Alström Syndrome: A Review Focusing on Its Diverse Clinical Manifestations and Their Etiology as a Ciliopathy

ABSTRACT

Alström syndrome is a form of inherited obesity caused by a single gene abnormality and is inherited as an autosomal recessive trait. It is characterised by a variety of clinical manifestations, including progressive visual and hearing impairment, type 2 diabetes mellitus, dilated cardiomyopathy, and hepatic and renal dysfunction, in addition to obesity. Recent insights underline the pivotal involvement of the disease-associated gene (ALMS1) in cilia formation and function, leading to the classification of its clinical manifestations as a ciliopathy. This review delineates the diverse clinical indicators defining the syndrome and elucidates its pathological underpinnings.

CONCEPT AND DEFINITION

Alström syndrome (MIM #203800) is a genetic form of obesity inherited in an autosomal recessive manner.¹ Apart from obesity, it manifests as various other clinical symptoms, including progressive visual and hearing impairment, type 2 diabetes mellitus with hyperinsulinemia, dilated cardiomyopathy, and hepatic and renal dysfunction. Initially characterized by Alström in 1959, this syndrome differs from Bardet-Biedl syndrome, sharing a clinical resemblance but lacking polydactyly or intellectual disability.²

EPIDEMIOLOGICAL CHARACTERISTICS

Alström syndrome is classified as a rare disease, with an estimated incidence ranging from 1 in 100,000 to 1 in 1 million.^{3, 4} However, it has been noted that a considerable number of Alström syndrome cases might evade diagnosis because of its infrequent onset and the wide spectrum of clinical manifestations that vary in severity. To date, approximately 1,200 cases of Alström syndrome have been documented globally.^5,6,7,8

CLINICAL SYMPTOMOLOGY AND DIAGNOSTIC CRITERIA

The clinical presentation of Alström syndrome encompasses a spectrum of organ-related abnormalities and involves childhood onset of obesity, along with visual and hearing impairments, diabetes, cardiomyopathy, liver damage, renal damage, and gonadal dysfunction. Typically, children exhibit visual impairment in infancy, followed by obesity in early childhood, hearing loss in late childhood, and the onset of type 2 diabetes with severe insulin resistance in childhood and adolescence. Additional manifestations include dilated cardiomyopathy,progressive liver and kidney dysfunction, and hypogonadism. Diagnosis poses a challenge owing to the variability of the severity of these disorders among affected individuals, their progressive nature, and the wide range of onset time extending from infancy to adulthood.^{9, 10}Table 1 provides an overview of the diverse clinical signs suggestive of Alström syndrome.¹¹

Table 1.  Suggestive signs of Alström syndrome¹¹.

1)	Cone-rod dystrophy with decreased vision and secondary nystagmus and photodysphoria (light sensitivity / photophobia) usually within the first year of life. Full-field electroretinography, required to establish the diagnosis of cone-rod dystrophy, is abnormal from birth, eventually with impairment of both cone and rod function. Fundus examination in the first decade may be normal or may show a pale optic disc and narrowing of the retinal vessels.
2)	Early childhood-onset obesity, primarily truncal with a body mass index (BMI: kg/m2) greater than 25 (for adults) or greater than the 95th centile on age- and sex-appropriate growth charts*
3)	Progressive bilateral sensorineural hearing impairment (initially in the high-frequency range), usually diagnosed between ages one and ten years, although onset can vary
4)	Acute infantile-onset cardiomyopathy and/or adolescent- or adult-onset restrictive cardiomyopathy
5)	Insulin resistance / type 2 diabetes mellitus (T2DM), the result of tissue resistance to the actions of insulin, usually present in childhood and manifest as elevated plasma insulin concentration and glucose intolerance. Insulin resistance ranges from hyperinsulinemia to glucose intolerance to T2DM, depending on the age of the individual. T2DM can develop in childhood or adolescence.
6)	Normal stature in childhood; short stature in adulthood
7)	Hypogonadism, non-autoimmune hypothyroidism, and female hyperandrogenism
8)	Urologic dysfunction / detrusor instability
9)	Progressive decrease in renal function
10)	Hepatic disease that is variable and ranges from elevated transaminases to steatohepatitis / nonalcoholic fatty liver disease (NAFLD). The liver and spleen may be enlarged. Extensive fibrosis, cirrhosis, portal hypertension, and liver failure have been described.
11)	Hypertriglyceridemia
12)	Hypertension
13)	Gradual thickening of subcutaneous tissues (e.g., thick ears)
14)	Alopecia

*Marked obesity is not always present in adulthood.

