- Clinical phenotype
- Key investigations
- Current research
- Further information and support
- Alström Syndrome: for patients
|Genes involved (OMIM No.)|
|Molecular diagnosis||Next generation sequencing|
|Therapies under research|
Alström syndrome (AS) is a rare multisystemic disease caused by pathogenic mutations in the ALMS1 gene, affecting the normal formation and functioning of the primary cilia of various cells in the body (ciliopathy). It is a progressive phenotype with onset usually in early childhood but there is great variability in terms of severity and its natural history. Intra- and interfamilial phenotypic heterogeneity are commonly observed, even among patients harbouring the same genotypes.
1) Progressive retinal dystrophy
The ocular phenotype is one of the earliest manifestations of AS, presenting as cone-rod dystrophy. Children typically present with nystagmus and profound photophobia, where onset can be as early as during infancy. As a result, some may be diagnosed as Leber Congenital Amaurosis instead. Photoreceptor function deteriorates progressively at a rapid rate throughout childhood which usually leads to blindness (Snellen visual acuity worse than 6/60) in the first or second decade of life. However, the age of onset, severity of symptoms and rate of progression are highly variable among patients.
Ocular findings are also variable, which may include:
- Posterior sub-capsular cataracts (relatively common)
- Vessel attenuation
- Optic disc pallor
- Retinal pigment epithelium (RPE) atrophy in the mid-periphery
- Macular RPE pigmentation/bull’s eye maculopathy
2) Sensorineural hearing loss
Bilateral progressive sensorineural hearing loss is a common feature and usually develops in the first decade of life. The rate of progression varies, with some experiencing moderate to severe hearing impairment in childhood or adolescence requiring hearing aids or cochlear implants.
3) Childhood-onset obesity and metabolic disorders
Infants usually have normal birthweight initially but the body mass index (BMI) rapidly increases in the first few years of life, with excess accumulation of subcutaneous and visceral adipose tissue primarily in the truncal region. Along with the lack of/limited physical activity due to dual sensory impairment, obesity in AS may also be caused by leptin resistance, an essential hormone that maintains body weight and energy homeostasis.[5,6]
Insulin resistance is usually present from early childhood, which may eventually progress to type 2 diabetes mellitus (T2DM) if there are no interventions. Patients tend to display acanthosis nigricans, a characteristic dermatological feature of insulin resistance. Interestingly, diabetic peripheral neuropathy is rare in AS, which is in stark contrast to patients with adolescent-onset T2DM without AS.
In addition, hyperlipidaemia and hypertriglyceridaemia are also commonly observed among AS patients.
4) Dilated cardiomyopathy
In two-thirds of AS patients, dilated cardiomyopathy (DCM) and congestive cardiac failure (CCF) can occur at some stage during their lives, which lead to significant morbidity and mortality. Patients can be divided broadly into two groups:
- Infant onset: DCM and CHF during infancy (as early as 1 week old) with apparent recovery of cardiac function after medical treatment, followed by sudden recurrence in adolescence/adulthood with poor prognosis
- Adolescent/adult-onset: No cardiac history during infancy but subsequently develop DCM during adolescence/adulthood, which appears to be due to a fibrotic process leading to restrictive impairment of both ventricles; usually associated with a poor clinical prognosis
5) Genitourinary disease and renal failure
AS patients may have various genitourinary and renal abnormalities:
- Recurrent urinary tract infections (common)
- Detrusor instability
- Vesicoureteral reflux
- Urethral stenosis
- Progressive renal impairment due to glomerular and interstitial fibrosis leading to end stage renal disease (as early as mid to late teens)
- Hypertension due to renal failure
The available evidence so far suggest that glomerular function deterioration is a primary manifestation of AS rather than secondary to T2DM, hypertension or cardiomyopathy.[7,10]
6) Liver dysfunction
Hepatic disease is variable, ranging from elevated serum transaminase levels to non-alcoholic fatty liver disease (NAFLD) and fibrosis. Hepatosplenomegaly may be observed. Extensive fibrosis, cirrhosis, portal hypertension, oesophageal varices and hepatic encephalopathy have been reported in end-stage liver disease.
7) Pulmonary dysfunction
Patients are frequently affected by respiratory tract infections from early childhood. Other pulmonary abnormalities include:
- Chronic bronchitis
- Chronic sinusitis
- Chronic obstructive pulmonary disease (COPD)
- Acute respiratory distress syndrome (ARDS)
- Pulmonary fibrosis
1) Endocrine disturbances
Apart from the aforementioned metabolic disorders, patients may also be affected by:
- Short stature during adulthood possibly due to abnormalities of the insulin-like growth factors (IGFs) system, growth hormone deficiency and advanced skeletal maturity leading to early epiphyseal fusion (height above the 50th percentile before puberty)[7,11,12]
- Hypogonadrotrophic hypogonadism (males and females) leading to infertility
2) Developmental delays
Early onset of dual sensory deficits can lead to delays in reaching developmental milestones including intellectual development, gross and fine motor skills.
