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Infantile-onset cerebellar atrophy (CA) is a clinically and genetically heterogeneous trait. Galloway-Mowat syndrome (GMS) is a rare autosomal recessive disease, characterized by microcephaly with brain anomalies including CA in some cases, intellectual disability, and early-infantile-onset nephrotic syndrome. Very recently, WDR73 deficiency was identified as the cause of GMS in five individuals. To evaluate the role of WDR73 mutations as a cause of GMS and other forms of syndromic CA, we performed Sanger or exome sequencing in 51 unrelated patients with CA and variable brain anomalies and in 40 unrelated patients with a diagnosis of GMS. We identified 10 patients from three CA and from two GMS families with WDR73 mutations including the original family described with CA, mental retardation, optic atrophy, and skin abnormalities (CAMOS). There were five novel mutations, of which two were truncating and three were missense mutations affecting highly conserved residues. Individuals carrying homozygous WDR73 mutations mainly presented with a pattern of neurological and neuroimaging findings as well as intellectual disability, while kidney involvement was variable. We document postnatal onset of CA, a retinopathy, basal ganglia degeneration, and short stature as novel features of WDR73-related disease, and define WDR73-related disease as a new entity of infantile neurodegeneration., (© 2015 WILEY PERIODICALS, INC.)

Familial Mediterranean fever (FMF) is an autosomal recessive inflammatory disorder predominantly affecting people living in or originating from areas around the Mediterranean Sea. It is caused by a number of mutations within the MEFV gene, which differently affect the severity of the disease phenotype. Because patients usually present with rather nonspecific clinical symptoms, MEFV genotyping can confirm and refine FMF diagnosis and improve treatment of affected individuals. We have performed a method comparison study on 100 Lebanese FMF patients to evaluate the potential of a rapid reverse-hybridization teststrip-based assay (FMF StripAssay) to serve as a first-line screening test for our population. When results obtained by reverse-hybridization and DNA sequencing of exons 2, 3, 5, and 10 were compared, the FMF StripAssay identified 144/149 mutations, and correctly typed all 12 different MEFV mutations covered. We conclude that reverse-hybridization provides a very rapid, accurate and easy-to-perform screening method, and, in combination with more comprehensive diagnostic methods, represents an efficient strategy for FMF genotyping.

Background: Familial mediterranean fever (FMF) is a recessively inherited disease characterized by recurrent crises of fever, abdominal, articular and/or thoracic pain. The most severe complication is the development of renal amyloidosis. Over 35 mutations have been discovered so far in the gene responsible for the disease, MEFV. This article aims at determining a correlation between the MEFV genotype and the occurrence of amyloidosis in FMF patients, in addition to the study of the modifying effects of the SAA1 (type 1 serum amyloid A protein) and MICA (Major Histocompatibility Complex (MHC) class-I-chain-related gene A) genes on this severe complication., Methods: Fourteen MEFV mutations were screened and the SAA1 and MICA polymorphisms tested in 30 FMF patients with amyloidosis and 40 FMF patients without amyloidosis., Results: The M694V and V726A allelic frequencies were, respectively, significantly higher and lower in the group with amyloidosis, compared to the control FMF group. The beta and gamma SAA1 alleles were more frequently encountered in the group without amyloidosis, whereas the alpha allele was significantly more observed in FMF patients with amyloidosis (p < 0.025). All the MICA alleles were encountered in both patients' groups, but none of them was significantly associated with amyloidosis., Conclusions: The results suggest a protective effect of the SAA1 beta and gamma alleles on the development of amyloidosis and show the absence of a MICA modifying effect on amyloidosis development. Testing these polymorphisms on a larger sample will lead to more definite conclusions.

Seventy-nine unrelated Lebanese patients were tested for 15 mutations in the MEFV gene: A761H, A744S, V726A, K695R, M694V, M694I, M694del, M6801 (G --> C), M680I (G --> A) in exon 10, F479L in exon 5, P369S in exon 3, T267I, E167D and E148Q in exon 2, using PCR digestion, ARMS, DGGE and/or sequencing. Mutations were detected in patients belonging to all communities, most interestingly the Maronite, Greek orthodox, Greek catholic, Syriac and Chiite communities. The most frequent mutations are M694V and V726A (27% and 20% of the total alleles respectively). M694I, E148Q and M680I mutations account respectively for 9%, 8% and 5%. Each of the K695R, E167D and F479L mutations was observed once and all the remaining mutations were not encountered. Of the alleles 33% do not carry any of the studied mutations. The mutation spectra, clinical features and severity of the disease differed among the Lebanese communities. The genotype-phenotype analysis showed a significant association (P < 0.001) between amyloidosis and the presence of mutations at codon 694 in exon 10 (both M694V and M694I). None of the patients carrying other mutations developed amyloidosis.