DiagnosisClinical DiagnosisThe diagnosis of Alström syndrome is based on cardinal clinical features that emerge throughout infancy, childhood, and young adulthood (see Table 1 and Figure 1).FigureFigure 1. Age range of onset of features in Alström syndrome Cardinal features that evolve as affected individuals age are as follows [Marshall et al 2005]:Major featuresCone-rod dystrophy with secondary nystagmus and photodysphoria (light sensitivity/photophobia) usually occurs within the first year of life. Obesity, primarily truncal with a body mass index (BMI: kg/m²) greater than 25 or greater than the 95th centile, develops in early childhood. Progressive bilateral sensorineural hearing impairment usually develops between ages one and ten years, but onset can be variable. The hearing impairment is initially in the high frequency range. Dilated cardiomyopathy with infantile onset or restrictive cardiomyopathy in adolescents and adults occurs in more than 60% of affected individuals. Pulmonary disease ranges in severity from frequent bronchial infections to pulmonary fibrosis and pulmonary hypertension. Insulin resistance/type 2 diabetes mellitus. Insulin resistance ranges from hyperinsulinemia to glucose intolerance to type 2 diabetes mellitus, depending on the age of the individual. Type 2 diabetes can develop in childhood or adolescence.Hepatic disease is variable, ranging from elevated transaminases to steatohepatitis. The liver and spleen may be enlarged. Extensive fibrosis, cirrhosis, portal hypertension, and liver failure are described.Renal disease is progressive; severity of the glomerulosclerosis is highly variable. Minor featuresHypothyroidismDental abnormalities (e.g., discolored enamel bands, abnormally located or extra teeth) Wide, flat feetHypogonadism in males/hyperandrogenism in femalesUrologic dysfunction/detrusor instabilityDelay in early developmental milestones, including fine and gross motor delays as well as expressive and receptive language delaysAbnormal head MRI findings (empty sella turcica in some affected individuals); tonic-clonic seizuresDistinctive facial features (deep-set eyes, round face, hyperostosis frontalis interna, thick ears, premature frontal balding, thin hair)As described in Marshall et al [2007a], diagnostic criteria have been revised to take the age of the affected person into consideration (Table 1). Table 1. Diagnostic Criteria by AgeView in own windowAge RangeDiagnostic CriteriaOther Variable Supportive EvidenceMajor Minor Minimum RequiredBirth - 2 yrs 1• ALMS1 mutation in 1 allele
AND/OR
• Family history of Alström syndrome
• Vision (nystagmus, photophobia) • Obesity
• DCM/CHF2 major criteria
OR
1 major + 2 minor criteria• Recurrent pulmonary infections
• Normal digits
• (History of) delayed developmental milestones3-14 yrs• ALMS1 mutation in 1 allele
AND/OR
• Family history of Alström syndrome
• Vision (nystagmus, photophobia, diminished acuity, if old enough for testing: cone dystrophy by ERG)• Obesity and/or insulin resistance and/or T2DM
• (History of) DCM/CHF
• Hearing loss
• Hepatic dysfunction
• Renal failure
• Advanced bone age2 major criteria
OR
1 major + 3 minor criteria• Recurrent pulmonary infections
• Normal digits
• (History of) delayed developmental milestones
• Hyperlipidemia
• Scoliosis
• Flat wide feet
• Hypothyroidism
• Hypertension
• Growth hormone deficiency
• Recurrent UTI15 yrs - adult• ALMS1 mutation in 1 allele
AND/OR
• Family history of Alström syndrome
• Vision (history of nystagmus in infancy/childhood, legal blindness, cone and rod dystrophy by ERG)• Obesity and/or insulin resistance and/or T2DM
• (History of) DCM/CHF
• Hearing loss
• Hepatic dysfunction
• Renal failure
• Short stature
• Males: hypogonadism
• Females: irregular menses and/or hyperandrogenism2 major + 2 minor criteria
OR
1 major + 4 minor criteria• Recurrent pulmonary infections
• Normal digits
• (History of) delayed developmental milestones
• Hyperlipidemia
• Scoliosis
• Flat wide feet
• Hypothyroidism
• Hypertension
• Growth hormone deficiency
• Recurrent UTI / urinary dysfunction
