Alström syndrome

Alström syndrome (AS) is a rare (1 per million OMIM 203800) autosomal recessive condition characterised by childhood onset retinal dystrophy, neuronal hearing loss, obesity and insulin resistance. The original phenotype was described by C H Alström in 1959 from clinical observations of first one case and then two cousins in whom he noted preservation of intellect as well as the dual Carl Henry Alström 1907 to 1993
Carl Henry Alström 1907 to 1993
sensory loss and obesity.[1] The phenotype has subsequently been shown to include acanthosis nigricans, cardiomyopathy, type 2 diabetes, renal and hepatic dysfunction, smooth muscle disorders and increased vascular risk. The ALMS1 Gene has been identified and the ALMS protein localised to the centrosome linking it to cilia in all cells. This has led to the inclusion of AS in the recently discovered group of conditions known as ciliopathies, which include Bardet Beidl syndrome, primary ciliary dyskinesia, polycystic kidney disease, Joubert and Usher syndromes. AS is thus characterised by dual sensory loss, severe insulin resistance, widespread major organ fibrosis and a cluster of potent causes for atherosclerosis including insulin resistance often but not invariably progressing to type 2 diabetes. The dyslipidaemia is characteristic of post receptor insulin resistance with low serum HDL-cholesterol and hypertriglyceridaemia often severe enough to cause pancreatitis.

Genetics

The ALMS1 gene was co-discovered in 2002 [2][3], and the ALMS protein localised to the centrosome in 2006 [4]. The very large size of the gene and protein, and multi-organ involvement make it unlikely that direct gene therapy or protein replacement will be feasible.

Clinical history

- Infancy and childhood

Dark glasses provide protection from profound photophobia (Thank you to patient & family for giving permission to use this photo).
Dark glasses provide protection from profound photophobia (Thank you to patient & family for giving permission to use this photo).
Most cases present with nystagmus and pronounced photophobia in the first 6 months of life, often when fixation develops at 7-8 weeks. In approximately 40%, sudden collapse occurs between 6 and 12 weeks of age due to dilated cardiomyopathy. Recovery is usual if the condition is recognised and treated. Recurrence of cardiac dysfunction in adolescence is well described. Visual loss is progressive throughout the first three decades of life[5]. Sensorineural hearing loss is frequently noted during childhood with slow progression over a period of decades[6]. Many parents describe hyperphagia and an absence of satiety after meals. Observational studies suggest pronounced subcutaneous fat is present in contrast to insulin resistant syndromes associated with lipodystrophy. Visceral fat accumulation also occurs as shown on cross-sectional imaging [7][8].

Developmental milestones are usually normal, though the sensory impairment, severe hypoxia occurring during infant cardiomyopathy and other clinical features of the condition can result in educational challenge. The author’s experience from reviews of over 100 families in the national specialist commissioned clinics in England and Alström International meetings in the USA has highlighted impressive achievements amongst subjects with the syndrome, including education to degree level, memorising a small company telephone directory as telephonist, success in national chess championships, leadership on committees, the legal profession and many sporting activities.

Adolescence and early adult life

In the second or third decades of life recurrence of cardiomyopathy[9], development of diabetes, dyslipidaemia, hepatic or renal impairment often brings the young person with Alström syndrome to medical attention[10][11]. Although these features can occur simultaneously, the fibrotic processes are independent of diabetes as such. Death from severe cardiomyopathy, hepatic cirrhosis and progression to end stage renal failure can occur even when glucose tolerance has remained normal. So far neither genotype-phenotype interaction nor a modifier gene has been found which might explain the wide variation in severity of these complications. The development of multiple co-morbidities, is coupled with progressive loss of sight can unsurprisingly give rise to severe emotional distress. Emotional, psychological and practical support for families at this time is crucial.

Premature deaths from infantile cardiomyopathy, adolescent cardiomyopathy, hepatic cirrhosis and pulmonary infections have resulted in a median life expectancy of 21 years. However a substantial minority of patients now remain alive and well in the fourth and fifth and even sixth decades of life. [12]

Treatment

- Psychosocial needs

From diagnosis all active family members should be involved in full discussion of the implications of the syndrome as appropriate for the age of the child. Whether mainstream or special schooling for the blind is chosen a care plan including nutrition, access to exercise and integration in the community is the ideal. The Alström Syndrome UK support group has been an effective agency in this work.

