Full-Field Electroretinography and Marked Variability in Clinical Phenotype of Alstro¨M Syndrome

CLINICAL SCIENCES Full-Field Electroretinography and Marked Variability in Clinical Phenotype of Alstro¨m Syndrome

Eva Malm, MD; Vesna Ponjavic, MD, PhD; Patsy M. Nishina, PhD; Ju¨rgen K. Naggert, PhD; Elizabeth G. Hinman, BS; Sten Andre´asson, MD, PhD; Jan D. Marshall, BA; Claes Mo¨ller, MD, PhD

Objectives: To characterize the clinical phenotype Results: Electroretinography demonstrated cone-rod de- and to study the course of disease in patients with generation in all 3 patients. A concomitant impairment of Alstro¨m syndrome, with an emphasis on retinal func- color vision and visual fields was also observed as well as tion assessed with full-field electroretinography marked variation in retinal function and in disease severity. (ERG). Conclusions: Full-field ERGs confirmed that Alstro¨m syndrome is associated with a cone-rod type of retinal Methods: Three age- and sex-matched patients with Al- degeneration. In this study, we have shown a striking vari- stro¨m syndrome were selected from our retinitis pig- ability in retinal function and disease onset and sever- mentosa register for repeated ophthalmologic examina- ity, which has, to our knowledge, not been described pre- tions that included tests for color vision and visual fields viously in Alstro¨m syndrome. using Goldmann perimetry and for repeated assessment of full-field ERGs. Arch Ophthalmol. 2008;126(1):51-57

LSTRÖM SYNDROME (ON- tual renal failure is a late finding.9-11,13-15 line Mendelian Inherit- Accelerated skeletal maturity and low ance in Man [OMIM] growth hormone levels that result in short 203800) is an autosomal stature, scoliosis, and kyphosis have also recessive inherited disor- been documented in some patients.9,11,13,14,16 der first described in 1959 by Alstro¨m et The ALMS1 gene encodes a protein A1 al. The gene, ALMS1, was mapped to chro- lacking previously described domains. The mosome 2p13,2-4 and several disease- protein is found primarily in centro- causing mutations have been identi- somes and basal bodies of ciliated cells, fied.5-8 Cardinal clinical features of this suggesting a function in cilia formation, disorder are early-onset cardiomyo- maintenance, and function.17,18 This places pathy, progressive pigmentary retinal dys- Alstro¨m syndrome among a growing num- trophy, progressive sensorineural hear- ber of ciliopathies that include Bardet- ing loss, and childhood obesity.9-14 Most Biedl syndrome (BBS), Senior-Loken syn- affected individuals develop severe insu- drome, and polycystic kidney disease.19 lin resistance, hyperinsulinemia, or type Ocular manifestations occurring in the 2 diabetes mellitus in early adulthood.9 first years of life include nystagmus and Other metabolic disturbances, such as hy- photophobia with diminished visual acu- pothyroidism, hyperuricemia, and hyper- ity. Narrowing of retinal vessels, chorio- Author Affiliations: triglyceridemia, as well as dermatologic retinal atrophy, bone spiculae pigmen- Department of Ophthalmology, findings, such as acanthosis nigricans and tary changes, and optic atrophy are seen 9-14 Lund University Hospital, alopecia, may also occur. Dilated car- in the fundus, and posterior subcapsular Lund, Sweden (Drs Malm, diomyopathy with infantile or adoles- cataracts may be present.15,20-24 Previous Ponjavic, and Andre´asson); The cent onset and subsequent congestive heart electrophysiologic examinations have Jackson Laboratory, Bar Harbor, failure occur in more than 60% of indi- demonstrated an early cone dysfunction Maine (Drs Nishina and viduals with Alstro¨m syndrome.9 followed by a rapid deterioration of the rod Naggert and Mss Hinman and Other variable clinical manifestations responses and early loss of vision in the Marshall); and Department of 21-23 Audiology and The Swedish include respiratory failure with recurring second decade of life. Institute for Disability Research, infections, and asthma is often observed In Alstro¨m syndrome, considerable University Hospital O¨ rebro, in infancy.9,13,14 Urinary problems and pro- phenotypic interfamilial and intrafamil- O¨ rebro, Sweden (Dr Mo¨ller). gressive chronic nephropathy with even- ial variability exists, with differences in

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Table 1. Medical History and Clinical Features in the 3 Patients During Infancy and Childhood

