NP-C is a rare autosomal recessive neuro-metabolic disease that leads to a defect in cellular lipid trafficking. The intracellular accumulation of cholesterol and gangliosides particularly affects the central nervous system. The time of disease onset and initial symptoms are highly variable and can affect infants, children and adults. Early diagnosis is crucial to allow timely initiation of therapy.
Signs and Symptoms
Variable systemic, neurological and psychiatric symptoms can be observed in NP-C patients. The progressive nature of the disease leads to progressive disabling neurological problems and premature death in most patients. Vertical supranuclear gaze palsy (VSGP) with slowing of first downward and then upward saccades (saccade palsy) is one of the most specific neurological signs of NP-C, making the examination of eye movements a valuable tool for early detection of NP-C. Enlarged spleen, often accompanied by an enlarged liver, can be consistently seen in NP-C patients. In children, dystonia, gelastic cataplexy and epilepsy are frequent symptoms. Juvenile and adult patients present with cerebellar ataxia, dystonia or in late stages spasticity, along with psychiatric disorders, such as therapy-resistant psychosis or depression and develop early subcortical dementia.
NP-C often remains undetected or is misdiagnosed due to the wide range of possible symptoms. Examination of eye movement is crucial for the detection of NP-C, since VSGP is observed in more than 95% of patients. Typically, vertical downward saccades are affected first, followed by vertical upward saccades. With disease progression horizontal saccades and smooth pursuit also become impaired. Patients blink frequently and use head movement to compensate for the loss of vertical saccades. This is often one of the first signs of NP-C recognized by friends and family.
As a tool for diagnosis the NP-C Suspicion Index tool was developed by a group of NP-C experts to provide a risk prediction score and to identify patients who should undergo testing for NP-C. The tool was subsequently included in the recommendations of the NP-C Guidelines Working Group for the diagnosis and management of Niemann-Pick type C disease.
Observable ocular motor disorders
- Vertical supranuclear gaze palsy: initially impairment of vertical (downward) saccades followed by horizontal saccades and smooth pursuit.
0.0 Normal horizontal smooth pursuit 0.06 Impaired smooth pursuit with restriction of gaze, especially up 0.16 Slow horizontal saccades with restriction of gaze in the eccentric positions 0.37 Vertical saccade palsy 1.08 Present horizontal optokinetic nystagmus, absent vertical optokinetic nystagmus 2.00 Video-oculographic data of vertical saccades. Extremely slow, staircase-patterned and in range-restricted saccades (red arrows), indicating vertical saccade palsy 2.07 Slow, staircase-patterned horizontal saccades 2.09 Normal horizontal smooth pursuit, abnormal vertical smooth pursuit 0.00 Saccadic smooth pursuit 0.19 Slightly hypometric horizontal saccades, especially to the left 0.40 Normal vertical saccades with full range of movement 0.58 Normal vestibulo-ocular reflex, no catch-up saccades 1.09 Normal horizontal optokinetic nystagmus 1.20 Normal vertical optokinetic nystagmus 1.35 Video-oculographic data of vertical saccades. Note slight hypometrias at the end of the saccades. Black line indicates the stimulus, blue line indicates the eyes, green dot the saccade onset, red dot the saccade end. 1.40 Video-oculographic data of smooth pursuit. Note the remarkably saccadic smooth pursuit both horizontally and vertically. Turqouis line indicate the horizontal stimulus, purple line indicates the vertical stimulus, blue line indicates the horizontal eye movement, red line the vertical eye movement 0.00 Normal smooth pursuit 0.23 Abnormally slow saccades with “zigzag” movements indicating activation of the horizontal saccade system. Note the examiner holding the eye lids in order to not having patient blinking 0.50 Normal horizontal saccades 1.08 Pathological vertical optokinetic nystagmus. Note pronounced blinking- typical also whilst initiating vertical saccades 1.37 Video-oculographic data of vertical saccades. Note pronounced slowing of vertical saccades and staircase pattern (red arrows). Black line indicates the stimulus, blue line indicates the eyes. 1.45 Video-oculographic data of horizontal saccades. Note saccade precision and high velocity. Black line indicates the stimulus, blue line indicates the eyes, green dot the saccade onset, red dot the saccade end. 1.53 Slightly saccadic horizontal smooth pursuit with normal vertical smooth pursuit. Turquois line indicate the horizontal stimulus, purple line indicates the vertical stimulus, blue line indicates the horizontal eye movement, red line the vertical eye movement 0.20 Examination of the range of eye movements, first looking to the right, then upward, then to the left 0.37 Movements downward: normal range of eye movements. 0.45 Smooth pursuit horizontally. 0.55 Smooth pursuit vertically. 1.10 Horizontal saccades: normal velocity, accuracy and conjugacy. 1.19 Vertical saccades: significant slowing of downward saccades with some diagonal saccades, slight impairment of upward saccades. The major finding is the slowing of the downward saccades. This is typical of Niemann Pick Type C and is found in 95% of the affected patients. 2.00 Optokinetic nystagmus: normal optokinetic nystagmus in the horizontal plane. 2.20 Vertical optokinetic nystagmus: reduced optokinetic nystagmus for upward and downward movements. 2.40 Head-impulse test to generate eye movements via the vestibuloocular reflex: normal findings. This supports the diagnosis of a supranuclear vertical saccade palsy.
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Patterson MC, et al. Recommendations for the diagnosis and management of Niemann-Pick disease type C: an update. Mol Genet Metab. 2012;106:330–44. PubMed
Salsano E, et al. Vertical supranuclear gaze palsy in Niemann-Pick type C disease. Neurol Sci, 2012, 33:1225-1232. PubMed