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Alström syndrome: for patients

Overview

Alström syndrome (AS) is a rare condition affecting approximately 1 in every 1,000,000 individuals.[1] It is a condition that affects multiple organ systems in the body due to mutations in the ALMS1 gene. The mutations cause malfunctioning of thin hair-like projections on the surface of many cell types in the body called the primary cilium (plural: cilia). They act like antennae that allow cells to communicate with each other and are essential to the normal functioning of multiple organs such as the eyes, heart, lungs, kidneys, liver and the nervous system among others.

The main features of AS include progressive sight loss from cone-rod dystrophy, dilated cardiomyopathy (weakening of the heart muscles), hearing loss, childhood-onset obesity, diabetes, kidney failure, liver dysfunction and breathing problems. Additional symptoms include hormonal disturbances leading to growth restriction and developmental delays. Among these features, vision and heart problems are the earliest manifestations, which may be present as early as within the first months of life whereas the other symptoms usually occur later. It is important to note that not all children with AS have all of these features, and they often vary in severity, even among members within the same family.

There is no effective cure for AS currently, however supportive treatment is available to alleviate the associated symptoms and provide a better quality of life.

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The condition

Symptoms

1) Progressive visual loss

Children with AS are usually affected by cone-rod dystrophy (CORD). This is usually one of the earliest signs of AS. Parents may notice that their child experiences significant light sensitivity (photophobia) and the eyes “wobble” involuntarily (nystagmus). In cone-rod dystrophy, the cone photoreceptors, and to a lesser extent the rods, undergo progressive degeneration, which crucially lead to decreased visual sharpness (visual acuity) and problems recognising colours. As a result, children may experience increasing difficulties in tasks requiring good central vision such as recognising faces, reading print and watching TV from a young age. Overtime, they may also experience difficulties seeing in dim light or at night (night blindness) and seeing with their peripheral vision. Visual function tends to deteriorate rapidly among patients, and most are certified blind by 16 years old.[2] However, the age of onset, severity of symptoms and the rate of visual deterioration are highly variable among individuals.

Nystagmus

In addition to cone-rod dystrophy, children affected by AS may also have early cataract formation, which can cause further deterioration in visual quality.

2) Dilated cardiomyopathy (DCM)

Two-thirds of patients with AS can develop dilated cardiomyopathy (DCM),[3] a heart condition where one of the pumping chambers (ventricle) is abnormally enlarged and the heart muscle becomes weaker, subsequently leading to heart failure. As a result, the heart cannot efficiently pump out adequate amount of blood that is required to maintain normal bodily functions. Children with heart failure may develop shortness of breath (dyspnoea), labored and rapid breathing (tachypnoea), wheezing and coughing

DCM and heart failure may occur in infancy (birth-16 months of age) or in adolescence/early adulthood.[3] In the first group, cardiac function recovers in the majority of the affected infants but tends to recur in adolescence or adulthood.[3] In those with adolescent or adult-onset DCM, there is usually no history of heart issues during infancy. The underlying pathology is postulated to be due to progressive scarring of the heart muscles.[4]

[Insert illustration of the heart showcasing the characteristics of dilated cardiomyopathy]

The heart is a muscle divided into 4 chambers. In dilated cardiomyopathy, all the heart chambers are enlarged due to stretching of the muscle fibres, causing it to be less effective at pumping blood to the rest of the body.
Dilated cardiomyopathy

Credit: Blausen.com staff (2014). ‘Medical gallery of Blausen Medical 2014’. WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436; licensed under CC-BY 3.0

3) Hearing impairment

70% of AS patients develop a type of progressive hearing loss that involves the inner ear, called sensorineural hearing loss during the first decade of life.[5] Similar to the inability of the retinal cells to transmit visual signals to the brain in cone-rod dystrophy, in sensorineural hearing loss the auditory nerves are unable to transmit sensory input to the brain for further processing. Some patients tend to have the middle part of the ear (behind the eardrum) filled with thick fluid, a condition called “glue ear” that further deteriorates hearing. The middle ear can also be affected by chronic infection or inflammation (otitis media).

4) Childhood-onset obesity and metabolic syndrome  

Despite having a normal birth weight, children with AS can rapidly become obese in the first few years of life, with the body mass index (BMI) usually exceeding 25 kg/m2. The excess fat tissues tend to accumulate primarily in the abdomen and chest, instead of other areas in the body (truncal obesity). As a result of the increased weight, children are at risk of developing insulin resistance, which can proceed to type 2 diabetes mellitus if lifestyle changes such as exercise and diet control are not implemented.

