proband with suggestive findings and biallelic pathogenic variants in either NPC1 or NPC2 identified by molecular genetic testing.

Management: Treatment of manifestations: No curative therapy for NPC exists. Supportive therapy is provided by specialists from multiple disciplines including among others: neurology, physical therapy, occupational therapy, speech therapy, nutrition, feeding, psychology, social work, and medical genetics.

Treatment with miglustat, approved for the management of neurologic manifestations of NPC in several countries but not the United States, has increased survival by five years from date of diagnosis or approximately ten years from onset of neurologic manifestations.

Surveillance: Routine follow up by multidisciplinary specialists to monitor disease progression and supportive management including psychosocial support to identify new manifestations of disease, and, for those on miglustat, to assess compliance, possible side effects, and appearance of conditions that would prompt discontinuation of therapy.

Agents/circumstances to avoid: Drugs that cause excessive salivation or that may exacerbate seizures directly by interacting with anti-seizure medication; alcohol as well as many drugs that exacerbate ataxia.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who are symptomatic and would benefit from prompt initiation of treatment.

Genetic counseling: NPC is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an NPC-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a heterozygote, and a 25% chance of being unaffected and not a heterozygote. Once the NPC-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.