Diagnostic criteria for this condition were proposed by Marshall et al.,¹² in which they set out major and minor criteria. The major criteria include the presence of a pathogenic allele of the syndrome or a family history of the syndrome and visual impairment such as nystagmus, blindness, and cone and rod dystrophy, while the minor criteria include obesity, diabetes mellitus, cardiomyopathy, hearing loss, hepatic dysfunction, renal failure, short stature, hypogonadism. hearing loss, hepatic dysfunction, renal failure, short stature, hypogonadism, etc. Two major criteria or one major criterion and 2–4 minor criteria are required for diagnosis, with the number of minor criteria required depending on age (birth - 2 years, 3 - 14 years, 15 years- adulthood).

Visual impairment

The onset of retinitis pigmentosa in a patient leads to a progressive decline in visual function. This deterioration is indicated by symptoms such as nystagmus and photophobia emerging within the first year of life, followed by noticeable visual impairment before the age of 3 y. The condition steadily advances thereafter, with photophobia recurring around the age of 10 y, and frequently culminating in complete blindness by approximately the age of 15 y.^11,12,13

Hearing impairment

Patients with Alström syndrome typically exhibit mild to moderate progressive sensorineural hearing loss, often detected before primary school entry. Hearing impairment usually manifests after the acquisition of language; hence, instances of language impairment are rare. However, in approximately 10% of cases, severe hearing loss may coincide with blindness, necessitating the reliance on tactile communication.^{11, 12, 14}

Endocrine/metabolic disorders

Obesity

In Alström syndrome, the onset of obesity typically occurs in infancy and is often inevitable.¹⁵ While their weight at birth is within the normal range, affected individuals typically become obese (≥ 95th percentile) by the age of 3 y, and progress from childhood obesity to adult obesity.^{11, 12} The obesity associated with this condition is characterized by increased visceral fat³ or subcutaneous fat.¹⁶ Exacerbation of obesity serves as a contributing factor to the development of diabetes mellitus as well. While obesity is considered a feature of the syndrome, some reports suggest that obesity is not always present in adulthood.^{17, 18}

Short stature

Although short stature may not be evident during childhood, individuals with Alström syndrome often experience rapid attainment of final height owing to accelerated bone maturation. Ultimately, the average adult stature is 158.7 ± 0.9 cm for men and 150.4 ± 1.5 cm for women (< 5th percentile).^{11, 12}

Diabetes mellitus

Affected individuals present with type 2 diabetes characterized by severe insulin resistance, evident through hyperinsulinemia typically observed between 18 mo and 4 y of age. Concurrently, manifestations of acanthosis nigricans appear on areas such as the neck, axilla, elbows, and knees.^{11, 12, 19} The onset of diabetes varies considerably among individuals, occurring as early as 4 y and an average of 16 y of age. Apart from insulin resistance, the exhaustion of pancreatic beta cells is considered a contributing factor to the onset of diabetes as well.²⁰

Hypogonadism

In affected males, pubertal development of testicles, penis, and related structures is delayed, often accompanied by gynecomastia and male infertility. This is indicative of hypergonadotropic hypogonadism. Testicular biopsies show atrophy with few Leydig cells and fibrosis in the seminiferous tubules.^{11, 12, 21} Conversely, in affected females, the development of external genitalia and mammary glands proceeds normally, and the timing of menarche is typical. However, menstruation commonly exhibits irregularities. While gonadotropin and estrogen levels remain within normal ranges, hyperandrogenemia is observed. Ovarian cysts are reported in approximately 20% of all cases.^{11, 12}

Hyperlipidemia

Elevations in serum triglyceride and cholesterol levels have been documented.^{11, 12, 16}

Urinary diseases and renal dysfunction

Alström syndrome manifests with renal tubular dysfunction, including panaminoaciduria, urine concentration disorder, and hypercalciuria. Histologically, observations reveal glomerular loop abnormalities and thickening of the basement membrane of the renal tubular epithelium. As the disease advances, interstitial fibrosis and glomerulosclerosis become apparent. Renal dysfunction, although varying in severity among individuals, tends to progress and culminate in renal failure in the later stages. The extent of renal damage can significantly impact the prognosis of the disease.^{11, 12, 22}

Liver dysfunction

Fatty liver, liver fibrosis, cirrhosis, esophageal varices, and portal hypertension are commonly observed in affected individuals. Histologically, findings include chronic active hepatitis and non-alcoholic steatohepatitis.^{11, 12, 23} Additionally, an association between the onset of liver dysfunction and insulin resistance has been speculated.

