Alström Syndrome

Literature and regulatory information updated: 29 October 2026. Single-gene multisystem autosomal recessive ciliopathy (ALMS1; OMIM 203800; Orphanet ORPHA:64), with infant-onset cone-rod dystrophy, progressive sensorineural hearing loss, infantile and restrictive cardiomyopathy, obesity with extreme insulin resistance and progressive liver and kidney disease

0. Initial Reference Table

1. Introduction

Alström syndrome is a progressive multisystem genetic disease caused by biallelic variants in the ALMS1 gene and inherited in an autosomal recessive manner. The 2020 international consensus defines it by the association of visual and hearing impairment, cardiomyopathy, kidney dysfunction, extreme insulin resistance and their complications, with symptoms beginning in the first year of life and great variability in age at onset and severity, even between siblings [1, 7]. The feature that distinguishes it from almost all other obesity syndromes is the temporal sequence: the infant presents with nystagmus and photophobia, or with heart failure, long before there is obesity, diabetes or hearing loss, and the complete syndromic picture becomes recognisable only over the course of childhood and adolescence [1, 7].

The first description is owed to Carl-Henry Alström and colleagues, who in 1959 published, in a supplement of Acta Psychiatrica et Neurologica Scandinavica, the association of retinal degeneration, obesity, diabetes mellitus and "neurogenic" deafness in three cousins from a large pedigree, presenting it as a syndrome distinct from Laurence-Moon-Bardet-Biedl syndrome [7, 19]. The authors emphasised the absence of intellectual disability and polydactyly, and the different retinal lesion, with nystagmus and early loss of central vision, unlike the pigmentary retinopathies in which the peripheral field is lost first [2]. In 1973 Goldstein and Fialkow described three sisters, reviewed the known families and considered autosomal recessive inheritance indisputable; they added slowly progressive chronic nephropathy and acanthosis nigricans to the phenotype [2, 7].

The phenotype was gradually broadened by successive reports: late-onset dilated cardiomyopathy, at 36 and 37 years, with myocardial fibrosis, in two brothers described by Weinstein in 1969 and re-evaluated by Warren in 1987, liver disease in a Mennonite child from British Columbia (Connolly, 1991) and growth hormone deficiency (Alter and Moshang, 1993) [2]. In 1996 Michaud and colleagues showed that five of eight children had had dilated cardiomyopathy between 3 weeks and 4 months of life, a finding not previously recognised, and that photophobia and nystagmus appeared between 5 and 15 months [20]. The following year, Marshall and colleagues described a large Acadian family with eight patients descended from a common ancestral couple, which allowed the locus to be mapped [2, 21].

Genetic localisation was achieved by homozygosity mapping in this Acadian family, with a lod score of 3.84 in a 14.9 cM region at 2p14-p13 (Collin et al., 1997), refined to 2p13-p12 in an Algerian family (Macari et al., 1998) and confirmed in 12 additional families, with a multipoint lod score of 9.16 (Collin et al., 1999) [2]. In 2002 two groups identified the gene simultaneously: Collin and colleagues, by analysis of positional candidate genes in six families, and Hearn and colleagues, from a patient compound heterozygous for a maternal balanced reciprocal translocation t(2;11)(p13;q21), which disrupted the gene between exons 4 and 5, and a paternal frameshift variant [2, 22, 23]. ALMS1 was the first gene for a human autosomal recessive disease identified from a balanced reciprocal translocation [2].

The series of 182 patients published by Marshall and colleagues in 2005 established the frequencies and ages at onset of the manifestations that still serve as a reference today, and in 2007 age-stratified diagnostic criteria were proposed [11, 24]. The prospective cohorts of 38 patients from the United States National Institutes of Health (NIH) characterised the heart, kidney, hearing, respiratory system and metabolism in comparison with body mass index (BMI)-matched controls [25–29]. In 2020 the first international clinical management consensus was published, with 49 graded recommendations [7]. A year earlier, the French Haute Autorité de Santé had published the PNDS for the syndrome, prepared by the reference centre for rare diseases in ophthalmic genetics (CARGO, Strasbourg) within the SENSGENE filière, with the FIRENDO, CARDIOGEN and ORKID filières, based on the literature published up to June 2018 and the opinion of a multidisciplinary group, without formal grading of the recommendations [10].

The disease is classified as a non-motile ciliopathy, because the ALMS1 protein is located in the basal body of the primary cilium and is required for the formation and maintenance of cilia [1, 4]. The 2020 consensus itself keeps this classification under discussion among its research questions, because ALMS1 also has non-ciliary functions (actin organisation, endosomal trafficking, regulation of the cardiomyocyte cell cycle) [1, 7]. In the classification of cellular trafficking disorders, ALMS1 appears in the group of cytoskeletal genes, and Alström syndrome is listed among the genetic causes of cutaneous hyperpigmentation [30]. There are no formally classified clinical or genetic subtypes; a typical form and attenuated late-onset forms are described, whose real frequency is unknown [1, 31, 32]. Bardet-Biedl syndrome is the main differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1 The ALMS1 gene and protein

The ALMS1 gene is located at 2p13.1, spans about 224 kb and contains 23 coding exons [1, 7]. The full-length cDNA described in 2002 had 12,871 base pairs and a reading frame of 4169 amino acids, for a predicted protein of 461.2 kDa [4, 33]. The protein begins with a stretch of 17 consecutive glutamates, followed by a large domain of 34 imperfect repeats of 47 amino acids, a probable leucine zipper, histidine-rich and serine-rich regions and a conserved C-terminal domain, called the ALMS domain; unlike many centrosomal proteins, it has little capacity to form coiled-coil structures [4]. A splice variant that includes exon 2, with 42 additional residues, is rarely expressed [4].

ALMS1 is located at the proximal ends of the centrioles and in the basal bodies of primary cilia, and also at non-centrosomal sites [1, 4]. It participates in PCM1-dependent intracellular transport, is required for the localisation of NCAPD2/CNAP1 at the proximal ends of the centrioles and contributes to centriole cohesion: its depletion in human cells reduces CNAP1 at the centrosome, increases the distance between the centrioles and disturbs the trafficking of centriolar satellites [4, 6]. In mouse renal collecting duct cells, depletion of Alms1 produces short cilia, unable to increase calcium influx in response to mechanical stimulation, a defect corrected by expression of the N-terminal 1282 amino acids [4]. Expression is broad and context-dependent: it increases during terminal differentiation of neonatal cardiomyocytes and during formation of the primary cilium, and decreases when preadipocytes differentiate into mature adipocytes [1, 34].

2.2 Tissue mechanisms

The disease mechanism is loss of function of ALMS1 [1]. The multiplicity of the protein's functions helps to explain the extent of the phenotype. In the retina, the mouse model with disrupted Alms1 shows accumulation of vesicles in the photoreceptor inner segments and abnormal localisation of rhodopsin in the outer nuclear layer, pointing to a defect in transport through the connecting cilium; reduction of the photopic b-wave precedes photoreceptor degeneration [2]. In the cochlea, the defect lies in the outer hair cells and develops after birth, which explains why infants pass newborn hearing screening [1, 7].

In the infant heart, severe infantile cardiomyopathy has its own histological signature: autopsies show markedly increased mitotic activity in the cardiomyocytes, termed mitogenic cardiomyopathy, a consequence of failure of cell-cycle exit and terminal differentiation of perinatal cardiomyocytes [1, 35, 36]. In the juvenile and adult form, diffuse interstitial fibrosis and coarse replacement fibrosis predominate; patients' fibroblasts, even when not derived from a fibrotic lesion, increase collagen production and have a constitutively activated myofibroblast phenotype [7, 37]. The 2020 consensus leaves open whether multiorgan fibrosis results directly from ALMS1 dysfunction or from secondary metabolic changes [7]. The French PNDS lists, among the organs affected by progressive fibrosis, the heart, lungs, liver, kidneys, gonads and pancreas, and likewise leaves open whether it is primary or secondary [10].

In metabolism, ALMS1 is required for translocation of the glucose transporter GLUT4 to the plasma membrane in adipose tissue, through organisation of the actin cytoskeleton, for adipogenesis and for regulation of pancreatic beta-cell mass [1, 33, 34]. Patients' fibroblasts have normal insulin receptor binding and response, so insulin resistance is not a receptor defect [2]. In mouse models (ALMS1 GT/GT, fat Aussie foz/foz), hyperinsulinaemia is early and accompanied by beta-cell proliferation; hyperphagia precedes weight gain [7]. In zebrafish, loss of Alms1 decreases beta-cell production, and the cells are unable to expand under prolonged hyperglycaemia [7]. Ectopic fat deposition in the liver and possibly in muscle, preferentially subcutaneous accumulation, adipose tissue with a pro-inflammatory and fibrotic profile and leptin resistance complete the picture [7, 29, 38]. Collin and colleagues used the term "diabesity" to describe this joint susceptibility to obesity and diabetes due to alteration of a single gene [4].

In the kidney, the mouse with a protein truncated at amino acid 2130 develops dilated cortical tubules at 6 months and loses cilia in the proximal tubule with age, with foci of apoptosis and proliferation [2]. Mutant mice also have defective spermatogenesis; in the Alms1 S701X mouse model (published designation of the mouse allele, with no correspondence in the numbering of the human gene), sperm count and motility are about a quarter and a half of those of controls (29.03 vs 110.6 × 10⁶/mL; 34.77% vs 70.18%) [2, 39].

2.3 Variant spectrum and nomenclature

More than 200 pathogenic variants had been described by 2019 and 268 by 2020; 96% are nonsense or frameshift, predicted to result in a truncated or absent protein [1, 7, 40]. Splice variants, deletions of one or more exons, a 333 bp Alu Ya5 retrotransposon insertion in exon 16, a LINE-1 element insertion in exon 8 and a balanced translocation have also been described [1, 23, 32, 41, 42]. Exons 8 (6.1 kb, about 49% of the coding sequence), 10 (1.9 kb) and 16 (1.2 kb) concentrate 85–97% of the mutational load [1, 7]. In the series of 250 patients from 206 families of Marshall and colleagues (2007), there were 32 variants in exon 16, 19 in exon 10 and 17 in exon 8 [2]. Missense variants are rare: of the 24 recorded in the ALMS1 database in 2020, 11 (45.8%) were considered pathogenic, 4 (16.7%) likely pathogenic, 4 (16.7%) benign or likely benign and 5 (21%) of uncertain significance [7]. Given the clinical overlap with other ciliopathies, classifying an ALMS1 missense variant as pathogenic requires caution, and a patient with a mild or atypical phenotype and only missense variants should be studied with a ciliopathy panel [1].

Nomenclature requires attention. The MANE Select transcript is NM_001378454.1 (protein NP_001365383.1), with 4168 amino acids; the transcript used in most of the literature, NM_015120 (version 4, protein NP_055935.4, 4169 amino acids), has one extra codon in exon 1, in the glutamate stretch [4, 8, 33]. For variants located after exon 1 validated in VariantValidator, the c. position on MANE is three nucleotides lower and the amino acid position one unit lower than on NM_015120.4; some articles use earlier versions of NM_015120 whose numbering coincides with MANE [3, 8]. Table 2.1 shows recurrent variants or variants cited in this article, normalised in VariantValidator (GRCh38).

Table 2.1 — Normalised ALMS1 variants (VariantValidator, GRCh38)

Other historical variants recorded in OMIM are the 19 bp insertion in exon 16 in the Acadian family, with termination at codon 3530 and homozygosity in the five affected individuals studied, the nonsense substitution 8383C>T in a consanguineous Italian family, 8164C>T p.Arg2722Ter in three Turkish sisters and 10992G>A p.Trp3664Ter in compound heterozygosity with 10775delC, all in the old NM_015120 numbering [4]. The 2020 consensus mentions a recurrent insertion in French Acadians (c.10534_10535ins), without the full notation [7].

2.4 Inheritance, penetrance and expressivity

Inheritance is autosomal recessive; heterozygotes are asymptomatic [1, 7]. The sources consulted do not describe any other inheritance pattern for ALMS1. The consensus recommends considering de novo variants, rare in this gene, and confirming paternity when one of the variants is not found in the parents [7]. Penetrance of the retinal dystrophy is complete, but the expressivity of the remaining manifestations is highly variable, even between siblings with the same genotype: in the Acadian family, all presumably carriers of the same variant, four of eight had scoliosis, two had had infantile cardiomyopathy, two were hypothyroid and four had asthma [21]. Two young British men with the same variant c.10775delC had infantile cardiomyopathy in the first two months, but one had recurrence of the cardiomyopathy at 18 years without liver disease and the other severe liver failure at 20 years without cardiac recurrence, suggesting the action of genetic or environmental modifiers [4, 45, 46].

