Delineating SPTAN1 associated phenotypes: from isolated epilepsy to encephalopathy with progressive brain atrophy.

De novo in-frame deletions and duplications in the SPTAN1 gene, encoding the non-erythrocyte αII spectrin, have been associated with severe West syndrome with hypomyelination and pontocerebellar atrophy. We aimed at comprehensively delineating the phenotypic spectrum associated with SPTAN1 mutations. Using different molecular genetic techniques, we identified 20 patients with a pathogenic or likely pathogenic SPTAN1 variant and reviewed their clinical, genetic and imaging data. SPTAN1 de novo alterations included seven unique missense variants and nine in-frame deletions/duplications of which 12 were novel. The recurrent three-amino acid duplication p.(Asp2303_Leu2305dup) occurred in five patients. Our patient cohort exhibited a broad spectrum of neurodevelopmental phenotypes, comprising six patients with mild to moderate intellectual disability, with or without epilepsy and behavioural disorders, and 14 patients with infantile epileptic encephalopathy, of which 13 had severe neurodevelopmental impairment and four died in early childhood. Imaging studies suggested that the severity of neurological impairment and epilepsy correlates with that of structural abnormalities as well as the mutation type and location. Out of seven patients harbouring mutations outside the α/ß spectrin heterodimerization domain, four had normal brain imaging and three exhibited moderately progressive brain and/or cerebellar atrophy. Twelve of 13 patients with mutations located within the spectrin heterodimer contact site exhibited severe and progressive brain, brainstem and cerebellar atrophy, with hypomyelination in most. We used fibroblasts from five patients to study spectrin aggregate formation by Triton-X extraction and immunocytochemistry followed by fluorescence microscopy. αII/ßII aggregates and αII spectrin in the insoluble protein fraction were observed in fibroblasts derived from patients with the mutations p.(Glu2207del), p.(Asp2303_Leu2305dup) and p.(Arg2308_Met2309dup), all falling in the nucleation site of the α/ß spectrin heterodimer region. Molecular modelling of the seven SPTAN1 amino acid changes provided preliminary evidence for structural alterations of the A-, B- and/or C-helices within each of the mutated spectrin repeats. We conclude that SPTAN1-related disorders comprise a wide spectrum of neurodevelopmental phenotypes ranging from mild to severe and progressive. Spectrin aggregate formation in fibroblasts with mutations in the α/ß heterodimerization domain seems to be associated with a severe neurodegenerative course and suggests that the amino acid stretch from Asp2303 to Met2309 in the α20 repeat is important for α/ß spectrin heterodimer formation and/or αII spectrin function.

Early onset of type I diabetes mellitus, Hashimoto's thyroiditis and celiac disease in a 7-yr-old boy with Down's syndrome.

Patients with Down's syndrome are at higher risk for developing autoimmune diseases than those of the general population. Autoimmune diseases like Hashimoto's thyroiditis, Graves' disease, diabetes mellitus type I, celiac disease, autoimmune chronic active hepatitis, alopecia, vitiligo and hypoparathyroidism are recognized associations with Down's syndrome. We describe the case of a very young boy with Down's syndrome who was diagnosed with diabetes mellitus type I, Hashimoto's thyroiditis and celiac disease before 8 yr of age. Unspecific symptoms like weight loss, unstable blood sugar with high amplitudes, behavioural problems and dry skin were suspicious for other endocrine disorders or celiac disease in our case. The boy was showing the typical human leukocyte antigen profile for these autoimmune diseases. The prevalence of these autoimmune diseases is higher in Down's syndrome than in general population. Therefore, we advice to follow children with Down's syndrome who develop more than two autoimmune diseases very carefully.

[Changes in carbohydrate metabolism and insulin resistance in patients with Prader-Willi Syndrome (PWS) under growth hormone therapy]. / Veränderung des Kohlenhydratstoffwechsels und der Insulinresistenz bei Patienten mit Prader-Willi-Syndrom unter einer Wachstumshormontherapie.

BACKGROUND: Life expectance and life quality have markedly changed in PWS patients within the last 10-15 years. A strict diet, improved physical activity and an additive growth hormone treatment have led to these changes. Growth hormone therapy decreases body fat and improves final height. But growth hormone also antagonizes insulin and therefore increases the diabetic potential. The purpose of our study was to investigate incidence and multiple dependencies of development of impaired carbohydrate metabolism in patients with PWS under growth hormone therapy and to determine suitable parameters for the work-up. PATIENTS AND METHODS: 34 patients with genetically approved PWS have been treated with growth hormone for at least 0.5 years. The mean duration of growth hormone treatment was 2.15 years (0.5-4.51). At the start of growth hormone treatment patients were 1.33 to 16.47 years old. The clinical picture and the nutritional situation of children with PWS change age-dependent and can be divided up into three phases. The patients were duty subdivided into three age-groups at the beginning of growth hormone treatment. Group 1: 15 PWS patients, mean age 2.62 years (1.33-3.78). Group 2: 10 PWS patients, mean age 5.54 years (4.08-7.61). Group 3: 9 PWS patients, mean age 11.35 years (8.89-16.47). Data were collected within 0.3-0.38 years before start of treatment and every 6 months throughout the treatment period. Anthropometrical data, fat mass by bioelectric impedance analysis (BIA), fasting insulin, HbA1c, C-peptide, blood fats and the blood sugar profile in oral glucose tolerance tests (OGT/1.75 g glucose/kg body mass) were obtained. Growth hormone therapy was started with an average dose of 0.031 mg/kg body mass in all groups. Insulin resistance was based on Homeostasis Model Assessment-Test (HOMA). RESULT: No IR or pathological OGT were detected when growth hormone therapy started before the 4th year of life. When therapy started between the 4th and 8th year, PWS patients with normal weight did not develop an IR under GH therapy. 6% developed a glucose tolerance (IGT) disorder and 4% developed an increased fasting glucose (IFG). 5 of 9 PWS patients older than 8 years at therapystart showed a transient disorder of glucose metabolism: 11% of the results obtained in these patients presented an IR with no pathological OGT, 13% showed an IR with IGT, 7% showed an IR with IFG, and 2% showed an IR with transient diabetes. For 4% the IFG persisted with no IR, for 4% the IGT persisted with no IR. These patients differed from younger ones by an increased average BMI, an increase fat body ratio and an increase fasting insulin as well as an already reached puberty. No difference was found in C-peptide, HbA1c or GH dose/kg/body mass. CONCLUSION: Transient glucose metabolism disorders with no development of manifest insulin resistance are shown by PWS patients with normal weight starting from 4th year under GH therapy. Changes in the glucose metabolism with and with no development of IR appear after start of puberty and weight increase. Changes persisted partially for 18 months. GH therapy was not interrupted for any patient, whereby physical training and dietetic measurements were increased for all patients. HOMA-index and OGT shall be used in parallel to monitor glucose metabolism as both show independently distinctive features. HbA1c and C-peptide are not suitable parameters for monitoring carbohydrate metabolism in PWS patients under GH treatment.