Characteristic Patient 1 Patient 2 Patient 3 Sex Female Female Female Mutation c.[11726delC]ϩ[?] c.[11316_94delAGAG]ϩ[9901ins4dupC] c.[10483CϾT]ϩ[?] Bilateral hearing loss Present Present Present Hearing aid Bilateral Bilateral Bilateral Bilateral vestibular loss Present Absent Absent Cardiomyopathy Absent Present Present Respiratory failure Present Present Absent Diabetes mellitus Absent Absent Present Hyperinsulinemiaa Absent Absent ? Hypertriglyceridemia Present Absent Absent Obesity Present Present Present Acanthosis nigricans Absent Absent Absent Hypothyroidism Unknown Present Present Urologic problems Present Present Absent Anomalies of fingers Absent Absent Absent Scoliosis Absent Absent Present Other skeletal anomalies Absent Absent Presentb

Abbreviation: ?, not known. a Hyperinsulinemia or glucose intolerance. b Syndactyly (toes 2-3, bilateral).

clinical expression and rate of progression of nearly all amined with Goldmann kinetic perimetry using standardized the features.9,11,13 However, only a few studies have in- targets V:4e and I:4e with white light stimulus. Color vision vestigated the visual outcome in these patients. There- was tested using the Farnsworth D-15 color vision test. fore, the present study focuses on the evaluation of reti- Full-field ERGs were recorded using an analysis system (Vi- nal function in 3 patients with Alstro¨m syndrome by king; Nicolet Biomedical Instruments, Madison, Wisconsin). Each eye was tested after maximal pupil dilatation with topi- repeated electroretinograms (ERGs). cal 1% cyclopentolate hydrochloride and 10% phenylephrine hydrochloride and 45 minutes of dark adaptation. In patients METHODS younger than 8 years, pupils were dilated with topical 0.85% cyclopentolate and 1.5% metaoxedrine prior to the examina- PATIENTS tion. All patients were examined at least once with full-field ERG using general anesthesia with disoprofol.25 A Burian- Three female patients, ages 12, 10, and 11 years, were selected Allen bipolar contact lens ERG electrode was applied on the for the study from the Swedish retinitis pigmentosa registry. topically anesthetized (oxybuprocaine hydrochloride) cornea They had had prior examinations, including ERG, but were first together with a ground electrode applied on the forehead. Dark- clinically diagnosed with Alstro¨m syndrome at ages 6, 9, and 7 adapted responses were obtained using a wide-band filter (−3 years, respectively. None of the patients had a family history dB at 1 Hz and 500 Hz) with stimulation with single full-field of inherited eye disorders. All 3 patients had the following fea- flashes (30 microseconds) of blue light (Wratten filter Nos. 47, tures characteristic of Alstro¨m syndrome: childhood obesity, 47A, and 47B combined) and white light (0.81 candelas [cd]/s per m2). Cone responses were obtained with a 30-Hz flicker- sensorineural hearing loss, and probable vestibular hypofunc- 2 tion. In early childhood all had recurring upper respiratory tract ing white light (0.81 cd/s per m ) averaged from 20 sweeps with infections, and 2 of them had repeated urinary tract infec- no previous light adaptation. tions. Infantile dilated cardiomyopathy occurred in 2 of the pa- This procedure adheres to the standardized protocol for clinical electroretinography of the International Society for Clini- tients, and both developed subsequent mitral valve prolapse. 26 Other features associated with Alstro¨m syndrome such as hy- cal Electrophysiology of Vision with a few minor modifica- pothyroidism, type 2 diabetes mellitus, hypercholesterolemia, tions: recordings of isolated cone responses were obtained and hypertriglyceridemia have been assessed in single indi- without background illumination on the full-field screen. If re- viduals within this group. One patient had syndactyly and sco- sponses measuring less than 10 µV were recorded with single liosis (Table 1). white flashes, recordings were also obtained using computer Approval for DNA analysis was obtained from the Ethics averaging (30 flashes), a bipolar artifact rejecter, and a line fre- Committee, Lund University, and the institutional review board quency notch filter (50 Hz). To obtain small cone responses, of The Jackson Laboratory. Informed consent was obtained from stimulation also included 200 flashes of flickering white light all participants and parents. (30 Hz) and a digital, narrow bandpass filter added to the Nico- let machine. The narrow bandpass filter was tuned at 30 Hz (12 dB at 29 Hz and 31 Hz) to enable measurements of signals OPHTHALMOLOGIC EXAMINATION as low as 0.1 mV.27 All patients underwent an ophthalmologic examination, including testing of best-corrected visual acuity, slitlamp biomi- MOLECULAR GENETICS croscopy examination, and indirect ophthalmoscopy, but only 2 of the patients had remaining visual function and could be We obtained peripheral blood samples from all family mem- further examined after the age of 6 years. Visual fields were ex- bers using standard venipuncture techniques. Genomic DNA

