Alstrom's Syndrome: An Experience of Tertiary Care Center

Abstract

Alstrom's syndrome (AS) is an autosomal recessively inherited multisystemic disorder that falls under the umbrella of ciliopathy. It is characterized by poor vision, hearing impairment, cardiomyopathy, childhood obesity, diabetes mellitus type 2, dyslipidemia, pulmonary, hepatic, and renal failure besides systemic fibrosis. Biallelic pathogenic variants in ALMS1 gene cause AS. Retrospective study (1990–2017) included 12 Saudi patients with AS based on their phenotype, biochemical markers, and genotype. The study was approved by Fisal Specialist Hospital and Research Centre, Riyadh (RAC number 2131129) on October 2, 2012. This study showed clinical and genetic heterogeneity; six patients showed a founder mutation (IVS18–2A > T in exon 19), whereas six others showed private mutations. AS in Saudi Arabia is underdiagnosed probably because of its variable clinical manifestations. We report 12 Saudi patients with AS to enhance the awareness about this syndrome.

Introduction

Alstrom's syndrome (AS) (OMIM # 203800) is a rare autosomal recessively inherited disorder with estimated prevalence of 1:1,000,000. ¹ Patients with AS develop progressive cone-rod dystrophy that can lead to blindness, sensorineural hearing loss (SNHL), dilated cardiomyopathy, early-onset truncal obesity, insulin resistance, non–insulin-dependent diabetes mellitus (NIDDM), hypertriglyceridemia, short stature, developmental delay, recurrent respiratory infections, progressive hepatic, renal, and gonadal dysfunction. Fibrosis of unknown etiology develops in multiple organs. ^{1 2} Homozygosity mapping and linkage analysis has discovered that AS is the result of change in base pair sequence in ALMS1 gene located at chromosome 2p13 that comprises 23 exons. ^{3 4} ALMS1 gene is ubiquitously expressed in ciliated body tissues that are widely distributed in photoreceptor, endocrine, cardiopulmonary, reproductive, urological, hepatic, and central nervous system. ² Pathogenic variants of ALMS1 gene have been identified in various ethnic populations. ⁵ This study reports the morphological and molecular findings for 12 Saudi patients from nine unrelated families retrospectively.

Methods

This retrospective study was approved by the research and advice committee at King Faisal Specialist Hospital & Research Centre (KFSH&RC), Riyadh, Saudi Arabia, with RAC number 2131129 on October 2, 2012. The clinical diagnosis of AS patients was based on the cardinal clinical features that appear with age. This finding was reported by Marshall et al, (2007) ⁶ ( Table 1 ) which need to proofed by finding biallelic pathogenic variant in ALMS1 gene. The clinical information from medical records of 12 AS Saudi patients from nine unrelated families at (KFSH&RC), Riyadh, Saudi Arabia was reviewed retrospectively between 1990 and 2017. The collected data included age, sex, weight, height, body mass index, family history, consanguinity, developmental history, and endocrine assessment for NIDDM, hypothyroidism, and acanthosis nigricans. Ophthalmological and otolaryngological assessments for each patient were reviewed. The data also included the biochemical laboratory investigations of renal profile, hepatic profile, coagulation profile, bone profile, creatinine kinase, thyroid function test, luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, C-peptide, and hemoglobin A1c levels. Echocardiography and abdominal ultrasound results were reviewed for each patient. Genomic DNA was isolated from peripheral blood leukocyte, and the next-generation sequencing was used to detect the biallelic pathogenic variant in ALMS1 gene. No patient was excluded from the study.

Table 1. Cardinal diagnostic criteria for AS by Marshall et al (2007).

Age range	Major diagnostic criteria	Minor diagnostic criteria	Minimum required
Birth–2 y	ALMS1 pathogenic variant or positive family history of AS Nystagmus/photophobia/impaired vision Infantile cardiomyopathy	Obesity Sensorineural hearing loss	2 major criteria or 1 major + 2 minor criteria
3–14 y	ALMS1 pathogenic variant or positive family history of AS Nystagmus/photophobia/impaired vision (if old enough for testing: cone dystrophy by ERG) History of infantile cardiomyopathy	Sensorineural hearing loss Obesity and/or its complications (e.g., insulin resistance, T2DM, liver steatosis, hypertriglyceridemia) Cardiomyopathy ↓ renal function Hepatic dysfunction Advanced bone age	2 major criteria or 1 major + 3 minor criteria
15 y–adult	ALMS1 pathogenic variant or positive family history of AS Vision (history of nystagmus in infancy/childhood, impaired vision, legal blindness, cone and rod dystrophy by ERG)	Obesity and/or insulin resstance and/or T2DM History of cardiomyopathy sensorineural hearing loss Hepatic dysfunction Renal failure Short stature Males: hypogonadism Females: irregular menses and/or hyperandrogenism	2 major + 2 minor criteria or 1 major + 4 minor criteria

Abbreviations: AS, Alstrom's syndrome; CKD, chronic kidney disease; ERG, electroretinogram; T2DM, type 2 diabetes mellitus.

