A Novel GMPPA Mutation in Two Adult Sisters with Achalasia, Alacrima, Short Stature, Dysmorphism, and Intellectual Disability

[摘要] The alacrima, achalasia, and mental retardation syndrome (AAMR) is a newly described autosomal recessive disorder characterized by the onset of these 3 main features at birth or in early infancy. At present, only 16 cases have been reported. Recently, it was shown that AAMR is due to mutations in the guanosine diphosphate (GDP)-mannose pyrophosphorylase A (GMPPA) gene. These mutations induce a significant GDP-mannose overload, which may affect protein glycosylation. Herein, for the first time, we describe 2 adult sisters with AAMR with a previously not reported deleterious homozygous missense mutation c.1118G>C (p.Arg373Pro) in the GMPPA gene, born to healthy consanguineous heterozygous parents from an ancient endogamous population. The main symptoms in both sisters started soon after birth with achalasia and feeding difficulties, requiring surgical treatment. Both sisters showed alacrima identified during the first months of life, delayed psychomotor development, speech delay, facial dysmorphism, limb defects, short stature, and moderate intellectual disability. Alacrima and feeding difficulties due to achalasia during the neonatal period or first months of life, in the absence of adrenal cortical insufficiency, should spur to investigate AAMR by sequencing the GMPPA gene.

[学科分类] 基础医学

[关键词] AAMR syndrome;GMPPA;Novel mutation