• AlopeciaAdapted from Marshall et al [2007a]. Reprinted with permission of Nature Publishing Group Note: The diagnosis is established in individuals of all ages in whom two ALMS1 mutations are identified.ERG = electroretinogramT2DM = type 2 diabetes mellitusDCM/CHF = dilated cardiomyopathy with congestive heart failureUTI = urinary tract infections1. Children in this age group should be reevaluated for the presence of major and minor criteria after infancy.Molecular Genetic TestingGene. ALMS1 is the only gene in which mutations are known to cause Alström syndrome. Clinical testing Table 2. Summary of Molecular Genetic Testing Used in Alström SyndromeView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityALMS1Targeted mutation analysis19-bp insertion exon 16 2See footnote 2Clinical Sequence analysis of select exons: 16, 10, and 8 3Sequence variants 425%-40% 5, 6Sequence analysis of entire coding region 7Sequence variants 4Two mutant alleles in 8/12 individuals 6, 8Deletion / duplication analysis 9Exonic and whole-gene deletionsUnknown 6, 101. The ability of the test method used to detect a mutation that is present in the indicated gene2. Identifed in Acadian kindred [Collin et al 2002]3. Exons sequenced may vary by laboratory.4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.5. Collin et al [2002], Hearn et al [2002], Titomanlio et al [2004], Marshall et al [2007a] 6. Although there is no evidence for locus heterogeneity in Alström syndrome, possible other explanations for the low mutation detection frequency are sequence analysis of select exons misses mutations elsewhere in gene, deletion of an exon(s) would not be detected by sequence analysis, and diagnostic confusion may exist between Alström syndrome and other disorders such as Bardet-Biedl syndrome (BBS) (see Differential Diagnosis).7. Newer sequencing methodologies have also been applied [Bell et al 2011, Pereiro et al 2011].8. In a study of 12 individuals from the UK in which Minton et al [2006] sequenced the entire coding region; both mutations were identified in 8/12, one mutation in 2/12, and no mutation in 2/12.9. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.10. A gross deletion has been reported in a consanguineous family from northern Pakistan [Bond et al 2005].Test characteristics. Information on test sensitivity, specificity, and other test characteristics can be found at GeneCards [Marshall et al 2011a; click here for full text]. Interpretation of test resultsGiven the current detection rate, failure to identify a disease-causing sequence variant does not preclude the diagnosis of Alström syndrome. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a proband. The diagnosis of Alström syndrome relies primarily on clinical findings and/or family history. In some instances the diagnosis can be confirmed by molecular genetic testing. Sequence analysis of the coding region should be performed: tiered testing with sequencing of select exons first, followed by analysis of the entire gene. The frequency of deletions is unknown but deletion/duplication analysis may be clinically indicated in some instances. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be caused by mutations in ALMS1.}

Natural HistoryA wide range of clinical variability is observed among individuals with Alström syndrome, including among sibs [Hoffman et al 2005]. The first clinical presentation of Alström syndrome (Table 3) is usually nystagmus caused by cone-rod dystrophy and resulting in childhood blindness. Disease characteristics that are later in onset include truncal obesity that manifests during the first year of life, progressive sensorineural hearing loss, infantile-onset dilated cardiomyopathy or later-onset restrictive cardiomyopathy, insulin-resistant type 2 diabetes mellitus, and hepatic, pulmonary, and renal dysfunction.Table 3. Age of Onset and Incidence of Common Features of Alström SyndromeView in own windowFeatureAge of Onset Range (Mean)IncidenceCone-rod dystrophyBirth - 15 mos (5 mos)100%ObesityBirth - 5 years (2.5 yrs)98%Progressive sensorineural hearing loss2-25 yrs (9 yrs)88%Dilated cardiomyopathy2 wks - 4 mos42%Restrictive cardiomyopathyJuvenile - late 30s18%Insulin resistance / type 2 diabetes mellitus4-30 yrs / 8-40 yrs (16 yrs)92% / 68%Developmental delayBirth-adolescence25%-30%Short staturePuberty - adult98%Hypogonadotropic hypogonadism10+ yrs78% of malesUrologic diseaseAdolescence - adult48%Renal diseaseAdolescence - adultVariably progressive with age in all individualsHepatic disease8-30 yrs23%-92%Based on a study of 182 patients by Marshall et al [2005]Cone-rod dystrophy. In most affected individuals, visual problems present as progressive cone dystrophy resulting in visual impairment, photophobia, and nystagmus between birth and age 15 months. Full-field electroretinography (ERG), required to establish the diagnosis of cone-rod dystrophy, is abnormal from birth, eventually with impairment of both cone and rod function. Rod function is preserved initially but deteriorates as the individual ages, with visual acuity of 6/60 or less by age ten years, increasing constriction of visual fields, and no light perception by age 20 years. In some rare cases, some vision (e.g., the ability to read large print) is retained into the third decade. The severity and age of onset of the retinal degeneration vary among affected individuals [Malm et al 2008].Fundus examination in the first decade may be normal or may show a pale optic disc