Results

The patients were from different geographical regions of Saudi Arabia. A total of 12 patients (5 females and 7 males) were born to consanguineous marriages, and 75% of them showed positive family history. Patients were aged between 2 and 21 years, with median age 10 years ( Table 2 ).

Table 2. Phenotypic characteristics of each patient.

Variables	Patient1	Patient 2	Patient 3	Patient 4	Patient 5	Patient 6	Patient 7	Patient 8	Patient 9	Patient 10	Patient 11	Patient 12
Age	2 y	9 y	Died at the age of 3 y	13 y	11 y	13 y	18 y	21 y	6 y	9 y	7 y	18 y
Sex	Male	Female	Male	Female	Female	Male	Male	Male	Female	Male	Male	Male
Height	91 cm	102 cm	123 cm	133 cm	142 cm	143 cm	177 cm	176 cm	120 cm	125 cm	124 cm	156 cm
Weight	16.8 kg	23.2 kg	29.6 kg	88 kg	39.6 kg	55 kg	95.9 kg	95.9 kg	35.9 kg	36 kg	49.4 kg	72 kg
BMI							30.6	34.6				29.6
Consanguinity	Reported	Reported	Reported	Reported	Reported	Reported	Reported	Reported	Reported	Reported	Reported	Reported
Family history	Positive for AS	Negative for AS	Positive for AS	Positive for AS	Positive for AS	Positive for AS	Positive for AS	Positive for AS	Positive for AS	Negative for AS	Negative for AS	Positive for AS
ALMS gene mutation	c.2723C > G p.Ser910*	c.12148–1260 del13 p.Arg4050Glyfs*2	c.2723C > G, p.Ser908*	c.11870–2A > T	c.8158C > T p.Arg2720	c.8164C > T p.Arg2722X	c.11870–2A > T IVS 18–2A > T	c.11870–2A > T IVS 18–2A > T	c.5139T > G p.Tyr1713*	c.IVS 18–2A > T	c.11870–2A > T, IVS 18–2A > T	c.IVS 18–2A > T
Ophthalmology	Nystagmus	Nystagmus, rod cone dystrophy	Nystagmus	Rod cone dystrophy	Nystagmus, rod cone dystrophy	Rod cone dystrophy, hyperopia, ptosis	Nystagmus rod cone dystrophy	Rod cone dystrophy	Nystagmus, rod cone dystrophy	Nystagmus pigmentary retinal degeneration	Rod cone dystrophy	Nystagmus, retinal degeneration, pale optic disc
Hearing	No specific abnormality detected	Hearing impairment	data not available	Mild sensorineural hearing loss	Mild sensorineural hearing loss	Normal hearing test	Mild sensorineural hearing loss	Sensorineural hearing loss	No specific abnormality detected	Mild sensorineural hearing loss	Sensorineural hearing loss	Mild sensorineural hearing loss
Cardiology	DCM at the age of 1 mo, resolved by 11 mo of age	No specific abnormality detected	Data not available	No specific abnormality detected	DCM and pulmonary hypertension	No specific abnormality detected	Mild dilated left ventricle	No specific abnormality detected	Resolving DCM	No specific abnormality detected	Mild tricuspid and mitral regurge EJF: 56%	No specific abnormality detected
Development	Mild global delay	Severe global delay with autistic features	Data not available	Mild developmental delay with speech problems attending special school	Developmental delay, attending special school	Developmental delay, attending special school	Developmental delay attending special school	Developmental delay attending special school	Mild developmental delay	Mild developmental delay	Mild delay with linguistic impairment attending special school	Developmental delay attending special school
Lung	No specific abnormality detected	Asthma with recurrent chest infection	No specific abnormality detected	No specific abnormality detected	Recurrent chest infection post adenotonsillectomy	No specific abnormality detected	No specific abnormality detected	No specific abnormality detected	No specific abnormality detected	No specific abnormality detected	No specific abnormality detected	No specific abnormality detected
Acanthosis nigricans	No specific abnormality detected	No specific abnormality detected	No specific abnormality detected	No specific abnormality detected	Reported	Reported	No specific abnormality detected	Reported	No specific abnormality detected	No specific abnormality detected	Reported	Reported
Endocrine	No specific abnormality detected	Hypothyroidism	No specific abnormality detected	No specific abnormality detected	No specific abnormality detected	No specific abnormality detected	Diabetes mellitus type 2	No specific abnormality detected	No specific abnormality detected	Hypothyroidism	No specific abnormality detected	Diabetes mellitus type 2
US abdomen	Mild coarse extecture of the liver	Data not available	Data not available	Fatty liver infiltration, nephromegaly	Data not available	Echogenisity of the liver with no focal areas	Fatty liver infiltration	Fatty liver infiltration	Mild enlargement of left kidney	Mild heterogenous echogenicity of the liver related to hepatic venous congestion	Mild hepatomegaly with no focal lesion	Fatty liver infiltration

