Objective: To evaluate genetic and phenotypic variability and correlations in adult Niemann Pick disease type C (NPC) patients.

Background: NPC is an autosomal recessive inherited lysosomal storage disorder caused by mutations in NPC1 and NPC2 genes. It is a neuro-visceral disease with a heterogeneous phenotype. Clinical features depend on the age at onset. Visceral manifestations are more prominent in early onset (infantile) form and neuro-psychiatric symptoms are more prominent in late disease onset (juvenile and adult forms).

Method: NPC patients diagnosed at the Neurology Clinic, University Clinical Centre of Serbia in a period from 2009 – 2020 were included in analysis.

Results: 15 patients originating from 14 families have been genetically diagnosed with NPC. Detected mutations are shown in [table1].
The mean age at disease onset was 20.3±11.9 years (range 10-51 years). Ten patients (66.7 %) had juvenile onset (JO-NPC) (≤15 years); the remaining 5 patients had adolescent/adult onset (AAO-NPC) (>15 years). Average age at the first neurological manifestation was 21±12.0 years. Only three patients (20%) haven’t had any neurological symptoms at disease onset (hearing impairment in one and depression in two patients), but in all three neurological symptoms appeared after 3.7±0.6 years (ataxia, dysphagia and ataxia respectively). Findings at the last examination are shown in [figure1]. Positive correlation was found for c.2861C>T, p.S954L mutation and age at first neurological manifestation (correlation coefficient 0.596, p=0.019). When analysed combinations of two mutations (in homozygotes or compound heterozygotes state) with clinical features, positive correlation was found for the same mutation in homozygous state (c.2861C>T, p.S954L) and age at neurological onset (correlation coefficient 0.859, p<0.001). The two patients, homozygotes for c.2861C>T, p.S954L, had very late disease onset (at 42 and 51 years).

Conclusion: Clinical findings were in line with expected. We hypothesize that the presence of c.2861C>T mutation, in homozygous or heterozygous state, may have a “protective” role due to its association with older age at first neurological symptom onset.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genotype-phenotype-correlations-in-niemann-pick-disease-type-c/