Insulin is a hormone secreted by the pancreas that allows glucose, the main energy source of the body, to enter into cells to be metabolised. Insulin resistance is a condition whereby muscle, fat and liver cells respond weakly to insulin and the uptake of blood glucose is subsequently impeded. Hence, the pancreas produces more insulin (hyperinsulinemia) to transfer glucose into cells to be used as energy sources and to keep glucose levels in the blood within a healthy range. Type 2 diabetes is established when the pancreas fails to keep up the insulin production or the body becomes resistant to its effects; thus blood sugar eventually rises (hyperglycemia).

In addition, individuals affected by AS also tend to have increased cholesterol levels in the body. As a result, individuals with AS are at increased risk of getting coronary heart disease (or ischaemic heart disease) due to excessive build-up of cholesterol-containing plaques, which narrows the arteries of the heart and thus limiting its blood supply.

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5) Endocrine abnormalities

The endocrine system is a series of glands in the body that produce and secrete hormones to regulate various bodily functions. A range of endocrine abnormalities are associated with AS:

  • Hypogonadism—Reduced production of male and female sex hormones can result in delayed puberty and infertility issues. Some females may also develop polycystic ovarian syndrome
  • Short stature in adulthood despite having normal height during childhood due to growth hormone deficiency and advanced maturity of bone tissues
  • Reduced production of thyroid hormones (“under-active thyroid” or hypothyroidism) are reported in one-third of patients.[6] Symptoms include fatigue, weight gain and  cold intolerance

6) Urologic abnormalities and renal (kidney) disease

Around 50% of affected individuals will experience at least one urologic disorder.[5] Examples include:

  • Recurrent urinary infections
  • Difficulty in initiating urination
  • Inefficient co-ordination of the bladder and urethral muscles

Renal dysfunction starts at a young age and gradually progresses into advanced renal disease by mid or late- adolescence in approximately 60% of AS patients.[7] Excessive fluid retention as well as waste build-up in the body are the main complications. The clinical manifestations include:

  • Swelling of the feet and ankles
  • High blood pressure
  • Shortness of breath due to fluid accumulation in the lungs
  • Fatigue
  • Confusion
  • Itching
  • Increased susceptibility to infections

7) Hepatic (liver) dysfunction

Children with Alström syndrome can present with a wide spectrum of liver dysfunction ranging from asymptomatic (no symptoms) derangement of various liver enzymes to non-alcoholic fatty liver disease (NAFLD) and cirrhosis (scarring of the liver).

NAFLD describes the excessive storage of fat in the liver of patients who consume little or no alcohol. Some individuals progress to liver inflammation, cirrhosis and liver failure.

8) Respiratory/breathing problems

The spectrum of respiratory diseases in AS patients include:

9) Other features

Affected children with AS may additionally present with:

  • Kyphoscoliosis — Abnormal forward curvature of the spine with a simultaneous twist sideways. This spinal change can cause neck and back aches and reduced lung function by impeding chest expansion
  • Reflux oesophagitis — A condition associated with chest pain, heartburn and difficulty in swallowing due to the gastric acids leaking up into the oesophagus, the muscular tube that connects the mouth to the stomach
  • Developmental delays — Developmental milestones such as sitting, standing, and walking can be delayed by 1–2 years in approximately 20% of children, with concomitant defects in coordination, balance, and fine motor skills. Roughly 3 out of 10 children also have a learning disability[3]

The list of symptoms is not exhaustive. Please visit Alstrom Syndrome UK for more information.

Cause

Alström Syndrome is caused by mutations in the ALMS1 gene.[8,9] The gene carries information for the production of the ALMS1 protein, the function of which remains unclear. It is found in the primary cilia of multiple cell types in the body, which explains why so many organs are affected in Alström syndrome.

How is it diagnosed?

As the clinical features of Alström Syndrome are highly variable and certain symptoms only become apparent in later childhood, adolescence or even young adulthood, it can often be difficult to diagnose accurately before the age of five years.[10] Therefore, genetic testing should be performed to identify changes in the ALMS1 gene. Children suspected of AS usually undergo tests with multiple specialists. The tests include:

1) Eye examination

An ophthalmologist is often the first point of contact for many patients due to the early onset of visual symptoms. Patient are diagnosed with cone-rod dystrophy based on their presenting symptoms, clinical examination and performing an electro-diagnostic test of the retina called electroretinogram (ERG). The ERG is used to assess the overall function of the photoreceptor cells in the retina.

