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Review
. 2020 Jul 17;21(14):5059.
doi: 10.3390/ijms21145059.

Clinical and Molecular Features of Early Infantile Niemann Pick Type C Disease

Berna Seker Yilmaz  1   2 , Julien Baruteau  1   3   4 , Ahad A Rahim  5 , Paul Gissen  1   3   4
Affiliations
Review

Clinical and Molecular Features of Early Infantile Niemann Pick Type C Disease

Berna Seker Yilmaz et al. Int J Mol Sci. .

Abstract

Niemann Pick disease type C (NPC) is a neurovisceral disorder due to mutations in NPC1 or NPC2. This review focuses on poorly characterized clinical and molecular features of early infantile form of NPC (EIF) and identified 89 cases caused by NPC1 (NPC1) and 16 by NPC2 (NPC2) mutations. Extra-neuronal features were common; visceromegaly reported in 80/89 NPC1 and in 15/16 NPC2, prolonged jaundice in 30/89 NPC1 and 7/16 NPC2. Early lung involvement was present in 12/16 NPC2 cases. Median age of neurological onset was 12 (0-24) and 7.5 (0-24) months in NPC1 and NPC2 groups, respectively. Developmental delay and hypotonia were the commonest first detected neurological symptoms reported in 39/89 and 18/89 NPC1, and in 8/16 and 10/16 NPC2, respectively. Additional neurological symptoms included vertical supranuclear gaze palsy, dysarthria, cataplexy, dysphagia, seizures, dystonia, and spasticity. The following mutations in homozygous state conferred EIF: deletion of exon 1+promoter, c.3578_3591 + 9del, c.385delT, p.C63fsX75, IVS21-2delATGC, c. 2740T>A (p.C914S), c.3584G>T (p.G1195V), c.3478-6T>A, c.960_961dup (p.A321Gfs*16) in NPC1 and c.434T>A (p.V145E), c.199T>C (p.S67P), c.133C>T (p.Q45X), c.141C>A (p.C47X) in NPC2. This comprehensive analysis of the EIF type of NPC will benefit clinical patient management, genetic counselling, and assist design of novel therapy trials.

Keywords: Niemann Pick disease type C; early infantile onset; neurological manifestations.

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Conflict of interest statement

B.S.Y., J.B. and A.A.R has no conflict of interest. P.G. is an investigator on Malinckrodt, IntraBio, and Orphazyme sponsored clinical trials and received speaker and advisory board honoraria.

Figures

Figure 1
Figure 1
Flowchart of the selection process for the publications included.
Figure 2
Figure 2
Presence of visceromegaly reported in NPC1 cases. HSM: hepatosplenomegaly, VM: visceromegaly, SM: splenomegaly. Blue: hepatomegaly; orange: splenomegaly; grey: visceromegaly; yellow: none; light blue: unknown
Figure 3
Figure 3
Presenting neurological signs and symptoms of all NPC1 patients. Blue: developmental delay; orange: hypotonia; silver: developmental regression; yellow: frequent falls, ataxia, and lack of motor coordination; light blue: nystagmus; green: spasticity; navy blue: swallowing difficulties; orange-red: severe encephalopathy; grey: dystonia; mustard: speech problems.
Figure 4
Figure 4
Distribution of age of onset for the neurological symptoms in NPC1 patients. In yellow 0–12 months, blue 13–24 months, green 24+ months.
Figure 5
Figure 5
Distribution of reported developmental delay in NPC1 patients.
Figure 6
Figure 6
Age of onset of presentation for neurological symptoms in NPC2 patients. In yellow 0–12 months, blue 12–24 months, green 24+ months.
See this image and copyright information in PMC

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