2.5 Genotype-phenotype correlations

The search for correlations is difficult because almost all variants are null and most patients are compound heterozygous for rare variants observed in few families [1, 40]. In the 2007 series, in a subgroup of 58 patients, exon 16 variants were associated with a more severe phenotype, with retinal degeneration before 1 year (p = 0.02), urological dysfunction (p = 0.02), dilated cardiomyopathy (p = 0.03) and diabetes (p = 0.03), and exon 8 variants with absent, mild or late kidney disease (p = 0.0007) [2]. In the Chinese cohort of 127 genetically confirmed patients (2025), truncating exon 16 variants were associated with infantile-onset cardiomyopathy (72.7% vs 30.4%; p < 0.05; echocardiography in 34 patients) [43]. Some mild forms, with slow visual loss, preserved or slightly affected hearing and mild metabolic complications, have been associated with variants located upstream of exon 7, without a general correlation having been demonstrated [31]; the first LINE-1 insertion described in exon 8 was associated with comparatively mild phenotypes in Taiwan [32]. The 2020 consensus suggests investigating "protein-phenotype" rather than genotype-phenotype correlations [7].

2.6 Allelic disorders and partial phenotypes

The 2019 GeneReviews did not recognise other phenotypes due to biallelic ALMS1 variants, while acknowledging that untargeted sequencing would come to identify partial forms [1]. The 2025 GeneReviews review on Leber congenital amaurosis and early-onset severe retinal dystrophy (LCA/EOSRD) includes ALMS1 in less than 1% of cases, with profound visual loss before 1 year, preservation of the outer retina until about 7 years and later progression to macular atrophy [9, 47]. A consanguineous Saudi family with a diagnosis of Leber congenital amaurosis was homozygous for the variant E3649X (historical numbering 10945G>T, = NM_015120.4:c.10945G>T p.(Glu3649Ter) = NM_001378454.1:c.10942G>T p.(Glu3648Ter)), with no hearing loss or obesity reported [4, 8]. In practice, a child labelled as having non-syndromic retinal dystrophy and biallelic variants in ALMS1 should be monitored as having Alström syndrome, with attention to the heart and metabolism [6, 9]. Two Japanese siblings with end-stage chronic kidney disease and retinal degeneration, interpreted as a partial form, have also been described [48].

3. Clinical Spectrum and System-Specific Manifestations

3.1 Frequencies and ages at onset

Table 3.1 summarises the series of 182 patients of Marshall and colleagues (2005), reproduced in GeneReviews, and the Chinese cohort of 127 genetically confirmed patients (2025). Because many manifestations are age-dependent, the percentages from a cross-sectional series underestimate lifetime risk; infantile cardiomyopathy is further underestimated because some infants die before diagnosis [1, 35].

Table 3.1 — Age at onset and frequency of manifestations

Sources: [1, 11, 43].

The 2007 review by Marshall and colleagues, written when about 450 cases were known, adds age-specific proportions not included in the table: about a third of patients were totally blind by 9 years, 50% by 12 and 90% by 16; about 10% progressed to profound deafness, requiring tactile communication; dilated cardiomyopathy affected about two thirds of patients, and more than 60% of these had heart failure in the first months of life, with improvement in function by 3 years in many; type 2 diabetes appeared from 4 years of age, with a median onset at 16; acanthosis nigricans was described in about a third, with or without diabetes; primary hypothyroidism in about 20% and subclinical hypothyroidism in about 30%; ovarian cysts in more than 20% of female patients; and arterial hypertension in about 40%, sometimes from 2 years of age [24]. In the same review, menarche occurred at a mean of 12 years, motor milestones (sitting, standing, walking) were delayed by 1–2 years with usually normal intelligence, and height, above the 50th centile in childhood with bone age advanced by 2–3 years, fell below the 50th centile between 14 and 16 years [24]. These values come from the accumulated experience of the Jackson Laboratory group, without an explicit denominator for each proportion, and predate systematic molecular confirmation [24].

3.2 Eye

Retinal dystrophy is present in all patients and is the first manifestation in most [1, 7]. At birth the infant appears normal; within a few weeks the parents notice nystagmus, photophobia and very poor eye contact, and the first ophthalmology visit usually takes place before 1 year [7]. Nystagmus is horizontal or pendular and strabismus is frequent, particularly exotropia [7]. Unlike other syndromic dystrophies, night blindness is not a frequent initial complaint: dysfunction begins in the cones, with photophobia and loss of central vision [2, 7]. The full-field electroretinogram (ERG), indispensable for diagnosis, is abnormal from birth, with an early and profound reduction of photopic responses and relative, transient preservation of scotopic responses; in Michaud's series, the first ERG showed severe cone dysfunction with mild (2/8) or no (6/8) rod involvement, and repeat ERGs between 9 and 22 years were extinguished [1, 20]. In a series of 19 children studied before diagnosis (2010–2014), the ERG was always recordable up to 7 years, often with a near-electronegative waveform, and unrecordable after that age [2, 49].

Refraction almost always shows hypermetropia, between +3.5 and +12 dioptres, with astigmatism; myopia is uncommon [7]. In the 19 children mentioned, hypermetropia was symmetrical, from 3.50 to 8.00 dioptres (median 5.5) [2, 49]. The fundus may be normal or near normal in the first decade, or show attenuated vessels, disc pallor and optic nerve drusen; later, hypopigmentation with visible choroidal vessels, macular pigmentary changes, bull's-eye maculopathy, waxy disc pallor, pigmentary mottling and crystalline deposits appear, and classic bone spicules are rare [1, 7, 49]. Visual acuity is very low from an early age (below 1/10, or 6/60 Snellen), progresses to residual light perception at around 10 years and, in most, to no light perception by the end of the second decade; legal blindness is usually reached in the first decade [1, 7]. The series of Nasser and colleagues places loss of light perception at 35 years, and a minority read large print in the third decade, which illustrates the variability [1, 50, 51]. Visual fields are usually unrecordable [7].

Optical coherence tomography (OCT) is difficult to obtain in children with nystagmus and photophobia. Early studies described macular thinning and persistence of the inner foveal layers (foveal immaturity); later studies showed mild macular changes in the first decade, followed by loss of photoreceptors and retinal pigment epithelium, with severity correlating with acuity; in adults, there is atrophy of the inner and outer layers and constant thinning of the outer nuclear and outer plexiform layers outside the fovea [1, 7, 52]. Fundus autofluorescence has rarely been described [7]. Posterior subcapsular cataracts are frequent, even without diabetes, and in Khan's series they appeared bilaterally in five children between 12 and 16 years [1, 49]. In Taiwan, eight patients had onset of visual changes between 0 and 8 years, and a late-onset form with little extraocular involvement was associated with a LINE-1 insertion [32].

3.3 Hearing and ear

Progressive bilateral sensorineural hearing loss is the second most frequent manifestation, with a lifetime risk close to 100% according to the consensus [7]. Most infants pass newborn hearing screening; hearing loss may be detected from 1 year, is diagnosed before 10 years in about 70% and the mean age at detection is 7 years [1, 7, 27]. It first affects the high frequencies and may progress to the moderately severe to severe range (40–70 dB) by the end of the first or second decade; in 33 patients from the NIH cohort, mean progression was 10–15 dB per decade [1, 27]. Absent otoacoustic emissions with intact speech discrimination and disproportionately normal auditory brainstem responses (ABR) localise the lesion to the outer hair cells of the cochlea, which makes these patients good candidates for hearing aids and cochlear implantation [1, 27]. Recurrent otitis media was universal (92%) in a cohort of 38 patients, with ventilation tubes in 50%, and more than 42% of children require myringotomy; adhesive otitis media adds a conductive component [1, 7, 28]. The French PNDS adds that otitis media with effusion and sinusitis in early childhood cause transient conductive hearing loss with few sequelae, that upper airway obstruction due to tonsillar or adenoidal hypertrophy is common and that sensorineural hearing loss, usually beginning in the first decade, is almost constant in adults and, in most, mild to moderate and compensable with hearing aids; it describes more severe forms, with a single cochlear implant in the literature it reviewed (up to 2018) [10]. This description of severity in adults is more benign than that of GeneReviews (section 7.17).

3.4 Heart

Almost two thirds of patients have congestive heart failure at some point in life, due to infantile, juvenile or adult cardiomyopathy [1, 7]. Infantile cardiomyopathy affects about 40% of infants, begins between 3 weeks and 4 months and is severe but transient; the first manifestation of the syndrome is nystagmus or this cardiomyopathy in 42% in the first 4 months [7, 11, 25]. Many infants with severe disease die within weeks or months, and autopsy reveals mitogenic cardiomyopathy; most survivors recover apparently completely by 2 years [1, 35, 36]. Among those who recover, about 1 in 5 has relapse or new heart failure later; among those who did not have infantile cardiomyopathy, the disease appears de novo in about 1 in 5 [7]. The Great Ormond Street series, with 22 children, had 18 with infantile cardiomyopathy, a number inflated by the ascertainment bias of a paediatric cardiology hospital [2]. The proportion of infantile cardiomyopathy has decreased over the series: the first described 81% and the more recent ones less than 62%, a fall that the French PNDS attributes to an initial selection bias, because the syndrome was more easily recognised when heart disease was present, and to subsequent improvement in the diagnosis of patients without cardiac involvement [10]. Because it is transient, the infant episode is often interpreted as viral myocarditis, and only the later appearance of visual impairment, hearing loss or obesity corrects the diagnosis [10]. In the Chinese cohort, ejection fraction improved with treatment in the 11 infants with infantile cardiomyopathy, but cardiac dilatation progressed [43]. In the series of 128 Chinese children with dilated cardiomyopathy studied by exome sequencing, five had ALMS1 variants [44].

About 20% develop, between adolescence and the end of the fourth decade, a progressive restrictive cardiomyopathy, characterised by diffuse interstitial and replacement myocardial fibrosis [1, 7]. The PNDS describes the late chronic form mainly as dilated cardiomyopathy, with restrictive forms possible but very rare, and minimal forms with preserved ejection fraction and moderate segmental wall motion abnormality on CMR or strain echocardiography [10]. In the largest autopsy series, there was myocardial fibrosis in 3 of 4 patients with cardiomyopathy and mild fibrosis in one patient without cardiovascular disease; cardiac magnetic resonance (CMR) showed mid-wall late enhancement of the left ventricle in 5 of 7 adults, and T1 mapping with extracellular volume quantification revealed diffuse interstitial fibrosis in most adults [7, 37, 53, 54]. Fibrosis is associated with subclinical left ventricular dysfunction, detectable by deformation analysis (global longitudinal strain), and strain echocardiography suggests some degree of fibrosis in almost all patients, including asymptomatic children [25, 37]. On CMR, adult volumes, mass and wall thickness are usually normal, and a frank reduction in ejection fraction is present in about a third [7]. The electrocardiogram is abnormal in a third, with axis deviation, left ventricular hypertrophy criteria, poor R-wave progression and non-specific ST changes [7]. The prognostic value of strain is not known [7].

Symptoms of heart failure (exercise intolerance, dyspnoea, orthopnoea, oedema, nocturnal cough) are poorly specific in this population, because of physical deconditioning, obesity and airway disease; physical signs are difficult to interpret, tachycardia is insensitive and blood pressure is often normal or treated [7]. Coronary artery disease is occult in a third of adults before 50 years, there is no symptomatic disease in children and it is rare in adults; post-mortem histology has documented asymptomatic infarcts [7, 55]. GeneReviews estimates flow-limiting coronary disease at about 10%, unrelated to fibrosis [1]. In a UK cohort, duration of diabetes was associated with aortic pulse wave velocity, which in turn predicted vascular events [56]. Arterial hypertension affects about 30%, often from childhood [1].

3.5 Obesity, growth and metabolism

Birth weight is normal; rapid weight gain begins between 2 and 36 months, with hyperphagia, and obesity is mainly truncal [1, 7]. According to the PNDS, excess weight sets in during the first year, with a BMI curve rising from the outset or an early adiposity rebound; altered satiety reported by parents is not constant, the reduced physical activity imposed by the sensory deficit contributes to weight gain, and fat is distributed in the subcutaneous and visceral compartments [10]. Hyperinsulinaemia may be secondary to obesity: in an infant from Taiwan, caloric restriction between 9 and 18 months reduced BMI from 25.0 to 20.7 with normal insulin and glucose levels [2]. Resting energy expenditure is similar to that of controls and the hyperphagia score is higher, so the main driver of obesity is intake; leptin is raised in proportion to weight, with signs of leptin resistance [7, 29]. Waist circumference, BMI and percentage fat mass tend to decrease in adulthood, and in some patients weight normalises after adolescence, while insulin resistance increases [1, 7, 57].

