Niemann-Pick Disease Type C (NPC) is an autosomal recessive rare disease characterised by progressive neurovisceral manifestations. The collection of on-going large-scale NPC clinical data may generate better understandings of the natural history of the disease. Here we report NPC patient data from the International Niemann-Pick Disease Registry (INPDR). The INPDR is a web-based, patient-led independent registry for the collection of prospective and retrospective clinical data from Niemann-Pick Disease patients. Baseline data from NPC patients enrolled into the INPDR from September 2014 to December 2019 was extracted to analyse the demographic, genetic and clinical features of the disease. A total of 203 NPC patients from six European countries were included in this study. The mean age (SD) at diagnosis was 11.2 years (14.2). Among enrolled patients, 168 had known neurological manifestations: 43 (24.2%) had early-infantile onset, 47 (26.4%) had late-infantile onset, 41 (23.0%) had juvenile onset, and 37 (20.8%) had adult onset. 10 (5.6%) patients had the neonatal rapidly fatal systemic form. Among the 97 patients with identified NPC1 variants, the most common variant was the c. 3182T > C variant responsible for the p.lle1061Thr protein change, reported in 35.1% (N = 34) of patients. The frequencies of hepatomegaly and neonatal jaundice were greatest in patients with early-infantile and late-infantile neurological onset. Splenomegaly was the most commonly reported observation, including 80% of adult-onset patients. The most commonly reported neurological manifestations were cognitive impairment (78.5%), dysarthria (75.9%), ataxia (75.9%), vertical supranuclear gaze palsy (70.9%) and dysphagia (69.6%). A 6-domain composite disability scale was used to calculate the overall disability score for each neurological form. Across all with neurological onset, the majority of patients showed moderate to severe impairments in all domains, except for 'swallowing' and 'seizure'. The age at diagnosis and death increased with increased age of neurological symptom onset. Miglustat use was recorded in 62.4% of patients and the most common symptomatic therapies used by patients were antiepileptics (32.9%), antidepressants (11.8%) and antacids (9.4%). The proportion of participants at each age of neurological onset was relatively equal across the cohort. Neurological manifestations, such as ataxia, dysphagia, and dysarthria, were frequently observed across all age categories.

Niemann-Pick disease Type C (NPC) is a rare autosomal recessive neurovisceral lysosomal disorder. Perinatal and early infantile onset NPC are the most severe types of the disease. Early infantile type is characterized by a rapidly progressive neurodegenerative course, which entails significant morbidity and usually results in death within 5 years. Miglustat, an iminosugar that selectively inhibits the glycosylceramide synthase enzyme, is known to stabilize or delay neurological progression in individuals with NPC, but its impact on affected infants is yet to be elucidated. We present two siblings with early infantile NPC due to the previously reported devastating homozygous mutation c.2279_2281delTCT in NPC1. Their considerably discrepant neurological disease courses were dependent on the timing of initiation of miglustat treatment. The outcomes support the significant role of early treatment with miglustat in the disease course of early infantile NPC and suggest that therapy should be considered even before the occurrence of neurological involvement. Moreover, this report emphasizes the importance of early diagnosis, in light of the availability of a potential disease-modifying medication.