and narrowing of the retinal vessels. Posterior subcapsular cataracts are common, even in the absence of diabetes. Obesity. Children with Alström syndrome have normal birth weight. Hyperphagia and excessive weight gain (some studies show weight gain greater than expected for intake) begin during their first year, resulting in childhood truncal obesity. In some individuals body weight tends to normalize, decreasing into the high-normal to normal range after adolescence. The degree of obesity may mirror cultural background, with higher levels in North America than in South America, Turkey, Japan, and parts of Europe [Koc et al 2006].Progressive bilateral sensorineural hearing loss. Hearing loss may be detected as early as age one year, initially in the high frequency range. Progressive sensorineural hearing loss presents in the first decade in as many as 70% of individuals with Alström syndrome. Hearing loss may progress to the severe or moderately severe range (40-70 db) by the end of the first to second decade [van den Abeele et al 2001]. A high incidence of glue ear (long-standing sticky fluid in the middle ear) can lead to an additional conductive hearing loss [Marshall et al 2005]. Cardiomyopathy. More than 60% of individuals with Alström syndrome develop congestive heart failure as a result of cardiomyopathy at some stage of their lives. Onset, progression, and clinical outcome of the cardiomyopathy vary, even within families [Makaryus et al 2003, Hoffman et al 2005]. More than 40% of affected infants have a transient but severe dilated cardiomyopathy with onset between age three weeks and four months [Marshall et al 2005]. Most of these children survive and make an apparently full recovery in infancy. At a later age about 10%-15% of this group have spontaneous recurrence of a progressive restrictive cardiomyopathy. The proportion of those with Alström syndrome who develop infantile-onset cardiomyopathy may be underestimated because some infants who succumb may have undiagnosed Alström syndrome.About 20% of individuals with Alström syndrome have later-onset progressive restrictive cardiomyopathy identified between the teens to late 30s. Postmortem myocardial fibrosis has been described [Marshall et al 2005]. Cardiac magnetic resonance imaging suggests that myocardial fibrosis may be present in clinically affected and asymptomatic individuals [Loudon et al 2009]. Insulin resistance/type 2 diabetes mellitus. Diabetes mellitus in Alström syndrome is the result of tissue resistance to the actions of insulin, as demonstrated by an elevated plasma insulin concentration and glucose intolerance that usually present in childhood. The age at which type 2 diabetes mellitus develops varies; it may be as early as age five years. Type 2 diabetes mellitus and insulin resistance are typically accompanied by the skin changes of acanthosis nigricans, i.e., velvety hyperpigmented patches in intertriginous areas.In a small study of 12 unrelated individuals with Alström syndrome, obesity (BMI and waist circumference) decreased with age, whereas insulin resistance increased with age [Minton et al 2006].Coronary artery disease as a result of insulin resistance, diabetes, dyslipidemia, and renal failure has been reported in one affected individual [Jatti et al 2012]. Diabetic peripheral neuropathy with risk of foot ulceration (which would be expected to develop) has been found to occur rarely if at all [Paisey et al 2009].Hyperlipidemia. Hyperlipidemia is primarily hypertriglyceridemia, but can sometimes include high serum concentration of total cholesterol. Affected individuals are at risk for sudden increase in triglycerides precipitating life-threatening pancreatitis [Wu et al 2003]. Developmental delay. About 20% of affected individuals have delay in early developmental milestones including delays in gross and fine motor skills and in expressive and receptive language. About 30% have a learning disability. Cognitive impairment (IQ <70) is very rare. Short stature. Growth rates for young children are normal, but accelerated skeletal maturity (2-3 years advanced bone age) and low-serum growth hormone concentrations result in adult stature that is typically less than the 25th centile. In about 98% of individuals over age 16 years height is below the fifth centile [Maffei et al 2007]. Scoliosis or kyphosis, beginning in puberty, is common [Maffei et al 2002].Male pubertal development. There is a variable mixture of hypogonadotropic hypogonadism and testicular fibrosis which can result in delayed or arrested puberty. As a result secondary sexual characteristics may be normal or immature; gynecomastia may be present [Marshall et al 2005]. This mixed causality has meant that puberty is induced and androgenization maintained with testosterone