Insulin resistance is extreme and disproportionate to the degree of obesity [1, 7]. In a study of 38 NIH patients compared with 76 controls matched for age, sex and BMI, insulin resistance was more than five times higher and metabolic syndrome ten times more frequent; the 2020 consensus, citing the same study, describes resistance as more than ten times that of obese individuals with the same BMI [1, 7, 29]. Hyperinsulinaemia appears between 18 months and 4 years, accompanied by acanthosis nigricans, and type 2 diabetes may be diagnosed from 5 years of age, with a median age at onset of 16 years; 82% of patients over 16 years in the series of 182 were diabetic [7, 11]. The PNDS estimates that 70–80% of patients become diabetic by the end of the second decade (on average at 16 years) or in the third, and that lifestyle measures already instituted against obesity may delay this point [10]. Obesity modulates the incidence of diabetes: Italian children, who were leaner, had much less diabetes up to adolescence than Canadian children [1, 58, 59]. Diabetic peripheral neuropathy with risk of foot ulcer is rare or absent in Alström syndrome, unlike the 30% of severe neuropathy in adolescent-onset type 2 diabetes without the syndrome [1, 60]. Diabetic retinopathy has not been described, because early retinal degeneration precedes it, and it has never been identified as a cause of visual loss; diabetes does, on the other hand, require closer monitoring of blood pressure and kidney function, and, although hypoglycaemia and ketoacidosis are rare, the patient and family should know their signs [10]. Beta-cell failure contributes, alongside resistance, to glycaemic deterioration [33].

More than 90% of patients have hypertriglyceridaemia, usually moderate to severe (2–5 mmol/L, or 177–443 mg/dL, according to GeneReviews; 200–1000 mg/dL, or 2.26–11.29 mmol/L, according to the consensus), with low HDL cholesterol (< 1 mmol/L, 39 mg/dL), low apolipoprotein A1 and total cholesterol of 5–7 mmol/L; LDL is unexpectedly lower than in matched controls [1, 7, 29, 61]. Triglycerides may rise suddenly above 1000 mg/dL (11.3 mmol/L) or even 20 mmol/L (1770 mg/dL), precipitating potentially fatal acute pancreatitis [1, 7].

Growth is rapid in childhood, with height above the 50th centile before puberty and bone age advanced by 1–3 years; final stature is below the 25th centile in most, and about 98% of patients over 16 years are below the 5th centile [1, 7, 62]. Up to 50% of patients of normal weight have insufficient growth hormone (GH) reserve, and short stature is related to the IGF-1 axis or to pituitary fibrosis; body proportions are normal [7, 62]. The sella turcica may be totally or partially empty [7]. The PNDS recommends referral to paediatric endocrinology for any growth abnormality, defined as a deflection of the curve or a deviation of more than 1.5 standard deviations from target height, but advises against systematic investigation of the somatotropic axis, because obesity makes interpretation of GH stimulation tests unreliable [10].

3.6 Endocrine and reproductive system

Hypothyroidism affects 11–36% (20–30% according to GeneReviews), primary or secondary, and is autoimmune in about 20% of cases according to the consensus, whereas GeneReviews describes it as non-autoimmune and frequently secondary [1, 7, 29]. The PNDS describes it as mainly peripheral and, in a small number of cases, central, and recommends systematic screening and replacement [10]. One patient in a cohort of 38 had central adrenal insufficiency; central diabetes insipidus has been described in one case; prolactin is normal [2, 7].

In boys, puberty begins at the appropriate age, but in a cohort from the United Kingdom and Italy (28 boys and 41 men) maximum testicular volume was 9 ± 3 mL at 14–15 years and 95% (39/41) of adults had hypogonadism due to primary gonadal failure [39]. GeneReviews and the consensus describe combinations of hypogonadotropic and hypergonadotropic hypogonadism, with testicular fibrosis and obliterated seminiferous tubules, and delayed or arrested puberty in some; microphallus, cryptorchidism, hypospadias and gynaecomastia may be present [1, 7]. Male fertility has not been studied systematically and there are no reports of paternity in men with a molecular diagnosis [1, 7].

In girls and women, the external genitalia, uterus and fallopian tubes are normal; hirsutism, alopecia, oligomenorrhoea or amenorrhoea, polycystic ovaries, raised testosterone, poor breast development, precocious puberty and endometriosis have been described [1, 7]. Post-mortem histology showed extensive ovarian fibrosis without oocytes or follicles, which led the 2020 consensus to consider female fertility unlikely [7]. In 2025 the first live birth after in vitro fertilisation was published in a woman with a mild form and regular cycles (section 8), and as early as 1994 a family of four siblings with late onset and preserved fertility had been described, without molecular confirmation [2, 31]. The 2019 PNDS mentions, without identifying them, some pregnancies carried to term in women with the syndrome, attributes the hyperandrogenism with hirsutism, oligomenorrhoea and polycystic ovaries to insulin resistance and considers that male and female fertility have not been studied in depth [10].

3.7 Liver and digestive system

Metabolic dysfunction-associated steatotic liver disease (referred to in the sources as non-alcoholic fatty liver disease, NAFLD) is frequent, with a tendency to steatohepatitis and fibrosis disproportionate to age, BMI and duration of diabetes [7, 38]. Patients have more liver fat than equally obese controls [29]. Transaminases rise from childhood, hepatomegaly is common, and cirrhosis and liver failure may appear in the second and third decades, with portal hypertension, splenomegaly, oesophageal varices, ascites and encephalopathy [1, 7]. In the UK adult cohort of 30 patients with type 2 diabetes there were cases of advanced disease; cirrhosis may appear in adolescence without severe obesity, diabetes or alcohol, and conversely some obese and diabetic patients had a normal liver at autopsy [7, 38]. Biopsies show variable degrees of steatohepatitis, fibrosis, cirrhosis and non-specific chronic active hepatitis with lymphocytic infiltrate and piecemeal necrosis; one child had acute liver failure and died at 8 years [1, 2]. The early stages of steatohepatitis may regress with weight loss, exercise and improvement in insulin resistance and glycaemia [7, 63].

Reflux symptoms (epigastric pain, nausea, regurgitation, heartburn) occurred in 19% of 178 patients, compared with 8% of children without the syndrome; two patients with severe reflux were treated, one with gastric plication [7]. The PNDS adds dysphagia, described in patients of all ages [10]. Spontaneous caecal volvulus has been described in two siblings, with no other cases, and may correspond to a co-inherited anatomical anomaly [7, 64].

3.8 Kidney and urinary tract

Chronic kidney disease is frequent, slowly progressive and highly variable; it begins between mid-childhood and adulthood, and end-stage chronic kidney disease may appear from mid to late adolescence [1, 7, 26]. Ultrasound mainly shows parenchymal hyperechogenicity, often limited to the medulla, and cysts in a small number [26, 65]. Biopsy reveals interstitial fibrosis, glomerular hyalinosis and tubular atrophy, without the signs of diabetic or reflux nephropathy, and glomerular function is not associated with diabetes, dyslipidaemia, cardiomyopathy or hypertension: the nephropathy is a primary manifestation of the syndrome, to which diabetes, hypertension and hyperuricaemia are added [1, 7, 65]. Microalbuminuria is common, but overt proteinuria is not, despite diabetes [7]. The French PNDS describes progressive deterioration of the filtration rate with the appearance of proteinuria, which it attributes to diabetes and renal fibrosis, polyuria with polydipsia due to a urinary concentrating defect, cases of acute kidney injury and progression to end-stage chronic kidney disease requiring dialysis or transplantation in about 50% of patients, without stating the age or denominator for this estimate [10].

Urological dysfunction affects up to 50%: detrusor-urethral dyssynergia, with urgency or long intervals without voiding (reduced bladder sensation), hesitancy, weak stream, frequency, incontinence and recurrent infections, more severe in women in late adolescence; severe forms (< 2%) alternate between incontinence and retention, and lower abdominal and perineal pain is frequent [1, 7]. Some women with detrusor spasm refractory to antispasmodics and self-catheterisation required urinary diversion with an ileal conduit [7]. In a Turkish family, three sisters had pelviureteric junction narrowing and calyceal deformities [2].

3.9 Respiratory system

Upper and lower respiratory infections are frequent, particularly in childhood; in the NIH cohort of 38 patients, 61% had a history of bronchitis or pneumonia and 50% of sinusitis [7, 28]. Manifestations of primary ciliary dyskinesia (laterality defects, unexplained neonatal respiratory distress, perennial nasal congestion, wet cough) are much less frequent than in primary ciliary dyskinesia, and mean nasal nitric oxide was 232 ± 57.1 nL/min, far from the threshold of below 77 nL/min used for that disease [28]. Lung function tests are difficult because of the dual sensory loss and the difficulty in coordinating forced inspiration and expiration; when possible, they show a restrictive pattern, usually extrapulmonary (obesity, kyphoscoliosis), with preserved carbon monoxide transfer coefficient, sometimes associated with alveolar and interstitial fibrosis [1, 7]. Pulmonary fibrosis and cardiomyopathy may lead to pulmonary hypertension. Sudden and severe hypoxaemia during or after anaesthesia, surgery or infection has been described [1, 7]. The PNDS stresses the frequency of asthma in childhood, the possibility of chronic hypoxaemia over time and the role of progressive pulmonary fibrosis as a cause of acute decompensation; lung function tests distinguish obstructive from restrictive disease (kyphoscoliosis, fibrosis), and pulmonary hypertension may be detected on echocardiography [10].

3.10 Musculoskeletal system, skin and other

Scoliosis, kyphosis or lordosis affect 30–70% (68% in the series of 182), with onset at puberty [1, 7]. In a UK series of 55 patients, all 13 assessed in detail had some deformity (partially correctable thoracic kyphosis, brachydactyly, femoral anteversion, flat foot), rarely limiting; 6 of the 55 (10.9%) required intervention for scoliosis, two with corrective surgery in adolescence [66]. Postural kyphosis is associated with the dual sensory loss [66]. Other findings are severe flat feet, dental anomalies, gradual thickening of the subcutaneous tissue (thick ears), alopecia, hyperostosis frontalis interna and acanthosis nigricans [1, 2].

3.11 Neurodevelopment, behaviour and nervous system

Intelligence is normal in most and cognitive impairment with an intelligence quotient (IQ) below 70 is very rare [1, 7]. Delay in early milestones, particularly motor, occurs in about 20% according to GeneReviews, but in the series of 182 patients milestones were delayed in 74 patients (46%); learning difficulties affect about 30%, and there are mixed receptive and expressive language delays [1, 7]. Autism spectrum behaviours are frequent, but the diagnosis of autism is very difficult in deafblindness [7]. Hyporeflexia occurred in 20% (9 months to 41 years), 12% of these with frequent absences, and 16% had sleep disorders; excessive startle, dystonia and unexplained muscle pain have been described [7]. The PNDS also mentions rare cases of intellectual disability, epilepsy, psychotic behaviours and sleep-wake rhythm disorders, as well as autism and depression, and calls for regular monitoring of development in children and of these aspects in adults [10]. Magnetic resonance imaging with morphometry and diffusion tensor imaging showed early vascular-type lesions, posterior grey and white matter atrophy and diffuse supratentorial white matter changes [7]. Anxiety, depression and nihilism are frequent in late adolescence, when visual loss becomes complete and the severity of the disease becomes evident [1, 7].

3.12 Natural history and treated disease

The frequencies in Table 3.1 come mainly from series predating the widespread use of multidisciplinary surveillance and modern therapy for diabetes and heart failure, and mix treated and untreated patients. The 2020 consensus reports longer survival in recent years, without quantifying it [7]. The comparison between the Canadian and Italian cohorts and data from lifestyle interventions show that obesity and diabetes respond to treatment, whereas retinal dystrophy, hearing loss and organ fibrosis progress independently of metabolic control [7, 58, 59, 63].

4. Clinical Recognition and Warning Signs

Diagnosis is late in most patients. In an Alström Syndrome UK survey of 17 newly diagnosed patients (2022), only 24% were diagnosed in the first year after symptom onset and 41% waited more than five years (seven waited between 5 and 20 years); the combination of visual impairment (88%) and cardiomyopathy (59%) was the most frequent initial presentation and the one that led to the quickest diagnosis [67]. In China, among 161 patients registered with a patient association, 31.9% were diagnosed in the first year and 28.7% after more than five years, and ophthalmology was the most common route to diagnosis (53.1%) [68]. The 2020 consensus associates diagnostic delay with rarity, the complexity of the syndrome and lack of experience, with inadequate treatment and loss of trust in the health system [7].

4.1 When to suspect, by age

In infants, the consensus recommends considering the syndrome in the presence of visual impairment and/or cardiomyopathy or heart failure in the first years of life (level B recommendation, strength 1) [7]. Nystagmus with intense photophobia and poor eye contact in the first weeks or months, with hypermetropia and a normal fundus, should prompt an ERG; dilated cardiomyopathy between 3 weeks and 4 months, particularly if it reverses, should prompt testing of ALMS1 [1, 42, 49]. The French PNDS formulates the same rule: cardiomyopathy in an infant with visual impairment should raise the possibility of the syndrome, and an ERG should be performed whenever nystagmus is suspected, because fundus changes may appear after the ERG changes [10]. The Oxford Desk Reference recommends echocardiography for an infant with nystagmus in whom Alström syndrome is possible [69]. The Great Ormond Street series suggested considering the syndrome in any infantile cone-rod dystrophy with weight above the 90th centile (16 of 18 cases) or with infantile cardiomyopathy [2].

