Title : A rare case report of two siblings with unique presentations of adult-onset Niemann-Pick disease type c
Abstract:
Background: Niemann-Pick Disease type C (NPC) is a genetic, lysosomal storage disorder characterized by an inability to transport cholesterol and lipids inside cells. This causes a patient-unique set of visceral and neurological symptoms that can include hepatosplenomegaly, dementia, cognitive decline, learning disabilities, dysphagia, or ataxia. Due to the nonspecific and masquerading nature of the symptoms, NPC tends to be misdiagnosed or undiagnosed in the majority of patients. Most patients develop NPC symptoms before or during adolescence, making the adult-onset form of NPC even more challenging to diagnose for many physicians.
Case Presentation: Two siblings were referred to the clinic in 2016 for assessment of neurological symptoms. There was no relevant family history. The then 33-year-old brother was previously diagnosed by a gastroenterologist with liver nodular regenerative hyperplasia after a history of portal hypertension and hyperbilirubinemia and presented to the clinic with progressive cognitive decline. Physical examination at the time revealed impaired tone, ataxia, normal DTR, and no cranial nerve deficits. Previous history was notable for elevated bilirubin
levels since birth. In 2022, five years after his last evaluation, the patient presented with worsening cognition and behavior and a genetic panel that found that the patient was heterozygous for two NPC1 gene variants. Later that year, an EEG, previously normal in 2016, showed abnormal mild diffuse slowing consistent with a diffuse encephalopathy of metabolic, degenerative, or vascular origin.
His then 41-year-old sister also presented in 2016 with complaints of recurrent facial paralysis, lack of balance, coordination, chronic cough, and attention deficit. Physical examination revealed hyperreflexia, mild appendicular ataxia, facial asymmetry, and dysarthria. In contrast to her brother, the patient has no relevant previous medical history. An EEG at the time was consistent with a diffuse encephalopathy of metabolic, degenerative, or vascular origin. After her brother was genetically diagnosed with NPC in 2022, a genetic panel was also ordered for her and the family which showed she was heterozygous for two NPC variants. In 2023, she started to progressively develop dysarthria and dysphagia, which may be related to progression of the disease. Now that both siblings have been correctly diagnosed, they are receiving treatment with Miglustat and Aqneursa.
Conclusions: This case report exhibits the complex presentation and genetics of NPC that provide a difficult path towards early diagnosis, especially in patients with juvenile or adult onset of the disease. Arriving at the diagnosis for these two siblings took six years due to delays in not only recognizing the rare disorder as a possibility, but also in the approval of genetic testing within the medical system. The eventual diagnosis was due to the ability of several physicians to recognize a pattern worth investigating further due to the progressive decline of the patients with no absolute clinical explanation. This shows how suspecting NPC as a potential diagnosis in patients with unexplained ataxia, cognitive decline, and liver disease is crucial to provide the patients with the proper work-up that can lead to early targeted care that can slow the progression of the disease.