Cardiomyopathy

Dilated or restrictive cardiomyopathy affects over 60% of all patients with Alström syndrome, with the highest incidence observed during the neonatal stage to early infancy and adolescence to adulthood. The majority of affected individuals, approximately two-thirds, develop cardiomyopathy and heart failure between 1 wk and 16 mo of age, although most cases resolve by the age of 3 y.Nonetheless, there are instances where the disease recurs during adolescence or adulthood and progresses to a fatal outcome.^{11, 12, 24} Mitogenic cardiomyopathy, characterised by persistent markers of mitotic activity in cardiomyocytes, is seen in infants who have undergone heart transplantation for the disease.²⁵

Respiratory diseases

Reports have indicated the presence of chronic lung disease, sinusitis, and recurrent pneumonia in affected individuals. Frequently, these infections lead to fatal outcomes.^{11, 12} Despite the similarity of respiratory symptoms to primary ciliary dyskinesia, electron microscopic analysis of a bronchial or nasal ciliary biopsy in this syndrome does not reveal ultrastructural abnormalities consistent with primary ciliary dyskinesia.²⁶

Neurological findings

Patients usually have normal intelligence or mild intellectual impairment.^{11, 12} However, it has been reported that half of Alström syndrome patients with normal intelligence have early vascular-like lesions, grey and white matter atrophy, or diffuse supratentorial white matter derangement.²⁷

Typical presentation

The clinical presentation of Alström syndrome, diagnosed based on visual impairment, obesity, and positive glucose urine test, is depicted in Fig. 1.²⁸

Fig. 1.

 Clinical findings of a case of Alström syndrome²⁸

DIFFERENTIAL DIAGNOSES

The diagnosis of Alström syndrome is generally straightforward owing to its characteristic clinical signs, although there is some overlap with Bardet-Biedl syndrome. Common manifestations between these two syndromes include retinitis pigmentosa (typically manifests earlier in Alström syndrome), central obesity, insulin resistance or type 2 diabetes, non-alcoholic fatty liver disease, renal dysfunction, and hypogonadism. However, distinctive features of Alström syndrome include normal cognitive function, cardiomyopathy (present in approximately 60% of all cases), progressive sensorineural hearing loss, and chronic lung disease. Conversely, polydactyly is a hallmark feature of Bardet-Biedl syndrome.^{29, 30}

ETIOLOGICAL/PATHOLOGICAL CHARACTERISTICS

ALMS1 gene

In 2002, Collin et al.³¹ and Hearn et al.³² independently identified ALMS1 (12.9 kb, 4,169 aa, MIM *606844), the gene associated with Alström syndrome. Situated on chromosome 2q13, the ALMS1 gene is 224 kb long and comprises 23 exons. The ALMS1 protein is a substantial molecule weighing 461 kDa and composed of 4,169 amino acids.^{31, 32} Expression of the ALMS1 gene is observed across various organs, including the pituitary gland, eyes, thyroid, heart, liver, pancreas, kidney, urinary tract, testis, ovary, uterus, lungs, large intestine, adrenal gland, mammary gland, placenta, and thymus.^{31, 32}

Relationship between genotype and phenotype

To date, approximately 80 pathogenic variants of the ALMS1 gene have been documented, predominantly comprising nonsense mutations, deletions, and insertions.^{5, 7, 31, 32, 33} Notably, a higher frequency of pathogenic variants is observed in exons 8, 10, and 16, which are recognized as hot spots for variants. Regarding the disease phenotype, it is observed that variants in exon 16 tend to manifest with an earlier onset and more severe symptoms, whereas variants in exon 8 often present with milder symptoms, or in some cases, exhibit either delayed onset or are asymptomatic.^{11, 12, 33} However, recent reports suggest that genetic variants are not always associated with clinical symptoms.³⁴