In children, rapidly developing truncal obesity in the first years, associated with an already known visual impairment, is the warning sign that the British survey recommends taking into account [67, 70]. Acanthosis nigricans, a marker of severe insulin resistance, is looked for from 5 years of age; the Oxford Desk Reference recommends, in obesity with a suspected syndrome, an oral glucose tolerance test and ophthalmological examination with ERG [1, 70, 71]. High-frequency sensorineural hearing loss with absent otoacoustic emissions, detected after normal newborn screening, in a child with retinal dystrophy, should suggest Alström syndrome before Usher syndrome [1, 72].

In adolescents and adults, the combination of infantile-onset blindness, hearing loss, type 2 diabetes with extreme insulin resistance, hypertriglyceridaemia, advanced steatosis and chronic kidney disease disproportionate to the duration of diabetes is suggestive; the Oxford Desk Reference includes the syndrome among the syndromic forms of diabetes with pigmentary retinopathy and with severe obesity [7, 73]. A 2026 case report describes diagnosis in an adult on the basis of diabetes and hepatic fibrosis [74].

4.2 Warning and urgent signs

Table 4.1 — Warning signs

There is no newborn screening for Alström syndrome, and newborn hearing screening is usually normal [1, 7].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Clinical criteria by age

The criteria proposed by Marshall and colleagues in 2007, adapted in GeneReviews, combine major and minor criteria that change with age, because manifestations appear over the course of life (Table 5.1) [1, 24]. Their accuracy is low before 5 years, particularly in the absence of infantile cardiomyopathy, and children should be reassessed as they grow [1].

Table 5.1 — Diagnostic criteria for Alström syndrome by age

Source: [1, 24].

The original table of Marshall and colleagues (2007) differs from the GeneReviews adaptation on points with practical consequences, and is therefore reproduced below [24].

Table 5.1b — Original criteria of Marshall and colleagues (2007)

Source: [24]. At all ages, proof of diagnosis is two pathogenic ALMS1 variants, confirming that each comes from one parent; in children, the criteria should be reassessed with growth [24].

In the original version, infantile cardiomyopathy is a minor criterion up to 2 years, whereas the GeneReviews adaptation raises it to a major criterion; liver dysfunction, renal failure, advanced bone age and short stature count as minor criteria; and a single pathogenic ALMS1 variant is already a major criterion [1, 24]. The text of the article does not entirely coincide with its table: for 0–2 years it admits the diagnosis with one major criterion and obesity or cardiomyopathy, and for 3–14 years it refers to two major criteria and at least one minor, whereas the table requires 1 major + 2 minor and 2 major or 1 major + 3 minor, respectively [24]. The authors proposed genetic testing when the combination of visual and minor criteria did not allow a firm diagnosis, because, in this context, the identification of a single variant would be sufficient to establish it; in a patient with a firm clinical diagnosis, molecular confirmation was considered necessary before carrier testing or prenatal or presymptomatic diagnosis in the family, when medical support depended on it and when a child with a clinical diagnosis grew up without developing the expected minor criteria [24]. Presymptomatic testing of a younger sibling was recommended because of the possibility of monitoring for cardiomyopathy from an early age, and carrier testing was limited to relatives preparing for prenatal or presymptomatic diagnosis [24]. The 2020 consensus goes further and recommends always looking for both variants [7].

The 2020 consensus acknowledges these criteria, but recommends, because of the overlap with other ciliopathies and syndromic retinopathies, always looking for both pathogenic variants to confirm or refute the diagnosis (level A, strength 1) [7]. There is no biochemical, histological or imaging test that confirms the syndrome; all laboratory and imaging findings are non-specific [6, 7].

The 2019 French PNDS uses a third version, adapted and updated from Marshall and colleagues (2007 and 2013), reproduced in Table 5.1c [10].

Table 5.1c — Diagnostic criteria of the French PNDS (2019)

Source: [10].

Compared with the earlier versions, the PNDS requires two ALMS1 variants, at least one loss-of-function, for the genetic finding to count as a principal criterion, whereas Marshall (2007) and GeneReviews accept a single variant; it keeps infantile cardiomyopathy as an additional criterion up to 2 years, like the original version and unlike GeneReviews; it moves advanced bone age to the supportive signs; and, from 15 years, it accepts two principal criteria without additional criteria, whereas the original version required 2 major + 2 minor [1, 10, 24]. For the PNDS, diagnostic certainty is molecular: two pathogenic variants, one of maternal and the other of paternal origin, established by segregation study or, exceptionally, by complementary molecular studies; the table guides suspicion and the request for testing, because the picture becomes complete with age and late diagnoses are possible in adults [10].

5.2 Genetic tests: strategy

The historical approach first sequenced exons 8, 10 and 16 and only then the whole coding sequence; today next-generation sequencing is used in panels for retinal diseases, syndromic ciliopathies, cardiomyopathy or syndromic obesity, all of which should include ALMS1, or exome [1, 7]. GeneReviews distinguishes two routes: targeted testing (single gene or panel) when the phenotype suggests Alström syndrome, and genomic testing (exome, or genome) when the syndrome has not been considered [1]. In practice, the diagnosis often comes from a cardiomyopathy panel in an infant with apparently isolated dilated cardiomyopathy, from a retinal panel in apparently isolated infantile dystrophy or in suspected Usher syndrome, and, in atypical cases with mild retinopathy, from an obesity panel [1]. Clinical Cardiogenetics includes ALMS1 among the dilated cardiomyopathy genes usually present in clinical panels, with autosomal recessive inheritance [75].

If sequencing finds only one or no variant, targeted deletion and duplication analysis (quantitative PCR, long-range PCR, MLPA or exon microarray) or genome sequencing, which detects copy number variants and non-coding variants, follows [1, 7]. The consensus makes it mandatory to check coverage and read length, because the gene is large and has repetitive regions [7]. Once the variants have been identified, a segregation study in the parents confirms that they are in trans [7]. The French PNDS makes family segregation systematic, adds consultation of international genomic databases and, when necessary, functional tests in patient cells (fibroblasts from skin biopsy) or in RNA extracted from blood; the panels it cites include those for ciliopathies, early visual impairment, early retinitis pigmentosa and early obesity, and it refers to the genetic decision trees of the Association Nationale des Praticiens de Génétique Moléculaire (ANPGM) [10].

5.3 Limitations of the tests

Sequencing of ALMS1 detects 85–90% of pathogenic variants and targeted deletion and duplication analysis about 5% [1, 40]. These proportions refer to the variants detectable by each method, not to the clinical sensitivity of the test: in about 10% of families with a clinical diagnosis no ALMS1 variant is identified, which may correspond to variants not detected by the methods used or to another diagnosis [1, 40]. The PNDS reports identification of pathogenic variants in 88% of patients with a clinical diagnosis, a proportion of solved cases in a clinically selected population and not the analytical sensitivity of a method [10]. The mobile element insertions (Alu, LINE-1), large deletions and balanced translocation described show that a negative exon sequencing result does not exclude the syndrome [23, 32, 41, 42]. In a patient with a mild or atypical phenotype and only missense variants, or no variants, a ciliopathy panel should be performed [1]. No mosaicism has been described in the sources consulted. The 2007 strategy, targeting exons 16, 10 and part of 8, had a sensitivity of about 65%: it detected both variants in about 42% of patients, only one in about half and none in about 10% [24]. The authors considered a single variant with clinical signs strong evidence, but noted that about 0.25% of healthy people would have the same result (estimate of carrier frequency, with no method described), and that the absence of variants neither excludes the diagnosis nor should delay surveillance [24]. These figures reflect the targeted sequencing of the time and do not apply to current complete sequencing.

5.4 Report content and interpretation

The report should state the gene, the transcript with version (MANE NM_001378454.1, or NM_015120.4 if that is the one used, with the correspondence), the nucleotide and protein HGVS notation, zygosity, phase when known and the classification according to the ACMG/AMP criteria. The difference in numbering between transcripts (section 2.3) is a source of error when comparing with databases and articles [8]. An example published in 2026 describes as a nonsense variant a change whose reference base does not match either transcript [8, 76]. Variants of uncertain significance should be studied by segregation and by the age-dependent phenotype.

5.5 Complementary clinical assessment at diagnosis

GeneReviews and the consensus recommend, after diagnosis, a baseline assessment of all organs (Table 5.2) [1, 7].

Table 5.2 — Initial assessment after diagnosis

The French PNDS organises the initial assessment into clinical examination, essential investigations, laboratory tests and allied health assessment, with conditional investigations (Table 5.3) [10]. The elements not included in Table 5.2 are the HOMA-IR index (fasting glucose in mmol/L × fasting insulin in mU/L ÷ 22.5), a systematic oral glucose tolerance test from 6 years of age, urinary β2-microglobulin, measurement of 17-hydroxyprogesterone and Δ4-androstenedione in post-pubertal women, lipase in the presence of abdominal pain, analysis of segmental wall motion by strain and of pulmonary pressures on echocardiography, and dobutamine stress scintigraphy in adults with suspected coronary artery disease, because exercise testing is almost impossible in these patients [10]. Diabetes is diagnosed by the general population criteria: fasting glucose above 1.26 g/L (7 mmol/L) on two occasions, random glucose above 2 g/L (11.1 mmol/L) with symptoms of hyperglycaemia, or glucose above 2 g/L (11.1 mmol/L) after ingestion of 75 g of glucose (1.75 g/kg in children, maximum 75 g) [10]. CMR is justified when obesity or lack of cooperation hinders echocardiography or to quantify fibrosis, which is almost impossible before adolescence, and liver elastography is difficult to interpret in the presence of heart failure [10].

Table 5.3 — Initial assessment according to the French PNDS (2019)

5.6 Prenatal and preimplantation diagnosis

Once both familial variants have been identified, prenatal diagnosis and preimplantation genetic diagnosis are possible (level A, strength 1) [1, 7]. In France, the PNDS allows prenatal diagnosis, followed, if the couple requests it, by termination of pregnancy for medical reasons on fetal grounds, given the possible severe multiple disability, and preimplantation diagnosis at the couple's request; both rely on the previously validated familial variants [10]. The syndrome has no specific fetal ultrasound signs described in the sources consulted.

6. Differential Diagnosis

The differential diagnosis depends on age and on the organ through which the disease presents: early-onset retinal dystrophies in infants, infantile dilated cardiomyopathies, obesity syndromes with sensory involvement in children and syndromic diabetes in adults [1, 7]. Polydactyly, cognitive impairment and structural cardiac or genitourinary defects are not typical of Alström syndrome and should prompt a search for another diagnosis, particularly Bardet-Biedl syndrome [1].

Table 6.1 — Differential diagnosis

The most frequent differential diagnosis is Bardet-Biedl syndrome, with which Alström syndrome shares retinal dystrophy, truncal obesity, hypogonadism and kidney disease [1]. The features that separate them are clinical and temporal: in Alström syndrome visual loss begins in the first weeks, with photophobia and nystagmus, whereas in BBS it begins at a mean of 8.5 years, with night blindness; polydactyly, common in BBS, has never been described in Alström syndrome; cognitive impairment is common in BBS and rare in Alström syndrome; hearing loss affects about 5% of patients with BBS and 88% of patients with Alström syndrome; diabetes affects 5–10% in BBS and 68% in Alström syndrome; and infantile cardiomyopathy, which may be the first manifestation of Alström syndrome, is not part of BBS [1, 6]. The PNDS adds the kidney: in BBS renal cysts and urinary tract malformations are frequent, sometimes with kidneys already enlarged prenatally, whereas the nephropathy of Alström syndrome is progressive and later; it also notes that multigene panels frequently reveal Alström syndrome in patients with an initial suspicion of BBS, Leber congenital amaurosis or achromatopsia [10]. Both were studied in the same European registry (EURO-WABB) and in the same phase 3 trial of setmelanotide, but the trial result separated them (section 7) [12, 18].

In an infant with nystagmus and photophobia, achromatopsia is the closest differential diagnosis: only the retina is affected, OCT frequently shows atrophy or cavitation of the central outer retina, which is not described in Alström syndrome, and Alström syndrome more often shows retention of the inner foveal layers [1, 49]. Non-syndromic Leber congenital amaurosis is distinguished by the absence of involvement of other organs and by the oculodigital sign, but ALMS1 itself causes a small fraction of these cases, and only genetic testing and follow-up reveal the syndromic picture [1, 9]. In a series of 19 children, eight had only ophthalmological findings at presentation [2, 49].

