Alacrima, achalasia, and mental retardation syndrome (AAMR) is an autosomal recessive disorder characterized by onset of these 3 main features at birth or in early infancy. More variable features include hypotonia, gait abnormalities, anisocoria, and visual or hearing ... Alacrima, achalasia, and mental retardation syndrome (AAMR) is an autosomal recessive disorder characterized by onset of these 3 main features at birth or in early infancy. More variable features include hypotonia, gait abnormalities, anisocoria, and visual or hearing deficits. The disorder shows similarity to the triple A syndrome (231550), but patients with AAMR do not have adrenal insufficiency (summary by Koehler et al., 2013). See also 300858 for a phenotypically similar disorder that shows X-linked inheritance.
Koehler et al. (2013) reported 13 patients from 9 unrelated families with alacrima, achalasia, and mental retardation. The families originated from several different regions, including Pakistan, Turkey, Palestine, and Morocco, and most were consanguineous. The patients presented at ... Koehler et al. (2013) reported 13 patients from 9 unrelated families with alacrima, achalasia, and mental retardation. The families originated from several different regions, including Pakistan, Turkey, Palestine, and Morocco, and most were consanguineous. The patients presented at birth or in the first years of life with alacrima, feeding difficulties due to achalasia, and delayed psychomotor development with speech delay. Most also had muscular hypotonia. More variable features included gait abnormalities, spasticity, nasal speech, visual problems, and hearing impairment. A few patients had autonomic problems, such as decreased sweating, postural hypotension, and anisocoria. Affected members of 1 family had hyperkeratosis. None had signs of adrenal insufficiency. Koehler et al. (2013) noted the considerable clinical overlap with triple A syndrome, but none of the patients had mutations in the AAAS gene (605378).
In 13 patients from 9 unrelated families with AAMR, Koehler et al. (2013) identified 9 different homozygous mutations in the GMPPA gene (see, e.g., 615495.0001-615495.0005). The mutation in the first family was found by linkage analysis and whole-exome ... In 13 patients from 9 unrelated families with AAMR, Koehler et al. (2013) identified 9 different homozygous mutations in the GMPPA gene (see, e.g., 615495.0001-615495.0005). The mutation in the first family was found by linkage analysis and whole-exome sequencing. The subsequent families were identified by sequencing of the GMPPA gene in 63 families with alacrima and achalasia who were negative for mutations in the AAAS gene. Immunoblot analysis of patient cells with missense mutations showed lower levels of GMPPA compared to controls, consistent with a loss of function. However, GDP-mannose levels were significantly higher in patient cells compared to controls, whereas other nucleotide diphosphate sugars were unchanged. There was no evidence of alterations in N-glycosylation profiles in patients: serum transferrin, immunoglobulin G, and serum Apo-CIII glycosylation profiles were similar to those in controls. Koehler et al. (2013) suggested that changes induced by GDP-mannose overload might only be significant in restricted cell types or affect other glycosylation types, or may lead to perturbations in the levels of other guanine nucleotides. Alternatively, GMPPA might serve as a regulatory subunit. The clinical features of the patients with mutations indicated that GMPPA is important in neurons and autonomic nerve fibers innervating the distal esophageal sphincter or the lacrimal glands.