LIS1-associated classic lissencephaly: A retrospective, multicenter survey of the epileptogenic phenotype and response to antiepileptic drugs.

BACKGROUND: Patients with LIS1-associated classic lissencephaly typically present with severe psychomotor retardation and drug-resistant epilepsy within the first year. AIM: To analyze the epileptogenic phenotype and response to antiepileptic therapy in LIS1-associated classic lissencephaly. METHOD: Retrospective evaluation of 22 patients (8 months-24 years) with genetically and radiologically confirmed LIS1-associated classic lissencephaly in 16 study centers. RESULTS: All patients in our cohort developed drug-resistant epilepsy. In 82% onset of seizures was noted within the first six months of life, most frequently with infantile spasms. Later in infancy the epileptogentic phenotype became more variable and included different forms of focal seizures as well generalized as tonic-clonic seizures, with generalized tonic-clonic seizures being the predominant type. Lamotrigine and valproate were rated most successful with good or partial response rates in 88-100% of the patients. Both were evaluated significantly better than levetiracetam (p<0.05) and sulthiame (p<0.01) in the neuropediatric assessment and better than levetiracetam, sulthiame (p<0.05) and topiramate (p<0.01) in the family survey. Phenobarbital and vigabatrin achieved good or partial response in 62-83% of the patients. CONCLUSION: Our findings suggest that patients with LIS1-associated lissencephaly might benefit most from lamotrigine, valproate, vigabatrin or phenobarbital.

Analysis of the C19orf12 and WDR45 genes in patients with neurodegeneration with brain iron accumulation.

BACKGROUND: Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of diseases presenting with movement disorders and brain iron deposits. In addition to NBIA subtypes caused by mutations in PANK2 and PLA2G6, mutations in the C19orf12 gene were recently described as the third frequent cause of NBIA (called mitochondrial membrane protein-associated neurodegeneration, MPAN). Additionally, the X-linked gene WDR45 was found causative for a special subtype named static encephalopathy in childhood with neurodegeneration in adulthood (also called BPAN); however, analysis of this gene in a broader spectrum of NBIA has not been reported yet. METHODS: In a heterogeneous cohort of 69 patients with suspected NBIA that did not carry mutations in PANK2 and PLA2G6, the coding region of C19orf12 was evaluated by Sanger sequencing. The WDR45 gene was analyzed via high resolution melting and subsequent sequence analysis. RESULTS: Previously described homozygous C19orf12 mutations were found in 3/69 NBIA patients (4.3%). Analysis of the WDR45 gene revealed a novel heterozygous missense mutation in one female NBIA patient showing psychomotor retardation with secondary decline. CONCLUSIONS: C19orf12 mutations were confirmed in our heterogeneous NBIA cohort, while WDR45 mutations appear to be restricted to the subtype showing encephalopathy in childhood with neurodegeneration in adulthood.

Unexpected recovery from longterm renal failure in severe diffuse proliferative lupus nephritis.

BACKGROUND: Severe renal manifestation of systemic lupus erythematosus (SLE) is not uncommon and is associated with an indeterminate prognosis. Complete remission can be obtained, however, at least in the young when chronic lesions are absent and adequate anti-inflammatory therapy is immediately initiated. CASE PRESENTATION: We report the unusual case of a 12-year-old girl who presented with severe oliguric renal failure, macrohematuria and skin rash. Renal biopsy revealed the diagnosis of severe diffuse proliferative glomerulonephritis (GN) with cellular crescents in 15 out of 18 glomeruli and full-house pattern in immunofluorescence indicating lupus nephritis IVB according to WHO, IV-G(A) according to ISN/RPS classification. The serological parameters confirmed the diagnosis of SLE and the patient was immediately treated with methylprednisolone, cyclophosphamide and immunoadsorption. Initially, despite rapid amelioration of her general condition, no substantial improvement of renal function could be achieved and the patient needed hemodialysis treatment for 12 weeks. Unexpectedly, in the further follow-up at first diuresis increased and thereafter also creatinine levels substantially declined so that hemodialysis could be discontinued. Today, 6 years after the initial presentation, the patient has normal renal function and a SLEDAI score of 0 under a continuous immunosuppressive therapy with Mycophenolate mofetil (MMF) and low dose steroid. CONCLUSION: Despite the severity of the initial renal injury and the unfavourable renal prognosis the kidney apparently has a tremendous capacity to recover in young patients when the damage is acute and adequate anti-inflammatory therapy is initiated without delay.