- Visual impairment

No known treatments are available to alter the progressive visual loss caused by the severe cone rod dystrophy. The most distressing early symptom often evident in the first 6 months of life is photophobia, this is helped by use of dark glasses. Braille and computer speech synthesisers have been enormously helpful to many Alström young people and both should be discussed and introduced as promptly as is feasible. Mobility can be greatly improved by proper training in the use of a white stick, help of a "buddy" and by a guide dog.

- Deafness

The onset and extent of sensori-neural deafness is much more variable than the blindness. Digital hearing aids should be introduced in good time to enhance learning and social interaction. Cochlear implants have been successful.

- Cardiomyopathy

In infancy prompt recognition and treatment of infant cardiomyopathy is crucial. Cardiomyopathy develops in 25% in adolescence sometimes in the context of previous infant cardiac failure but also de novo. Standard heart failure treatments are successful for long periods. More studies are required to define the key indications and optimum timing of cardiac transplantation in the syndrome.[13]

- Metabolism

Reduced calorie intake (restricting carbohydrate to 100grams daily) and exercise are often sufficient to minimise glucose intolerance in the first two decades. In diabetes Metformin is effective, most usefully followed by the addition of incretin analogues if required. A minority require the addition of insulin to control osmotic symptoms in the third decade but earlier if obesity is severe. [14][15][16]Mild hypertriglyceridaemia (2 to 5 mmol/l) is an almost invariable finding, in some levels persist at >20 mmol/l requiring treatment to prevent pancreatitis.[17]

- Atherosclerosis

Risk factors for atheroma will have been in present for over 20 years by the time that an Alström person has reached 25 years of age. Statin therapy is usually introduced in adolescence. Coronary artery disease has been described in the syndrome.[18]

- Renal failure

A growing number of Alström patients have been offered haemodialysis for up to 3 years successfully and a number have had successful live related donor or cadaveric renal transplantation.

- Gastro-oesophageal disorders

Reflux oesophagitis is frequent and usually responds to protein pump inhibitors in conventional doses. Caecal volvulus has also been described suggestive of a generalised intestinal smooth muscle dysfunction.[19]

- Infection

Early intensive antibiotic treatment is indicated for respiratory tract infections. Planned post-operative ventilation has proven to be successful in pre-empting surgery associated hypostatic pneumonia. Annual influenza vaccine and 5 yearly pneumococcal vaccinations are strongly recommended.

- Musculoskeletal

The most notable change is kyphoscoliosis occurring in adolescence in both sexes in 20% of subjects. Corrective surgery has been undertaken in severe cases.

Summary

Alström friends and families at the end of 230 mile cycle ride
Alström friends and families at the end of 230 mile cycle ride
Alström syndrome is a rare and challenging condition with dual sensory loss, metabolic dysfunction and major organ fibrosis. However social and educational support and conventional surgical and medical therapies can vastly improve quality and length of life. Two comments from friends with Alström syndrome stand out-“Alström syndrome is a diagnosis not a career move” and “Those of us with Alström syndrome may not live very long lives but we all accomplish a lot in our lives”.

References

  1. ^ Alstrom CH, Hallgren B, Nilsson LB, Asander H. Retinal degeneration combined with obesity, diabetes mellitus and neurogenous deafness: a specific syndrome (not hitherto described) distinct from the Laurence-Moon-Bardet-Biedl syndrome: a clinical, endocrinological and genetic examination based on a large pedigree. Acta Psychiatr. Neurol. Scand. Suppl. 1959;129:1–35.

  2. ^ Collin GB, Marshall JD, Ikeda A, So WV, Russell-Eggitt I, Maffei P, et al. Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alström syndrome. Nat. Genet. 2002;31:74–8.

  3. ^ Hearn T, Renforth GL, Spalluto C, Hanley NA, Piper K, Brickwood S, et al. Mutation of ALMS1, a large gene with a tandem repeat encoding 47 amino acids, causes Alström syndrome. Nat. Genet. 2002;31:79–83.

