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Background:A distinct clinical syndrome characterized by megalencephaly, mild to moderate cognitive decline, slowly progressive spasticity, ataxia, occasional seizures, and extensive white matter changes with temporal cysts by imaging studies has been described in a particular ethnic group (Agarwals) in India. This disorder is very similar to megalencephalic leukoencephalopathy with subcortical cysts (MLC), a newly characterized leukodystrophy whose molecular basis was recently shown to be mutations in a gene (KIAA0027) that has been renamedMLC1.Objective:To determine if this disorder among the Agarwals is due to mutations inMLC1by a mutation screening study conducted on affected Agarwal patients.Methods:Genomic DNA from these Indian leukodystrophy patients was screened for mutations in the entire coding region, including the exon–intron boundaries, of theMLC1gene.Results:Thirty-three affected individuals whose clinical and imaging presentations were consistent with MLC were screened. All were from northern India and included 31 known Agarwals, 1 non-Agarwal, and 1 adopted patient whose ethnicity is unknown. All 31 Agarwal patients tested positive for a homozygous insertion of a cytosine in exon 2. The adopted patient was homozygous for A157E. No mutation in the coding region was found in the non-Agarwal patient.Conclusions:Indian patients with megalencephaly and MRI changes that show extensive white matter changes with temporal cysts should raise suspicion for MLC. Members of the Agarwal ethnic group affected with the disorder present with a mildly progressive course and show a common mutation (320insC) in theMLC1gene, suggesting a founder effect.

Objective: To characterize Alexander disease (AxD) phenotypes and determine correlations with age at onset (AAO) and genetic mutation. AxD is an astrogliopathy usually characterized on MRI by leukodystrophy and caused by glial fibrillary acidic protein ( GFAP ) mutations. Methods: We present 30 new cases of AxD and reviewed 185 previously reported cases. We conducted Wilcoxon rank sum tests to identify variables scaling with AAO, survival analysis to identify predictors of mortality, and χ 2 tests to assess the effects of common GFAP mutations. Finally, we performed latent class analysis (LCA) to statistically define AxD subtypes. Results: LCA identified 2 classes of AxD. Type I is characterized by early onset, seizures, macrocephaly, motor delay, encephalopathy, failure to thrive, paroxysmal deterioration, and typical MRI features. Type II is characterized by later onset, autonomic dysfunction, ocular movement abnormalities, bulbar symptoms, and atypical MRI features. Survival analysis predicted a nearly 2-fold increase in mortality among patients with type I AxD relative to those with type II. R79 and R239 GFAP mutations were most common (16.6% and 20.3% of all cases, respectively). These common mutations predicted distinct clinical outcomes, with R239 predicting the most aggressive course. Conclusions: AAO and the GFAP mutation site are important clinical predictors in AxD, with clear correlations to defined patterns of phenotypic expression. We propose revised AxD subtypes, type I and type II, based on analysis of statistically defined patient groups.

We have reported on a patient with thrombocytopenia, impaired platelet aggregation, secretion, phosphorylation of pleckstrin and myosin light chain (MLC), and GPIIb-IIIa activation, associated with a heterozygous mutation in transcription factor CBFA2 (core binding factor A2, RUNX1 or AML1). To obtain insights into the abnormal platelet mechanisms and CBFA2-regulated genes, we performed platelet expression profiling in four control subjects and the patient using the Affymetrix U133 GeneChips. In the patient, 298 probe sets were significantly downregulated at least 2-fold. MLC regulatory polypeptide (MYL9 gene) was decreased approximately 77-fold; this is an important finding because agonist-stimulated MLC phosphorylation is decreased in patient platelets. Genes downregulated > or = 5-fold include those involving calcium binding proteins (CABP5), ion transport (sodium/potassium/Ca exchanger, SLC24A3), cytoskeletal/microtubule proteins (erythrocyte membrane protein band 4.1-like 3, EPB41L3; tropomyosin 1, TPM1; tubulin, alpha 1, TUBA1), signaling proteins (RAB GTPase activating protein 1-like, RABGAP1L; beta3-endonexin, ITGB3 BP) and chemokines (platelet factor 4 variant 1, PF4V1; chemokine CXCL5, CXCL5). These and other downregulated genes are relevant to the patient's platelet defects in function and production. These studies provide the first proof of concept that platelet expression profiling can be applied to obtain insights into the molecular basis of inherited platelet defects.