rather than gonadotropins. Male fertility has not been systematically studied in the syndrome but has not been reported in an affected individual with pathologic mutations in both copies of ALMS1.Female pubertal development. Endocrine disturbances in females include reduced plasma gonadotropin concentrations, hirsutism, polycystic ovarian syndrome consistent with insulin resistance, precocious puberty (pubertal onset before age 8 years), endometriosis, irregular menses, or amenorrhea. External genitalia are normal in females, though breast development is often poor. Fertility in females has not been systematically studied. Although a molecular diagnosis was not confirmed, one clinical report describes two unrelated females with late presentation of the syndrome, each of whom had healthy children [Iannello et al 2004]. Urologic disease. Urinary problems affect approximately 50% of individuals with Alström syndrome. Urologic disorders of varying severity, characterized by detrusor-urethral dyssynergia (lack of coordination of bladder and urethral muscle activity), have been described. The greatest problems appear to occur in females in their late teens. Minor symptoms include urgency and long intervals between voiding, which suggests a decrease in bladder sensation, hesitancy, and poor urinary flow. Moderate symptoms include urinary frequency, incontinence, and symptoms associated with recurrent infections. More severe urinary symptoms include worsening urinary incontinence or retention; these symptoms may alternate. Lower abdominal and perineal pain is common and may relate to abnormal bladder/sphincter function [MacDermott 2001]. Intermittent self-catheterization has been helpful in a small number of affected individuals and cystectomy with an ileal conduit has been performed in isolated severe cases.Renal disease is common, slowly progressive, and highly variable, and may be unrelated to diabetes; it manifests as tubulo-interstitial disease resulting from interstitial fibrosis. Initial signs of mildly elevated serum concentrations of creatinine and blood urea nitrogen (BUN) may be followed by polyuria and polydipsia resulting from a concentrating defect. Onset can be in mid-childhood through adulthood. End-stage renal disease (ESRD) can occur as early as the mid- to late teens.Renal biopsy often shows interstitial fibrosis, glomerular hyalinosis, and tubular atrophy [Marshall et al 2005].Obstructive uropathy is rare. Hepatic disease. Elevated plasma concentration of liver enzymes is common in early childhood. Macrovesicular steatosis and hepatomegaly can be present or absent. Progression to cirrhosis and hepatic failure can occur in the second to third decades, and the complications of portal hypertension, ascites, splenomegaly, hepatic encephalopathy, and esophageal varices are also seen. Liver biopsies and postmortem examination have revealed varying degrees of steatohepatitis, hepatic fibrosis, cirrhosis, chronic nonspecific active hepatitis with lymphocytic infiltration, patchy necrosis, and fatty liver [Quiros-Tejeira et al 2001, Marshall et al 2005].Gastrointestinal disease. General GI disturbances such as epigastric pain and gastroesophageal reflux disease (GERD) are common. Cecal volvulus without adhesions or obstructive lesions was reported in a sibling pair, raising the possibility of a generalized smooth muscle dysfunction in the syndrome [Khoo et al 2009].Pulmonary involvement. Recurrent chest infections are common at all ages, but establishment of COPD is problematic because of difficulty in accurate performance of spirometry. Most frequently there is a combination of restrictive lung disease due to kyphoscoliosis and sometimes pulmonary fibrosis, which has been confirmed in post mortem tissue and may be detected in life with high-resolution chest CT scan. This may progress (with the added effects of cardiomyopathy) to pulmonary hypertension. The resulting susceptibility to severe hypoxia postoperatively or during episodes of pneumonia has been reported [Khoo et al 2009, Florentzson et al 2010].Other Scoliosis and kyphosis of varying severity are reported in 30%-70% of individuals with Alström syndrome [van den Abeele et al 2001, Marshall et al 2005]. Severe flat feet and dental abnormalities have been observed [Koray et al 2001, Marshall et al 2005]. Hypothyroidism has been reported in nearly 20% of individuals [Marshall et al 2005]; hyperthyroidism occurs infrequently [Ozgül et al 2007]. Hypertension, often beginning in childhood, has been described in 30% of individuals [Marshall et al 2005].Neurobehavioral manifestations such as absence seizures, excessive startle response, severe and unexplained peripheral pain, and mild autistic spectrum behaviors have been reported [Marshall et al 2005].

