Clinical Findings

Typical findings. Presentations may be conveniently considered by age of onset, although this grouping is of necessity arbitrary and includes considerable overlap.

• Early infantile (age <2 years). Fetal ascites or neonatal liver disease, particularly when the latter is accompanied by prolonged jaundice and pulmonary infiltrates
• Late infantile (ages 2 to <6 years). Often presents with hypotonia and developmental delay. With time, vertical supranuclear saccadic palsy becomes apparent. Children later develop clumsiness that evolves into ataxia.
• Juvenile (ages 6 to <15 years). These children may present initially with clumsiness that evolves into ataxia, often with academic difficulties that may be misdiagnosed as attention deficit disorder. With time, more global cognitive impairment and regression become evident. Vertical supranuclear gaze palsy (sometimes called vertical supranuclear saccadic paresis) is almost invariably present in children with neurologic manifestations (and is often present before the emergence of other symptoms). Some children develop seizures, gelastic cataplexy, dystonia, and/or spasticity.
• Adolescent/adult (age >15 years). May include all of the neurologic manifestations, which are often overshadowed, at least initially, by cognitive impairment (early-onset dementia) or psychiatric manifestations (e.g., treatment-resistant depression, schizophreniform illness, apparent bipolar disease).
• Other. Some individuals present with isolated splenomegaly in childhood, and may not develop neurologic manifestations for many years. Occasionally, adults have splenomegaly without neurologic manifestations.

Atypical findings include ataxia, splenomegaly, vertical supranuclear gaze palsy, dysarthria, dysphagia, early-onset dementia, treatment-resistant psychiatric symptoms in young adults, gelastic cataplexy, dystonia, and epilepsy (particularly if treatment-resistant) (see Patterson et al [2017], Table 1).

Suspicion index. The sensitivity of a quantitative scoring system that weighs the manifestations of NPC to assist clinicians in identifying individuals appropriate for further laboratory investigation [Wijburg et al 2012] was improved by separating children into two age groups: ≤4 years and >4 years [Pineda et al 2019].

Preliminary Laboratory Findings

Assay of oxysterols has largely replaced skin biopsy (see Clinical Description), and is now regarded as both a robust screening test and a first-line diagnostic test for NPC [Porter et al 2010, Jiang et al 2011, Geberhiwot et al 2018].

Family History

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Option 1

A multigene panel that includes NPC1, NPC2, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Panels to consider include those for lysosomal disorders, treatable neurometabolic disorders, mendelian disorders with psychiatric symptoms, and metabolic nonimmune fetal hydrops. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including NPC1 and NPC2) that cannot be detected by sequence analysis.

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Neonatal and Infantile Presentations

The presentation of NPC in early life is nonspecific and may go unrecognized by inexperienced clinicians. On occasion, ultrasound examination in late pregnancy has detected fetal ascites; infants thus identified typically have severe neonatal liver disease with jaundice and persistent ascites.

Infiltration of the lungs with foam cells may accompany neonatal liver disease or occur as a primary presenting feature (pulmonary failure secondary to impaired diffusion).

Many infants succumb at this stage. Of those who survive, some are hypotonic and delayed in psychomotor development, whereas others may have complete resolution of symptoms, only to present with neurologic disease many years later. Liver and spleen are enlarged in children with symptomatic hepatic disease; however, children who survive often "grow into their organs," so that organomegaly may not be detectable later in childhood. Indeed, many individuals with NPC never have organomegaly. The absence of organomegaly never eliminates the diagnosis of NPC.

Another subgroup of children has minimal or absent hepatic or pulmonary dysfunction and presents primarily with hypotonia and delayed development. Children in this group usually do not have vertical supranuclear gaze palsy (VSGP) at the onset but acquire this sign after a variable period, when other evidence of progressive encephalopathy supervenes.

Childhood Presentations

The classic presentation of NPC is in middle-to-late childhood, with clumsiness and gait disturbance that eventually become frank ataxia. Many observant parents are aware of impaired vertical gaze, which is an early manifestation. VSGP first manifests as increased latency in initiation of vertical saccades, after which saccadic velocity gradually slows and is eventually lost. In late stages of the illness, horizontal saccades are also impaired. The physical manifestations are accompanied by insidiously progressive cognitive impairment, often mistaken at first for simple learning disability. Some children are thought to have primary behavioral disturbances, reflecting unrecognized dyspraxia in some instances. As the disease progresses, it becomes clear that the child is mentally deteriorating.

In addition to the manifestations outlined above, many children develop dystonia, typically beginning as action dystonia in one limb and gradually spreading to involve all of the limbs and axial muscles. Speech gradually deteriorates, with a mixed dysarthria and dysphonia. Dysphagia progresses in parallel with the dysarthria, and oral feeding eventually becomes impossible.

