Introduction

Niemann–Pick disease type C (NPC) is an atypical, ultra-rare, lysosomal storage disease [1]. In contrast to classic lysosomal storage diseases [2], the lysosomal storage of macromolecules is not caused by an enzyme deficiency, but rather by a deficiency of the protein products of two distinct genes, NPC1 and NPC2 [3, 4]. These two proteins are highly conserved across species; despite intense study for many years, their basic functions and the sequence of pathogenic events remains uncertain. It is apparent that NPC1 and NPC2 are intimately involved in endosomal–lysosomal trafficking of macromolecules, and a deficiency of either one is associated with lysosomal storage of cholesterol, glycosphingolipids, and a variety of other molecules, as part of a cascade of events that includes inflammation, synaptic and neuronal dysfunction, and eventually cell death by apoptosis [5].

The tissues contain an abundance of maldistributed free cholesterol, particularly in the liver and spleen, and there is also an increase in the mass of glycosphingolipids, including glucosylceramide and GM2 ganglioside, which is more pronounced in the central nervous system than in peripheral tissues [6]. At a light microscopic level, involved neurons are swollen, and show both ectopic dendritogenesis and the presence of axonal spheroids. The most severely affected neurons are the Purkinje cells [7], which may show abnormal storage even before birth [8]. There is a stereotyped pattern of cell loss [9]. Neurons in the brainstem [10], basal ganglia, diencephalon, and cortex are also involved [11], as are dorsal root ganglion cells, although peripheral neuropathy is only rarely clinically apparent in humans [12, 13] or mice with NPC [14].

The disease may present at any age, from fetal life to maturity [15]. Fetal or neonatal organomegaly, with or without ascites, may be associated with pulmonary infiltration and a significant morbidity and mortality. Although the liver, and more frequently the spleen, may be enlarged, the course of the disease beyond infancy is largely characterized by progressive neurodegeneration. All levels of the central nervous system are involved in NPC, accounting for its diverse manifestations (see Table 14.1). Given the widespread involvement of the nervous system in NPC, it is not surprising that movement disorders are frequent manifestations of the disease. Of note, one (retrospective) study of movement disorders in children with lysosomal diseases found that NPC was the disorder most frequently associated with movement disorders [16] and that ataxia was the most frequent manifestation in NPC, as in other lysosomal diseases, consistent with the high burden of disease in Purkinje cells.

Eye Movements

Vertical supranuclear saccadic palsy (VSSP) (also, but somewhat less accurately, known as vertical supranuclear gaze palsy or VSGP), is a hallmark of NPC [17]; the pathology is exquisitely localized to the rostral interstitial nucleus of the medial longitudinal fasciculus [18]. The evolution of the gaze palsy has been observed in a relatively small number of patients. It first manifests as increased saccadic latency, most often in down gaze, followed by a progressive loss of speed and amplitude of vertical saccades. Impairment of horizontal saccades (HSSP) follows that of vertical saccades. Patients who survive long enough lose all saccadic eye movements. Parents of children with VSSP will sometimes recognize characteristic head thrusting, with or without eye blinking, which represents an adaptive response to the saccadic impairment. Eye blinking breaks fixation, and the subsequent head thrust generates a vestibulo-ocular reflex that initiates a saccade in the same plane. Reading may also be impaired by VSSP (and HSSP), which causes difficulty moving from the end of one line of text to the next, as well as in scanning texts. In adults, a “round the houses” sign has been observed in NPC, demonstrating that this finding is not specific for progressive supranuclear palsy [19].

The clinician must systematically examine saccades to recognize this sign, which is often overlooked, even when present in full-blown form. This author believes that reports on the clinical manifestations of NPC that describe older children or adults who lack this finding must be treated with skepticism, unless a formal assessment of eye movements has been performed in a systematic fashion by experienced clinicians or using neurophysiological measurements of saccades, or both.