The ALMS1 gene encodes for the centrosome and basal body associated protein (ALMS1). It is expressed ubiquitously throughout the body and is localised to the centrosomes and the base of primary cilia. While the exact function of the protein remains to be elucidated, it is thought to be involved in ciliogenesis and maintenance, cytoskeletal organisation and intracellular protein trafficking. ALMS1 has also been shown to be involved in the trafficking of the GLUT4 insulin receptor to the plasma membrane, adipogenesis and regulation of pancreatic beta cell mass.
1) Fundus autofluorescence imaging (FAF)
FAF is a sensitive modality to assess the state of the RPE and the extent of retinal degeneration. Areas of RPE atrophy will appear hypoautofluorescent.
2) Optical coherence tomography (OCT)
OCT scans tend to show progressive outer retinal thinning and attenuation, with more severe changes seen outside the fovea reported in a case series. 
In full-field electroretinogram (ERG), the dark-adapted stimuli (DA 0.01, DA 3 and DA 10 flashes) predominantly measures rod function. The DA 0.01 dim flash elicits a rod-specific response while the stronger DA 3 and DA 10 flashes have some cone contribution. Cone function is selectively assessed with light-adapted stimuli (LA 3 flash and 30 Hz flicker).
Diminished cone responses and subnormal rod responses (cone-rod dystrophy) can be observed in the earliest stages of AS. Both rod and cone responses gradually diminish over time, becoming unrecordable in the late stages of the disease.
Pattern ERG is difficult to perform in young children and it is expected to be severely reduced or extinguished.
Patients are often seen in the eye clinic initially as the ocular phenotype is one of the earliest manifestations. If a child is suspected of having AS, he/she should be referred to a paediatrician, who can then co-ordinate onward referrals to other relevant specialists for further assessment and investigations. The assessments may include but not limited to:
- General physical examination including assessment of height, weight (BMI), head circumference and plotting of growth chart
- Blood tests (haematology and biochemistry profiles including renal and liver function, plasma glucose level, bone chemistry, cholesterol, triglycerides and other endocrine bloods if indicated)
- Cardiac assessment (echocardiogram and electrocardiogram)
- Renal assessment (renal ultrasound)
- Respiratory assessment (if indicated)
- Dietetic input
Clinical diagnosis of AS is based on the cardinal features that are present throughout infancy, childhood and young adulthood. The accuracy of clinical diagnosis is low before age of five years, especially if infant-onset cardiomyopathy is absent. A list of diagnostic criteria based on age has been proposed to aid this process. 
However, given the similarity of features with Bardet-Biedl syndrome and the intra- and inter-familial phenotypic heterogeneity observed among AS patients, genetic testing is needed to confirm the diagnosis.
This can be achieved through a variety of next generation sequencing (NGS) methods:
- Targeted gene panels (Retinal)
- Whole exome sequencing (WES)
- Whole genome sequencing (WGS)
- Genomics England PanelApp for inherited retinal dystrophy
- Clinical genetic testing: for professionals
There is currently no treatment for AS and patients are usually managed symptomatically in a multidisciplinary setting. 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 who are interested in being referred to 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.
Management is mainly supportive which include:
- Correcting any refractive errors
- Referral to low vision services
- Tinted glasses/contact lens for photophobia
- Directing patients to supporting organisations
- Encourage the use of assistive technology that may improve quality of life
- Encourage a healthy diet consisting of fresh fruit and green leafy vegetables
- Blue light screen protectors on mobile devices or computer screens*
- Monitoring and treating associated complications such as cataract
*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.
1) Hearing loss
Early audiological assessment in children is advised to maintain educational and social development. Hearing aids or in severe cases, cochlear implants can help in alleviating this issue. Children with AS are also prone to recurrent otitis media. This can be addressed with myringotomy and tympanostomy tube insertion.
Weight management is a pressing issue for AS patients. Lifestyle modifications such as dieting and exercise are first-line treatment options. Low carbohydrate intake is advised. Dietician input is crucial so that dietary plans can be tailored to each individual’s needs.