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 was isolated using a standard protocol for DNA extraction. For RESULTS mutation analysis, ALMS1 primers were designed to amplify exon and splice-site sequences from genomic DNA. Primer sequences are available on request. Polymerase chain reaction OPHTHALMOLOGIC EXAMINATION (PCR) amplification was carried out as previously described.5 Briefly, each reaction was run in an 11-µL volume containing The 3 patients had a history of visual symptoms since approximately 100 ng of genomic DNA, 2µM of each primer, 100µM of each dNTP, and1UofTaq DNA polymerase in PCR early childhood, with low visual acuity and varying de- reaction buffer (Roche Diagnostics, Indianapolis, Indiana). Am- grees of glare and nystagmus. Patients 1 and 3 had been plification was performed in a 96-well thermal cycler (PTC- visually handicapped with photophobia and nystagmus 100; MJ Research, Waltham, Massachusetts), as previously re- since birth and 3 months of age, respectively. Patient 2 ported, with the following conditions: an initial denaturation was less severely affected by visual problems, although at 95°C for 2 minutes was followed by 50 cycles at 94°C for 20 she developed photophobia during her first year of life seconds, 50°C for 30 seconds, 72°C for 40 seconds, and a final (Table 2). extension at 72°C for 7 minutes. The PCR-amplified products The visual impairment progressed, and patients 1 and underwent electrophoresis on a 1.5% agarose gel to ensure 3 had a visual acuity of less 20/200 at the age of 3 years. predicted size, were purified (AMPure; Agencourt, Beverly, Patient 2, who developed photophobia later in infancy, Massachusetts), and were sequenced (ABI Prism 3730xl; Ap- plied Biosystems, Inc, Foster City, California). The sequenced did not have nystagmus, and her visual acuity has been products were then compared with the ALMS1 transcript stable at 20/100 from 3 to 10 years of age (Table 2). (GenBank Accession No. NM_015120.4). Numbering for At the age of 5 years, it was possible to perform ex- both nucleotide position and amino acid position was started aminations for refractive changes in which different de- at the open reading frame (methionine). grees of hyperopia were demonstrated in the patients. Hy- peropia was ϩ9.0 diopters (D) in patient 1, ϩ6.0 D in patient 3, and ϩ2.25 D in patient 2. This hyperopia was ϩ Table 2. Ophthalmologic Manifestations in the 3 Patients still prominent in patient 1 at 12 years of age ( 10.0 D), whereas patient 2 had become slightly myopic (−1.0 D). Characteristic Patient 1 Patient 2 Patient 3 In early life, patients 1 and 3 demonstrated similar fundus changes with narrowing of retinal vessels and de- Photophobia Birth 1-2 y of age 2-3 mo of age pigmentation, indicating initiation of the degenerative pro- Nystagmus Birth Absent 2-3 mo of age Refraction cess. Follow-up examinations in these 2 patients at the 3y ϩ9.0 ϩ2.5 Unknown ages of 12 and 11 years revealed significant retinal changes, 5y ϩ9.0 ϩ2.25 ϩ6.0 including pallor of the optic disc, thread-narrow ves- 10-12 y ϩ10.0 −1.0 Unknown sels, and depigmentation. This was most pronounced in Visual acuitya patient 3, who had a bull’s-eye phenomenon in the macula. 3 y 20/500 binoc 20/67 binoc 20/1000 binoc Patient 2 demonstrated a completely different appear- 5-6 y 20/500 binoc 20/200 to 20/133 binoc PϩL 10-12 y 20/2000 to 20/800 20/100 P ? ance, with almost normal vessels and optic disc but some- ERG 5 y (A) 6 y (A) 4mo(A) what diminished pigmentation of the fundus at the ages 12 y 8 2⁄3 y 6 y (A) of 8 years (Figure 1) and 10 years. 10 y Patient 1 developed posterior subcapsular cataracts and had bilateral cataract surgery with lens implantation at 9 Abbreviations: A, anesthesia; binoc, binocular, visual acuity with both eyes years of age. Later, she had a bilateral laser capsulotomy open; ERG, electroretinography; L, localization; P, perception; ?, uncertain answer. (Nd:YAG) owing to posterior capsule opacification. None aThe best-corrected visual acuity is reported. of the other patients have developed cataracts.