  4. ^ Knorz VJ, Spalluto C, Lessard M, Purvis TL, Adigun FF, Collin GB, et al. Centriolar association of ALMS1 and likely centrosomal functions of the ALMS motif-containing proteins C10orf90 and KIAA1731. Mol. Biol. Cell. 2010;21:3617–29.

  5. ^ Marshall JD, Bronson RT, Collin GB, Nordstrom AD, Maffei P, Paisey RB, et al. New Alström syndrome phenotypes based on the evaluation of 182 cases. Arch. Intern. Med. 2005;165:675–83.

  6. ^ Amy Farmer SA. EURO-WABB: an EU rare diseases registry for Wolfram syndrome, Alstrom syndrome and Bardet-Biedl syndrome. BMC Pediatr. 2013;13:130.

  7. ^ Minton JAL, Owen KR, Ricketts CJ, Crabtree N, Shaikh G, Ehtisham S, et al. Syndromic obesity and diabetes: changes in body composition with age and mutation analysis of ALMS1 in 12 United Kingdom kindreds with Alstrom syndrome. J. Clin. Endocrinol. Metab. 2006;91:3110–6.

  8. ^ Paisey RB. New insights and therapies for the metabolic consequences of Alström syndrome. Curr. Opin. Lipidol. 2009;20:315–20.

  9. ^ Russell-Eggitt IM, Clayton PT, Coffey R, Kriss A, Taylor DS, Taylor JF. Alström syndrome. Report of 22 cases and literature review. Ophthalmology. 1998;105:1274–80.

  10. ^ Connolly MB, Jan JE, Couch RM, Wong LT, Dimmick JE, Rigg JM. Hepatic dysfunction in Alström disease. Am. J. Med. Genet. 1991;40:421–4.

  11. ^ Paisey RB, Carey CM, Bower L, Marshall J, Taylor P, Maffei P, et al. Hypertriglyceridaemia in Alström’s syndrome: causes and associations in 37 cases. Clin. Endocrinol. (Oxf.). 2004;60:228–31.

  12. ^ Paisey R, Barrett T, Carey C, Hiwot T, Cramb R, White A, et al. Rare disorders presenting in the diabetic clinic: an example using audit of the NSCT adult Alström clinics. Pract. Diabetes. 2011;28:340–3.

  13. ^ Hitz M-P, Bertram H, Köditz H, Görler H, Happel CM, Wessel A, et al. Levosimendan for bridging in a pediatric patient with Alström syndrome awaiting heart-lung transplantation. Clin. Res. Cardiol. Off. J. Ger. Card. Soc. 2008;97:846–8.

  14. ^ Bettini V, Maffei P, Pagano C, Romano S, Milan G, Favaretto F, et al. The progression from obesity to type 2 diabetes in Alström syndrome. Pediatr. Diabetes. 2012;13:59–67.

  15. ^ Mokashi A, Cummings EA. Presentation and course of diabetes in children and adolescents with Alstrom syndrome. Pediatr. Diabetes. 2011;12:270–5.

  16. ^ Paisey RB, Geberhiwot T, Waterson M, Cramb R, Steeds R, Williams K, et al. Modification of severe insulin resistant diabetes in response to lifestyle changes in Alström syndrome. Eur. J. Med. Genet. 2014;57:71–5.

  17. ^ Wu W-C, Chen S-C, Dia C-Y, Yu M-L, Hsieh M-Y, Lin Z-Y, et al. Alström syndrome with acute pancreatitis: a case report. Kaohsiung J. Med. Sci. 2003;19:358–61.

  18. ^ Jatti K, Paisey R, More R. Coronary artery disease in Alström syndrome. Eur. J. Hum. Genet. EJHG. 2012;20:117–8.

  19. ^ Khoo EYH, Risley J, Zaitoun AM, El-Sheikh M, Paisey RB, Acheson AG, et al. Alström syndrome and cecal volvulus in 2 siblings. Am. J. Med. Sci. 2009;337:383–5.

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