Clinical and genetic characterization of families with triple A (Allgrove) syndrome.
Triple A (Allgrove) syndrome is characterized by achalasia, alacrima, adrenal abnormalities and a progressive neurological syndrome. Affected individuals have between two and four of these relatively common clinical problems; hence the diagnosis is often difficult in all but the classical presentation. The inheritance is autosomal recessive, and most cases of triple A have no family history. Using genetic linkage analysis in a small number of families, a locus on chromosome 12q13 was identified. The triple A gene was identified recently at this locus and called ALADIN (alacrima, achalasia, adrenal insufficiency neurologic disorder). Mutations in this gene were reported in families from North Africa and Europe. The majority of mutations were homozygous. We have identified 20 families with between two and four of the clinical features associated with the triple A syndrome. Sequencing of the triple A gene revealed five families that had a total of nine compound heterozygous mutations, and one Portuguese family (previously published) had two homozygous mutations; these changes were spread throughout the triple A gene in exons 1, 2, 7, 8, 10, 11, 12, 13 and 16, and the poly(A) tract. Those bearing mutations had the classical triple A syndrome of achalasia, alacrima, adrenal abnormalities and a progressive neurological syndrome. We identified a spectrum of associated neurological abnormalities in these cases, including pupil and cranial nerve abnormalities, frequent optic atrophy, autonomic neuropathy and upper and lower motor neurone signs including distal motor neuropathy and amyotrophy with severe selective ulnar nerve involvement. In these families, we have made genotype-phenotype correlations. Mutations in the triple A gene are thus an important cause of this clinically heterogeneous syndrome, and sequencing represents an important diagnostic investigation. Identifying further mutations and defining their phenotype along with functional protein analysis will help to characterize this neuroendocrine gene.
Houlden
Henry
H
Department of Clinical Neurology, Institute of Neurology, London, UK. hhoulden@ion.ucl.ac.uk
Smith
Stephen
S
De Carvalho
Mamede
M
Blake
Julian
J
Mathias
Christopher
C
Wood
Nicholas W
NW
Reilly
Mary M
MM
D000293:Adolescent; D000328:Adult; D002874:Chromosome Mapping / Q000379:methods; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins; D009422:Nervous System Diseases / Q000235:genetics* / Q000503:physiopathology*; D028861:Nuclear Pore Complex Proteins; D010375:Pedigree; D011506:Proteins / Q000235:genetics*; D013577:Syndrome
C416506:AAAS protein, human; D009419:Nerve Tissue Proteins; D028861:Nuclear Pore Complex Proteins; D011506:Proteins