Genotype-Phenotype CorrelationsIn one study involving fewer than 12 kindreds, no correlations were found between mutation positions and the occurrence of specific clinical features, such as dilated cardiomyopathy [Minton et al 2006].A separate genotype-phenotype association study of 58 affected individuals [Marshall et al 2007b] found suggestive associations between disease-causing variants in exon 16 of ALMS1 and the following findings:Onset of retinal degeneration before age one year (P=0.02)
and Occurrence of urologic dysfunction (P=0.02), diabetes mellitus (P=0.03), and dilated cardiomyopathy (P=0.03) A more significant association was found between alterations in exon 8 and absent, mild, or delayed renal disease (P=0.0007). This preliminary observation may have implications for the understanding of how alternative splicing of ALMS1 contributes to the severity of the disease, and thus provide useful information to clinicians.

Differential DiagnosisBardet-Biedl syndrome (BBS) shares some features of Alström syndrome. The major clinical features of BBS are rod-cone dystrophy, postaxial polydactyly, central obesity, cognitive impairment, hypogonadism, and renal dysfunction [Goldstone & Beales 2008]. A major difference between Alström syndrome and BBS is the timing of the onset of visual problems: in Alström syndrome, visual problems are usually apparent in the first two years of life; in BBS, the average age of onset of visual problems is 8.5 years. Polydactyly, which is common in BBS, has not been described in Alström syndrome. Cognitive impairment is well described in BBS, while in most persons with Alström syndrome intelligence is normal, but delays in early milestones have been reported. Other differences include the relative infrequency of hearing problems (~5%) and diabetes mellitus (5%-10%) in BBS compared with Alström syndrome. Mutations in at least 14 different genes are causative. Inheritance is autosomal recessive. Achromatopsia, a disorder that affects only the retina, is characterized by reduced visual acuity, pendular nystagmus, increased sensitivity to light (photophobia), a small central scotoma, eccentric fixation, and reduced or complete loss of color discrimination. Most individuals have complete achromatopsia with total lack of function of all three types of cones (i.e., the long-wavelength-sensitive cones [red], the middle-wavelength-sensitive cones [green] and the short-wavelength-sensitive cones [blue]). Rarely, individuals have incomplete achromatopsia, in which one or more cone types may be partially functioning resulting in symptoms similar to but less severe than those of complete achromatopsia. Nystagmus and increased sensitivity to bright light develop shortly after birth. Best visual acuity ranges from 20/200 or less in complete achromatopsia to as high as 20/80 in incomplete achromatopsia. Visual acuity is usually stable over time. The diagnosis of achromatopsia is based on case history, color vision testing, electrophysiologic examination, and absent or only minor fundus changes. The fundus is usually normal. Mutations in three genes, CNGA3, CNGB3, and GNAT2, are causative. Inheritance is autosomal recessive. Leber congenital amaurosis (LCA), a severe dystrophy of the retina without other organ system involvement, typically becomes evident in the first year of life. Reduced vision is accompanied by nystagmus, sluggish pupillary responses, photophobia, hyperopia, and keratoconus. The electroretinogram (ERG) is characteristically "nondetectable" or severely subnormal. The oculo-digital sign (repeated eye rubbing, poking, and pressing of the eyes) is characteristic. Although the retina may appear normal in infancy, a pigmentary retinopathy reminiscent of retinitis pigmentosa is frequently observed later in childhood. The 15 genes currently known to be associated with LCA are: GUCY2D (locus name: LCA1), RPE65 (LCA2), SPATA7 (LCA3), AIPL1 (LCA4), LCA5 (LCA5), RPGRIP1 (LCA6), CRX (LCA7), CRB1 (LCA8), CEP290 (LCA10), IMPDH1 (LCA11), RD3 (LCA12), RDH12 (LCA13), LRAT (LCA14), TULP1 (LCA15) and KCNJ13 (LCA16) . Depending on the survey, these genes together are estimated to account for from one third to one half of all LCA. Three other disease loci for LCA have been reported. Most often, Leber congenital amaurosis is inherited in an autosomal recessive manner. Rarely, LCA is inherited in an autosomal dominant manner as a result of mutations in CRX. Early-onset dilated cardiomyopathy. Dilated cardiomyopathy, characterized by cardiac dilation and reduced systolic function, is the end stage of a number of inherited and acquired disorders. Familial dilated cardiomyopathy