Niemann-Pick disease type C: analysis of 7

patients

Hui Xiong, Xin-Hua Bao, Yue-Hua Zhang, You-Ning Xu, Jiong Qin, Hui-Ping Shi, Xi-Ru Wu

Beijing, China

Author Affiliations: Department of Pediatrics, Peking University First Hospital, Beijing 100034, China (Xiong H, Bao XH, Zhang YH, Qin J, Wu XR); Department of Pediatrics, Beijing Changping District Hospital, Beijing, China (Xu YN); Department of Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (Shi HP)

Corresponding Author: Xi-Ru Wu, MD, Department of Pediatrics, Peking University First Hospital, Beijing 100034, China (Tel: 0086-10-83573238; Fax: 0086-10-66530532; Email: xh_bjbj@yahoo.com.cn)

doi: 10.1007/s12519-011-0284-6

Background: Niemann-Pick disease type C (NP-C), derived from mutation of the NPC1 or NPC2 gene, is one of the recessive lysosomal lipid storage disorders that are difficult to diagnose and treat. Since NP-C has been rarely reported in China, we reviewed 7 patients with NP-C.

Methods: The 7 patients had been diagnosed with NP-C from 2007 to 2010 at our department and their laboratory and clinical data were analyzed.

Results: The 7 patients, 5 males and 2 females, included 4 patients of late infantile subtype and 3 patients of juvenile subtype, in which patients 2 and 3 were siblings. Their clinical symptoms occurred from 4 to 10 years of age, exhibiting as progressive cognitive and language impairment as well as motor retrogression. Six patients were caught by focal or generalized seizures from 1 to 4 years after the onset of the disease. Vertical supranuclear gaze palsy, dysarthria, dysphagia, internal rotation and adduction of bilateral hands and splenomegaly occurred following the progress of clinical symptoms. Five patients had laughter-cataplexy. MRI showed mild brain atrophy in 6 patients. Reduction of total cholesterol, high density lipoprotein cholesterol and low density lipoprotein cholesterol occurred in 6 patients. Sea-blue cells and Niemann-Pick cells were found in bone marrow smears. The activity of acid sphingomyelin enzyme was normal or only slightly lower. Supporting or symptomatic treatment improved common clinical symptoms.

Conclusions: NP-C is a rare autosomal recessive inherited lysosomal storage disease that affects the intellectual development of children and may lead to dementia, vegetative state or death. Clinical features of this disease include vertical supranuclear gaze palsy, seizures and cataplexy. Laboratory features include abnormal plasma cholesterol level, and sea-blue cells and Niemann-Pick cells in bone marrow smears. The treatments of the disease include supporting or symptomatic administration.

Key words: Niemann-Pick disease type C; sea-blue cells; vertical supranuclear gaze palsy

World J Pediatr 2012;8(1):61-66

Introduction

Limited progress has been made in treatment of NP-C in North America or Europe. The strategies of the treatment include weekly cyclodextrin administration to normalize cholesterol metabolism,^[6] and inhibition of lysosomal acid lipase by thiadiazole carbamates^[7] and miglustat (Zavesca) to stabilize neurological pathology.^[8] However, there are few reports on NP-C in Chinese children except two reports from Taiwan province.^[9,10] In order to improve the early diagnosis and treatment of NP-C, we reviewed 7 patients with NP-C treated at our Department of Pediatric Neurology.

Methods

Patients

The 7 patients who had been treated at our department from 2007 to 2010 comprised 5 males and 2 females with the onset of the disease at age of 4 to 10 years. Their clinical characteristics are shown in Table 1. Patients 2 and 3 were siblings. According to the method described by Wraith,^[11] the patients were grouped into one of the five subtypes by age: neonatal subtype (≤3 months), early infantile subtype (3 months-2 years), late infantile subtype (2-6 years), juvenile subtype (6-15 years), and adolescent and adult subtype (≥15 years).

Diagnostic criteria

The patients were enrolled with the reported diagnostic criteria:^[12] (1) slow progress of central nervous system degradation characterized by progressive ataxia, dysarthria, dysphagia, language disorder, dystonia and seizure; (2) progressive vertical supranuclear gaze palsy; (3) hepatosplenomegaly, predominantly in the spleen; (4) sea-blue histiocyte in bone marrow morphology smears; and (5) normal or slightly abnormal activity of acid sphingomyelin enzyme.