Abbreviations: AS, Alstrom's syndrome; DCM, dilated cardiomyopathy; EJF, ejection fraction.

Vision and Hearing

Retinal dystrophy was a consistent feature in all the patients (100%) in this study. Hearing loss was found in 8 out of 12 patients (66%) with an average age of onset 7 years ( Table 2 ).

Endocrine and Metabolic Dysfunction

Obesity phenotypes reported in 7 patients out of 12 (58%). Acanthosis nigricans observed in Five (41%) patients; two had diabetes mellitus (16%). Hypertriglyceridemia observed in three (25%) and hypothyroidism in two (16%) patients. LH, FSH, and testosterone reports were evaluated in 4 out of 12 patients: LH was found to be high in 1 out of 4, FSH high in 2 out of 4, and testosterone was normal in all the 4 patients ( Table 3 ).

Table 3. Biochemical markers.

Laboratory investigations	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5	Patient 6	Patient 7	Patient 8	Patient 9	Patient 10	Patient 11	Patient12
Liver enzyme	Normal	Normal	High	Slightly high	Normal	High	High	Normal	Normal	Normal	Normal	High
Coagulation profile	NA	Normal	NA	High	High	Normal	Normal	Normal	Normal	Normal	NA	Normal
GGT	NA	NA	NA	High	NA	High	High	High	NA	Normal	NA	Normal
Lipid profile	High TG	Normal	Normal	Normal	NA	Normal	High TG	Normal	Normal	High TG	NA	Normal
Renal profile	Normal	Normal	Normal	Normal	Normal	Normal	Normal	Normal	Normal	Normal	Normal	Normal
Urine albumin/creatinine	NA	NA	NA	High	NA	NA	High	High	NA	NA	Normal	Normal
TFT	Normal	High TSH, low T4	NA	Normal	NA	Normal	Normal	Normal	Normal	High TSH	Normal	Normal
HbA1C	NA	NA	NA	Normal (5.9%)	NA	Normal (4.5%)	High (7.2%)	Normal	Normal (4.8%)	Normal (5.9%)	Normal (5.4%)	High (8.2%)
LH	NA	NA	NA	Normal	NA	NA	Normal	Normal	NA	NA	NA	Slightly high
FSH	NA	NA	NA	Normal	NA	NA	High	Normal	NA	NA	NA	Slightly high
Testosterone	NA	NA	NA	Normal	NA	NA	Normal	Normal	NA	NA	NA	Normal
Insulin	NA	NA	NA	Normal	NA	Normal	High	Normal	NA	NA	NA	High
Estrogen	NA	NA	NA	Normal	NA	NA	Normal	NA	NA	NA	NA	NA
C-peptide	NA	Normal	NA	NA	NA	High	Normal	Normal	NA	NA	NA	Slightly high
CK	NA	NA	NA	Normal	NA	Normal	Normal	Normal	NA	NA	NA	Normal
Aldosterone	NA	NA	NA	Normal	NA	NA	Normal	Normal	NA	NA	NA	NA

Abbreviations: CK, creatinine kinase; FSH, follicle-stimulating hormone; GGT, gamma-glutamyl transferase; HbA1c, hemoglobin A1c; LH, luteinizing hormone; NA, not available; PT, prothrombin time; T4, free thyroxine; TFT, thyroid function test; TG, triglyceride; TSH, thyroid-stimulating hormone.

Cardiopulmonary

Echocardiography reports were documented for 11 patients: reports were normal in 6 (54%) patients, dilated cardiomyopathy observed in 3 (27%) patients, and tricuspid and mitral regurgitation observed in 1 (9%) patient. Recurrent chest infection was reported in two (18%) patients, one of them was found with asthma ( Table 2 ).

