Niemann–Pick type C disease with a novel intronic mutation: three Turkish cases from the same family

Objectives Niemann–Pick type C (NPC) disease is a rare progressive neurodegenerative condition that is characterized by the accumulation of cholesterol, glycosphingolipids, and sphingosine in lysosomes. Patients have various systemic and neurological findings depending on their age at onset. This disease is caused by the autosomal recessive transmission of mutations in the NPC1 and NPC2 genes; patients have mutations mainly in the NPC1 gene (95%) and the majority of them are point mutations located in the exonic regions. Case presentation Here, we presented three cousins with hepatosplenomegaly and progressive neurodegeneration who were diagnosed with visceral-neurodegenerative NPC disease. Their parents were relatives, and they had a history of sibling death with similar complaints. Bone marrow smear showed foamy cells in patient 1. Vertical supranuclear gaze palsy was not present in all cases. Sphingomyelinase (SM) activities were almost normal to exclude NPA or NPB. Filipin staining was performed in patient 2 and showed a massive accumulation of unesterified cholesterol The NPC1 gene analysis of the three patients showed a novel homozygous c.1553+5G>A intronic mutation. cDNA analysis was performed from the patient 3 and both parents. It was observed that exon 9 was completely skipped in the homozygous mutant baby. Both the normal and the exon 9-skipped transcripts have been detected in the parents. Conclusions When combined with the filipin staining and the patients’ clinical outcomes, this mutation is likely to be deleterious. Moreover, cDNA sequencing supports the pathogenicity of this novel variant.

Claustrum hyperintensity: a rare radiological correlate in Niemann-Pick disease

A 5-year-old male child of consanguineous parentage, without any adverse perinatal history, presented with progressive cognitive regression predominantly in the language and attention domains, for 2 years. He had simultaneous pyramidal and extrapyramidal involvement, frequent generalised tonic-clonic seizures and recurrent respiratory tract infections. Examination was significant for vertical supranuclear gaze palsy, coarse facial features and splenomegaly. Given the clinical features, in the background of consanguinity and mother’s history of spontaneous pregnancy losses, inborn errors of metabolism were suspected. Following relevant investigations including tailored genetic study, Niemann-Pick disease type C (NPC) was diagnosed. Interestingly, MRI brain showed bilateral T2/fluid-attenuated inversion recovery claustrum hyperintensities, which are more commonly associated with autoimmune encephalitis and febrile infection-related epilepsy syndrome and not reported previously in NPC. Additionally, language regression as a presenting manifestation in NPC as opposed to classical dysarthria makes this case truly unique.

Bilateral, vertical supranuclear gaze palsy following unilateral midbrain infarct

A 60-year-old man recently admitted for bipedal oedema, endocarditis and a persistently positive COVID-19 swab with a history of anticoagulation on rivaroxaban for atrial fibrillation, transitional cell carcinoma, cerebral amyloid angiopathy, diabetes and hypertension presented with sudden onset diplopia and vertical gaze palsy. Vestibulo-ocular reflex was preserved. Simultaneously, he developed a scotoma and sudden visual loss, and was found to have a right branch retinal artery occlusion. MRI head demonstrated a unilateral midbrain infarct. This case demonstrates a rare unilateral cause of bilateral supranuclear palsy which spares the posterior commisure. The case also raises a question about the contribution of COVID-19 to the procoagulant status of the patient which already includes atrial fibrillation and endocarditis, and presents a complex treatment dilemma regarding anticoagulation.

Genetics of Progressive Supranuclear Palsy: A Review

Progressive supranuclear palsy (PSP) is an atypical parkinsonism with prominent 4R-tau neuropathology, and the classical clinical phenotype is characterized by vertical supranuclear gaze palsy, unprovoked falls, akinetic-rigid syndrome and cognitive decline. Though PSP is generally regarded as sporadic, there is increasing evidence suggesting that a series of common and rare genetic variants impact on sporadic and familial forms of PSP. To date, more than 10 genes have been reported to show a potential association with PSP. Among these genes, the microtubule-associated protein tau (MAPT) is the risk locus with the strongest effect size on sporadic PSP in the case-control genome-wide association studies (GWAS). Additionally, MAPT mutations are the most common cause of familial PSP while the leucine-rich repeat kinase 2 (LRRK2) is a rare monogenic cause of PSP, and several other gene mutations may mimic the PSP phenotype, like the dynactin subunit 1 (DCTN1). In total, 15 MAPT mutations have been identified in cases with PSP, and the mean age at onset is much earlier than in cases carrying LRRK2 or DCTN1 mutations. GWAS have further identified several risk loci of PSP, proposing molecular pathways related to PSP. The present review focused on genetic studies on PSP and summarized genetic factors of PSP, which may help to elucidate the underlying pathogenesis and provide new perspectives for therapeutic strategies.