may be inherited in an autosomal dominant manner and less frequently in an autosomal recessive manner with ventricular dilatation and systolic dysfunction becoming apparent in the third and fourth decades.Inherited mitochondrial disorders represent a heterogeneous group of complex disorders that may be caused by mutations in mitochondrial DNA or nuclear DNA. Clinical features common to mitochondrial disorders and Alström syndrome include cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus; however, central nervous system involvement and muscle weakness occur in individuals with mitochondrial disorders, while they are not reported in Alström syndrome. Generally, mitochondrial disorders present in late childhood or in adulthood, unlike Alström syndrome, which usually presents during the first year of life.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Alström syndrome, a complete history of disease should direct detailed physical examination and investigations. A multidisciplinary team should be established to formulate and coordinate monitoring, management, and therapeutic interventions.Cone-rod dystrophy. Ophthalmologic evaluation, including electroretinogram and visual field testing Obesity. Measurement of weight and height; calculation of body mass index (BMI) Progressive sensorineural hearing loss. Audiometry with auditory brain stem response (ABR) and otoacoustic emissions (OAE) to detect sensorineural or conductive hearing loss; assessment of otitis media and conductive hearing loss Dilated cardiomyopathy. A detailed cardiac history and examination, including auscultation, echocardiography and ECGs. Echocardiography is required to demonstrate ventricular dilation, fibrosis, and decreased myocardial function. Insulin resistance/type 2 diabetes mellitus Fasting plasma glucose, even in infancy A glucose tolerance test (GTT) as early as age six years Plasma insulin concentration, as hyperinsulinemia may be present from infancy Hyperlipidemia. A fasting lipid profile, including triglycerides Endocrine abnormalitiesAssessment of thyroid function, including plasma TSH and free T4 concentration. If hyperthyroidism is suspected, free T3 concentration should be done. Measurement of pituitary hormonesUrologic History to document urinary difficulties If the individual is symptomatic or if urinalysis is abnormal, renal ultrasound examination to detect pelvi-calyceal dilatation and bladder ultrasound examination to measure post-voiding residual volumes Renal disease Baseline blood pressure; 24-hour blood pressure monitoringMeasurement of plasma BUN, creatinine, urea and electrolytes. If renal function testing is abnormal, ultrasound examination. If abnormalities, refer to a nephrologist. Hepatic disease Measurement of plasma ALT, AST, and GGT concentration Liver ultrasonography to evaluate for possible hepatomegaly and portal hypertension If clinically indicated, screening esophagogastroduodenoscopy for varices Pulmonary disease. Detailed assessment of pulmonary function by chest radiography, combined with pulmonary function testsDevelopmental assessment. Educational evaluation for intervention and IEP Other Gastrointestinal. If symptoms of reflux esophagitis remain severe, despite acid blockers, perform barium swallow or upper gastrointestinal endoscopy. Skin. Note acanthosis nigricans (indication of insulin resistance/diabetes mellitus), alopecia, body hair, hirsutism on physical examination. Orthopedic abnormalities. Note flat feet, scoliosis, barrel chest, kyphoscoliosis on physical examination. Neurologic manifestations. Neurologic evaluation with EEG to examine for seizures. Note autistic-spectrum behavioral abnormalities, excessive startle, tactile defensiveness, unexplained joint or muscle pain, muscle dystonia, or hyporeflexia. Medical genetics consultationTreatment of ManifestationsNo therapy exists to prevent the progressive organ involvement. However, monitoring for developing problems and early intervention is essential.Rod-cone dystrophy Early on when photodysphoria is significant, the use of red-orange tinted prescription lenses may reduce symptoms. Early educational planning should be based on the certainty of blindness. Instruction in the use of Braille, mobility training, adaptive living skills, and computing skills (including voice recognition and transcription software), and the use of large print reading materials while vision is still present are crucial. Obesity. A healthful, reduced calorie diet and regular exercise, such as walking, hiking, biking, and swimming with adaptations for the blind, are recommended to control weight gain. Progressive sensorineural