In an infant with dilated cardiomyopathy, spontaneous or treatment-related reversal and the later appearance of nystagmus point to Alström syndrome; the absence of skeletal myopathy and raised CK distinguishes it from most syndromic forms, and neutropenia in a boy points to Barth syndrome [1, 3, 78]. In the presence of the combination of retinopathy, hearing loss, diabetes and cardiomyopathy in an adult, mitochondrial diseases are distinguished by neurological and muscular involvement and by later presentation [1]. Wolfram syndrome combines diabetes, hearing loss and visual loss, but through optic atrophy and without obesity, and was included with Alström syndrome and BBS in the EURO-WABB registry precisely because of diagnostic confusion [18, 73].

7. Treatments and Risk Management Strategies

7.1 General principles

Alström syndrome is not curable, but it is treatable: there is no therapy that prevents multiorgan progression, and management relies on early detection and standard treatment of each complication, coordinated by a multidisciplinary team [1, 7]. The 2020 consensus recommends multidisciplinary follow-up in a "one-stop" clinic, at an experienced centre, with a care coordinator as the point of contact, goals agreed with the patient and family and a team meeting after the visit (level B, strength 1; 94% full agreement) [7]. In a UK cross-sectional study cited by the consensus, patients with access to a highly specialised service reported greater satisfaction, better adherence and better quality of life than with usual care [7]. In China, a model linking consultant physicians and a patient association increased registrations from 50 to 161 patients between 2020 and 2024, but only 51.3% had had a multidisciplinary consultation [68]. The French PNDS organises the care pathway differently: follow-up is coordinated by a physician from a reference or competence centre (usually a geneticist or paediatrician and, in adults, an internist), with a systematic visit at least annually, more frequently if there are complications, in liaison with the general practitioner; the latter is responsible for raising the diagnosis, monitoring growth and nutritional status in children and blood pressure, glycaemic control and weight in adults, following development and rehabilitation, supporting the family and dealing with administrative formalities (section 9.6) [10]. It also recommends early liaison with a specialised facility for people with visual impairment and points out that each treatment should take the other comorbidities into account and result from multidisciplinary discussion [10]. The 6-monthly frequency that the consensus proposes for the general practitioner has no equivalent in the PNDS (section 7.17).

The evidence supporting management is mainly expert consensus and observational studies: the consensus graded its recommendations by the GRADE method (levels A to C, strength 1 or 2) and by a Delphi panel, and none results from randomised trials in the syndrome itself; several are level A recommendations only by transposition of evidence from the general population, such as heart failure therapy [6, 7]. Table 7.1 summarises the disciplines involved.

Table 7.1 — Multidisciplinary assessment recommended by the 2020 consensus

Source: [7].

7.2 Vision and rehabilitation

The consensus recommends a complete ophthalmological examination at diagnosis and then annually, first by an experienced ophthalmologist and then at a retinal dystrophy centre: best acuity or low-vision assessment, refraction, slit-lamp examination for cataracts, fundus and, if possible, OCT, autofluorescence and ERG (level B, strength 1) [7]. GeneReviews recommends maintaining the annual examination even after complete loss of vision, to assess ocular health [1]. Full-correction glasses should be prescribed while there is retinal function, and red-orange filters reduce photophobia [1, 7]. Cataract surgery, usually in the second or third decade, improves photophobia, but visual gain is limited by the underlying degeneration [7]. Educational planning should start from the certainty of blindness: Braille, orientation and mobility training (white cane, guide dog), daily living skills, computing with speech recognition and large-print materials while vision remains, and the tactile modality should be prioritised early [1, 7]. The PNDS adds light protection measures (adapted lighting, filters against glare and short and medium wavelengths, a peaked cap, avoiding unprotected sun exposure at the beach or in the mountains), assessment by a mobility instructor to make travel safe, training in optical aids (magnifiers, telescopes, magnifying glasses), technical aids (large-print books, talking watches, Braille) and electronic aids, and a guide dog in severe visual impairment; for cataract, surgery is decided case by case, prevents postoperative macular oedema and uses intraocular lenses suited to retinal dystrophy, and cystoid macular oedema is treated as in the other dystrophies [10]. There is no gene therapy in clinical trials, partly because of the size of the gene, and retinal implants have not benefited any known patient [7]. The PNDS, a year earlier, accepted that retinal implants might come to be offered in very advanced degenerations; specific pharmacological therapy, gene therapy and cell therapy were, for both, matters of research [10].

7.3 Hearing

Hearing assessment is performed at diagnosis and then annually, with air- and bone-conduction pure-tone thresholds, speech thresholds, word recognition, tympanometry and otomicroscopy (level B, strength 1) [7]. Bilateral digital hearing aids should be fitted and reviewed regularly; cochlear implantation should be considered in severe to profound hearing loss, with good functional results, given the cochlear location of the lesion [1, 7, 27]. Myringotomy and ventilation tubes treat recurrent otitis media [1, 7]. Lack of timely hearing aids is associated with withdrawal and depression [7]. The PNDS recommends speech and language therapy in moderate to severe hearing loss and an ENT visit with audiogram 1 to 2 times a year [10].

7.4 Heart

Infantile cardiomyopathy is treated as paediatric acute heart failure; the consensus does not define a specific protocol for infants, and the case in section 10 illustrates reversal with supportive therapy [3, 7]. In heart failure with reduced ejection fraction, the consensus recommends standard therapy: angiotensin-converting enzyme inhibitor (ACEi) and beta-blocker, titrated to the maximum tolerated evidence-based dose, with the addition of a mineralocorticoid receptor antagonist; in adults with ejection fraction below 35% and persistent symptoms, replacement of the ACEi with sacubitril/valsartan; ivabradine if heart rate remains above 72/min despite optimisation; resynchronisation if QRS above 130 ms with persistent symptoms; diuretics for congestion (level A, strength 1; 92% full agreement) [7]. The 2026 European heart failure guideline, which postdates the consensus, organises baseline therapy into four classes and grades each recommendation. At any ejection fraction with symptoms, it recommends an SGLT2 inhibitor (dapagliflozin or empagliflozin) and a mineralocorticoid receptor antagonist (class I, level A), with a loop diuretic at a dose adjusted to volume status in congestion (I A). In symptomatic reduced ejection fraction, it recommends a beta-blocker (I A) and an ACEi or an angiotensin receptor-neprilysin inhibitor (ARNI) (I A), replacement of the ACEi or angiotensin receptor blocker with an ARNI (I B1) and the angiotensin receptor blocker only in intolerance of the ACEi and ARNI (I A). Outside this core, ivabradine should be considered with ejection fraction ≤ 35%, sinus rhythm and resting heart rate > 70/min on the maximum tolerated doses of the four classes (IIa B1), or in beta-blocker intolerance (IIa C); digoxin or digitoxin with ejection fraction ≤ 40% despite optimised therapy (IIa B1); and vericiguat may be considered with ejection fraction < 45% (IIb B1). Titration is performed at least every 1–2 weeks, guided by symptoms, vital signs and laboratory tests, up to the trial doses, and therapy is maintained at the highest tolerated doses even when the patient becomes asymptomatic or ejection fraction improves (both I C); gradual withdrawal may be considered only in highly selected patients with complete normalisation of function, volumes and natriuretic peptides after correction of a reversible cause (IIb C); in Alström syndrome, the cause is not reversible and about 1 in 5 patients who recovered from infantile cardiomyopathy has relapse or new heart failure later, which argues against this option [7, 80]. In asymptomatic ventricular dysfunction (stage B), it recommends a beta-blocker with ejection fraction < 50% (I B1) and an ACEi, or an angiotensin receptor blocker in intolerance, with ejection fraction ≤ 40% (I A), which covers the minimal forms described by the PNDS and residual dysfunction after infantile cardiomyopathy when the patient reaches adulthood. At diagnosis, it recommends contrast-enhanced cardiac magnetic resonance in suspected cardiomyopathy and genetic testing in patients who meet cardiomyopathy criteria when it serves diagnosis, prognosis, therapeutic stratification, reproductive decision-making or cascade screening (both I C), and refers the rest to the 2023 European cardiomyopathy guideline; in carriers of cardiomyopathy variants without clinical disease, it recommends control of modifiable risk factors and suggests regular cardiac follow-up [80]. Compared with the consensus, three thresholds change: ivabradine moves from more than 72/min to more than 70/min with ejection fraction ≤ 35%, the SGLT2 inhibitor and the mineralocorticoid receptor antagonist become recommended at all ejection fractions, and resynchronisation requires, for a class I recommendation (level A), left bundle branch block with QRS ≥ 150 ms, ejection fraction ≤ 35% and sinus rhythm, with left bundle branch block with QRS of 130–149 ms and QRS ≥ 150 ms without left bundle branch block remaining indications to be considered (IIa C) [7, 80]. Doses are those of the general heart failure guidelines for each age, which the consensus adopts without modification [1, 7]. The PNDS, without syndrome-specific data, describes the same regimen (diuretic if symptomatic, ACEi, beta-blocker and aldosterone antagonist) and adds that, with left ventricular ejection fraction below 30%, an anticoagulant or antiplatelet agent may be discussed, weighing the risk of falls in a blind patient; in arterial hypertension, it treats as in the general population, with an ACEi as first choice under monitoring of kidney function and attention to the cardiac and renal effects of each drug [10]. Anticoagulation for this indication is not included in the 2020 consensus or in GeneReviews, and the criterion of ejection fraction alone has no support in adult trials: in WARCEF, 2305 patients in sinus rhythm with reduced ejection fraction, followed for a mean of 3.5 years, had no difference in the composite outcome of ischaemic stroke, intracerebral haemorrhage or death between warfarin (INR 2.0–3.5) and acetylsalicylic acid 325 mg/day (7.47 vs 7.93 events per 100 patient-years; HR 0.93; 95% CI 0.79–1.10); warfarin reduced ischaemic stroke (0.72 vs 1.36 per 100 patient-years), at the cost of twice as many major haemorrhages (1.78 vs 0.87) [81]. The 2026 European heart failure guideline maintains this position without a graded recommendation: the annual risk of stroke in heart failure is about 2.0 per 100 patient-years in sinus rhythm and 2.87 per 100 patient-years with atrial fibrillation, but randomised trials (WARCEF, COMMANDER-HF with rivaroxaban in patients with coronary artery disease, and the Cochrane meta-analyses of anticoagulation versus placebo and versus antiplatelet therapy) have shown no benefit of oral anticoagulation in reduced ejection fraction in sinus rhythm, so, without atrial fibrillation, there is no evidence for routine anticoagulation for stroke prevention [80]. With atrial fibrillation, the same guideline recommends oral anticoagulation according to CHA₂DS₂-VA, in which heart failure of stages B to D scores 1 point: a score ≥ 2 is recommended as an indicator of high thromboembolic risk and a score of 1 should be considered as such; direct oral anticoagulants are the agents of choice in the absence of a mechanical valve prosthesis and moderate to severe mitral stenosis [80]. The 2021 guideline added, likewise in the text, that low-dose rivaroxaban (2.5 mg twice daily) may be considered in concomitant chronic coronary or peripheral arterial disease with high stroke risk and without major bleeding risk, and that anticoagulation should be considered in the presence of visible intraventricular thrombus or high thrombotic risk, such as previous peripheral embolism or some patients with peripartum cardiomyopathy or left ventricular non-compaction; the main text of the 2026 guideline does not address intraventricular thrombus again, and that guidance remains the reference [80, 82]. Therefore, in adults in sinus rhythm, low ejection fraction alone is not an indication for anticoagulation; in a blind patient, the risk of falls worsens the bleeding balance [80, 81]. In infant cardiomyopathy, the decision follows paediatric heart failure guidelines, and the dose that of the drug chosen.

The implantable cardioverter-defibrillator (ICD) follows standard indications: secondary prevention after aborted sudden death or ventricular tachyarrhythmia with instability, and primary prevention with advanced symptoms and ejection fraction below 35% despite optimal therapy, always with expected survival of more than 1 year; the syndrome-specific arrhythmic risk is not defined (level B, strength 1) [7]. The 2026 European guideline recommends an ICD for secondary prevention after ventricular arrhythmia with haemodynamic instability, without a reversible cause and with expected survival of more than 1 year in good functional status (I A); in non-ischaemic cardiomyopathy, such as that of Alström syndrome, primary prevention should be considered in NYHA class II–III with ejection fraction ≤ 35% after at least 3 months of optimised baseline therapy and with the same survival expectation (IIa B1), and is not recommended in refractory class IV outside candidacy for resynchronisation, ventricular assist device or transplantation (III C); the wearable defibrillator may be considered as a temporary bridge to decision or while awaiting transplantation (IIb C) [80]. In refractory acute heart failure, mechanical circulatory support is considered as a bridge to transplantation; heart transplantation has been performed successfully in rare cases, and mechanical support as destination therapy has not yet been offered (level C, strength 2) [1, 7]. In the general population with advanced heart failure, the 2026 European guideline recommends long-term left ventricular assist devices in selected patients, as a bridge to transplantation, to candidacy or to recovery, or as destination therapy (I C), heart transplantation in selected patients refractory to medical and interventional therapy and without contraindications (I C), and histopathological examination of the explanted heart in non-ischaemic heart failure to clarify the aetiology (IIa C); in Alström syndrome, selection weighs kidney, liver and lung disease and insulin resistance [7, 80]. The PNDS discusses heart, lung and kidney transplantation case by case, with successful heart and kidney transplants in a very small number of patients [10]. In adults, the risk of premature ischaemic cardiovascular disease should be modified according to national secondary prevention guidelines (level B, strength 1), with attention to asymptomatic coronary artery disease and coronary CT angiography if there are symptoms or an unexplained fall in ventricular function [1, 7].

