Infantile form of Niemann-Pick disease type C with demyelination: An uncommon feature
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.263230
Source of Support: None, Conflict of Interest: None
Keywords: Autopsy, demyelination, late infantile form, Niemann-Pick type C
Niemann-Pick disease is a heterogenous group of neurovisceral lipid storage disorders characterized by increased tissue sphingomyelin and collection of “Niemann–Pick cells” within various visceral organs., Type C is distinct from type A and B as the defect here lies within the internal trafficking of cholesterol from lysosomes. It has an autosomal recessive mode of inheritance and in about 90% of cases mutations in NPC 1 gene has been detected. The clinical manifestations and progression of the disease is variable and depends on the age of presentation. The autopsy findings are mainly mentioned in the literature within the juvenile and adult forms of the disease. These include brain atrophy, neuronal loss/foaming, loss of cerebellar Purkinje cells, Lewy bodies and tauopathy. Demyelination, neurofibrillary tangles, and axonal spheroids are neuropathological features seldom encountered in the infantile form of Niemann-Pick disease type C.,, Herein, we describe autopsy findings in a 20-month old boy who died of suspected inborn error of metabolism. The neuropathological features are discussed in detail and highlight some of the rare features encountered in a case of Niemann-Pick disease type C.
A 20-month old boy with global development delay, presented with a history of low-grade fever, loose watery stools, (10-12 episodes/day) for 3 days and non-bilious, non-blood-stained vomiting (4–5 episodes) for one day. Subsequently, he developed decreased urine output, rapid breathing, irritability, altered sensorium, and intermittent abnormal body movements. Although he had delayed milestones with a developmental age of 10–12 months, he had never been evaluated. At 10 months of age, he had fever and was diagnosed with bilateral hydroureteronephrosis secondary to posterior urethral valves but did not seek further management. He was the first born of a non-consanguineous marriage and the family history was non-contributory. His antenatal history was uneventful. He was born full term, by normal vaginal delivery and had a birth weight of 3350 g. On examination at admission, he was found to have wasting and stunting, with a weight of 6.8 kg (<−3Zscores), height of 62 cm (<−3Zscores), and head circumference of 44 cm (−2 to −3Zscore). His vitals revealed a heart rate of 118/min, respiratory rate of 44/min, blood pressure of 93/52mmHg and SpO296% (room air). He was found to have pallor and severe dehydration. However, he had no cyanosis, clubbing, edema, or lymphadenopathy. His anterior fontanelle was open. He had thin, sparse, hypopigmented hair, angular stomatitis, cheilitis, frontal bossing, and rachitic rosary. No organomegaly was noted. He was irritable with intermittent dystonia. Cranial nerve examination showed no obvious deficits. He had increased tone in all 4 limbs with brisk reflexes though bilateral plantar reflexes were down-going. Meningeal signs were present with retracted and rigid neck. Investigations revealed a normocytic normochromic anemia (hemoglobin- 6.9gm/L), thrombocytopenia (platelet count- 96 × 109/L), and leucopenia (whie blood cell count- 3.9 × 109/L) later during the hospital stay. Renal function tests were deranged (serum creatinine-168μmol/L). There was vitamin D deficiency (Vitamin D- <3ng/ml, an intact parathyroid hormone (iPTH)- 425pg/ml) and severe metabolic acidosis (pH 7.06 and HCO3- 8.4mmol/L). His cerebro-spinal fluid (CSF) analysis revealed a mild increase in the white blood count (cells-74/μl: neutrophils43 lymphocytes46 monocytes11), elevated proteins (180mg/dl) and a low CSF-to-blood sugar ratio, suggestive of a partially treated bacterial or fungal meningitis. Blood and CSF cultures were sterile, though urine culture grew Proteus mirabilis. Chest radiograph was suggestive of consolidation. Ultrasonography of the abdomen revealed bilateral hydroureteronephrosis with small-sized kidneys with a normal liver and spleen. The child was intubated and started on peritoneal dialysis besides fluid resuscitation, parenteral antibiotics, and one blood transfusion. His dehydration was corrected and urine output improved. Encephalopathy persisted with intermittent dystonia, so a non-contrast computed tomography (NCCT) head was done to rule out cortical venous thrombosis. Axial NCCT revealed ill-defined hypodensities involving bilateral cerebellar peduncles and periventricular white matter [Figure 1]a and [Figure 1]b. In view of a significant developmental delay, a possibility of underlying degenerative brain disease/inborn error of metabolism was kept. His serum lactate (2.2mmol/L), serum ammonia (54 μg/dl), vitamin B12 (384pg/ml), and folate (>24ng/ml) were within the normal range. However, before complete work up could be done, the child succumbed to his illness.