Laboratory examination

Laboratory examination included urine metabolite screening, blood biochemical index, genetic diseases-related indexes (lactic acid, blood ammonia, uretic amino acid and organic acid) and activity of acid sphingomyelin enzyme. Revised Wechsler Intelligence Scale for Children (C-WISC) was used to test the intelligence of the patients. Abdominal B-ultrasonography was performed to check the abdominal organs. MRI of the brain was performed with a 1.5T machine. Video-electroencephalography (EEG) was conducted using scalp and ear lobe electrodes positioned according to the 10-20 International System. Bone marrow aspiration was made under local anesthesia and the smears were stained with the Wright-Giemsa method.

Treatment and follow-up

All patients were given supporting and symptomatic treatment including antiepileptic treatment for those with seizures and surgery for those with difficulty in swallowing.

The diagnosis, treatment and study of the patients were approved by the Ethic Committee of the hospital and written informed consents were obtained from all patients.

Results

Laboratory examination

The results of urine metabolic screening were normal in all patients. The activity of acid sphingomyelin enzyme was normal or slightly lower. Biochemical examination revealed that the levels of total cholesterol, high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) were reduced considerably in 6 patients.

Bone marrow smears showed that sea-blue cells were present in the bone marrow aspirations from the patients. The sea-blue cells were characterized by cytoplasm filled with dark blue granules varying in size but without obvious foaming (Fig. 1A). In bone marrow smears Niemann-Pick cells were noted in 2 patients but dubiously in one patient (Table 2). Niemann-Pick cells were characterized by a large cell body and a round- or oval-shaped and lateralized nucleus as single and abundant cytoplasm filled with hemophagocytes and round transparent drop-shaped vesicles that were mulberry-like or foam-like (Fig. 1B).

C-WISC showed a reduction in language ability and full scale IQs. Abdominal B-ultrasonograpy showed splenomegaly in all patients and hepatomegaly in 6 patients. Video-EEG showed abnormalities including slow waves, spike waves and spike-slow waves releasing from the anterior head. Cranial MRI demonstrated mild brain atrophy of the cerebellum and cerebrum in 6 patients (Fig. 2A and 2B; Tables 1 and 2).

Clinical features

The clinical features of the patients are shown in Tables 1 and 2. The symptoms of these patients were demonstrated as progressive cognitive and language impairments as well as motor retrogression. Seizures occurred within 1-4 years, including partial or generalized seizure (5 patients) and tonic-clonic seizure (1 patient). Vertical supranuclear gaze palsy occurred in all patients, accompanied with dysarthria or dysphagia in 7 patients and dystonia in 5. The dystonia occurred firstly to both-hands and feet and looked like intort, and then occurred to the whole body. Five patients had laughter-cataplexy. Moreover pyramidal sign was seen in 4 patients, and icterus or chorea in 2 patients.

Treatment and follow-up

All patients were subjected to supporting and symptomatic therapies. For patients with epilepsy, antiepileptic agents like topiramate, valproic acid, clonazepam, lamotrigine and levetiracetam were given in different combinations according to seizures and their situations. After the treatment, the frequency of seizure was reduced in the patients. Nasal feeding or gastrostomy was performed for patients with difficulty in drinking and swallowing, thus improving their general situation and nutritional status. With disease progression, 2 patients were paralyzed in bed with impairment of eye movement characterized by initially vertical saccadic difficulty, vertical saccadic fixture, horizontal saccadic difficulty, and finally limitation in the axis (Fig. 3).

