Hypocretin Deficiency in Niemann-Pick Type C with Cataplexy

Sir,

Hypothalamic hypocretin neurotransmission is deficient in the majority of patients with narcolepsy, a chronic sleep disorder characterized with excessive daytime sleepiness (EDS) and cataplexy. Cataplexy, a sudden loss of muscle tone evoked by strong emotion [[3], [4]], is a pathognonomic symptom for narcolepsy, and the deficiency in hypocretin neurotransmission plays a causative role in the occurrence of cataplexy in narcolepsy. On the other hand, cataplectic attacks were often (up to 10 %) seen in Niemann-Pick type C (NPC) cases [[5], [6]]. Cataplectic attacks in these patients appear alone or associated with excessive daytime sleepiness and react to common anticataplectic medication (i.e., tricyclic antidepressants) [[6]]. NPC is an autosomal recessive and congenital neurological disorder characterized by the accumulation of cholesterol and glycosphingolipids in the peripheral tissues and of the glycosphingolipids in the brain [[6]]. The patients often exhibit hepatosplenomegaly, vertical supranuclear gaze, palsy, ataxia, dystonia, dementia and cataplexy. We therefore are interested in assessing the hypocretin status in NPC associated with and without cataplexy.

Case 1

A 3-year-old boy was suspected of having NPC due to the presence of a liver dysfunction, hepatosplenomegaly and progressive neurological symptoms (such as ataxia, tremor and dysstasia). He had no familiy history of NPC. He was diagnosed as having NPC by Niemann-Pick cells in a bone marrow examination and a biochemical cell investigation (such as impaired cholesterol esterification and filipin-cholesterol staining in cultured fibroblasts). Cataplexy was evoked by laughter since the age of 2.3 years. The CSF hypocretin-1 levels were 178 pg/ml and 142 pg/ml at the age of 4 and 5 years old (age-matched control values; mean ± SD: 279 ± 57, n = 18, age range: 3 - 5) [[1]]. The severity of cataplexy was slightly increased during this period. Anticatplectic medication was not prescribed throughout the course of the attacks. EDS was not claimed by the patient, and normal sleep latency (16.5 min) without sleep onset REM periods was observed by a two nap sleep test. No abnormal findings in the hypothalamus were detected by MRI scans. He was human leukocyte antigen DR4 and DR8 positive, but DR2 negative.

Case 2

A 3-year-old girl was diagnosed for NPC by Niemann-Pick cells in the bone marrow, filipin-cholesterol staining in cultured fibroblasts and a point mutation of NPC1 gene. She had no family history of NPC. This patient exhibited neurological symptoms such as tremor, ataxia and akathisia, but did not exhibit cataplexy or EDS when she died at 4.7 years old. The hypocretin-1 concentration was 299 pg/ml in the CSF sample, collected when the patient was 3 years old. No abnormal findings in the hypothalamus were detected by MRI scans.

We reported a case of hypocretin deficiency in NPC associated with cataplexy. The hypocretin deficiency in this case is moderate, compared to most narcolepsy-cataplexy cases, but may play a role in the occurrence of cataplexy, since no deficiency was detected in the 2nd case without cataplexy. The clinical pictures and neuropathological findings in NPC indicate a generalized brain pathology [[2], [6]]. Although no obvious morphological changes in the hypothalamus were detected by brain MRIs in both NPC cases, a partial and progressive damage of the hypocretin system due to the abnormal lysosomal storage may exist in the case with cataplexy. We only reported one case of hypocretin deficient NPC case with cataplexy, and no pathological data regarding the hypocretin deficiency in NPC in postmortem human brain or animal models of NPC. Considering the high prevalence of cataplexy in NPC [[2], [5]], it is important to study hypocretin status in this disorder.

References

• 1 Kanbayashi T, Yano T, Ishiguro H, Kawanishi K, Chiba S, Aizawa R, Sawaishi Y, Hirota K, Nishino S, Shimizu T. Hypocretin-1 (Orexin-A) levels in human lumbar CSF in different age groups: Infants to elderly persons.  Sleep. 2002;  25 337-339
• 2 Kandt R S, Emerson R G, Singer H S, Valle D L, Moser H W. Cataplexy in variant forms of Niemann-Pick disease.  Ann Neurol. 1982;  12 284-288
• 3 Nishino S, Ripley B, Overeem S, Nevsimalova S, Lammers G J, Vankova J, Okun M, Rogers W, Brooks S, Mignot E. Low cerebrospinal fluid hypocretin (Orexin) and altered energy homeostasis in human narcolepsy.  Ann Neurol. 2001;  50 381-388
• 4 Ripley B, Overeem S, Fujiki N, Nevsimalova S, Uchino M, Yesavage J, Di Monte D, Dohi K, Melberg A, Lammers G J, Nishida Y, Roelandse F W, Hungs M, Mignot E, Nishino S. CSF hypocretin/orexin levels in narcolepsy and other neurological conditions.  Neurology. 2001;  57 2253-2258
• 5 Vanier M T. Maladie de Niemann-Pick: etude biochimique de 107 cas (97 familles). Manifestations clinique et approche physiopathologique du type C. Lyon; These 1983
• 6 Vanier M T, Suzuki K. Recent advances in elucidating Niemann-Pick C disease.  Brain Pathol. 1998;  8 163-174