Niemann Pick Type C Presenting as Familial Late-Onset Richardson Syndrome. A Case Series of Four Siblings

Niemann Pick Type C (NP-C) is a rare lysosomal disorder, characterized by clinical heterogeneity. Late age of onset (> 40 years) is exceedingly rare, with approximately 20 reports to date. Herein, we describe four siblings with disease onset over 40 years of age.

Two of the siblings fulfilled criteria for probable PSP with Richardson syndrome (PSP-RS), whereas the remaining cases had atypical clinical features, with prominent cerebellar symptoms and overt frontal-executive dysfunction, fulfilling criteria for probable PSP-RS and probable PSP with predominant frontal presentation (PSP-F). All patients reported hearing loss. DaT-scans were normal in two of the cases, and midbrain atrophy was absent. EEG was abnormal, with generalized paroxysms and short sequences of delta slow waves in one of the cases. All patients had a homozygous point mutation c.2861C>T, p.(Ser954Leu) in the NPC1 gene.

A literature review supported the association between the c.2861C>T, p.(Ser954Leu) mutation in the NPC-1 gene and late-onset NP-C. Cerebellar signs, early-onset hearing loss, normal DaT-scan and absence of midbrain atrophy in brain MRI are red flags for a PSP diagnosis and should prompt further investigations for alternative diagnoses, including NP-C.

Late onset (>40 years) NP-C, particularly due to c.2861C>T, p.(Ser954Leu) mutation in the NPC-1 gene, can mimic Richardson syndrome.