Niemann-Pick Disease, Type C.
The ultrastructural features of this case were thought to be consistent with a lysosomal storage disease. The possibilities of gangliosidosis, Niemann-Pick Disease or neuronal ceroid α-lipofuscinosis were suggested in the final pathology report. Subsequent genetic studies found two heterozygous mutations in the NPC1 gene (a heterozygous 410C>T mutation resulting in T137M and a heterozygous 2000C>T mutation resulting in S667L), confirming a diagnosis of Niemann-Pick Disease, Type C. The patient's asymptomatic younger brother also tested positive for the same mutation.
Niemann-Pick Disease, Type C (NPC) is a pan-ethnic, autosomal recessive lipid storage disorder with an estimated incidence of at least 1 in 120,000 live births (1-5). The clinical presentation of NPC is diverse, ranging from mild to severe forms with onset of disease anywhere from early infancy to adulthood (1,3). The most common type of NPC is the juvenile onset form, which presents between 6 and 15 years of age (3). Patients with this form have difficulties in school, particularly with attention and writing (3). Vertical supranuclear gaze palsy, a characteristic clinical finding described in nearly all cases of NPC (2,3), was also present in our patient. Laughter-induced cataplexy is common, as is progressive dysphagia, dysarthria and ataxia (1-3). In advanced disease, patients are bedridden with complete ophthalmoplegia, severe dementia and loss of voluntary movement (3). Lifespan varies from a days to over 60 years of age, but the majority of patients expire in the second decade of life due to complications of aspiration pneumonia (1,3).
The majority of NPC cases are caused by mutations in NPC1 (95%), with the remainder of cases linked to mutations in NPC2. At least 250 disease-causing mutations have been described in NPC1, supporting the heterogeneity in disease presentation (3). As expected, nonsense or frameshift mutations in NPC1 and NPC2 are associated with the most severe clinical phenotypes (3). NPC1 encodes a transmembrane protein found in late endosomes, while NPC2 encodes a small luminal soluble lysosomal protein (1,3-5). The disease pathogenesis and function of NPC1 and NPC2 are not well understood, but the clinical manifestations of NPC are attributed to an abnormality in intracellular trafficking of endocytosed cholesterol, leading to the accumulation of cholesterol and glycosphingolipids (particularly gangliosides GM2 and GM3) in the neuronal body and a progressively fatal neurodegeneration (1-5). Systemic disease (absent in 15% of patients) results from the accumulation of lipids in the spleen, liver, and rarely, the lung (1-3). Systemic disease always precedes neurological symptoms, and is often present years prior to the diagnosis of NPC (3). Recent studies have shown that cholesterol is initially bound by NPC2, which then transfers it to the N-terminal loop of NPC1 (1). Xie et al found that a single amino acid substitution that disrupts cholesterol binding in NPC1 results in findings comparable to those in Npc1-/- mice (6).
NPC is associated with several non-specific pathologic findings. Foam cells or sea blue histiocytes that stain strongly positive with filipin (a fluorescent compound that binds unesterified cholesterol) can be found in the bone marrow, spleen, or liver (3). In the brain, foamy to granular intracytoplasmic inclusions within neurons with meganeurite, ectopic dendrite formation and axonal spheroids are characteristic (2-5). Purkinje cells are especially sensitive to lipid accumulation, leading to selective Purkinje cell death (1-5). Polymorphous cytoplasmic bodies are observed on electron microscopy. These are small, compact, concentric membranous lamellations similar to the membranous cytoplasmic bodies of gangliosidosis (5). NPC is associated with formation of neurofibrillary tangles, particularly in the entorhinal cortex and hippocampus (2-5). In our case, rare neurofibrillary tangles were present (Figure 6, Bielschowsky).
An accurate molecular diagnosis of NPC is no longer simply of academic interest. Miglustat reversibly inhibits the first committed step of glycosphingolipid synthesis, thus, delaying the selective Purkinje cell death that causes a majority of the neurodegenerative symptoms (2,3). In a controlled clinical trial, disease course stabilized in 72% of patients treated for one year or more. In an international, multi-institutional cohort study, there was significant reduction in the annual rate of disease progression (3). Our patient was started on this medication.
In conclusion, NPC can present late and may be mistaken for other neurologic or psychiatric diseases, as in our case. Discussion with the primary clinical team is helpful when pathologic findings do not correlate with clinical history. Electron microscopy aids in confirming the presence of inclusions when a storage disease is suspected. Molecular studies are useful in classifying this disease.
Contributed by Nhu Thuy Can, MD, Amber Nolan MD, PhD, Darrel Waggoner, MD, Kenneth Silver MD,, Peter Pytel, MD