A multi-approach study in a series of 25 Czech and Slovak patients with acid sphingomyelinase deficiency revealed a broad phenotypic variability within Niemann-Pick disease types A and B. The clinical manifestation of only 9 patients fulfilled the historical classification: 5 with the rapidly progressive neurovisceral infantile type A and 4 with a slowly progressive visceral type B. Sixteen patients (64%) represented a hitherto scarcely documented 'intermediate type' (IT). Twelve patients showed a protracted neurovisceral course with overt or mild neurological symptoms, three a rapidly progressing fatal visceral affection with rudimentary neurological lesion. One patient died early from a severe visceral disease. The genotype in our patients was represented by 4 frameshift and 14 missense mutations. Six were novel (G166R, R228H, A241V, D251E, D278A, A595fsX601). The Q292K mutation (homoallelic, heteroallelic) was strongly associated with a protracted neurovisceral phenotype (10 of 12 cases). The sphingomyelin loading test in living fibroblasts resulted in total degradation from less than 2% in classical type A to 70-80% in classical type B. In the IT group it ranged from 5% to 49% in a 24 h chase. The liver storage showed three patterns: diffuse, zonal (centrolobular), and discrete submicroscopic. Our series showed a notable variability in both the neurological and visceral lesions as well as in their proportionality and synchrony, and demonstrates a continuum between the historical 'A' and 'B' phenotypes of ASM deficiency. This points to a broad phenotypic potential of ASM deficiency, suggesting the existence of still unknown factors independently controlling the storage level in the visceral and neuronal compartments. This report highlights the important position of the IT in the ASM deficiency phenotype classification. We define IT as a cluster of variants combining clinical features of both the classical types. The protracted neuronopathic variant with overt, borderline or subclinical neurology prevails and is important in view of future enzyme replacement therapy. It appears more common in central Europe. The visceral, rapidly progressing early fatal type has been recognized rarely so far.

By multiplex analysis, it may be possible, for example, to define the risk immunological response pattern among relatives or to monitor the immune response in patients on immune modulation therapy.

We consider our observations as a sign of a reaction directed against the self-antigen GAD65 that are closely connected to type 1 diabetes. In CF patients who do not develop diabetes autoreactive mechanisms are very probably efficiently suppressed by immune self-tolerance mechanisms. CFRD patients are a heterogenic group. To disclose those who may display features of autoimmune diabetes could have an impact for their therapy and prognosis.

Perfect maternal diabetes compensation is crucial for the outcome of the baby. However, little is known how hyperglycaemia influences the specific immune response. Furthermore, babies of type 1 diabetes (T1D) mothers have less risk of development T1D than babies with a T1D father. This study aimed to analyze the effect of maternal hyperglycaemia on newborns with focus on the response to diabetes‐associated autoantigens. Populations: (1) Newborns of T1D mothers split into groups according to maternal diabetes compensation during the 3rd trimester: perfect (n = 15) or acceptable (n = 25) compensation. (2) newborns with T1D father (n = 12) (3) newborns with a mother treated for either gestational or type 2 diabetes (n = 10) (4) control newborns (n = 25). Spontaneous as well as diabetes‐associated autoantigen‐stimulated production of 23 cytokines and chemokines were tested using protein microarray. In addition, the influence of glucose on cytokine and chemokine responsiveness was analyzed in vitro. The study groups differed in their spontaneous as well as stimulated cytokine and chemokine spectra. A prominent Th1 response (high IFN‐gamma) from autoantigen stimulation was observed especially in babies of T1D fathers (P = 0.001) and also in mothers with perfect diabetes compensation during the 3rd trimester (P = 0.016) in comparison with control newborns. By contrast, cord blood mononuclear cells cultivated in vitro in high glucose concentration decreased the diabetogenic stimulated Th1 cytokine response. Maternal ‘sweet’ as well as ‘autoimmune environment’ may both lead to lower occurrence of T1D within their offspring. Further studies will reveal the exact immunological mechanism of this observation.