Transition for adolescents with a rare disease: results of a nationwide German project.

PURPOSE: The transition process from paediatric/adolescent to adult medical care settings is of utmost importance for the future health of adolescents with chronic diseases and poses even more difficulties in the context of rare diseases (RDs). Paediatric care teams are challenged to deliver adolescent-appropriate information and structures. Here we present a structured transition pathway which is patient-focused and adoptable for different RDs. METHODS: The transition pathway for adolescents 16 years and older was developed and implemented as part of a multi-centre study in 10 university hospitals in Germany. Key elements of the pathway included: assessment of patients' disease-related knowledge and needs, training/educational and counselling sessions, a structured epicrisis and a transfer appointment jointly with the paediatric and adult specialist. Specific care coordinators from the participating university hospitals were in charge of organization and coordination of the transition process. RESULTS: Of a total of 292 patients, 286 completed the pathway. Deficits in disease-specific knowledge were present in more than 90% of participants. A need for genetic or socio-legal counselling was indicated by > 60%. A mean of 2.1 training sessions per patient were provided over a period of almost 1 year, followed by the transfer to adult care in 267 cases. Twelve patients remained in paediatric care as no adult health care specialist could be identified. Targeted training and counselling resulted in improved disease-specific knowledge and contributed to empowering of patients. CONCLUSION: The described transition pathway succeeds to improve health literacy in adolescents with RDs and can be implemented by paediatric care teams in any RD specialty. Patient empowerment was mainly achieved by individualized training and counselling.

Resistance to GHRH but Not to PTH in a 15-Year-Old Boy With Pseudohypoparathyroidism 1A.

Pseudohypoparathyroidism 1A (PHP1A) consists of signs of Albright hereditary osteodystrophy (AHO) and multiple, variable hormonal resistances. Elevated PTH levels are the biochemical hallmark of the disease. Short stature in PHP1A may be caused by a form of accelerated chondrocyte differentiation leading to premature growth plate closure, possibly in combination with GH deficiency in some patients. Treatment of short stature with recombinant growth hormone (rhGH) in pediatric patients may improve final height if started during childhood. The 10 11/12-year-old boy with clinical signs of AHO presented for evaluation of short stature [height standard deviation score (SDS) -2.72]. Clinically his mother was affected by AHO as well. A heterozygous mutation c.505G>A (p.E169K) in exon 6 of the GNAS gene confirmed a diagnosis of PHP1A in the boy. However, hormonal assessment was unremarkable except for low serum IGF-1 (SDS -2.67). On follow-up, GH deficiency due to GHRH resistance was suspected and confirmed by clonidine and arginine stimulation tests. Treatment with rhGH (0.035 mg/kg) for 2 years resulted in catch-up growth (height SDS -1.52). At age 15 years the PTH levels and bone age of the patient remain within the normal range. In patients with PHP1A, short stature is caused by the effects of Gs-α deficiency on the growth plate. However, resistance to GHRH and the resulting GH deficiency might also contribute. Recombinant GH treatment increases growth in these patients. Diagnostic workup for GH deficiency as a factor contributing to short stature is recommended even in the absence of other hormonal resistances.

Zonisamide block of cloned human T-type voltage-gated calcium channels.

SUMMARY: Zonisamide (ZNS) is a multi-target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures, with T-type Ca(2+) channel blockade being one of its proposed mechanisms of action. In this study, we systematically investigated electrophysiological effects of ZNS on cloned human Ca(v)3.1-3.3 Ca(2+) channels in a heterologous HEK-293 expression system using whole cell patch-clamp technique. Concentration-response studies were performed in the range from 5 microM to 2mM for Ca(v)3.2 Ca(2+) channels exhibiting a 15.4-30.8% reduction of Ca(2+) influx within the maximum therapeutic plasma range (50-200 microM ZNS). The other T-type Ca(2+) channel entities, Ca(v)3.1 and Ca(v)3.3, were even less sensitive to ZNS. Both voltage- and concentration-dependence of inactivation kinetics remained unchanged for Ca(v)3.2 VGCC, whereas Ca(v)3.1 and Ca(v)3.3 exhibited minor, though significant reduction of inactivation-tau. Interestingly, ZNS block of Ca(v)3.2 VGCCs was not use-dependent and remained unaffected by changes in the holding potential. Steady-state inactivation studies did not display a significant shift in steady-state availability of Ca(v)3.2 channels at 100 microM ZNS (DeltaV(1/2)=3.1mV, p=0.071). Our studies indicate that ZNS is a moderate blocker of human Ca(v)3 T-type Ca(2+) channels with little or no effect on Ca(v)3.2 Ca(2+) channel inactivation kinetics, use- and state-dependence of blockade. These results suggest that T-type Ca(2+) channel inhibition only partially contributes to the anti-absence activity of ZNS antiepileptic drug.