Niemann-Pick Disease Type C

Excerpt

Clinical characteristics: Niemann-Pick disease type C (NPC) is a slowly progressive lysosomal disorder in which the principal manifestations are age dependent.

Perinatal period and infancy: The initial presentation is predominantly visceral with hepatosplenomegaly, cholestatic jaundice, and (in some instances) pulmonary infiltrates. Many infants succumb at this stage; however, of those who survive, some are hypotonic and have delayed psychomotor development, whereas others may have complete resolution of disease manifestations, only to present with neurologic disease many years later.

Mid- to late childhood onset: The initial 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 as progressive dementia. Death from aspiration pneumonia usually occurs in the late second or third decade.

Adolescent to adult onset: The initial presentation may be neurologic manifestations like those in childhood, but with a much slower rate of progression and longer life expectancy. In others, the initial presentation can be predominantly early-onset dementia or psychiatric manifestations.

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: Targeted therapies: Treatment for the neurologic manifestations of NPC can include miglustat (approved in several countries but not currently FDA approved for standalone treatment of NPC), arimoclomol (approved for use in combination with miglustat), and levacetylleucine (standalone treatment approved by FDA).

Supportive care: No curative therapy for NPC exists. Supportive therapy is provided by specialists from multiple disciplines including neurology, physical therapy, occupational therapy, speech therapy, nutrition, feeding, psychology, social work, and clinical genetics.

Surveillance: Regularly scheduled follow up is recommended for multidisciplinary specialists to monitor disease progression, emergence of new disease manifestations, and response to supportive management including psychosocial support. For those on miglustat therapy, regularly scheduled follow up is recommended to monitor adherence, side effects, and conditions that would prompt discontinuation of therapy.

Agents/circumstances to avoid: Drugs that cause excessive salivation or 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 at-risk sibs of an affected individual in order to identify as early as possible those who might benefit from targeted therapy for NPC.

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 heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Heterozygotes may manifest clinical and biochemical abnormalities. Once the NPC-causing pathogenic variants have been identified in an affected family member, heterozygote testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.