An illustrative case

The male patient (No. 5 in Table 1) was admitted to the hospital for a seizure attack at age of 14 years. He had no obvious abnormality at birth and family history with normal intelligence and development. At 10 years old, he showed incoherent speech with little vague articulation and decreased academic performance. At 12 years old, he demonstrated ataxia, abnormal posture, and bilateral claw-like fingers. His speech speed slowed down with slurred articulation. He showed laughter-cataplexy, slobber, dysphagia and drinking cough sometimes. At 14 years old, he was attacked by seizures, exhibiting twisted head to one side, eyes upward, saccadic and stiff limbs. The seizures usually lasted about 20 minutes. The patient showed decreased appetite and gastrointestinal dysfunction such as diarrhea. Physical examination on admission demonstrated: (1) normal physical development, deficit in calculation, slowed speech speed, slurred articulation, ataxia, pes supinatusm while walking, bilateral upper arm involucrate and claw-like fingers, deeper insteps, right contracture of Achilles tendon, and bilateral limited vertical saccadic; (2) touchable spleen below ribs, myodynamia 4/5, hypertonia, bilateral knee tendon hyperreflexia and ankle clonus positive, bilateral Hoffmann sign positive and Babinski sign positive; (3) total bilirubin (TBIL) 23 μmol/L, direct bilirubin (DBIL) 5.01 μmol/L, total cholesterol 2.00 mmol/L, HDL-C 0.78 mmol/L, and LDL-C 1.03 mmol/L; (4) bilateral transduction delay in the peripheral pathway by audio-visual evoked potential; (5) splenomegaly at 5.3 cm below the rib edge with spleen portal internal diameter (ID) 0.8 cm and hepatomegaly at 2.3 cm below the rib edge by B-ultrasound; (6) unilateral or bilateral spike-slow waves and slow wave release in front head by EEG, predominantly on the right side and during sleep; (7) slight atrophy of the cerebrum and cerebellum shown by brain MRI; (8) active proliferation of sea-blue cells occasionally accompanied by Niemann-Pick cells in bone marrow smears; (9) activity of acidic sphingomyelinase at 14 nmol/17h/mgPr (normal 17-40 nmol/17h/mgPr). The patient was subjected to antiepileptic treatment with topiramate and followed up for 2 and half years.

Discussion

In the present study, the 7 patients with NP-C showed vertical supranuclear gaze palsy, seizures, abnormal EEG, intelligent and/or language impairment, sea-blue cells and splenomegaly. Brain atrophy, NP cells and abnormal LDL and HDL were observed in some patients. Supporting and symptomatic treatment improved some of these symptoms.

Unlike Niemann-Pick disease types A and B, which are associated with the deficiency of sphingomyelin degrading enzyme, NP-C is due to the mutation of the NPC1 or NPC2 gene.^[2] The functional deficiency of NPC1 and NPC2 gene products in a NP-C patient leads to transportation abnormalities of cellular cholesterol and sphingosine and subsequent deposition of these substances in lysosomes of the liver, spleen and brain. As the deposition of cholesterol in lysosomes inhibits the activity of acid sphingomyelin to cause secondary sphingomyelin deposition, this activity is normal or slightly reduced.^[3,13] This finding is consistent with that of the present study or that reported previously.^[14] In a drug-induced NP-C cellular model, sphingosine storage in the acid compartment results in calcium depletion in organelles, which leads to storage of cholesterol, sphingomyelin and glycosphingolipid in the compartment. Therefore, NPC1 causes altered calcium homeostasis, leading to the secondary storage of sphingolipids and cholesterol.^[15] Other studies suggested that the up-regulation of ATP-binding cassette transporter objects A1 (ABCA1) in NP-C patients prevents cholesterol release from lysosomes and the reduction of HDL-C.^[16,17] In the present study, most of the patients also showed abnormal cholesterol. Hence, plasma cholesterol can be determined as a useful biomarker.^[16] Another laboratory characteristic in NP-C patients is sea-blue cells in bone marrow smears often, foamy cells sometimes and Niemann-Pick cells,^[5,18] although it is not specific. In the current study, sea-blue cells were present in all patients and Niemann-Pick cells in 2 patients whereas suspicious Niemann-Pick cells were seen in 1 patient, suggesting that sea-blue cells are highly associated with NP-C.

In addition to laboratory examinations, image scanning, EEG and clinical signs are of diagnostic value for NP-C. Cranial MRI is able to show atrophy in the anterior part of the cerebellar vermis, thinning of the corpus callosum, cerebral atrophy with signal enhancement of the white matter due to secondary demyelination in some cases.^[10,19-21] Some studies indicated that EEG examination could detect slow waves or alpha rhythm in NP-C patients.^[21,22] Psychiatric changes are often followed by dystonia and cognitive impairment.^[23] These findings are consistent with MRI and EEG findings in the present study. Clinical signs for NP-C include common features like cataplexy, seizures and dystonia. Neurological disorders consist mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. The most characteristic sign is vertical supranuclear gaze palsy.^[3,24-26] In the present study, all patients showed cognitive impairment, psychological changes, partial or generalized seizures and abnormalities in eye movement. Other symptoms of NP-C patients in our study included icterus, unexplained intermittent diarrhea and thrombocytolytic purpura. These signs may be induced by the infiltration and damage of sea-blue cells in the bone marrow, liver, spleen, lungs, gastrointestinal tract, lymph nodes or other organs.^[11]