7.5 Obesity, insulin resistance and diabetes

The basis of treatment is a structured and personalised lifestyle programme, with a healthy hypocaloric diet, restriction of simple carbohydrates, weight management with a physician and dietitian and regular aerobic exercise adapted to blind people (walking, cycling, swimming), with the support of a companion or trainer (level B, strength 1) [1, 7]. The PNDS asks that dietary education begin in early childhood, with a dietitian from the outset, teaching of a normocaloric or hypocaloric diet and of a normal-carbohydrate diabetic-type diet, or a low-carbohydrate diet in hypertriglyceridaemia, even before diabetes appears; it recommends integration into a local therapeutic education network for obesity (in France, the RePPOP networks for children and the specialised obesity centres), adapted to visual impairment, a psychobehavioural approach or behavioural and family therapy when there are eating disorders, and a regular sports programme under medical supervision [10]. Bariatric surgery has not been evaluated for this indication [10]. In a British study, lifestyle modification improved diabetes with severe insulin resistance and early steatohepatitis [63]. Progression to diabetes and the severity of hyperglycaemia are attenuated by reducing severe obesity [1, 58, 59].

Diabetes is treated as in the general population, with the precautions imposed by heart, liver or kidney failure [1, 7]. All benefit from metformin; many respond to thiazolidinediones (glitazones) and dipeptidyl peptidase 4 inhibitors [1, 7, 83]. The PNDS places metformin first-line when diet does not normalise glycaemia, provided kidney function allows, accepts the efficacy of GLP-1 receptor agonists and decides on the other antidiabetic drugs case by case [10]. Without a syndrome-specific dose, the label dose for type 2 diabetes is used: in adults, 500 mg twice daily or 850 mg once daily with meals, with increases of 500 mg per week or 850 mg every 2 weeks, up to a maximum of 2550 mg/day in divided doses; from 10 years of age, 500 mg twice daily, with weekly increases of 500 mg up to 2000 mg/day; it is not started with an estimated glomerular filtration rate between 30 and 45 mL/min/1.73 m², continuation is reassessed below 45 and it is discontinued below 30 [84]. Glitazones are contraindicated in active or treated heart failure, and GeneReviews recommends stopping these treatments when serum creatinine exceeds 200 µmol/L (2.6 mg/dL) or cardiomyopathy becomes evident [1]. Young patients rarely need insulin, but some need very high doses in the long term [7]. Because of the sensory impairment, the PNDS calls for special attention to glucose monitoring systems, which must be usable by a blind or low-vision person, and insists on therapeutic education in diabetes [10]. The consensus recommends offering a sodium-glucose cotransporter 2 inhibitor (SGLT2 inhibitor), such as empagliflozin or canagliflozin, to all adults, unless contraindicated, because of the benefit in chronic kidney disease and heart disease, and adding a GLP-1 receptor agonist when weight loss is needed [7]. GeneReviews, from 2019, placed incretin analogues as second line, effective in two thirds of patients poorly controlled with diet, exercise and metformin [1]. These drugs are used in the indications and doses of their respective labels for type 2 diabetes or obesity, without a specific indication for Alström syndrome. The 2026 European heart failure guideline reinforces this choice on the grounds of cardiac prevention: it recommends an SGLT2 inhibitor in type 2 diabetes with risk of heart failure (multiple risk factors or established atherosclerotic disease) and in type 2 diabetes with chronic kidney disease (I A), finerenone in type 2 diabetes with albuminuric chronic kidney disease (I A), a GLP-1 receptor agonist in type 2 diabetes with at least one other cardiovascular risk factor (IIa A) and strict blood pressure control, with systolic pressure < 130 mmHg, in hypertension or stage B (I A); in symptomatic heart failure with ejection fraction ≥ 45% and BMI ≥ 30 kg/m², semaglutide or tirzepatide should be considered to reduce weight and improve exercise capacity and quality of life (IIa B1), and bariatric surgery may be considered with BMI ≥ 35 kg/m² when structured measures fail (IIb C) [80]. The trials supporting these recommendations did not include patients with Alström syndrome.

The most robust real-world data come from the Birmingham national centre: among 72 adults screened, 30 completed 6 months of semaglutide or exenatide and lost a mean of 5.4 ± 1.7 kg (95% CI 3.6–7), about 6% of weight (p < 0.01), with a fall in HbA1c of 12 ± 3.3 mmol/mol (95% CI 8.7–15.3), about 1.1% in absolute terms (p < 0.01), and improvement in lipids and ALT, of a magnitude comparable to that in polygenic obesity [85]. The study had no control group. Case reports from 2025 and 2026 describe responses to tirzepatide (in two men previously treated with semaglutide, loss of 26.9% of weight in 18 months, 83% reduction in daily insulin dose and resolution of steatosis on MRI in one, and loss of 7.2% in 9 months with a reduction in liver fat from 21% to 11% in the other), to semaglutide and dulaglutide in children and to ertugliflozin in two siblings, with improvement in HbA1c and a response of insulin resistance that waned in the younger sibling, in puberty [76, 86–88]. These reports do not allow efficacy or safety to be estimated.

As for growth hormone, few patients have been treated; after 1 year there was a reduction in fat mass, liver fat and lipids, and improvement in insulin sensitivity and acanthosis [7]. The consensus makes no recommendation on its use.

7.6 Dyslipidaemia and pancreatitis

Treatment of hypertriglyceridaemia begins with metabolic control [7]. In severe hypertriglyceridaemia, some patients responded to a low-fat diet with statins and nicotinic acid; the consensus adds omega-3 fatty acids and fibrates [7]. GeneReviews considers nicotinic acid derivatives useful in hypertriglyceridaemia above 20 mmol/L (1770 mg/dL), particularly after pancreatitis and with absent or controlled diabetes, and statins for prevention of atherosclerosis in adults with low HDL, high LDL and diabetes, although they may be of limited efficacy [1, 61]. In acute pancreatitis, in addition to the usual treatment, a 48-hour fast with intravenous normal saline allows circulating triglycerides to be metabolised; diet, exercise and treatment of diabetes then maintain lower values [1, 60]. The PNDS places the risk of pancreatitis in severe hypertriglyceridaemia above 10 g/L (about 11.3 mmol/L), teaches the patient to recognise the first signs (severe abdominal pain, vomiting) and to seek emergency care, accepts fasting during major hypertriglyceridaemia crises and treats cholesterol according to cardiovascular risk, as in the general population [10].

7.7 Liver

The consensus recommends annual surveillance of liver disease in adults with liver tests, platelets, ultrasound and non-invasive fibrosis tests (transient elastography and ELF test), which may avoid biopsy (level B, strength 1) [7]. In cirrhosis, upper gastrointestinal endoscopy is performed to look for varices, which are treated according to hepatology guidelines (beta-blockers and/or band ligation), and ultrasound every 6 months for hepatocellular carcinoma screening [1, 7]. Transjugular intrahepatic portosystemic shunt is an option when these measures fail, and patients with complications of advanced liver disease or portal hypertension should be assessed early for liver transplantation [1, 7].

7.8 Kidney and urinary tract

Kidney function should be monitored regularly, with referral to nephrology and early assessment for kidney transplantation in advanced disease (level B, strength 1) [7]. ACE inhibitors are recommended when there is proteinuria; intensive blockade of the renin-angiotensin-aldosterone axis (ACEi with angiotensin receptor blocker and spironolactone or eplerenone) carries a risk of hyperkalaemia and worsening kidney function [1]. Kidney transplantation has been successful in a growing number of patients, including a 42-year-old man, but is complicated by morbid obesity, uncontrolled diabetes and cardiomyopathy [1, 7, 89]. In advanced chronic kidney disease, the PNDS provides for an adapted diet, dialysis and discussion of transplantation according to the patient's physiological condition [10]. Symptoms of neurogenic bladder (recurrent urinary infections, nocturia, incomplete emptying, dribbling) should be sought and prompt urological assessment (level B, strength 1); dyssynergia may require self-catheterisation and, in severe refractory cases, urinary diversion [1, 7].

7.9 Endocrinology

Thyroid function should be assessed annually and hypothyroidism treated with levothyroxine, with monitoring of free thyroxine and TSH, because secondary hypothyroidism is frequent (level B, strength 1) [1, 7]. Around puberty, gonadotropins and pituitary hormones are assessed; adult male hypogonadism is almost universal and is treated with testosterone according to local guidelines, to preserve sexuality, muscle strength and bone health (level B, strength 1) [1, 7, 39]. In women, metformin, oestrogens, progestogens or their combination may regularise cycles [7]. The PNDS treats growth delay and pubertal delay with hormone therapy identical to that of the general population, after a paediatric endocrinology opinion, and recommends orchidopexy for cryptorchidism [10]. In confirmed GH deficiency, the label dose of somatropin (Genotropin®) for paediatric deficiency is 0.16–0.24 mg/kg/week subcutaneously, divided into 6 or 7 injections, and treatment for short stature is stopped at epiphyseal closure; there is no specific dose for Alström syndrome, and the scant published experience (section 7.5) does not allow routine treatment to be recommended [7, 90].

7.10 Respiratory system, perioperative care and vaccination

Respiratory assessment is performed at diagnosis and then if symptoms occur, starting with a chest radiograph, with a low threshold for high-resolution CT when there is unexplained cough or dyspnoea (level C, strength 2) [7]. Regular physical activity with breathing exercises reduces chronic hypoxia [1]. Annual influenza vaccination and pneumococcal vaccination should be offered proactively, and moderate to severe pneumonia treated aggressively in intensive care, with cardiorespiratory and renal support (level B, strength 2) [1, 7].

Anaesthesia and sedation require planning: the combination of myocardial dysfunction, pulmonary hypertension and pulmonary fibrosis can cause sudden and severe hypoxia after minor surgery or during infections; extubation should be careful, after adequate oxygenation, with monitoring of oxygenation and cardiac status until 24 hours after full recovery (level C, strength 2) [1, 7]. The PNDS requires a complete preoperative assessment and an anaesthesia team used to this context before, during and after surgery, with prolonged monitoring of oxygenation and cardiac function [10]. A 2026 report describes repeated extubation failures after surgery for colonic volvulus [91]. Severe progressive scoliosis may require surgery, and in less severe cases or those at high surgical risk orthoses are used; postural kyphosis responds to physiotherapy [7, 66]. In sleep apnoea, nocturnal ventilation should be supervised by a specialised team, and physiotherapy counteracts scoliotic posture and allows, in very sedentary patients, reconditioning to exercise under strict medical supervision [10]. Gastro-oesophageal reflux is treated with proton pump inhibitors [10]; without a syndrome-specific dose, the omeprazole label (Prilosec® in the USA) indicates for symptomatic reflux 20 mg once daily for up to 4 weeks in adults and, from 1 to 16 years, 5 mg (5 to < 10 kg), 10 mg (10 to < 20 kg) or 20 mg (≥ 20 kg) once daily before a meal, with reduction to 10 mg/day in hepatic impairment [92].

7.11 Development, mental health and transition

Early intervention (occupational therapy, physiotherapy, speech and language therapy, sensory impairment specialists) should begin in the first years, with an individual education plan that includes vision and hearing consultants [1]. The consensus calls for attention to the increased prevalence of anxiety, depression and behavioural problems, with a low threshold for referral to psychology and use of pharmacological or non-pharmacological treatment (level C, strength 2), and specialised deafblind care, including assessment of communication, mobility, assistive technologies and rehabilitation potential [7]. People with Alström syndrome describe themselves as able and willing to learn, with a need for lifelong support; they should be involved as advocates for their own needs [1]. Transition to adult services should begin early, with assessment of barriers to independence (level B, strength 1), and advance care planning, with access to palliative care at the end of life, should be coordinated between the specialist centre, the general practitioner and local services (level B, strength 1) [7]. The PNDS adds psychomotor therapy for motor delay related to visual impairment; psychology to screen for behavioural disorders and treat anxiety, mood disorders, depression, obsessive-compulsive behaviours and psychosomatic manifestations, and later to help the patient live with a progressive disease and find employment; early application to disability support services for special education and home care before school entry; career guidance adapted to vision, hearing and the other manifestations; and the warning that driving is, as a rule, impossible [10]. Transition to adult services should be organised by the end of adolescence to avoid interruption of follow-up, with the participation of the school physician, the occupational physician and social services [10].