hearing lossMyringotomy has been helpful in individuals with recurrent otitis media (‘glue ear’). Hearing can be maximized with bilateral digital hearing aids.Cochlear implantation has benefitted some patients [Florentzson et al 2010].Cardiomyopathy. Angiotensinogen-converting enzyme (ACE) inhibitors, diuretics, digoxin, and possibly beta-blockers should be used in the treatment of cardiac failure. Cardiac transplantation has been successful in isolated cases [Goerler et al 2007].Insulin resistance/type 2 diabetes should be treated as in the general population unless heart failure and/or liver dysfunction are present. The diabetes mellitus is characterized by insulin resistance, but some individuals respond to a low-sugar, low-fat diet; exercise; and metformin. Glitazones are added to further reduce insulin resistance but must be avoided in the presence of active or treated heart failure. These treatments should be discontinued when the serum creatinine concentration exceeds 200 µmol/L or if cardiomyopathy is evident. Incretin analogues given subcutaneously, as in nonsyndromic type 2 diabetes, are successful in two thirds of cases [Paisey et al 2008, Paisey 2009].Hypertriglyceridemia Nicotinic acid derivatives can be helpful in long-term reduction of severe hypertriglyceridemia (>20 mmol/l) especially if pancreatitis has occurred and diabetes is absent or well controlled [Paisey et al 2004, Paisey 2009]. Statins are unlikely to be effective but can be considered for long-term prevention of atherosclerosis in adults with low HDL, high LDL, and diabetes.Pancreatitis should be treated as in the general population. EndocrineAs children approach puberty, gonadotropin and pituitary hormones should be assessed to determine if hormonal adjustments are necessary.Male hypogonadism should be treated with testosterone according to local endocrine guidelines to preserve sexuality, muscle strength, and bone health.Thyroxine therapy should be initiated and monitored if the individual is hypothyroid. Urologic. Some individuals have required urinary diversion or self-catheterization to manage voiding difficulties [MacDermott 2001]. Renal disease The use of enzyme ACE inhibitors may be considered if proteinuria is detected. Successful renal transplantation has occurred in a growing number of individuals, but can be contraindicated in the presence of other complications including morbid obesity, uncontrolled diabetes, and cardiomyopathy.Hepatic disease. Portal hypertension may be treated with beta-blockade and sclerotherapy of the esophageal veins. Banding should be done in order to prevent upper-GI hemorrhage from varices. Patients who fail to respond to medication and banding are candidates for a transjugular intrahepatic portosystemic shunt (TIPS) to decrease risk of variceal bleeding caused by portal hypertension. Patients with significant portal hypertension should be evaluated early for liver transplantation. Pulmonary disease. General activity, including breathing exercises, can reduce chronic hypoxia and improve wellbeing. Coaching by an exercise expert may be necessary in order to achieve adequate spirometry results to determine the presence of obstructive airways disease. Other If skeletal abnormalities are present, referral to an orthopedist is appropriate. Reflux esophagitis, skin manifestations, orthopedic abnormalities, and neurologic manifestations should be treated as in the general population. Education intervention, as indicated by evaluation and IEP (individual education plan) with the expectation of total blindness and hearing loss.Prevention of Primary ComplicationsThe progression to diabetes mellitus and the severity of hyperglycemia can in some cases be mitigated by lifestyle changes and avoidance of severe obesity.Prevention of Secondary ComplicationsRoutine pediatric immunizations should be given and administration of pneumococcal vaccination should be considered. Care must be taken during sedation or operative procedures. The combination of dilated cardiomyopathy, congestive heart failure, pulmonary hypertension, and pulmonary fibrosis can cause sudden severe hypoxia in an affected individual following surgery or even during a minor infection. Close monitoring of cardiac status and oxygenation are necessary until the individual is fully recovered.SurveillanceRod-cone dystrophy. Annual ophthalmologic follow-up is indicated as long as the affected individual has vision. Obesity. Weight, height, and body mass index (BMI) should be recorded annually and plotted on growth curves. Progressive sensorineural hearing loss. Audiometry should be performed yearly. Cardiomyopathy A detailed cardiac