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ALMS1 gene

Overview

Gene (OMIM no.)
Function of gene/protein
  • Protein: centrosome and basal body associated protein
  • Localized to centrosomes and base of primary cilia
  • Ubiquitously expressed
  • Exact function unknown but thought to be involved in cilium formation, intracellular trafficking and cytoskeletal organisation
Clinical phenotype
(OMIM phenotype no.)
Inheritance
  • Autosomal recessive
Ocular features
  • Ocular features are one of the earliest manifestations
  • Cone-rod dystrophy
  • Nystagmus (during infancy)
  • Photophobia
  • Vascular attenuation
  • RPE atrophy in the mid-periphery
  • Bull’s eye maculopathy/macular pigmentary changes
  • Optic disc pallor
  • Posterior sub-capsular cataract may be present
Visual function
  • Rapid progressive photoreceptor dysfunction eventually leading to blindness (usually in the 1st to 2nd decade of life)
  • Intra- and interfamilial variability in terms of age of onset, disease severity and rate of progression
Systemic features
  • Systemic features may be absent initially and manifest later in life
  • Bilateral progressive sensorineural hearing loss
  • Childhood truncal obesity
  • Metabolic disorders (insulin resistance, hyperinsulinaemia, type 2 diabetes mellitus, leptin resistance, hypertriglyceridaemia, hyperlipidaemia)
  • Hypogonadotrophic hypogonadism
  • Short stature due to growth hormone deficiency and hypothyroidism
  • Dilated cardiomyopathy
  • Acanthosis nigricans
  • Can also be associated with renal, pulmonary and hepatic fibrosis
  • Life expectancy rarely exceeds 40 years of age
Key investigations
  • Full field ERG: cone-rod dystrophy progressing to generalised retinal dysfunction over time
  • FAF: Areas of hypo-AF indicating RPE atrophy
  • OCT: progressive outer retinal thinning and attenuation (more severe changes outside the fovea)
  • Assessment with a paediatrician and other relevant specialists
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (retinal)
  • Whole exome sequencing
  • Whole genome sequencing
Management
Therapies under research
Further information

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Supporting Organisation

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References

  1.  Hearn, T. (2019) ALMS1 and Alström syndrome: a recessive form of metabolic, neurosensory and cardiac deficits. Journal of Molecular Medicine, 97 (1), pp.1–17
  2.  Dotan, G., Khetan, V., Marshall, J.D., Affel, E., Armiger-George, D., Naggert, J.K., Collin, G.B. & Levin, A.V. (2017) Spectral-domain optical coherence tomography findings in Alström syndrome. Ophthalmic Genetics, 38 (5), pp.440–445
  3.  Nasser, F., Weisschuh, N., Maffei, P., Milan, G., Heller, C., Zrenner, E., Kohl, S. & Kuehlewein, L. (2018) Ophthalmic features of cone-rod dystrophy caused by pathogenic variants in the ALMS1 gene. Acta Ophthalmologica, 96 (4), pp.e445–e454
  4.  Xu Y, Guan L, Xiao X, et al. ALMS1 null mutations: a common cause of Leber congenital amaurosis and early-onset severe cone-rod dystrophy. Clin Genet. 2016;89(4):442-447
  5.  Girard D, Petrovsky N. Alström syndrome: insights into the pathogenesis of metabolic disorders. Nat Rev Endocrinol. 2011;7(2):77-88
  6.  Michaud JL, Héon E, Guilbert F, et al. Natural history of Alström syndrome in early childhood: onset with dilated cardiomyopathy. J Pediatr. 1996;128(2):225-229
  7.  Marshall JD, Bronson RT, Collin GB, et al. New Alström syndrome phenotypes based on the evaluation of 182 cases. Arch Intern Med. 2005;165(6):675-683
  8.  Marshall JD, Beck S, Maffei P, Naggert JK. Alström syndrome. Eur J Hum Genet. 2007;15(12):1193-1202
  9.  Marshall JD, Maffei P, Collin GB, Naggert JK. Alström syndrome: genetics and clinical overview. Curr Genomics. 2011;12(3):225-235
  10.  Romano S, Maffei P, Bettini V, et al. Alström syndrome is associated with short stature and reduced GH reserve. Clin Endocrinol (Oxf). 2013;79(4):529-536
  11.  Hoffman JD, Jacobson Z, Young TL, Marshall JD, Kaplan P. Familial variable expression of dilated cardiomyopathy in Alström syndrome: a report of four sibs. Am J Med Genet A. 2005;135(1):96-98

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Updated on November 30, 2020
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