A complete autopsy was performed after an informed consent had been taken. Externally, no significant facial dysmorphism was noted apart from upward slanting of eyes. The enlarged spleen (weight 100g) on microscopy revealed large vacuolated cells with granular cytoplasm filling up and expanding the red pulp. These cells were of histiocytic origin (cluster of differentiation [CD]68 positive) and contained weak and focally periodic-acid Schiff positive material within their cytoplasm. These foamy cells were also positive with Oil-red-O, thereby being consistent with storage cells of Niemann-Pick disease. These cells were forming large clusters and filling up the red pulp [Figure 2]a, [Figure 2]b, [Figure 2]c. Ultrastructural examination of the spleen revealed cells filled with electron-dense material along with many membrane-bound oligo-lamellar inclusions [Figure 2]d. Similar cells were noted filling up the sinuses in lymph nodes and sparsely in the liver parenchyma. However, these were not noted in other visceral organs and the bone marrow. The brain weighed 930gm (average normal weight for this age = 1050 g). The gyral pattern was normal and no exudates were noted on convexities and base of the brain. The vessels of circle of Willis were normal. On coronal slicing, two irregular, haemorrhagic areas were noted at grey-white junction (measuring 3.5cm and 2cm) involving the right inferior frontal gyrus and left superior frontal gyrus. In addition, multiple firm patches of demyelination were noted diffusely involving the central white matter [Figure 3]a, [Figure 3]b, [Figure 3]c. Another irregular, discoloured area with granularity was noted along the left anterior limb of internal capsule. The “U”fibres were preserved. On microscopy, the well-demarcated firm areas in the central white matter featured patches of demyelination, with loss of myelin highlighted by Luxol fast blue stain and the presence of axonal balls highlighted by neurofilament protein (NFP) stain [Figure 4]a, [Figure 4]b, [Figure 4]c, [Figure 4]d. The haemorrhagic areas at gray-white junction revealed features of fungal meningitis (Aspergillus) with boderzone encephalitis [Figure 5]a, [Figure 5]b, [Figure 5]c, [Figure 5]d. Thrombosed blood vessels containing fibrin within the lumen were seen in the subarachnoid space. Subtle swollen neurons were noted; however, this was not a dominant feature. There was no associated inflammation or macrophage infiltration around these patches of demyelination. Deep gray nuclei were within normal limits. Additionally, few neurons in the cerebral cortex of middle frontal gyrus demonstrated flame-shaped and thread-like neurofibrillary tangles within their axoplasm. No senile plaques with amyloid core were identified. Sections from the hippocampus and cerebellum were within normal limits.
Both lungs weighed 180g and were heavy with a dull pleura. Diffuse consolidation with abscess cavities bilaterally were noted on gross examination. On microscopy, features of bronchopneumonia with invasive aspergillosis were noted. The fungus was invading the vessel wall with formation of fibrin thrombi within a few of them. In other regions, diffuse alveolar damage with formation of hyaline membrane was seen. Early invasion of the fungal infection by the hematogenous route resulted in a discoloured patch in right and left atrial wall in the heart, and in the small intestine as an 8 mm ulcer, both of which microscopically demonstrated fungal hyphae within the myocardium and intestinal wall, respectively. The left kidney was small (2.5 × 1 × 0.7cm) and microscopically revealed features of dysplasia. The pelvicalyceal system was dilated with a hypertrophied bladder secondary to posterior urethral valve. Rest of the organs were within normal limits. The T and B lymphocyte population was maintained within lymph nodes, Peyer's patches and spleen. In summary, the histological findings were consistent with Niemann-Pick disease type C with demyelination. The foamy histocytes of Niemann-Pick disease were seen in the spleen and lymph nodes, and sparsely in the liver and brain. The lungs showed features of confluent bronchopneumonia with invasive aspergillosis with dissemination to the brain, small intestine and heart. The urinary system revealed posterior urethral valves with secondary hydronephrosis and a hypertrophied bladder wall along with hypoplastic-dysplastic left kidney.