3) Type 2 diabetes mellitus and dyslipidaemia
T2DM is usually managed based on standard protocols. Lifestyle modifications are usually trialled first before progressing to medications. Long-term statin therapy is indicated in milder dyslipidaemia but in cases with severe hypertriglyceridaemia (>20 mmol/L), treatment with nicotinic acid derivatives should be considered instead.
4) Cardiomyopathy and congestive cardiac failure
Treatment involves standard CCF therapies such as angiotensin converting enzyme (ACE) inhibitors, beta-blockers, aldosterone antagonists and furosemide. Clinicians should be aware that AS patients can become hypoxic and deteriorate rapidly during intercurrent illness and surgery. Oxygen saturation should be monitored routinely during any inpatient hospital stay.
5) Renal dysfunction
Regular monitoring of renal function and appropriate control of hypertension are advised. ACE inhibitors is recommended if proteinuria is present. Renal transplantations have been successful in a number of patients but surgery may be complicated by other co-morbidities.
6) Developmental impairment and intellectual disability
Visual impairment has 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. In addition, occupational therapists and physiotherapists may be involved as well for rehabilitation and mobility training.
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 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.
Family management and counselling
AS is inherited in an autosomal recessive manner. Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.
Emotional and social support
Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients and their parents in clinic. They provide emotional and practical support to help patients and parents deal with the diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.
Referral to a specialist centre
In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research.
Current research in AS is mainly focused on understanding the exact function(s) of the ALMS1 gene and how the associated mutations lead to the features seen in AS. These are achieved through stem cell and clinical studies of patients registered in the Alström Syndrome UK and Euro-WABB (Wolfram, Alström, Bardet-Biedl) databases. The main goals 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 (NCT 02739217). Pre-clinical data have shown that PBI-4050 is able to reduce fibrosis in the heart, lung, liver and kidneys while also reducing insulin resistance and normalising hyperglycaemia.[17-21] These observations have been confirmed in two open label phase 2 studies in patients affected by T2DM and idiopathic pulmonary fibrosis. Preliminary findings from the AS trial (at 48 weeks) have shown that PBI-4050 is safe and well-tolerated, with reduction in liver stiffness and normalisation of liver enzymes. The study duration has since been extended to 96 weeks (NCT 03184584) or until regulatory approval, whichever occurs first.
- Research Opportunities at Moorfields Eye Hospital UK
- Searching for current clinical research or trials
- Retina UK
- Alström Syndrome UK
- Alström Syndrome International
- Royal National Institute of Blind People (RNIB)
- Guide Dogs for the Blind Association
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- Zhou Y, Rui L. Leptin signaling and leptin resistance. Frontiers of medicine. 2013;7(2):207-222
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- Paisey RB, Paisey RM, Thomson MP, et al. Protection from clinical peripheral sensory neuropathy in Alström syndrome in contrast to early-onset type 2 diabetes. Diabetes Care. Mar 2009;32(3):462-4
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- Maffei P, Boschetti M, Marshall JD, et al. Characterization of the IGF system in 15 patients with Alström syndrome. Clin Endocrinol (Oxf). Feb 2007;66(2):269-75
- Mihai CM, Catrinoiu D, Toringhibel M, Stoicescu RM, Ticuta NP, Anca H. Impaired IGF1-GH axis and new therapeutic options in Alström Syndrome patients: a case series. Cases J. Jan 7 2009;2(1):19
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- Poli L, Arroyo G, Garofalo M, et al. Kidney Transplantation in Alström Syndrome: Case Report. Transplant Proc. May 2017;49(4):733-735
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- Tremblay M, Grouix B, Sarra-Bournet F, Felton A, Laurin P, Gagnon L. PBI-4050, A Novel First-In-Class Anti-Fibrotic Compound, Inhibits CTGF And Collagen I Production In Human Alveolar Epithelial Cells And Fibroblasts, And Reduces Lung Fibrosis In The Bleomycin-Induced Lung Fibrosis Model. A61 LUNG FIBROSIS: ANIMAL MODELS II. A1998-A1998
- Gagnon L, Leduc M, Grouix B, et al. SP102ORAL TREATMENT WITH PBI-4050 REDUCES KIDNEY FIBROSIS. Nephrology Dialysis Transplantation. 2015;30(suppl_3):iii411-iii412
- Simard J-C, Cloutier M-P, Laverdure A, et al. PBI-4050 Improves Metabolic Regulation and Diabetic Nephropathy through Reduction of ER Stress, Pro-Inflammatory/Fibrotic Markers, Galectin-3 Expression, and Inflammatory Cell Infiltration in ob/ob Mouse Model. Diabetes. 2018;67(Supplement 1):503-P
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