Impact of miglustat on evolution of atypical presentation of late-infantile-onset Niemann-Pick disease type C with early cognitive impairment, behavioral dysfunction, epilepsy, ophthalmoplegia, and cerebellar involvement: a case report.

BACKGROUND: Niemann-Pick disease type C is a rare inherited neurodegenerative disease involving impaired intracellular lipid trafficking and accumulation of glycolipids in various tissues, including the brain. Miglustat, a reversible inhibitor of glucosylceramide synthase, has been shown to be effective in the treatment of progressive neurological manifestations in pediatric and adult patients with Niemann-Pick disease type C, and has been used in that indication in Europe since 2010. CASE PRESENTATION: We describe the case of a 16-year-old white French boy with late-infantile-onset Niemann-Pick disease type C who had the unusual presentation of early-onset behavioral disturbance and learning difficulties (aged 5) alongside epileptic seizures. Over time he developed characteristic, progressive vertical ophthalmoplegia, ataxic gait, and cerebellar syndrome; at age 10 he was diagnosed as having Niemann-Pick disease type C based on filipin staining and genetic analysis (heterozygous I1061T/R934X NPC1 mutations). He was commenced on miglustat therapy aged 11 and over the course of approximately 3 years he showed a global improvement as well as improved cognitive and ambulatory function. During this period he remained seizure free on antiepileptic therapy, using valproate and lamotrigine. CONCLUSIONS: Miglustat improved the neurological status of our patient, including seizure control. Based on our findings in this patient and previous published data, we discuss the importance of effective seizure control in neurological improvement in Niemann-Pick disease type C, and the relevance of cerebellar involvement as a possible link between these clinical phenomena. Thus the therapeutic efficacy of miglustat could be hypothesized as a substrate reduction effect on Purkinje cells.

Doctor, my son is so tired... about a case of hereditary fructose intolerance.

We present the case of a 17-year-old male who was diagnosed at birth with hereditary fructose intolerance (HFI). The patient complained of morning-time asthenia and post-prandial drowsiness despite a correct sleep pattern. The physical examination and biological check-up only showed severe vitamin C deficiency (<10 mol/l; normal range: 26-84). The patient's tiredness was attributed to this vitamin C deficiency, which is a frequent side-affect of the fructose-free diet. A change in diet associated with a supplementation in vitamin C was advised, with an increase in vegetable intake, principally avoiding carrots, onions, leaks and tinned sweet-corn. This case offers the opportunity for a review of this rare disease. Two kinds of fructose metabolism disorders (both autosomal recessive) are recognized: 1) essential fructosuria caused by a deficiency of fructokinase, which has no clinical consequence and requires no dietary treatment; 2) HFI, linked to three main mutations identified in aldolase B gene that may be confirmed by fructose breath test, intravenous fructose tolerance test, and genetic testing. In HFI, fructose ingestion generally induces gastro-intestinal (nausea and vomiting, abdominal pain, meteorism) and hypoglycemic symptoms. Fasting is well tolerated. If the condition remains undiagnosed, it leads to liver disease with hepatomegaly, proximal tubular dysfunction, and slow growth and weight gain. In conclusion, endocrinologists should be aware of this rare metabolic disease in order to provide careful follow-up, particularly important when the patient reaches adulthood. Moreover, hypoglycemia induced by fructose absorption, unexplained liver disease, irritable bowel syndrome or familial gout in an adult is suggestive of the diagnosis.

Evaluation of nutritional status and pathophysiology of growth retardation in patients with phenylketonuria.

Recent European studies have shown that growth retardation is com-mon in people with phenylketonuria (PKU) during the first years of life while they receive a low-phenylalanine (Phe) diet. The aims of the present study were to assess the growth of our PKU patients and to search for nutritional and hormonal explanations for the growth delay. Twenty PKU patients aged 8 months to 7 years entered the study. The design was cross-sectional, a longitudinal study having already been performed in our centre. The following data were recorded: weight/height (W/H), height/age (H/A), and weight/age (W/A) Z-scores; fat-free mass (measured from bioelectrical impedometry (FFM1), and skinfold thickness (FFMA). Thyroid hormones, insulin-like growth factor I (IGF1), insulin-like growth factor binding protein (IGFBP3), selenium, zinc, and Phe blood levels were measured. Dietary intake was also recorded over 4 days. PKU patients were moderately but significantly shorter (H/A Z-score varied from -2.12 to 1.61; mean -0.49) and lighter (W/A Z-score varied from -2.58 to 1.49; mean -0.71) than the French reference population. Body composition was not different from that of controls matched for age and sex. IGF1, IGFBP3, and thyroid hormone levels were within normal range. All children received more than two-thirds of the recommended daily allowances for energy (91% +/- 18%) and for proteins (146% +/- 26%). The mean daily intake of our patients was sufficient in selenium, but markedly deficient in zinc (2.4 +/- 2.2 mg/day). No correlation was found between zinc daily intake or zinc plasma levels and growth retardation. Moreover, no relation was found between the plasma Phe concentrations, protein or caloric intake and the presence of growth retardation. Our results show that growth retardation in PKU patients is not related to hormonal or caloric deficiencies. Further studies are needed to investigate the effect of various nutrient supplementation regimens (especially zinc) on the growth of PKU patients.

Jun NH2-terminal kinase is constitutively activated in T cells transformed by the intracellular parasite Theileria parva.

When T cells become infected by the parasite Theileria parva, they acquire a transformed phenotype and no longer require antigen-specific stimulation or exogenous growth factors. This is accompanied by constitutive interleukin 2 (IL-2) and IL-2 receptor expression. Transformation can be reversed entirely by elimination of the parasites using the specific drug BW720c. Extracellular signal-regulated kinase and jun NH2-terminal kinase (JNK) are members of the mitogen-activated protein kinase family, which play a central role in the regulation of cellular differentiation and proliferation and also participate in the regulation of IL-2 and IL-2 receptor gene expression. T. parva was found to induce an unorthodox pattern of mitogen-activated protein kinase expression in infected T cells. JNK-1 and JNK-2 are constitutively active in a parasite-dependent manner, but have altered properties. In contrast, extracellular signal-regulated kinase-2 is not activated even though its activation pathway is functionally intact. Different components of the T cell receptor (TCR)-dependent signal transduction pathways also were examined. The TCRzeta or CD3epsilon chains were found not to be phosphorylated and T. parva-transformed T cells were resistant to inhibitors that block the early steps of T cell activation. Compounds that inhibit the progression of T cells to proliferation, however, were inhibitory. Our data provide the first example, to our knowledge, for parasite-mediated JNK activation, and our findings strongly suggest that T. parva not only lifts the requirement for antigenic stimulation but also entirely bypasses early TCR-dependent signal transduction pathways to induce continuous proliferation.