Renal and Hepatic Dysfunction

Elevated liver enzymes were reported in 5 out of 12 patients (41%). Gamma-glutamyl transferase was analyzed in six patients: elevated in four (66%) patients and normal in two patients (33%). Coagulation profile was documented for nine patients: elevated in two (22%) patients and normal in seven (77%) patients. Renal profile was found to be normal in all the 12 patients (100%); urine albumin/creatinine ratio was documented for 5 patients as follows: increased in 3 (60%) patients and normal in 2 (40%) patients ( Table 3 ). Abdominal ultrasound report was documented for 9 out of 12 patients, and the findings are as follows: fatty liver infiltration in 4 (44%) patients, hepatomegaly in 1 (11%) patient, hepatic vein congestion in 1 (11%) patient, increased hepatic heterogeneity with no focal region in 3 (33%) patients, and nephromegaly in 2 patients (22%) ( Table 2 ).

Psychomotor Development and Intelligence

Developmental history was documented for 11 patients as follows: 10 patients (90%) were found with mild developmental delay, and 1 patient had severe global developmental delay with autistic behavior. Seven of the patients were attending special school (63%) ( Table 2 ).

Molecular Findings for ALMS1 Gene Sequencing

All the patients had homozygous mutations in ALMS1 gene. The most common encountered mutation was the acceptor splice site mutation (IVS 18–2A > T) and was found in six patients. Other mutations were private mutations, five of them were nonsense mutations that led to stop codon and protein termination: c.2723C > G (p.Ser910*), c.2723C > G (p.Ser908*), c.8158C > T (p.Arg2720*), c.8164C > T (p.Arg2722*), c.5139T > G (p.Tyr1713*). and the last mutation was a deletion that led to protein termination: c.12148–12160 del13 (p.Arg4050Glyfs*2) ( Table 4 ).

Table 4. ALMS1 gene sequencing for each patient .

Patients	ALMS1 gene genomic sequencing result
Patient 1	Homozygous mutation c.2723C > G (p.Ser910*)
Patient 2	Homozygous mutation c.12148–12160 del13 (p.Arg4050Glyfs*2)
Patient 3	Homozygous mutation c.2723C > G (p.Ser908*)
Patient 4	Homozygous mutation c.11870–2A > T (IVS 18–2A > T)exon 19
Patient 5	Homozygous mutation c.8158C > T (p.Arg2720 *) exon 10
Patient 6	Homozygous mutation c.8164C > T (p.Arg2722*)
Patient 7	Homozygous mutation c.11870–2A > T (IVS 18–2A > T) exon 19
Patient 8	Homozygous mutation c.11870–2A > T (IVS 18–2A > T) exon 19
Patient 9	Homozygous mutation c.5139T > G (p.Tyr1713*) exon 8
Patient 10	Homozygous mutation: splice acceptor site mutation(IVS 18–2A > T) exon 19
Patient 11	Homozygous mutation:c.11870–2A > T exon 19
Patient 12	Homozygous mutation: splice acceptor site mutation IVS 18–2A > T exon 19

