RESUMO
Visceral myopathy with abnormal intestinal and bladder peristalsis includes a clinical spectrum with megacystis-microcolon intestinal hypoperistalsis syndrome and chronic intestinal pseudo-obstruction. The vast majority of cases are caused by dominant variants in ACTG2; however, the overall genetic architecture of visceral myopathy has not been well-characterized. We ascertained 53 families, with visceral myopathy based on megacystis, functional bladder/gastrointestinal obstruction, or microcolon. A combination of targeted ACTG2 sequencing and exome sequencing was used. We report a molecular diagnostic rate of 64% (34/53), of which 97% (33/34) is attributed to ACTG2. Strikingly, missense mutations in five conserved arginine residues involving CpG dinucleotides accounted for 49% (26/53) of disease in the cohort. As a group, the ACTG2-negative cases had a more favorable clinical outcome and more restricted disease. Within the ACTG2-positive group, poor outcomes (characterized by total parenteral nutrition dependence, death, or transplantation) were invariably due to one of the arginine missense alleles. Analysis of specific residues suggests a severity spectrum of p.Arg178>p.Arg257>p.Arg40 along with other less-frequently reported sites p.Arg63 and p.Arg211. These results provide genotype-phenotype correlation for ACTG2-related disease and demonstrate the importance of arginine missense changes in visceral myopathy.
Assuntos
Actinas/genética , Substituição de Aminoácidos , Arginina , Estudos de Associação Genética , Predisposição Genética para Doença , Pseudo-Obstrução Intestinal/diagnóstico , Pseudo-Obstrução Intestinal/genética , Mutação , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adulto , Colo/anormalidades , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , Masculino , Técnicas de Diagnóstico Molecular , Fenótipo , Bexiga Urinária/anormalidades , Sequenciamento do Exoma , Adulto JovemRESUMO
A neonate suffering from herpes simplex virus type 2 disease with central nervous system involvement developed an early recurrence under acyclovir therapy. Isolates from the cerebrospinal fluid and skin lesions were acyclovir resistant, while viruses from blood and trachea were not. Acyclovir combined with foscavir followed by long-term suppressive acyclovir therapy supported normal neurological development.