Approximately one third of individuals with NPC have partial and/or generalized seizures. Epilepsy may be refractory to medical therapy in some cases. Seizures usually improve if the child's survival is prolonged, this improvement presumably reflecting continued neuronal loss. About 20% of children with NPC have gelastic cataplexy, a sudden loss of muscle tone evoked by a strong emotional (humorous) stimulus. This can be disabling in those children who experience daily multiple attacks, during which injuries may occur.

Mild demyelinating peripheral neuropathy has been described in a child with otherwise typical late-infantile NPC [Zafeiriou et al 2003]. This finding is likely a rare manifestation of NPC because prospective nerve conduction studies in a cohort of 41 affected individuals participating in a clinical trial of miglustat have identified only one case to date [Patterson, personal communication].

Polysomnographic and biochemical studies have demonstrated disturbed sleep and variable reduction in cerebrospinal fluid hypocretin concentration in individuals with NPC, suggesting that the disease could have a specific impact on hypocretin-secreting cells of the hypothalamus [Kanbayashi et al 2003, Vankova et al 2003].

Death from aspiration pneumonia usually occurs in the late second or third decade [Walterfang et al 2012b].

Adolescent and Adult Presentations

Adolescents or adults may present with neurologic disease as described in the preceding section, albeit with a much slower rate of progression. The author has seen one individual who survived into the seventh decade, having first developed symptoms 25 years earlier. Older individuals may also present with apparent psychiatric illness [Imrie et al 2002, Josephs et al 2003], sometimes appearing to have major depression or schizophrenia. The psychiatric manifestations may overshadow neurologic signs, although the latter can usually be detected with careful examination. An adult presenting with bipolar disorder has been described [Sullivan et al 2005].

A German report describes two individuals with adult-onset dementia associated with frontal lobe atrophy and no visceral manifestations, as is common in adult-onset disease [Klünemann et al 2002].

Other Studies

Imaging. MRI of the brain is usually normal until the late stages of the illness. At that time, marked atrophy of the superior/anterior cerebellar vermis, thinning of the corpus callosum, and mild cerebral atrophy may be seen. Increased signal in the periatrial white matter, reflecting secondary demyelination, may also occur. In one adult, areas of confluent white matter signal hyperintensity mimicked multiple sclerosis [Grau et al 1997]. Quantitative MRI studies in adults with NPC have found widespread gray and white matter abnormalities [Walterfang et al 2010], and reduction in callosal volume as the disease progresses [Walterfang et al 2011]. In addition, the pontine:midbrain ratio correlates with oculomotor function and disease severity [Walterfang et al 2012a].

Studies of magnetic resonance spectroscopy (MRS) suggested that MRS may be a more sensitive imaging technique in NPC than standard MRI [Tedeschi et al 1998]. A French group has reported improvement in MRS parameters with miglustat therapy [Galanaud et al 2009].

Biochemical. Until recently, definitive diagnosis of NPC required demonstration of abnormal intracellular cholesterol homeostasis in cultured fibroblasts [Pentchev et al 1985]. These cells show reduced ability to esterify cholesterol after loading with exogenously derived LDL cholesterol. Filipin staining demonstrates an intense punctate pattern of fluorescence concentrated around the nucleus, consistent with the accumulation of unesterified cholesterol:

• Classic. Most individuals have zero or very low esterification levels with a classic staining pattern.
• Variant. About 15% of individuals have intermediate or "variant" levels of cholesterol esterification and a less distinctive staining pattern. More precise characterization of the biochemical defect in this group can be achieved by the use of BODIPY-lactosylceramide to identify lipid trafficking abnormalities [Sun et al 2001].

Histology. Other tests, including tissue biopsies and tissue lipid analysis, which were essential for diagnosis before recognition of the biochemical defect in NPC, are now rarely needed. These tests include examination of bone marrow, spleen, and liver, which contain foamy cells (lipid-laden macrophages); sea-blue histiocytes may be seen in the marrow in advanced cases. Electron microscopy of skin, rectal neurons, liver, or brain may show polymorphous cytoplasmic bodies [Boustany et al 1990].

Heterozygotes

In 2004, a report attributed tremor in an individual to presence of a heterozygous NPC1 pathogenic variant [Josephs et al 2004]. More recently a study of 20 obligate heterozygotes for NPC1 pathogenic variants found varying manifestations that are typically seen in compound heterozygotes, including hepatosplenomegaly, increased cholestane triol levels, hyposmia, REM sleep behavior disorder, and typical ocular motor abnormalities [Bremova-Ertl et al 2020]. It will be important for prospective studies of larger cohorts of heterozygotes to confirm these findings.