Clinical and Molecular Features of Early Infantile Niemann Pick Type C Disease

Niemann Pick disease type C (NPC) is a neurovisceral disorder due to mutations in NPC1 or NPC2. This review focuses on poorly characterized clinical and molecular features of early infantile form of NPC (EIF) and identified 89 cases caused by NPC1 (NPC1) and 16 by NPC2 (NPC2) mutations. Extra-neuronal features were common; visceromegaly reported in 80/89 NPC1 and in 15/16 NPC2, prolonged jaundice in 30/89 NPC1 and 7/16 NPC2. Early lung involvement was present in 12/16 NPC2 cases. Median age of neurological onset was 12 (0–24) and 7.5 (0–24) months in NPC1 and NPC2 groups, respectively. Developmental delay and hypotonia were the commonest first detected neurological symptoms reported in 39/89 and 18/89 NPC1, and in 8/16 and 10/16 NPC2, respectively. Additional neurological symptoms included vertical supranuclear gaze palsy, dysarthria, cataplexy, dysphagia, seizures, dystonia, and spasticity. The following mutations in homozygous state conferred EIF: deletion of exon 1+promoter, c.3578_3591 + 9del, c.385delT, p.C63fsX75, IVS21-2delATGC, c. 2740T>A (p.C914S), c.3584G>T (p.G1195V), c.3478-6T>A, c.960_961dup (p.A321Gfs*16) in NPC1 and c.434T>A (p.V145E), c.199T>C (p.S67P), c.133C>T (p.Q45X), c.141C>A (p.C47X) in NPC2. This comprehensive analysis of the EIF type of NPC will benefit clinical patient management, genetic counselling, and assist design of novel therapy trials.

The mind’s eye: A neuro-ophthalmological perspective on Niemann-Pick type C disease

Niemann-Pick disease type C (NPC) is a rare autosomal recessive genetic disease caused by mutations in the NPC1 and NPC2 genes with an estimated incidence of 1:120 000 live births. The clinical presentations vary across the ages. Children present with visceral symptoms related to cholesterol accumulation in the liver and adults have predominantly neuropsychiatric features such as dementia. However, vertical supranuclear gaze palsy can be present from the first year of life and is a strong feature in the diagnosis of NPC, which can be confirmed by a skin biopsy. A 36-year-old female with long-standing depression was referred for an evaluation of dystonia. She had progressive cognitive decline, dysarthria, dysphonia, dystonia of the trunk and limbs, ataxia and supranuclear gaze palsy. A similar course of illness affected her brother. Her parents were first cousins. She had positive Filipin stain of fibroblasts cultured from her skin biopsy, confirming the diagnosis of NPC. Miglustat, the approved drug for treatment, was not accessible. She had been on simvastatin since diagnosis, with a poor response, and had ongoing severe cognitive and physical disability. There are few conditions that present with neuropsychiatric symptoms and supranuclear gaze palsy. This patient had been managed as chronic depression with psychosis since her teenage years and her diagnosis was reviewed only when she had developed dystonia. Supranuclear gaze palsy is an early diagnostic clinical clue that could be present from infancy and should be sought in patients with neurocognitive presentations.

Late-onset Niemann–Pick disease type C overlapping with frontotemporal dementia syndromes: a case report

The diagnosis of adult-onset Niemann–Pick disease type C (NPC) could be difficult because its primary symptoms [dementia and vertical supranuclear gaze palsy (VSGP)] are mainly seen in neurodegenerative dementias and progressive supranuclear palsy (PSP). Our patient with dementia and asymmetric parkinsonism resembled corticobasal syndrome and after the appearance of VSGP, the criteria of PSP were fulfilled too. Cerebellar symptoms appeared late during the course of the disease, leading to the diagnosis of NPC at the age of 59 years.