Neurocognitive assessment and DNA sequencing expand the phenotype and genotype spectrum of Alström syndrome

Alström syndrome (OMIM#203800) is an ultra‐rare autosomal recessive monogenic disease presenting pathogenic variants in ALMS1 (chromosome 2p13). It is characterized by early onset of blindness, hearing loss and systemic comorbidities, with delayed development without cognitive impairment. We aimed t...

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Bibliographic Details
Published in:American journal of medical genetics. Part A 2021-03, Vol.185 (3), p.732-742
Main Authors: Dassie, Francesca, Lorusso, Riccardina, Benavides‐Varela, Silvia, Milan, Gabriella, Favaretto, Francesca, Callus, Edward, Cagnin, Stefano, Reggiani, Francesco, Minervini, Giovanni, Tosatto, Silvio, Vettor, Roberto, Semenza, Carlo, Maffei, Pietro
Format: Article
Language:English
Subjects:
ALMS
ALMS1
Apraxia
Blindness
Children
Chromosome 19
Cognition
Cognitive ability
DNA sequencing
Genotype & phenotype
Genotypes
Hearing loss
Memory
mild phenotype
neurocognitive assessment
Phenotypes
Short term memory
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Summary:Alström syndrome (OMIM#203800) is an ultra‐rare autosomal recessive monogenic disease presenting pathogenic variants in ALMS1 (chromosome 2p13). It is characterized by early onset of blindness, hearing loss and systemic comorbidities, with delayed development without cognitive impairment. We aimed to investigate the cognitive functions and describe new pathogenic variants in Alström syndrome patients. Nineteen patients (13 adults, 6 children) underwent a thorough clinical, genetic, laboratory, instrumental, and neurocognitive assessment. Six new pathogenic variants in ALMS1 including the first described in exon 6 were identified. Four patients displayed a “mild phenotype” characterized by slow disease onset or absence of complications, including childhood obesity and association with at least one pathogenic variant in exon 5 or 6. At neurocognitive testing, a significant proportion of patients had deficits in three neurocognitive domains: similarities, phonological memory, and apraxia. In particular, 53% of patients showed difficulties in the auditory working memory test. We found ideomotor and buccofacial apraxia in 74% of patients. “Mild phenotype” patients performed better on auditory working memory and ideomotor apraxia test than “typical phenotype” ones (91.9 + 16.3% vs. 41.7 + 34.5% of correct answers, Z = 64.5, p 
ISSN:1552-4825
1552-4833
DOI:10.1002/ajmg.a.62029