We report the case of Niemann-Pick disease type C with extensive phenotypic heterogeneity in two monozygotic twins. One of the twins presented with a history of obsessive-compulsive disorder and slowly progressive inferior limb clumsiness, dysphagia, dysarthria, limb dysmetria and downward vertical gaze palsy while neuropsychological assessment revealed global cognitive deficits in multiple domains.
METHODS AND RESULTS
Complete neurological and neuropsychological evaluation in the asymptomatic monozygotic twin only revealed mild neurological impairment. In the hypothesis of Niemann-Pick disease type C, Filipin staining and assessment of plasma oxysterols (cholestane-3®,5〈,6®-triol) were carried out. Filipin test showed massive intracellular accumulation of non-esterified cholesterol consistent with a “classical phenotype”. Plasmatic levels of oxysterols were above normal range in both twins. Molecular analysis of NPC1 and NPC2 genes revealed a homozygous mutation in the NPC1 gene in both twins, a heterozygous mutation in both parents and in the older brother while the sister was a non-carrier. Zygosity testing, undertaken in the twins, resulted positive for monozygosity. Brain MRI in the proband showed only a mild diffuse enlargement of cortical sulci.
Both patients underwent a 18F-FDG-PET/CT with single subject automated analysis, which demonstrated a reduced frontal and temporal glucose metabolism more widespread in the proband. This is in line with literature data supporting the idea of a progressive neuronal degeneration leading to a disconnection syndrome towards the frontal regions as biological substrate for the cognitive/neuropsychiatric manifestations of the disease.
Early recognition of NPC is important because of the recent development of a disease-specific therapy, miglustat (Zavesca, Actelion Pharmaceuticals, Allschwil, Switzerland), that reversibly inhibits glycosphingolipid synthesis and should be initiated at the earliest onset of neurological signs in order to stabilise or slow the disease progression. Therapy with miglustat was initiated in both subjects.
To our knowledge, only few cases of NPC in monozygotic twins have been reported in literature all of which affected by very similar phenotypes; little is known about phenotypic heterogeneity of patients carrying the same disease mutation. We report the first case of extensive phenotypic variability of NPC in monozygotic twins carrying the same homozygous mutation.
This case highlights the extreme phenotypic heterogeneity of NPC and underlines the importance of having markers of early diagnosis to consider NPC also in mild disease phenotypes which seem to be underestimated especially in the adult-onset presentation and severely delay the initiation of adequate therapy.
Further efforts are required to diagnose patients earlier in the natural history of disease and to initiate treatment before irreversible neurological impairment and to better elucidate disease pathogenesis for the development of synergic therapeutic strategies.