Various measurements of saccadic eye movements have been used as biomarkers in NPC. Horizontal eye movement saccadic velocity was selected as the primary outcome measure in a study of miglustat in NPC (most participants had complete, or near-complete, VSSP at entry) [20]. The relationship between saccadic eye movements and the clinical manifestations of NPC had not been formally assessed at the time, but this has been explored in later studies [21, 22].

Ataxia

Ataxia is almost universal in NPC, manifesting beyond infancy. It manifests most commonly as clumsiness in the first decade of life, and insidiously progresses to ataxia of gait and limb movement. Over a period of years, sometimes decades, patients become dependent on walking aids, and eventually require a wheelchair for mobility. This disease progression is paralleled by gradual atrophy of the cerebellum, which has been quantitated, and which is a promising surrogate marker of disease progression [22].

Ataxia also correlates closely with a loss of Purkinje cells in the murine and feline models of the disease [7, 23]. As might be anticipated, there is substantial Purkinje cell involvement in animal models before the presumed symptomatic threshold is crossed, and symptoms and signs appear. This has clear implications for therapy – a substantial proportion of Purkinje cells are dysfunctional or dead by the time symptoms and signs are detectable, thus limiting the scope of disease-modifying therapies, and challenging symptomatic treatments. Physical and occupational therapies have an important place in the management of ataxia in NPC, although their role has not been systematically studied in this disease; rehabilitation is recommended by the American Academy of Neurology as part of the treatment of cerebellar motor dysfunction, based on limited data [24]. Indeed, it is difficult to imagine how such a study might be ethically pursued. Clinical experience suggests that such interventions are of benefit, and expert opinion supports their use [25]; their cessation is often accompanied by a clear regression in function.

Many drugs (alcohol, antiseizure drugs, benzodiazepines, and others) can provoke or exacerbate ataxia through their effects on Purkinje cells, but few, if any, agents improve ataxia. N-acetyl-DL-leucine has been studied in patients with NPC. The drug has been used to treat acute vertigo in France since 1957, and one study found that it partially normalized the abnormal transmembrane potential in deafferented vestibular neurons [26]. Based on similarities between vestibular and cerebellar neurons [27], it was hypothesized that N-acetyl-DL-leucine might be effective in ataxia. An open-label study showed improvement in the Scale for the Assessment and Rating of Ataxia (SARA) and the Spinocerebellar Ataxia Functional Index (SCAFI) in 12 out of 13 patients with a variety of degenerative cerebellar ataxias exposed to the tablet form of N-acetyl-DL-leucine [28]. In contrast, a study of the liquid form of this agent in somewhat older patients with different degenerative cerebellar ataxias, assessed by blinded evaluation of video recordings, found no evidence of benefit on objective measures, although seven out of ten patients reported a subjective benefit [29]. A multicenter, multinational, randomized, double-blinded, placebo-controlled, crossover phase III trial of N-acetyl-DL-leucine in 108 patients with adult-onset cerebellar ataxia is currently in progress, and should provide a clearer picture of the role of this agent in adult-onset ataxias. Twelve patients with NPC were given N-acetyl-DL-leucine in a dose of 3 g per day for 1 week, followed by 5 g per day for 3 weeks, followed by a washout period of 1 month. They were assessed using the SARA, SCAFI, modified Disability Rating Scale (mDRS), EuroQol 5Q-5D-5L, and the visual analog scale (VAS) at baseline, after 4 weeks exposure to the experimental drug, and after the washout period. All measures showed evidence of benefit; the mean SARA score fell from the baseline value of 10.8 at baseline to 7.0 following 4 weeks of N-acetyl-DL-leucine, returning to 10.5 after a month of washout [30]. Further studies of this agent in NPC are planned.

Dystonia

Dystonia is frequent in NPC. It often begins as action or stress dystonia, appearing in one foot while walking, or in the feet and/or hands during activities such as heel walking. Axial and bulbar muscles may also be involved, including those of facial expression. For example, one report described a 29-year-old woman who exhibited bi-brachial and facial dystonia with grimacing [19], accompanied by hyperreflexia and vertical gaze palsy. Another patient began to exhibit slowed running at 8 years, and finger dystonia 2 years later [31].