Because NP-C is one kind of genetic mutation disease and there is no specific therapy,^[3,5,26] therapeutic attempts to date have focused on reduction of the accumulating molecules that are presumed to have direct or indirect toxic effects. Therefore, supporting and symptomatic managements of patients are crucial. Miglustat has been used in Europe and other countries for specific treatment of the neurological manifestations of NP-C,^[3,8,27] but it is expensive and not available in China. Other strategies like bone marrow transplantation,^[28,29] weekly cyclodextrin administration to normalize cholesterol metabolism,^[6] and inhibition of lysosomal acid lipase by thiadiazole carbamates^[7] are therapeutic potential for NP-C.

In summary, NP-C is a rare autosomal mutation disease that affects severely the life of patients and its diagnosis and treatment are complicated. It is a pity that our patients received neither genetical nor biochemical examination to confirm the disease. Further diagnosis is dependent on the determination of cholesterol esterification or filipin staining of cultured fibroblasts, or eventual test of the NPC1 or NPC2 gene.^[11,16,30] The reported 7 NP-C cases are helpful to the diagnosis and treatment of the disease in the Chinese population.

Funding: None.

Ethical approval: This study was approved by the data inspectorate of China and by the regional committee for medical research ethics.

Competing interest: None.

Contributors: All authors reviewed relevant articles and they contributed to the intellectual content and approved the final version.

References

1   Kolodny EH. Niemann-Pick disease. Curr Opin Hematol 2000;7:48-52.

2   Tang Y, Li H, Liu JP. Niemann-Pick disease type C: from molecule to clinic. Clin Exp Pharmacol Physiol 2010;37:132-140.

3   Vanier MT. Niemann-Pick disease type C. Orphanet J Rare Dis 2010;5:16.

4   Garver WS, Francis GA, Jelinek D, Shepherd G, Flynn J, Castro G, et al. The National Niemann-Pick C1 disease database: report of clinical features and health problems. Am J Med Genet A 2007;143A:1204-1211.

5   Grau AJ, Weisbrod M, Hund E, Harzer K. Niemann-Pick disease type C―a neurometabolic disease through disturbed intracellular lipid transport. Nervenarzt 2003;74:900-905.

6   Ramirez CM, Liu B, Taylor AM, Repa JJ, Burns DK, Weinberg AG, et al. Weekly cyclodextrin administration normalizes cholesterol metabolism in nearly every organ of the Niemann-Pick type C1 mouse and markedly prolongs life. Pediatr Res 2010;68:309-315.

7   Rosenbaum AI, Cosner CC, Mariani CJ, Maxfield FR, Wiest O, Helquist P. Thiadiazole Carbamates: potent inhibitors of lysosomal acid lipase and potential Niemann-Pick type C disease therapeutics. J Med Chem 2010;53:5281-5289.

8   Wraith JE, Vecchio D, Jacklin E, Abel L, Chadha-Boreham H, Luzy C, et al. Miglustat in adult and juvenile patients with Niemann-Pick disease type C: long-term data from a clinical trial. Mol Genet Metab 2010;99:351-357.

9   Lyu RK, Ko YM, Hung IJ, Lu CS. Type C Niemann-Pick disease: report of a Chinese case. J Formos Med Assoc 1993;92:829-831.

10 Yang CC, Su YN, Chiou PC, Fietz MJ, Yu CL, Hwu WL, et al. Six novel NPC1 mutations in Chinese patients with Niemann-Pick disease type C. J Neurol Neurosurg Psychiatry 2005;76:592-595.

11 Wraith JE, Baumgartner MR, Bembi B, Covanis A, Levade T, Mengel E, et al. Recommendations on the diagnosis and management of Niemann-Pick disease type C. Mol Genet Metab 2009;98:152-165.

12 Elleder M, Jirasek A, Smid F, Ledvinova J, Besley GT. Niemann-Pick disease type C. Study on the nature of the cerebral storage process. Acta Neuropathol 1985;66:325-336.