Activity of childhood lupus nephritis is linked to altered T cell and cytokine homeostasis.

PURPOSE: Standard therapy for lupus nephritis is based on non-specific immunosuppression. We aimed to identify specific alterations in T cell and cytokine homeostasis and possible associations with disease activity in children with lupus nephritis (LN). METHODS: The phenotype of circulating T cells from children with LN and healthy controls (HC) was analyzed by flow cytometry. Intracellular expression of IL-17 and INF-γ was assessed after stimulation with anti-CD3 and anti-CD28. Serum concentrations of IP10, CCL2, TGF-ß, IL-17, and IL-23 were measured by ELISA. Disease activity was determined using the Systemic Lupus Erythematosus Disease Activity Index 2000 update (SLEDAI-2K). RESULTS: Children with active LN displayed increased frequencies of effector memory CD4(+)CD45RO(+)CCR7(-) and terminal differentiated CD4(+)CD45RA(+)CCR7(-) T cells and reduced naive CD4(+)CD45RA(+)CCR7(+) T cells compared to those with inactive LN or HC. Circulating CD4(+)CXCR3(+) and CD4(+)CCR2(+) T cells correlated inversely with the renal SLEDAI-2K, whereas IP10 and CCL2 showed a positive correlation. Reduced CD4(+)Foxp3(+) T cells and serum TFG-ß levels in active LN were associated with high serum IL-17 and IL-23 levels and correlated inversely with the renal SLEDAI-2K (r = -0.5855, p = 0.0013 and r = -0.6246, p = 0.0005, respectively), whereas IL-17 and IL-23 correlated positively (r = 0.5516, p = 0.0029 and r = 0.6116, p = 0.0007, respectively). Expansion of Th17 and Th1/Th17 cells in children with LN was significantly greater than in HC (p = 0.0304 and p = 0.0067, respectively). CONCLUSION: Children with active LN display high levels of pro-inflammatory cytokines associated with an increase in effector T cells and reduction of regulatory T cells. Therapeutic regulation of the aberrant cytokine profile might specifically interrupt pathogenic mechanisms.

Markers of childhood lupus nephritis indicating disease activity.

Current treatment regimens for childhood lupus nephritis (LN) are associated with significant side-effects and toxicity in vulnerable phases of growth and development. The paucity of biomarkers particularly in childhood impedes the appropriate clinical management and the development of new therapeutics. We analyzed markers of immune system (BAFF, RANTES), complement (Bb, C1q, C3d-CIC, C5a) and endothelial cell activation (sVCAM-1) in children with LN (n=22, mean age 14.8±4.7 years), nephrotic syndrome (n=13) and age-matched healthy controls (n=20) to define parameters that correlate with LN activity. Complement fragments of the alternative (Bb, p=0.0004) classical (C3d-CIC, p<0.0001) and common pathway (C5a, p<0.0001) and the levels of BAFF (p<0.0001), RANTES (p=0.0002) and sVCAM-1 (p=0.0004) were significantly higher in active compared to inactive LN. Activation of complement was associated with the occurrence of anti-C1q antibodies and reduced complement C1q. Complement-activation fragments highly correlated with the markers for immune system and endothelial cell activation. The ensemble of these parameters may be of great value in identifying early flares or remissions of childhood LN, and moreover may prove useful in the assessment of new treatments and in determining the optimization of their use.