7.12 Agents and circumstances to avoid

Drugs contraindicated in kidney, liver or myocardial disease should be avoided [1]. Therapy for one organ may harm another: glitazones are contraindicated in heart failure, and dual or triple blockade of the renin-angiotensin-aldosterone system increases the risk of hyperkalaemia [1]. Sedation and anaesthesia without prolonged monitoring are risk situations [7].

7.13 Pregnancy

The only report of pregnancy with a confirmed molecular diagnosis is that of an Italian woman with a mild form, who became pregnant after in vitro fertilisation in 2025 (section 8); the pregnancy was complicated by gestational diabetes and chronic hypertension, treated with methyldopa (500 mg 3 times daily), and included ursodeoxycholic acid (300 mg/day), acetylsalicylic acid until 35 weeks, folic acid and vitamin D; monthly maternal echocardiography was normal and delivery was by emergency caesarean section at 38 weeks for cord prolapse [31]. The sources consulted contain no formal recommendations for pregnancy; the consensus calls for a complete hormonal assessment before a desired pregnancy [7].

7.14 Regulatory status

There is no medicine authorised specifically for Alström syndrome in the United States or the European Union. Setmelanotide (Imcivree®), a melanocortin 4 receptor agonist, was studied in Alström syndrome but did not obtain an indication (Table 7.2) [12, 13, 93].

Table 7.2 — Setmelanotide and Alström syndrome: regulatory status

Sources: [12, 13, 93].

7.15 Clinical trials

Table 7.3 — Interventional trials that included patients with Alström syndrome

The setmelanotide trial combined two diseases to obtain a viable sample size, and the authors themselves acknowledge that the inclusion of Alström syndrome introduced heterogeneity; with only six patients, the trial lacks power to exclude an effect in Alström syndrome, but neither does it provide any evidence of benefit, and the authors classified the results in this syndrome as inconclusive [12]. The most frequent adverse events were skin hyperpigmentation (60.5%) and injection-site erythema (48%); two patients had serious events (blindness, anaphylaxis and suicidal ideation), considered unrelated [12]. The results of PBI-4050 in Alström syndrome, a trial designed on the hypothesis that fibrosis is the common mechanism of cardiac, hepatic and renal injury, had not been published at the date of this review, and the absence of a located publication does not allow conclusions about efficacy or inefficacy [94, 95]. The real-world study of GLP-1 agonists shows a response similar to that in common obesity, but without a control group, and cannot be compared indirectly with the setmelanotide trial, which had a different population, design and outcome [12, 85].

7.16 Developments in the last 12 months and level of evidence

Table 7.4 — Developments (November 2025 to October 2026, and relevant 2025 publications)

No therapeutic trial specific to Alström syndrome active on ClinicalTrials.gov was located in October 2026, nor any marketing authorisation application, opinion of the Committee for Medicinal Products for Human Use (CHMP) or regulatory decision directed at the syndrome [94]. The active registered studies are cohort and natural history studies (BBS and Alström cohort in Strasbourg, until 2035; Sanford Health rare disease registry) [94]. Gene therapy remains preclinical [3, 7].

7.17 Divergences between sources

The 2020 consensus and the 2019 GeneReviews agree on the essentials, but diverge on details with clinical consequences. The consensus proposes CMR every 3–5 years in older children and adults, whereas GeneReviews proposes every 3 years from 18 years of age or with any clinical change [1, 7]. The consensus recommends SGLT2 inhibitors for all adults and places GLP-1 agonists as an option when weight loss is needed, whereas GeneReviews presented them as second line; the consensus does not mention the GeneReviews creatinine threshold for stopping glitazones [1, 7]. The consensus describes hypothyroidism as autoimmune in 20% of cases and GeneReviews as non-autoimmune; insulin resistance is described as more than five times (GeneReviews) or more than ten times (consensus) that of controls with the same BMI, from the same study; and delay in developmental milestones is about 20% in GeneReviews and 46% in the series of 182 patients cited by the consensus [1, 7, 29]. Regarding fertility, both sources considered reproduction unlikely, which the 2025 case corrects for mild forms [1, 7, 31]. The surveillance intervals in this article follow the most demanding schedule whenever the sources diverge, indicating the source (section 11). The 2007 review, predating both sources, already recommended long-term ACE inhibitors in cardiomyopathy, with diuretics, digitalis, beta-blockers and spironolactone; prescription glasses with a dark red filter for photophobia and early teaching of Braille and mobility; metformin and/or glitazones with hepatic, cardiac and renal monitoring; simultaneous measurement of TSH and free T4, because TSH alone may be misleading; intermittent bladder self-catheterisation in detrusor-urethral dyssynergia and, in rare cases, ileal diversion; band ligation of varices with a beta-blocker and, in candidates, transjugular intrahepatic portosystemic shunt (TIPS) in portal hypertension; and vaccination against influenza and hepatitis B [24]. At that date, growth hormone was considered experimental, liver transplantation of unproven efficacy, kidney transplantation successful in a few patients and heart transplantation of uncertain feasibility, with a single successful heart-lung transplant in a patient without diabetes or renal failure [24].

The 2019 French PNDS diverges from the two sources on several points [1, 7, 10]. In the diagnostic criteria, it requires two ALMS1 variants for the principal genetic criterion and accepts, from 15 years, two principal criteria without additional criteria (Table 5.1c); this requirement for biallelic confirmation coincides with the consensus level A recommendation to always look for both variants. In surveillance, it proposes an audiogram 1 to 2 times a year (annual in the other sources), CMR every 2–5 years when echocardiography is poor or to quantify fibrosis (3 years in GeneReviews, 3–5 years in the consensus), stress imaging every 2–5 years in adults with coronary risk (GeneReviews reserves coronary CT angiography for symptoms or an unexplained fall in ventricular function), OGTT from 6 years and then every 3–5 years in non-diabetics (GeneReviews starts glycaemic assessment at 4 years, annually), a systematic visit at least annually (the consensus proposes every 6 months for the general practitioner) and densitometry every 3–5 years according to gonadal function (the other sources link it to chronic kidney disease stage ≥ III). In treatment, it places metformin first-line and GLP-1 agonists as probably effective, without SGLT2 inhibitors, which the 2020 consensus came to recommend for all adults; it allows an anticoagulant or antiplatelet agent with ejection fraction below 30%, absent from the other sources and without support in WARCEF or in the 2021 and 2026 European heart failure guidelines, which in adults in sinus rhythm require another indication; and it advises against systematic investigation of the somatotropic axis, whereas GeneReviews and the consensus call for IGF-1 in short stature. In the clinical description, it considers restrictive cardiomyopathy very rare (about 20% in the consensus and GeneReviews), adult hearing loss as a rule mild to moderate (moderately severe to severe by the end of the first or second decade according to GeneReviews), hypothyroidism mainly peripheral (frequently secondary according to GeneReviews), proteinuria as a progressive manifestation (the consensus describes common microalbuminuria and rare overt proteinuria) and mentions term pregnancies in women, whereas the 2020 consensus knew of none with a molecular diagnosis. The therapeutic differences mainly reflect the date: the PNDS is based on the literature published up to June 2018, before the consensus incorporated the cardiorenal benefit of SGLT2 inhibitors and before the same consensus assessed the lack of benefit of retinal implants. Table 11.1 adopts the shortest interval when the sources diverge and indicates the source of each.

8. Reproductive Options and Family Counselling

Alström syndrome is autosomal recessive. The parents of a patient are obligate heterozygotes, asymptomatic and not at risk of developing the disease; each sibling has, at conception, a 25% chance of being affected, a 50% chance of being an asymptomatic carrier and a 25% chance of being neither affected nor a carrier [1, 7]. Each sibling of the parents has a 50% chance of being a carrier [1]. The consensus recommends a segregation study in the parents once the variants have been identified in the proband, and, when a variant is not found in either parent, considering a de novo variant, rare in this gene, and confirming paternity (level A, strength 1) [7]. Carrier testing in relatives requires prior knowledge of the family's variants [1].

The French PNDS asks that the diagnosis be disclosed at a dedicated consultation, possibly with a geneticist, paediatrician, ophthalmologist, psychologist and social worker, which explains the diagnosis, plans follow-up, introduces the team and the patient associations and provides information on natural history, prognosis, treatments and their adverse effects and the schedule of examinations, with continuous support at each difficult stage; the genetics clinic visit should be as early as possible and repeated when there is a wish for pregnancy [10]. For a healthy relative planning a family, the risk of affected offspring is low, because of the rarity of heterozygotes in the general population, provided that consanguinity with the partner is excluded; molecular testing of the partner of a heterozygote is decided case by case [10].

In populations with consanguinity or isolation, the risk of a couple being carriers is greater: the Alu allele found in two Turkish cousins was present in 2 of 29 (6.9%) unaffected inhabitants of the same village and absent in 50 unrelated Turkish controls [2, 41]. In the Acadian family, the ten parents of the five affected sibships shared an ancestral couple [2, 21].

Asymptomatic siblings, older or younger, should have their genetic status clarified, because early diagnosis allows cardiac and metabolic surveillance to be started before complications; testing of minors is justified here by the direct medical benefit of surveillance [1]. The ideal time to determine risk, clarify carrier status and discuss prenatal and preimplantation diagnosis is before pregnancy, and counselling should be offered to young adults who are carriers or at risk [1]. Prenatal diagnosis and preimplantation genetic diagnosis are possible once the familial variants have been identified, and the decision to use them is personal [1, 7]. In probands without a molecular diagnosis, DNA banking is recommended [1].

As for the offspring of affected people, until 2020 there were no reports of paternity in men or pregnancy in women with a molecular diagnosis [1, 7]. Men almost always have primary gonadal failure in adulthood, and the consensus recommends offering semen analysis to those who wish to know their fertility [7, 39]. In women, insulin resistance with hyperinsulinaemia alters ovarian steroidogenesis and follicular maturation, with anovulation similar to that of polycystic ovary syndrome, but there is also a risk of premature ovarian insufficiency due to ovarian fibrosis [31]. In 2025 the first live birth to a woman with Alström syndrome was published: a 32-year-old nulliparous Italian woman, with a mild form and homozygous for the nonsense variant c.1043G>A p.(Trp348Ter) (NM_001378454.1; c.1046G>A p.(Trp349*) in the article's notation), with regular cycles, a BMI of 27 and two years of infertility attributed mainly to the partner; after two intracytoplasmic sperm injections with preimplantation genetic testing for aneuploidy, transfer of a euploid blastocyst resulted in a pregnancy [8, 31]. The partner was not a carrier and the risk of an affected child was estimated at less than 1 in 15,000, so preimplantation testing for the monogenic disease was not performed [31]. The offspring of an affected person are obligate heterozygotes; the risk of disease depends on the carrier status of the partner. Before a pregnancy, the consensus recommends a complete hormonal assessment [7].

Counselling should also address the prospect of progressive deafblindness, the family impact of a severe chronic disease and the patient associations, referral to which the consensus recommends at the time of diagnosis [7].

9. Special Considerations: Population Diversity and Epidemiology

9.1 Frequency

Prevalence is difficult to estimate, because attenuated forms may go undiagnosed and diagnosis is often late [1, 67]. Estimates range from 1:100,000, derived from 12 families in the United Kingdom, to 1:1,000,000, the value used by Orphanet and by reviews; the 2020 consensus adopts an incidence of 1 case per 1,000,000 live births (level C, strength 2) [1, 7, 57, 97]. The 2019 French PNDS places prevalence between 1 and 9 cases per 1,000,000 births, a range that corresponds to a prevalence class and not to a direct measurement, and counts about 900 published cases worldwide [10]. These estimates should be read as minimum values [6]. The number of known patients rose from 37 published cases up to 1998 to about 450 in 2007 and about 950 in 2019 (Orphanet), reflecting mainly molecular diagnosis and greater awareness of the syndrome [1, 2].

9.2 Europe and North America

European specialised services knew of at least 263 patients in 2020: 89 in the United Kingdom, 64 in France, 60 in Turkey, 39 in Italy and 15 in Spain [7]. In France, patients are followed in a network organised around the CARGO reference centre in Strasbourg, which coordinated the PNDS, and Strasbourg also hosts the BBS and Alström natural history cohort registered until 2035 (section 7.16) [10, 94]. The United Kingdom had 88 diagnosed patients in 2025 according to the national association [67]. The variant c.10775delC (MANE c.10772del) accounted for 12% of mutated alleles in the international series of 250 patients and up to 20% of patients of English ancestry, with shared haplotypes indicating a founder effect [4, 7]. In North America, the syndrome is frequent among French Acadians of Nova Scotia (Yarmouth County) and Louisiana, where it was sometimes confused with Bardet-Biedl syndrome, and it has been described in an isolated Mennonite community in British Columbia [2, 21]. The most detailed North American cohorts are the NIH cohort (38 patients assessed prospectively) and the Canadian paediatric cohort studied for diabetes [29, 58].