Niemann-Pick disease type C belongs to a heterogenous group of neurovisceral lipid storage disorders and is distinct from Niemann-Pick disease type A and B as there is no genetic defect in acid sphingomyelinase. The defect lies in the cellular transportation of exogenous cholesterol resulting in lysosomal accumulation of unesterified cholesterol and glycospingolipids. It is inherited as an autosomal recessive disorder with mutations in NPC1 or NPC2 gene. The spectrums of the disease vary and the manifestations depend on the age of onset and severity of disease. Thus, depending on the age of presentation, it is categorized as perinatal, early or late infantile, juvenile, and adolescent/adult form.,
The diagnosis of Niemann-Pick disease type C needs a high index of suspicion as the clinical presentations may range from systemic to neurological features which are non-specific, thus leading to a long lag time between the disease onset and diagnosis. Recent categorization of patients according to the age of clinical presentation is helpful for the management and prognostication of these patients. The observations of one of the largest international cohort of patients with Niemann-Pick disease type C reveals that 16 (11%) patients had the early-infantile onset form. In these patients, almost 60–70% had a developmental delay. However, dystonia was more common in adolescents and adults. Although the diagnosis of Niemann-Pick disease is confirmed by biochemical investigations or genetic testing, which unfortunately could not be performed in the index case, the presence of storage histocytes replacing the splenic parenchyma, their simultaneous presence in other organs, and the nature of stored material, is histologically characteristic of the disease.
From the neuropathologists' perspective, demyelination is an uncommon feature in Niemann-Pick disease type C, with only a few prior case reports describing it more in the infantile form than the others. Although the cellular mechanism of demyelination is unclear, it is believed that the accumulated glycosphingolipids alter the function and development of oligodendrocytes. Axonal spheroids and neuronal cell loss can also induce demyelination. Attributing demyelination to terminal fungal meningitis with early boder-zone encephalitis is unlikely as it far exceeded the neuronal damage and the inflammation in proportion. Moreover, areas of demyelination were not surrounded by inflammation. Neurofibrillary tangle is another histological feature seen in Niemann-Pick disease and reported sporadically in the earlier literature., Suzuki et al., have reported the presence of neurofibrillary tangles in the orbital gyrus, cingulate gyrus, and entorhinal region of the cerebral cortex, basal ganglia, thalamus, and hypothalamus. The distribution of these neurofibrillary tangles parallels the presence of swollen storage neurons. In the present case, the amount of swollen storage neurons was subtle and occasional neurofibrillary tangles were observed. The altered cholesterol metabolism and altered intracellular cholesterol trafficking is believed to play a role in the formation of neurofibrillary tangles as these are devoid of an amyloid core.
Severe neuronal loss in various regions of cerebral cortex and brainstem has been reported. The neuronal loss in the index case was proportionately less, mostly seen in sections taken from the frontal lobe near the central sulcus. While the neuronal manifestations were beginning to appear in the index child, it is hypothesized that had the child lived for some more time, the neuropathological features would have become more florid and widespread.
The etiology of chronic kidney disease (CKD) in the index case was the posterior urethral valve, which is a common cause of urinary tract obstruction in children., Patients with chronic kidney disease have a higher risk of acquiring infections, which explains the susceptibility of the child to pneumonia and meningitis. There is no data on fungal infections in such children; however, the emergence of fungal infections in various settings has been described. Lastly, the association of Niemann-Pick disease type C with associated congenital structural anomaly is incidental.
In conclusion, this case highlights non-specific clinical features of Niemann-Pick disease type C, developmental delay and dystonia together with some rare neuropathologic features, which are seldom encountered in these patients, and these should be kept in mind while treating them.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]