history and examination including echocardiography annually even in the absence of symptoms related to left ventricular dysfunction (signs of cardiac failure, such as sweating, fatigue, lethargy, asthma, decreased physical activity) ECGs in parallel with echocardiography and 24-hour ECG monitoring if indicated In individuals who have had infantile cardiomyopathy, annual monitoring by a pediatric cardiologist, even if the individual has recovered from cardiomyopathy and is asymptomatic Insulin resistance/type 2 diabetes Annual measurement of plasma insulin concentration, as hyperinsulinemia may be present from early infancy Measurement of fasting plasma glucose concentration every two to three months If fasting blood glucose is greater than 7 mmol/L, or postprandial blood glucose is greater than 11 mmol/L, measurement of HbA1c concentration and serum glucose concentration regularly (every 6 months, although glucose estimations may be performed more frequently as determined by the 'diabetic control' of the affected individual) Hyperlipidemia. Annual total lipid profile determination is appropriate unless hyperlipidemia is present, in which case more frequent monitoring may be indicated. When the affected individual is ill and/or dehydrated, pancreatitis precipitated by hyperlipidemia can be life threatening. Renal disease Urinalysis and measurement of plasma concentrations of electrolytes, uric acid, BUN, and creatinine twice yearly Renal and bladder ultrasound examinations every one to two years if the individual is symptomatic or if urinalysis is abnormal Hepatic disease Annual measurement of plasma ALT, AST, and GGT concentration Ultrasonography to evaluate for possible steatosis, hepatomegaly, cirrhosis, and portal hypertension Pulmonary disease. Pulmonary function tests should be performed yearly to evaluate general lung function, even if symptoms of pulmonary fibrosis are not yet present. Hypothyroidism. Patients should be monitored annually for thyroid abnormalities. Agents/Circumstances to AvoidAny substance contraindicated in persons with renal or cardiac failure should be avoided. Therapy directed at one system may have adverse effects on other systems; for example, the use of glitazone therapy in diabetes mellitus is contraindicated in the presence of cardiac failure. Evaluation of Relatives at RiskEarly evaluation and/or molecular genetic testing (if the two disease-causing mutations in a family are known) of at-risk sibs allows for early diagnosis and early treatment of manifestations. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementThere are no data to guide the management of a pregnancy should it occur in a female with Alström syndrome. Potential maternal complications during pregnancy could include development or worsening of cardiac, renal, or hepatic failure; severe dyslipidemia; and hyperglycemia. The fetus could be affected by placental dysfunction resulting from maternal diabetes and cardiorenal disease. Intensive multidisciplinary surveillance of any pregnancy would be mandatory. Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Alstrom Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDALMS12p13​.1Alstrom syndrome protein 1Leeds Mutation Database
ALMS1 homepage - Mendelian genesALMS1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Alstrom Syndrome (View All in OMIM) View in own window 203800ALSTROM SYNDROME; ALMS 606844ALMS1 GENE; ALMS1Normal allelic variants. ALMS1 is a novel gene that does not share significant sequence homology with any other genes. There are 23 exons in ALMS1 (Reference sequence NM_015120.4).Pathologic allelic variants. To date, more than 130 causative mutations in ALMS1 have been reported in Alström syndrome. The majority of these are nonsense and frameshift variations (insertions or deletions) that are predicted to cause premature protein truncation [Collin et al 2002, Hearn et al 2002, Joy et al 2002, Kinoshita et al 2003, Titomanlio et al 2004, Bond et al 2005, Minton et al 2006, Marshall et al 2007b, Malm et al 2008, Aldahmesh et al 2009, Liu et al 2009, Aliferis et al 2012, Izzi et al 2011, Kocova et al 2011, Marshall et al 2011a, Marshall et al 2011b, Pereiro et al 2011, Wang et al 2011, Taşkesen et al 2012]. Normal gene product. The 12.9 kb ALMS1 transcript encodes a ubiquitously expressed protein of 4,169 amino acids of unknown function 9 (Reference sequence NP_055935.4). Abnormal gene product. ALMS1 protein localizes to the centrosomes and basal bodies of ciliated cells, suggesting a role for ALMS1 in intracellular trafficking and ciliary function [Collin et al 2005; Hearn et al 2005, Li et al 2007, Jagger et al 2011].