Objective: To analyze the clinical manifestations, therapeutic efficacy, prognosis and characteristics of NPC1 mutation in Chinese patients with Niemann-Pick disease type C(NPC). Methods: Ten unrelated Chinese NPC patients were diagnosed by NPC1 mutation analysis from July 2013 to February 2017 in Beijing Tian Tan Hospital of Capital Medical University. Clinical data of 10 cases were analyzed retrospectively which included clinical manifestations, laboratory results and NPC1 gene mutation features, and a series of follow-up were carried out about therapeutic efficacy and prognosis. Results: Ten patients suffering from NPC included 5 males and 5 females, aged from 42 days to 14 years when they presented to Tian Tan Hospital. According to their age of neurological onset, 4 were in early infantile period, 2 in late infantile period, 2 in juvenile periods, and the other 2 cases in neonatal period. They all presented with splenomegaly, 5 of 10 accompanied with hepatomegaly. Two cases of neonatal subtype presented mainly with delayed neonatal cholestatic jaundice and hepatosplenomegaly, accompanied with decreased muscle tone and slight psychomotor retardation. The other 8 cases presented with severe neurological involvement, such as progressive encephalopathy, ataxia and language impairment, 4 with dystonia, 3 with decreased muscle tension, 5 with vertical supranuclear gaze palsy, 5 with gelastic cataplexy, and 4 with epilepsy. Eight of 9 cases presented with foam cells in their bone marrow. Head MRI showed diffuse cerebral atrophy in 8 cases, thin corpus callosum in 2 cases, and brain white matter abnormal signals in 2 cases. Among 10 cases, 18 different mutations of NPC1 allelic genes were identified including 11 reported mutations, 3 novel missense mutations: c. 3683T>C (p.Met1128Thr), c.1926G>C (p.Met642Iie) and c. 3006C>G (p.Phe1002Leu), 2 novel nonsense mutation: c. 1142G>A(p.Trp381Ter ) and c. 3229C>T(p.Arg1077Ter), 1 novel minimal deletion mutation: c. 1385-1386del, and 1 novel intron mutation: c. 1757+ 5G>A. In 5 cases, the symptom of gelastic cataplexy was alleviated by imipramine, and the convulsion was relieved by valproate in 2 cases, by carbamazepine in 1 case at the beginning of seizure. During the 25 (3-66) months of follow-up, 4 cases died, the others' neurological symptoms were deteriorated progressively. Conclusions: The NPC1 gene mutation were high heterozygous in this group, and 7 novel mutations enriched the gene mutation spectrum of NPC1. The neurological manifestations were complicated in patients with NPC, and the symptomatology would be different according to their onset age of neurological symptoms. There might be effective symptomatic treatment for gelastic cataplexy by imipramine and for convulsion by valproate or carbamazepine. 目的：分析尼曼匹克病C型(NPC)患者的临床表现和基因突变特点，观察疾病的治疗效果和预后。 方法：收集2013年7月至2017年2月在首都医科大学附属北京天坛医院就诊的10例NPC患者，对其临床表现、常规化验检查和基因突变特点进行分析，并随访其治疗效果和预后。 结果： 10例NPC患者，男5例，女5例，就诊年龄42 d～14岁；包括2例新生儿型、4例早期婴儿型、2例晚期婴儿型和2例青少年型。所有患者均有明显的脾大，5例伴有肝大。头部磁共振示8例脑萎缩、2例胼胝体变细及2例脑白质区异常信号。10例患者共检出18种NPC1基因突变，其中11种为已知突变，另7种为新突变，包括3种错义突变：c.3683T>C (p.Met1128Thr)、c.1926G>C(p.Met642Iie)和c.3006C>G(p.Phe1002Leu)；2种无义突变：c.1142G>A(p.Trp381Ter )和c.3229C>T(p.Arg1077Ter)；1种微小缺失突变：c.1385-1386del；1种剪切位点突变：c．1757＋5G>A。平均随访25(3～66)个月，丙咪嗪使5例患者的痴笑猝倒发作减轻，丙戊酸钠和卡马西平分别使2例和1例患者的癫痫发作程度减轻，随访结束时4例死亡，其余患者的病情均呈进行性加重。 结论： NPC1基因突变谱具有高度异质性，中国人NPC1基因的突变热点可能与欧州国家不同。NPC患者的神经系统表现与其发病年龄有关。丙咪嗪对控制痴笑猝倒发作有效，卡马西平或丙戊酸钠可能在病程早期对控制癫痫发作有效。.

Twenty-five patients with Niemann Pick disease type C (age range: 7 months to 44 years) were enrolled in an Italian independent multicenter trial and treated with miglustat for periods from 48 to 96 months. Based on the age at onset of neurological manifestations patients' phenotypes were classified as: adult (n = 6), juvenile (n = 9), late infantile (n = 6), early infantile (n = 2). Two patients had an exclusively visceral phenotype. We clinically evaluated patients' neurological involvement, giving a score of severity ranging from 0 (best) to 3 (worst) for gait abnormalities, dystonia, dysmetria, dysarthria, and developmental delay/cognitive impairment, and from 0 to 4 for dysphagia. We calculated a mean composite severity score transforming the original scores proportionally to range from 0 to 1 to summarize the clinical picture of patients and monitor their clinical course. We compared the results after 24 months of treatment in 23 patients showing neurological manifestations. Stabilization or improvement of all parameters was observed in the majority of patients. With the exception of developmental delay/cognitive impairment, these results persisted after 48-96 months in 41 - 55% of the patients (dystonia: 55%, dysarthria: 50%, gait abnormalities: 43%, dysmetria: 41%, respectively). After 24 months of therapy the majority of the evaluable patients (n = 20), demonstrated a stabilization or improvement in the ability to swallow four substances of different consistency (water: 65%, purée: 58%, little pasta: 60%, biscuit: 55%). These results persisted after 48-96 months in 40-50% of patients, with the exception of water swallowing. Stabilization or improvement of the composite severity score was detected in the majority (57%) of 7 patients who were treated early (within 3.5 years from onset) and rarely in patients who received treatment later. The results of this study suggest that miglustat treatment can improve or stabilize neurological manifestations, at least for a period of time; the severity of clinical conditions at the beginning of treatment can influence the rate of disease progression. This conclusion applies particularly to patients with juvenile or adult onset of the disease. EudraCT number 2006-005842-35.