Often, children also undergo other more specialised tests so that the ophthalmologist can assess the retina in more detail and determine the level of visual function. These additional tests include:

  • Colour vision testing
  • Visual field testing for the detection of blind spots. Patients are asked to press a button when they detect flashing lights and a map of their visual field is created.
  • Optical coherence tomography (OCT), a camera that allows detailed visualisation of all the retinal layers and reveal abnormalities in the retinal structure if present.
  • Autofluorescence imaging (FAF) is another camera that can visualise and assess the health of the retina.

2) General medical assessment

Children with features suggestive of Alström Syndrome are referred to a paediatrician and other relevant specialists for further investigations. These may include:

  • General physical examination including assessment of height, weight (BMI), head circumference and overall development
  • Blood tests
  • Heart and lung function assessment
  • Audiometry to detect for signs of hearing loss
  • Ultrasound scan of the kidneys
  • Dietetic input

How is it inherited?

1) Autosomal recessive (AR) inheritance

Two faulty copies of the ALMS1 gene are required to have the condition. Both parents are usually unaffected carriers (only have one faulty copy of the gene) while the affected child inherits one faulty copy of the gene from each parent. This means that every newborn of the parents has the following risks regardless of gender:

  • 25% chance of being affected by AS
  • 25% chance of being unaffected and not a carrier
  • 50% chance of being a carrier with no symptoms
If the mother has 1 copy of the faulty gene in her X chromosome (a carrier) while the father is unaffected, there is 50% chance that a daughter is a carrier and a 50% chance that a son is affected by the condition.
Autosomal recessive inheritance

If your child is affected by AS, it is advisable to see a genetic counsellor to obtain more information and advice on inheritance and family planning options.

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Treatment

Is there any treatment?

There is currently no treatment available for the underlying genetic changes causing Alström syndrome. Patients are managed supportively in a multidisciplinary setting, focusing on alleviating the associated symptoms and optimising quality of life.

In the UK, children and adults affected by AS can be referred to two specialised multidisciplinary clinics in Birmingham (one each for children and adults), which is commission by NHS England. Patients or parents interested in getting seen in these clinics can get in touch with Alström Syndrome UK. In addition to helping co-ordinate the clinics, they also offer advice and support such as arranging overnight accommodation if needed.

1) Cone-rod dystrophy

Treatment is focused on alleviating visual symptoms and optimising remaining sight. These include:

  • Regular monitoring of visual function and prescribing glasses (if required)
  • Visual aids and assistive technology; Teaching of the Braille alphabet at an early age is advisable
  • Tinted glasses/contact lenses for light sensitivity
  • Blue light screen protectors on mobile devices or computer screens*
  • A healthy diet consisting of fresh fruit and green leafy vegetables

*Current available evidence shows that blue light emitted from screens do not damage the retina but it can disrupt our sleep cycle. The screen protectors are used as a precautionary measure.

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2) Cardiac disease

It can be difficult to prevent the onset of cardiomyopathy and heart failure in Alström Syndrome. However, the symptoms can be reduced with medications that can improve heart function. Some cardiologists may also suggest implanting a defibrillator to prevent the heart from suddenly stopping. As the severity of symptoms are highly variable among children with Alström Syndrome, you should discuss with your child’s cardiologist about the best option to manage his/her heart condition.   

3) Hearing loss

Hearing aids may help some patients while grommets are inserted for children with hearing loss due to recurrent otitis media (middle ear infection).[5]

4) Obesity

Lifestyle modifications such as dieting and exercise are first-line management options. Low carbohydrate intake is advised. Dietician input is crucial so that dietary plans can be tailored to each individual’s needs.

5) Type 2 diabetes mellitus and high cholesterol

Type 2 diabetes management primarily focuses on lifestyle modifications, and in cases where there is inadequate blood sugar control, medications such as tablets and occasionally insulin injections may be required to gain better control.

To lower the blood cholesterol levels, a combination of regular exercise, having a healthy diet and medications may be utilised.

6) Renal dysfunction

Regular monitoring of renal function and appropriate control of hypertension are advised. Depending on the severity of the kidney disease, medications, dialysis or a kidney transplant may be recommended. Kidney transplantations have been successful in a number of patients but surgery may be complicated by other issues associated with Alström Syndrome.[11] More information can be found on Kidney Care UK and Alström Syndrome UK.

5) Developmental delays and intellectual disability

Visual impairment can have a negative impact on a child’s early general development. Therefore, timely referral to practitioners familiar with developmental surveillance and intervention for children with visual impairment (VI), such as developmental paediatricians as well as a Qualified Teacher of children and young people with Visual Impairment (QTVI) is crucial to optimise their developmental potential. Speech therapy is crucial to ameliorate the ability of oral communication, given the severity of visual and hearing impairment.