ALMS1 protein abnormality and development of Alström syndrome

In 2005, Hearn et al. demonstrated through immunofluorescence analysis that the ALMS1 protein exhibits distribution across multiple organs of the body. Intracellularly, it localizes in the centrosomes and the base of cilia, which serve as initiation sites for microtubule formation.³⁵ Additionally, in fibroblasts obtained from individuals with Alström syndrome, seemingly normal centrosomes, microtubules, and primary cilia were observed, indicating a potential role for ALMS1 protein in ciliary function rather than its formation.³⁵

In 2005, Collin et al. demonstrated that Alms1^−/− mice exhibit symptoms reminiscent of Alström syndrome, encompassing obesity, hypogonadism, hyperinsulinemia, retinitis pigmentosa, and hearing loss. Additionally, they illustrated the involvement of ALMS1 protein in the intracellular transport within the cilia of the photoreceptor cells.³⁶

In a subsequent study in 2007, Li et al. observed that while cilia formation occurred in collecting duct cells within the renal medulla of Alms1-knockdown mice, their growth was notably impaired. This study revealed that the normal calcium influx response to mechanical stimuli was compromised. Furthermore, they attributed renal damage observed in Alström syndrome to impaired cilia formation and function resulting from ALMS1 abnormalities. It was also noted that in mice with Alms1 knockdown, age-related changes such as disappearance of cilia in the proximal renal tubular cells occurred.³⁷

In 2010, Jagger et al. reported that ALMS1 protein is implicated in planar cell polarity in the cochlear hair cells. Their findings indicated that in Alms1−/− mice, cilia loss in hair cells progressed with age, suggesting the involvement of ciliary dysfunction in the hearing loss associated with Alström syndrome.³⁸

Subsequent investigations have underscored the multifaceted roles of ALMS1 protein within the body, including roles in energy metabolism homeostasis, cell differentiation, signal transduction within the cilia, cell cycle regulation, and intracellular transport.³⁹

Features as a ciliopathy

Recent investigations have elucidated that the pathogenesis of Alström syndrome and Bardet-Biedl syndrome, both categorized as genetic obesity disorders, stems from genetic abnormalities affecting the formation and function of primary cilia (non-motile cilium) throughout the body.^{40, 41} Consequently, these conditions have increasingly been recognized as forms of ciliopathy.^{42, 43} Additionally, emerging research has unveiled associations between alterations in the morphology and function of primary cilia in neurons of the leptin-melanocortin system within the hypothalamus and the onset of obesity.^44,45,46,47 These findings offer promise for future elucidation of the mechanisms underlying obesity, a common symptom shared by both diseases.

TREATMENT AND PROGNOSIS

Given the current lack of understanding regarding the precise onset mechanisms of Alström syndrome, fundamental treatment remains unavailable. Consequently, symptomatic management is employed to address the diverse array of symptoms associated with the condition.^{11, 12, 48} Given the progressive nature of renal dysfunction in this disease, ongoing monitoring of renal function is imperative. Renal protection is typically managed through the administration of ACE inhibitors. In cases of decompensated renal failure, kidney transplantation may be indicated.^{11, 12} For cardiomyopathy management, a combination of diuretics, spironolactone, digitalis, beta-blockers, and ACE inhibitors is commonly prescribed.^{11, 12} Regarding diabetes management, therapeutic approaches include carbohydrate restriction, high-dose subcutaneous insulin administration, biguanides, thiazolidines, and GLP-1 agonists.^{49, 50} Thiazolidine drugs have also demonstrated efficacy against insulin resistance in Alström syndrome.⁵¹

CONCLUSION

Advancements in understanding the role of primary cilia in vivo are concurrently shedding light on the pathology of Alström syndrome. With ongoing research efforts, there is optimism for the development of novel treatment modalities aimed at addressing the underlying mechanisms of the condition in the future. However, as Alström’s syndrome is estimated to account for approximately 20% of all inherited retinal diseases, with a prevalence of 1 in 1000-4000 people,⁵² the current prevalence rate suggests that many of the syndrome are being missed. It is hoped that by the time the development of a cure for the syndrome is on the horizon, a medical system will be established to ensure that all patients with the syndrome are correctly diagnosed.

Overall, this review summarizes the characteristics of Alström syndrome and its clinical manifestations, enabling better diagnosis and treatment of this disease.