A few studies have quantitated the frequency or character of dystonia. A French study of five adolescents and adults with NPC found that all had movement disorders [32]. Dystonia was reported in two out of five patients, all of whom had ataxia.

Myoclonus

Myoclonus occurs frequently in NPC. In one series of five juvenile onset patients, all exhibited fragmentary myoclonus [33]. All of the subjects had disrupted sleep and one had cataplexy as well. Stimulus-sensitive myoclonus has been observed [34]. Myoclonus was present in three out of five late (adolescent and adult) cases in a French series [32], and was found in five out of eight late-onset Dutch cases [35]. It was the presenting finding in three subjects. EEG–EMG coherence analysis showed that the myoclonus was of cortical origin in this series. No study has formally evaluated the management of myoclonus in NPC. In the experience of this author, both levetiracetam and clonazepam may be helpful in ameliorating this symptom when it is troubling to the patient.

Spasticity

Spasticity often coexists with dystonia in NPC, and the contribution of each to a patient’s function may be difficult to disentangle at the bedside. Patients are often hyperreflexic, but usually have flexor plantar responses.

Tremor

Fifteen patients with NPC were studied with accelerometry and surface electromyography of the upper extremities [36]. Almost half of these exhibited postural tremor, which was usually bilateral. The frequencies ranged between 0.3 Hz and 3 Hz, with an average amplitude of 1.2±0.98 mm. Just fewer than 90% of patients had bilateral action tremor, whose frequencies ranged between 2 Hz and 3.7 Hz, with an average amplitude of 5.25±3.76 mm. The surface EMG recordings revealed long but variable duration, variable-amplitude muscle burst discharges during action in some patients, as well as short, high-frequency, irregularly timed bursts in others. The findings on accelerometry were most strongly correlated with cerebellar outflow tremor. The surface EMG findings were mixed, being most consistent with dystonic, myoclonic, and choreiform movements, including dystonic tremor.

A later study assessed 14 subjects with NPC and 14 age-matched controls using spiral analysis [37]. The spirals drawn by the patients were abnormal, exhibiting lines which were wavy, crossing, and with irregularly spaced loops. The spirals were drawn more slowly and were more tremulous than in controls. The NPC patients tended to use a constant elevated pressure when drawing. The fluctuation in loop width was thought to be analogous to cerebellar ataxia, and was in keeping with the previous studies using accelerometry and surface EMG. The increased pressure and slow speed of drawing were suggestive of focal dystonia, and the slow speed together with diminished acceleration was more suggestive of parkinsonism, although the absence of micrographia would not be typical.

Management

There are no controlled studies on the management of movement disorders in NPC, although one open-label study has suggested that ataxia may be improved by the administration of N-acetyl-DL-leucine; controlled studies of this agent for the management of ataxia in NPC are currently being planned. Thus, patients should be offered standard physical and pharmacological therapies for these movement disorders [1, 25].

There is currently no approved therapy in the United States for NPC. Miglustat, an iminosugar that inhibits glucosylceramide synthase, has shown survival benefit in animal models of NPC [23]. There is evidence that miglustat may have beneficial effects on eye movements in human NPC as well as on disease progression [20] [38–45], particularly swallowing and ataxia. Preclinical studies of 2-hydroxypropyl-β-cyclodextrin (cyclodextrin) in mice and cats have shown evidence of improved survival [46–48], and a report of NPC subjects treated through (uncontrolled) expanded access programs suggested benefits in slowing disease progression [49], but the preliminary results of a double-blinded, randomized clinical trial of intrathecal cyclodextrin in NPC (NCT02534844) showed no difference in the primary endpoint between controls and patients receiving the active agent. Complete data from this study are yet to be released or published at the time of writing (November, 2018).