The Developmental Journal for babies and young children with visual impairment (DJVI) is a structured early intervention programme designed to track developmental and vision progress in children from birth to three years of age. It is mainly used by qualified healthcare professionals working in services providing support to babies and young children with VI in conjunction with the child’s parents.

Children with VI may be referred to specialist services such as the developmental vision clinic in the Great Ormond Street Hospital for Children or other specialist developmental services for further management.

This is not an exhaustive list. Further information on the management of other manifestations of AS and surveillance can be obtained from Alström Syndrome UK.

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Current research in Alström Syndrome

Current research in Alström Syndrome is mainly focused on understanding the exact function(s) of the ALMS1 gene and how the associated mutations lead to the features seen in this condition.  To achieve this, experiments using stem cells and clinical studies of patients registered in the Alström Syndrome UK and Euro-WABB (Wolfram, Alström, Bardet-Biedl) databases are being conducted. The main objectives of these research programmes are so that more affected individuals are diagnosed sooner and to enable the development of therapeutic options.

One of the treatments that has progressed to clinical trial is a novel drug called PBI-4050. The safety and tolerability of this oral medication is being investigated in patients with AS. A phase 2 trial (NCT 02739217) has been completed and a phase 2/3 trial is underway (NCT 03184584). PBI-4050 is a drug with anti-inflammatory and anti-scarring (anti-fibrotic) action that has been shown to reduce scarring in the heart, lung, liver and kidneys, while also reducing insulin resistance and normalising blood glucose levels. Preliminary findings from the phase 2 trial have shown that PBI-4050 is safe and well-tolerated, with reduction in liver stiffness and normalisation of liver enzymes when participants have taken the medication for 48 weeks. Investigators are now looking if the safety findings are maintained when it is taken continuously for 96 weeks.

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Referral to a specialist centre

If you are based in the UK and would like to be seen in the nearest specialist centre for your eye condition, either to receive a more comprehensive genetic management or just to find out more about current research, you can approach your GP to make a referral or alternatively arrange for a private appointment. 

More information can be found in our “How to see a genetic eye specialist?” page.

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Further information and support

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References

  1.  Marshall JD, Maffei P, Collin GB, Naggert JK. Alström syndrome: genetics and clinical overview. Curr Genomics. May 2011;12(3):225-35. doi:10.2174/138920211795677912
  2.  Marshall JD, Beck S, Maffei P, Naggert JK. Alström syndrome. European Journal of Human Genetics. 2007;15(12):1193-1202
  3.  Marshall JD, Bronson RT, Collin GB, et al. New Alström syndrome phenotypes based on the evaluation of 182 cases. Arch Intern Med. Mar 28 2005;165(6):675-83. doi:10.1001/archinte.165.6.675
  4.  Loudon MA, Bellenger NG, Carey CM, Paisey RB. Cardiac magnetic resonance imaging in Alström syndrome. Orphanet J Rare Dis. Jun 10 2009;4:14. doi:10.1186/1750-1172-4-14
  5.  Paisey RB, Steeds R, Barrett T, et al. Alström Syndrome. 2003 Feb 7 [Updated 2019 Jun 13]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1267/
  6.  Han JC, Reyes-Capo DP, Liu CY, et al. Comprehensive Endocrine-Metabolic Evaluation of Patients With Alström Syndrome Compared With BMI-Matched Controls. J Clin Endocrinol Metab. Jul 1 2018;103(7):2707-2719. doi:10.1210/jc.2018-00496
  7.  Baig S, Paisey R, Dawson C, et al. Defining renal phenotype in Alström syndrome. Nephrol Dial Transplant. Jun 1 2020;35(6):994-1001. doi:10.1093/ndt/gfy293
  8.  Collin GB, Marshall JD, Ikeda A, et al. Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alström syndrome. Nat Genet. May 2002;31(1):74-8. doi:10.1038/ng867
  9.  Hearn T, Renforth GL, Spalluto C, et al. Mutation of ALMS1, a large gene with a tandem repeat encoding 47 amino acids, causes Alström syndrome. Nat Genet. May 2002;31(1):79-83. doi:10.1038/ng874
  10.  Paisey RB, Steeds R, Barrett T, Williams D, Geberhiwot T, Gunay-Aygun M. Alström Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews(®). University of Washington, Seattle Copyright © 1993-2020, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.; 1993
  11.  Poli L, Arroyo G, Garofalo M, et al. Kidney Transplantation in Alström Syndrome: Case Report. Transplant Proc. May 2017;49(4):733-735. doi:10.1016/j.transproceed.2017.02.018

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Updated on November 30, 2020
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