Discussion

AS is an autosomal recessive ciliopathy. As the disease progresses, multiple organ failure may occur. This syndrome was first described by Carl-Henry Alstrom in 1959 as a progressive retinal degeneration, obesity, neuronal hearing loss, and insulin resistance. ^{7 8} AS is diagnosed based on the cardinal signs that appear with age and proofed by biallelic pathogenic variant in ALMS1 gene. The clinical findings of AS are similar to a variety of diseases such as Leber congenital amaurosis, idiopathic dilated cardiomyopathy, Bardet–Biedl's syndrome, and mitochondrial disease. Despite the challenges of clinical diagnosis because of its heterogeneous nature and the gradual emergence of the clinical signs, genetic studies are of great help in confirming the diagnosis and facilitating the prevention and development of customized therapy. ^{9 10} The earliest clinical manifestations of AS are usually ophthalmological problems including nystagmus, photophobia, and impaired vision caused by progressive cone-rod dystrophy. The other common initial presentation is infantile-onset cardiomyopathy. ⁷ Most patients older than 15 to 20 years are legally blind, ^{8 11} More than 60% of AS cases develop congestive heart failure at some stage of their lives as a result of infantile-, adolescent-, or adult-onset dilated cardiomyopathy. ⁷ Approximately 20% of AS patients develop a later onset progressive restrictive cardiomyopathy identified between the teens and late 30s. A characteristic feature of these individuals is myocardial fibrosis documented at postmortem. ^{7 10} The progressive bilateral SNHL is a well-known manifestation of AS with a median age of 7 years. ⁷ Majority of AS newborn patients pass the screening for hearing loss. ¹² The sensory deficits for hearing and vision were reflected by receptive and expressive language delay while the intelligence (IQ) is normal in most of the AS individuals. ⁶ The comprehensive analysis led by Marshall et al, who defined the phenotype for 182 AS cases, showed that developmental milestones were delayed in 46%. Fine and gross motor skill and mixed receptive-expressive language delays besides autistic spectrum behavioral disorders were also reported. ¹¹ Metabolic and endocrine system disturbances commonly observed in AS lead to body weight gain, insulin resistance, acanthosis nigricans, NIDDM (median age of onset 16 years), dyslipidemia mainly hypertriglyceridemia, hypothyroidism, and gonadal dysfunction. ^{8 11 13} Randomized controlled trials have shown that low-carbohydrate diet is more effective than low-fat diet to control hyperglycemia and hyperinsulinism in AS. ¹⁴ Additional systemic involvement includes pulmonary, hepatic (mainly nonalcoholic fatty liver disease), renal, and urological dysfunctions, and systemic fibroses. ^{7 8 9 11} No obvious differences were observed in the clinical manifestation of 12 Saudi participants in this study in comparison to a systemic literature review on AS. ⁸ The visual impairment was the earliest and the most consistent observation in all patients, except in one patient who presented initially with neonatal cardiogenic shock and subsequently developed ophthalmologic symptoms. Other clinical manifestations of variable degrees were seen with increasing age. More than 268 ALMS1 gene pathogenic variants were reported, of which the most encountered types were nonsense or frameshift changes that could produce truncated, nonfunctional protein. Most of the deleterious variants were clustered in exons 8, 10, and 16, which were considered as mutational hotspots. ⁸ Four Saudi studies have been published on the molecular bases of AS ^{9 13 15 16} ( Table 5 ). Aldahmesh et al (2009) ¹⁵ discussed the allelic heterogeneity in inbred populations and identified four novel pathogenic homozygous variants in ALMS1 gene. These pathogenic variants include c.5534 C > G (S908*) mutation and c.5981delCAGA leading to premature truncation in exon 8, R2720* mutation in exon 10, and acceptor splice site mutation in exon 19. Safieh et al (2016) ¹⁶ reported two cases from two different consanguineous families who presented with retinal dystrophies and identified novel pathogenic nonsense variant in ALMS1 gene which resulted in protein truncation (c.8441C > A, p.S2814*). Bakar et al (2017) ¹³ in their study reported a girl with a history of NIDDM, vision and hearing deficits, and empty sella turcica with significant family history. A ALMS1 gene homozygous deletion was identified in exon 20 (c.12154_12166del) (p. Arg4052Glyfs∗2). Kamal et al (2020) evaluated the genetic bases of the familial form of AS in their study of five AS patients from two different Bedouin families from Saudi Arabia. Family A showed two different homozygous ALMS1 variants including c.1159A > T T376S located in exon 5 and c.2759C > G S909* located in exon 8. Family B showed homozygous (c.8194 C/T R2721*) variant at exon 10 of ALMS1 gene. ⁹ All the mutations in this study, nonsense, deletion, or splice site, predicted premature truncation in ALMS1 protein: six patients with founder mutation (IVS18–2A > T) of exon 19, ¹⁵ the remaining six patients showed private mutations ( Table 4 ). No clear genotype-to-phenotype correlation was observed in the 12 AS cases; even patients with the same founder pathogenic variant in ALSM1 gene (IVS18–2A > T) had variable appearance of clinical features.

Table 5. ALMS1 gene molecular findings in each study .

Study	ALMS1 gene molecular findings
Aldahmesh et al (2009)	1-c.5534 C > G (S908*) 2-c.5981delCAGA leading to premature truncation in exon 8 3-R2720* mutation in exon 10 4-acceptor splice-site mutation in exon 19
Safieh et al (2016)	c.8441C > A, p.S2814*
Bakar et al (2017)	c.12154_12166del, p. Arg4052Glyfs∗2 exon20
Kamal et al (2020)	Family A: showed two different homozygous ALMS1 variants including (c.1159A > T T376S) located in exon 5 and (c.2759C > G S909*) located in exon 8 Family B: showed (c.8194 C/T, R2721*) variant at exon 10

Conclusion

This was the largest retrospective study on AS in Saudi Arabia, which was conducted in a single center. Wide clinical variability was observed among affected individuals, even within the same family with the same biallelic pathogenic ALMS1 variant. The phenotypes of 12 Saudi patients from nine unrelated families were described in this study to raise the awareness of the variable clinical manifestations that may overlap a variety of other differentials.