13 Vanier MT, Millat G. Niemann-Pick disease type C. Clin Genet 2003;64:269-281.

14 Tamura H, Takahashi T, Ban N, Torisu H, Ninomiya H, Takada G, et al. Niemann-Pick type C disease: novel NPC1 mutations and characterization of the concomitant acid sphingomyelinase deficiency. Mol Genet Metab 2006;87:113-121.

15 Lloyd-Evans E, Morgan AJ, He X, Smith DA, Elliot-Smith E, Sillence DJ, et al. Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium. Nat Med 2008;14:1247-1255.

16 Garver WS, Jelinek D, Meaney FJ, Flynn J, Pettit KM, Shepherd G, et al. The National Niemann-Pick Type C1 Disease Database: correlation of lipid profiles, mutations, and biochemical phenotypes. J Lipid Res 2010;51:406-415.

17 Infante RE, Wang ML, Radhakrishnan A, Kwon HJ, Brown MS, Goldstein JL. NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes. Proc Natl Acad Sci U S A 2008;105:15287-15292.

18 Candoni A, Grimaz S, Doretto P, Fanin R, Falcomer F, Bembi B. Sea-blue histiocytosis secondary to Niemann-Pick disease type B: a case report. Ann Hematol 2001;80:620-622.

19 Lossos A, Schlesinger I, Okon E, Abramsky O, Bargal R, Vanier MT, et al. Adult-onset Niemann-Pick type C disease. Clinical, biochemical, and genetic study. Arch Neurol 1997;54:1536-1541.

20 Sevin M, Lesca G, Baumann N, Millat G, Lyon-Caen O, Vanier MT, et al. The adult form of Niemann-Pick disease type C. Brain 2007;130:120-133.

21 Watanabe Y, Akaboshi S, Ishida G, Takeshima T, Yano T, Taniguchi M, et al. Increased levels of GM2 ganglioside in fibroblasts from a patient with juvenile Niemann-Pick disease type C. Brain Dev 1998;20:95-97.

22 Canafoglia L, Bugiani M, Uziel G, Dalla Bernardina B, Ciano C, Scaioli V, et al. Rhythmic cortical myoclonus in Niemann-Pick disease type C. Mov Disord 2006;21:1453-1456.

23 Battisti C, Tarugi P, Dotti MT, De Stefano N, Vattimo A, Chierichetti F, et al. Adult onset Niemann-Pick type C disease: a clinical, neuroimaging and molecular genetic study. Mov Disord 2003;18:1405-1409.

24 Lengyel D, Weissert M, Schmid L, Gottlob I. Eye movement abnormalities as a sign for the diagnosis in Niemann-Pick disease type C. Klin Monbl Augenheilkd 1999;214:50-52.

25 Omarini LP, Frank-Burkhardt SE, Seemayer TA, Mentha G, Terrier F. Niemann-Pick disease type C: nodular splenomegaly. Abdom Imaging 1995;20:157-160.

26 Patterson M. Niemann-Pick Disease Type C. In: Pagon RA, Bird TC, Dolan CR, Stephens K, eds. Gene Reviews. Seattle: University of Washington, 2008.

27 Pineda M, Perez-Poyato MS, O'Callaghan M, Vilaseca MA, Pocovi M, Domingo R, et al. Clinical experience with miglustat therapy in pediatric patients with Niemann-Pick disease type C: a case series. Mol Genet Metab 2010;99:358-366.

28 Bae JS, Carter JE, Jin HK. Adipose tissue-derived stem cells rescue Purkinje neurons and alleviate inflammatory responses in Niemann-Pick disease type C mice. Cell Tissue Res 2010;340:357-369.

29 Hsu YS, Hwu WL, Huang SF, Lu MY, Chen RL, Lin DT, et al. Niemann-Pick disease type C (a cellular cholesterol lipidosis) treated by bone marrow transplantation. Bone Marrow Transplant 1999;24:103-107.

30 Yanjanin NM, Velez JI, Gropman A, King K, Bianconi SE, Conley SK, et al. Linear clinical progression, independent of age of onset, in Niemann-Pick disease, type C. Am J Med Genet B Neuropsychiatr Genet 2010;153B:132-140.

Received July 27, 2010 Accepted after revision September 13, 2010