9.3 Founder populations and other regions

Turkey contributes a high number of patients, with frequent consanguinity and private variants, including the Alu insertion; 44 Turkish families have been described [41, 98]. In China, the Alström Syndrome Greater China Association registered 161 patients in 2024, in 29 of the 34 provincial-level regions, with recurrent variants different from the European ones (c.10825C>T, c.2090C>A and c.10831_10832del, in NM_015120.4 numbering), and the 19 bp deletion of exon 16 appears frequent in Asian populations [32, 43, 68]. In the Chinese population, 41.3% of patients lived in rural areas and 22.8% attended special schools [68]. An Algerian family contributed to mapping, a consanguineous Saudi family was described with a Leber congenital amaurosis phenotype, and a recent case documents late diagnosis in rural Pakistan [2, 4, 99].

9.4 Portugal and Brazil

The sources consulted contain no data on prevalence, cohorts or variants of Alström syndrome in Portugal or Brazil. In 2007, the Centro de Genética Clínica (Porto and Lisbon), to which one of the authors of the Marshall review belonged, was among the laboratories licensed for ALMS1 testing, and there was a Brazilian patient association, Alström Syndrome-Brazil, based in Brasília [24]. Absence from these sources does not demonstrate the absence of patients or publications in the two countries.

9.5 Special populations

In children, obesity and diabetes respond to weight control, and early cardiac surveillance determines detection of cardiomyopathy [7, 59]. In deafblind people, the usual psychological and autism assessment instruments are poorly suited, and communication, mobility and daily living require specialised assessment [7]. In resource-limited settings, clinical diagnosis may be delayed until adulthood [99].

9.6 European networks and patient associations

The syndrome cuts across several European reference networks: Endo-ERN, whose thematic group 5 covers growth and genetic obesity syndromes, ERN-EYE for retinal dystrophy and ERKNet for kidney disease; the Endo-ERN public page does not list Alström syndrome by name, and the 2020 consensus was promoted by the European patient association, with specialised centres in the United Kingdom, France, Italy, Turkey and Spain [7, 14, 33]. The European EURO-WABB registry, created for Wolfram, Alström and Bardet-Biedl syndromes, collects clinical, genetic and patient experience data and facilitates access to genetic testing [1, 18]. Patient associations include Alström Syndrome Europe (www.alstromeurope.org), Alström Syndrome UK (www.alstrom.org.uk), Alström Syndrome International (www.alstrom.org), the Ciliopathy Alliance (ciliopathyalliance.org) and the Alström Syndrome Greater China Association [1, 15–17, 68].

In France, the organisation of care is based on the SENSGENE rare sensory disease health filière, often the first point of entry through visual impairment, which can build an individual care pathway in the territory and propose participation in trials, with the collaboration of the FIRENDO (rare endocrine diseases), CARDIOGEN (inherited cardiac diseases) and ORKID (rare kidney diseases) filières [10]. The PNDS lists four reference centres for rare ophthalmic disorders — CARGO (Strasbourg University Hospitals, coordinator), REFERET (Centre hospitalier national d'ophtalmologie des Quinze-Vingts, Paris), OPHTARA (Hôpital Necker-Enfants malades, Paris) and MAOLYA (Gui-de-Chauliac Hospital, Montpellier) — and competence centres in Clermont-Ferrand, Grenoble, Brest, Lille, Nantes, Marseille, Nice, Bordeaux, Poitiers, Toulouse and Saint-Denis de La Réunion [10]. The syndrome is not on the list of long-term conditions and may be recognised as an "hors liste" long-term condition, with exemption from co-payment through the care protocol established by the attending physician; the PNDS serves as the reference for this protocol and for reimbursement of products and services not usually covered, and disability support, school placement and guide dogs are applied for through the Maison Départementale des Personnes Handicapées (MDPH) [10]. The associations indicated are France Alström, Retina France and the Fédération des Aveugles de France [10].

10. Illustrative Clinical Case

Wang and colleagues published in 2026, according to the CARE guidelines, the case of a Chinese female infant in whom neonatal dilated cardiomyopathy preceded nystagmus and led to the diagnosis [3]. The child, the second daughter from a third pregnancy, was born by caesarean section at 38 weeks and 5 days, weighing 3750 g, and the prenatal and family history were unremarkable. At 25 days of life she was admitted with an eight-day history of cough and three days of respiratory distress, with signs of cardiac dysfunction. She had mild anaemia (haemoglobin 102 g/L), troponin I of 1.299 µg/L (reference < 0.058), B-type natriuretic peptide (BNP) of 5315 pg/mL (reference < 100), raised CK-MB and lactate dehydrogenase and interleukin 6 of 71.5 pg/mL; liver and kidney function were normal. Chest CT showed bronchopneumonia and a slightly enlarged cardiac silhouette. Echocardiography revealed dilatation of the left atrium (22 mm) and left ventricle (end-diastolic diameter 31 mm), ejection fraction of 39%, fractional shortening of 18%, apical trabecular thickening, moderate mitral and mild tricuspid regurgitation; the electrocardiogram showed sinus tachycardia at 155/min with T-wave changes [3].

With the diagnoses of dilated cardiomyopathy with moderate dysfunction (modified Ross score of 7), pneumonia and myocardial injury, she received amoxicillin-clavulanate, digoxin (6.15 µg/kg/day), milrinone (bolus of 30 µg/kg and infusion of 0.41 µg/kg/min), spironolactone (2 mg/kg/day), hydrochlorothiazide (2 mg/kg/day) and captopril (from 0.38 to 0.86 mg/kg/day), as well as phosphocreatine, fructose-1,6-diphosphate, levocarnitine, intravenous immunoglobulin and prednisone [3]. At discharge, ejection fraction was 43%, the left ventricle measured 28 mm and BNP had fallen to 317 pg/mL; she continued digoxin, prednisone, furosemide, spironolactone, captopril and potassium and calcium supplements. At 4 months the symptoms had disappeared and cardiac function was normal [3].

At 6 months binocular nystagmus and limb tremor appeared; the fundus and brain and orbital magnetic resonance imaging were normal. The child had no polydactyly, intellectual disability or hypogonadism [3]. Exome sequencing revealed compound heterozygosity for two frameshift variants in exon 8 of ALMS1: c.4293_4296delCACA p.(His1431Glnfs*40), inherited from the father and previously described, and c.5492delT p.(Leu1831*), inherited from the mother and novel, both classified as pathogenic; in MANE nomenclature they correspond to NM_001378454.1:c.4293_4296del p.(His1431GlnfsTer40) and c.5492del p.(Leu1831Ter) [3, 8]. Figure 1 of the article shows the electropherograms of the proband and parents (https://pmc.ncbi.nlm.nih.gov/articles/PMC13189838/figure/F1/) [3].

The case brings together the elements that make the syndrome difficult to recognise in infants: dilated cardiomyopathy between 3 weeks and 4 months, severe but reversible, as the presenting manifestation; nystagmus with a normal fundus months later; and the absence of obesity, hearing loss and metabolic abnormalities at that age [1, 7]. In the light of the age-based criteria, the child met two major criteria (infantile cardiomyopathy and nystagmus) before genetic testing, which confirmed the diagnosis [1]. Part of the therapy used (immunoglobulin, corticosteroid, phosphocreatine, fructose-1,6-diphosphate) is not part of the consensus recommendations, which advocate standard heart failure therapy; the report does not allow the recovery to be attributed to any of these drugs, because spontaneous recovery of infantile cardiomyopathy is the usual course in survivors [1, 3, 7]. After the diagnosis, the child is indicated for the 6-monthly cardiac surveillance appropriate to patients with a history of infantile cardiomyopathy, because of the risk of relapse, and for the ophthalmological, audiological and metabolic schedule in section 11 [1, 7].

11. Prognosis and Long-Term Follow-Up

11.1 Prognosis

The disease is progressive and may cause premature death [7]. Mortality is concentrated in two periods: in the first year, due to infantile cardiomyopathy, whose real lethality is unknown because some infants die before diagnosis, and in adulthood, due to heart, kidney or liver failure [1, 35]. According to the analysis of the series of 182 patients, cited in a 2026 report, heart failure caused about 90% of deaths in childhood and heart or kidney failure about 60% of deaths in adults; the same authors report a mean life expectancy of less than 50 years, without their own survival study [3, 11]. The sources consulted do not include an actuarial survival study, and the 2020 consensus reports longer survival in recent years without quantifying it [7]. Death in adolescence from multiorgan failure after acute gastroenteritis, at 14 years, and from acute liver failure, at 8 and 26 years, illustrates the variability [2].

Blindness is practically universal before 20 years, although a minority read large print in the third decade, and hearing loss progresses by 10–15 dB per decade [1, 7, 27]. End-stage chronic kidney disease may appear from adolescence, and cirrhosis in the second and third decades [1, 7]. Most young people reach adulthood with complex medical and psychosocial needs, and quality of life improves with access to specialised services [7]. Mild forms, with slow visual loss and few metabolic complications, allow a longer adult life and, in at least one case, reproduction [31, 32].

11.2 Surveillance

Table 11.1 integrates the GeneReviews schedule, based on the monitoring guidelines of Alström Syndrome International (last modified in January 2017), the recommendations of the 2020 consensus and those of the 2019 French PNDS, which sets a systematic multidisciplinary visit at least annually, more frequently if there are complications [10]. The frequencies apply to stable and controlled patients; many patients need more frequent assessments [1, 7].

Table 11.1 — Recommended surveillance

After each clinical event (cardiac decompensation, severe infection, surgery), reassessment should be brought forward, and the recommendation of monitoring until 24 hours after recovery from anaesthesia applies at all ages [7]. Transition to adult services and advance care planning are part of follow-up [7]. The 2007 schedule was less demanding: ERG once, as soon as age allowed, to support the diagnosis; acuity and fundus every 1–3 years; electrocardiogram every 1–3 years and annual echocardiography in asymptomatic patients, with an annual 6-minute walk test in patients with a history of cardiomyopathy; respiratory tests every 1–3 years; annual audiometry and otoacoustic emissions; kidney function at baseline and annually after 14 years; annual fasting glucose, HbA1c and TSH from 3 years; male gonadal function every 1–3 years from 12; annual vestibular function in childhood; liver tests and lipids every 1–3 years from 3 years; urine and growth every 1–3 years; and annual orthopaedic examination [24]. Table 11.1 replaces these intervals with those of the later sources, which are more frequent for the kidney and liver [1, 7].

12. Summary and Final Considerations

Alström syndrome is an autosomal recessive ciliopathy caused by loss of function of ALMS1, a giant centrosomal and basal body protein with ciliary and non-ciliary functions. Its recognition depends on chronology: nystagmus, photophobia and hypermetropia in the first weeks, sometimes preceded by severe and reversible dilated cardiomyopathy between 3 weeks and 4 months; truncal obesity with hyperphagia in the first years; cochlear sensorineural hearing loss after normal newborn screening; extreme insulin resistance, disproportionate to weight, with type 2 diabetes from childhood, severe hypertriglyceridaemia and steatosis with accelerated fibrosis; and, in adolescence and adulthood, fibrotic restrictive cardiomyopathy, primary chronic kidney disease, primary male hypogonadism and short stature. Intelligence is usually normal and polydactyly is not part of the picture, which separates it from Bardet-Biedl syndrome.

The diagnosis is confirmed by identification of two pathogenic variants, almost always truncating and concentrated in exons 8, 10 and 16; sequencing should be supplemented by a search for structural variants when one or no variant is found, and numbering should refer to the MANE transcript NM_001378454.1, which differs from NM_015120.4 by one codon. Retinal, cardiomyopathy, ciliopathy and obesity panels should include ALMS1, because the diagnosis often arrives through a single organ.

There is no disease-modifying therapy. The phase 3 trial of setmelanotide showed no benefit in the six patients with Alström syndrome, the results of the antifibrotic PBI-4050 have not been published and gene therapy has not reached the clinic. The value of care lies in structured multidisciplinary surveillance, defined by the 2020 international consensus and the GeneReviews schedule, and in standard and timely treatment of each complication: evidence-based heart failure therapy, lifestyle programmes adapted to blindness, metformin, SGLT2 inhibitors and GLP-1 agonists, triglyceride control, screening for hepatic fibrosis and varices, nephroprotection and transplantation, testosterone and levothyroxine, hearing aids and cochlear implantation, visual rehabilitation and deafblind support. In France, the 2019 PNDS organises the care pathway through the SENSGENE filière and the reference centres for ophthalmic genetics, with a multidisciplinary visit at least annually and diagnostic criteria that require biallelic confirmation. Anaesthesia and respiratory infections are times of risk, and glitazones and multiple blockade of the renin-angiotensin-aldosterone system require caution.

Recent research has added data on male gonadal failure, the possibility of pregnancy in mild forms, the variant spectrum outside Europe and the response to incretin agonists, but the therapeutic evidence continues to be based on small observational studies. Data from Portugal and Brazil are not included in the sources consulted, and registration of patients in European networks and patient associations is the means to better understand the natural history and enable future trials.

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