Niemann‐Pick Type C Disease: From Variant of Uncertain Significance to Pathogenic Variant

Niemann‐Pick type C (NPC) disease is a slowly progressive lysosomal autosomal recessive disorder with variable age of onset. Adult patients usually have a neurological‐dominant phenotype with supranuclear gaze palsy, neuropsychiatric manifestations, early‐onset dementia and movement disorders. ¹ We report on a patient with a typical clinical phenotype, but a missense variant of uncertain significance (VUS) in the NPC1 gene, which could lead to its reclassification as likely pathogenic.

A 38‐year‐old female patient presented to our Movement Disorders Clinic due to abnormal involuntary movements that started 2 years ago. She described her first symptom as torsional involuntary trunk and cervical movements with trunk extension. Shortly thereafter, she developed depression, anxiety, compulsive behaviors (repetitive hand washing), memory loss and excessive diurnal somnolence. She lost her functional independence, and eventually developed a multi‐domain dementia syndrome. There was no family history of neurological disorders and parents were non‐consanguineous.

Neurological examination was remarkable for slow and hypometric saccades as well as vertical supranuclear gaze palsy with limitation of conjugate downward ocular pursuit that could be overcome by the oculocephalic maneuver (Video 1). Muscle strength was normal but there was generalized hypotonia. There were dysmetria and dysdiadochokinesia. There was generalized dystonia with opisthotonic posturing and retrocollis. The patient had generalized bradykinesia, hypomimia with reduced blinking frequency and retropulsion on pull test. Her gait had a combination of wide base, dystonic posturing and postural instability.

Video 1.

Segment 1–Relatively unimpaired smooth horizontal pursuit, cervical dystonia with right head‐tilt and hypomimia. Segment 2–Smooth downward pursuit is significantly more impaired than upward pursuit. The downward pursuit restriction could be overcome by the oculocephalic maneuver and internally generated saccades were slow (not shown in video). Segment 3–Overview of the patient's nine positions of gaze.

Routine blood tests, including thyroid hormones, electrolytes, liver and kidney function and copper studies, were normal. Abdominal ultrasound was also normal. Brain MRI showed moderate diffuse atrophy. Cerebrospinalspinal fluid (CSF) analysis, including VDRL, was normal.

Next‐generation sequencing (NGS) gene panel disclosed heterozygous compound mutations in the NPC1 gene: chr18:23.533.446 GA>G (p.Phe1221Serfs*21 ENST 00000269228)—known to be pathogenic ¹ —and chr18:23.561.510 G>A (p.Arg161Trp ENST 00000269228)—a reported missense VUS. ² No pathogenic variants in the NPC2 gene, a less frequent cause of NPC accounting for approximately 5% of cases, ³ were identified.

Chr18:23.561.510 G>A (p.Arg161Trp ENST 00000269228) is rare and has been identified as a heterozygous variant in just 5 out of 14,000 subjects in the population‐based database gnomAD (approximately 0.005% prevalence). To the best of our knowledge, no homozygous cases have been so far reported in databases or published articles. Modeling output from Abracadabra®, an in‐house in silico prediction tool ⁴ developed by Mendelics, the laboratory responsible for the patient's genetic testing, favored this variant as potentially deleterious.

As limitations, NGS cannot unequivocally state that the patient's VUS is not in cis (in the same allele) with the pathogenic variant. However, given the classical NPC clinical phenotype of our patient, it is very likely the variants are in trans (in different chromosomes). The patient was lost to follow‐up and further confirmatory biochemical analysis or fibroblast culture could not be obtained.

According to the most recent guidelines on human genetics, ⁵ , ⁶ we have provided moderate (PM2) and supportive (PP3 and PP4) evidence of pathogenicity for the NPC1 Chr18:23.561.510 G>A (p.Arg161Trp ENST 00000269228) missense variant. We therefore propose reclassification of this variant as likely pathogenic. If our proposal is confirmed by additional investigations, patients carrying this mutation will be candidates for available disease‐modifying treatments for NPC. ⁷

Author Roles

(1) Manuscript preparation: A. Writing of the first draft, B. Review and Critique.

L.B.R.: 1A

C.N.A.: 1B

J.M.V.B.: 1B

D.P.M.: 1B

R.H.M.: 1B

S.T.C.: 1B

F.C.: 1B

Disclosures

Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was not required for this work. The patient's family has provided written informed consent for the publication of this article with video. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: The authors declare that there are no funding sources or conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional financial disclosures to report.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.