A B

Figure 1. Fundus photographs from 2 of the patients. A, Left eye of patient 1 at the age of 10 years. B, Right eye of patient 2 at the age of 8 years.

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 These differences in ophthalmoscopic features corre- sine residue at position 11726 in exon 18 (c.11726delC; sponded to the following differences in retinal function p.T3909fs); 59% of the coding region of ALMS1 has been among the patients. sequenced in this patient. Patient 2 is a compound het- erozygote harboring a 4–base pair deletion in exon 16 VISUAL FIELDS (c.11316_11319delAGAG; p.R3772fs) and a single– base pair insertion in exon 10 (c.9904dupC; p.S3301fs). Patients 1 and 2 have been tested frequently with Gold- Only 1 mutant allele, a nonsense mutation in exon 16 mann kinetic perimetry. At the age of 7 years, patient 1 (c.10483CϾT; p.Q3495fs), has been identified in pa- had severely constricted peripheral visual fields to ap- tient 3. However, 38% of the coding region of ALMS1 re- proximately 25° (V:4e), which decreased to less than 5° mains to be sequenced in this patient. (V:4e) by 12 years of age (Figure 2). At age 6 years, the visual fields in patient 2 demonstrated substantially normal peripheral limits, including 65° with object V:4e and COMMENT greater than 50° with object I:4e, and these limits remained unchanged at the age of 10 years (Figure 2). The Alstro¨m syndrome is a rare autosomal recessive disease children’s difficulties in cooperation during the exami- with approximately 415 patients identified world- nation may indicate that they had small scotomas, which wide.9,13,14 The disorder is characterized by progressive were hard to identify. The visual fields of patient 3 have pigmentary retinal dystrophy, sensorineural hearing loss, not been tested because of low visual acuity. The visual childhood obesity, type 2 diabetes mellitus, and dilated fields in patients 1 and 2 seemed to correlate with the cardiomyopathy.9-14 Some of the pathologic features ob- retinal function reflected by the full-field ERG. served in Alstro¨m syndrome, such as the retinal degeneration, sensorineural hearing loss, and renal dysfunc- COLOR VISION tion, can be directly related to the role of the ALMS1 protein in ciliary function, as rhodopsin transport through Color vision, assessed using the Farnsworth D-15 test, the connecting cilium in photoreceptor cells is im- was considered normal in patient 2 at the age of 10 years. paired,28 stereo cilia in the inner ear are disorganized (G. Patient 2 had confusion regarding color discs that were B. Collin, MA, unpublished data, 2007), and primary cilia close together (6 OD and 2 OS), which is not consid- in the kidney tubules degenerate.18 ered significant, and the lines in both eyes remained along Diagnosis of Alstro¨m syndrome is difficult because of the outside of the circle. Patient 1 could not see any dif- the variable clinical phenotypes observed as well as simi- ference between the color discs at the age of 12 years, larities with other syndromes featuring severe visual im- suggesting complete lack of color vision. pairment in children, such as BBS,29 achromatopsia, and cone-rod degeneration.15,22,30 In cone-rod dystrophy, the ELECTROPHYSIOLOGIC EXAMINATIONS full-field ERG may be quite similar to the ERG in Al- stro¨m syndrome, with early cone involvement and sub- Full-field ERG, objectively reflecting retinal function, dem- sequent rod degeneration. However, the progression of onstrated a similar cone-rod type of retinal degeneration the retinal dystrophy in Alstro¨m syndrome appears to be in all 3 patients. However, the age at onset and rate of dis- more rapid. Achromatopsia often manifests with similar ease progression varied considerably among the patients. early symptoms as in Alstro¨m syndrome, and the ERG In patient 3, at the age of 4 months, the isolated cone can reveal cone dysfunction at an early age, but in achro- response (tested with 30-Hz flickering white light stimu- matopsia, rod function is preserved. Although BBS shares lation) was undetectable, confirming a complete loss of similar features with Alstro¨m syndrome, such as obe- cone function. There was some remaining cone func- sity, skeletal abnormalities, and atypical pigmentary de- tion at the age of 5 years in patient 1, whereas there was generation,31-33 BBS is usually associated with a rod- only a slight reduction in cone response in patient 2 at cone type of retinal degeneration, a slower disease 10 years of age. This variability in cone dysfunction cor- progression, and much better visual function in the first related with their loss of visual acuity. decade of life.33,34 Notably, although the presence of digi- In 2 of the patients (patient 3 at age 4 months and pa- tal abnormalities usually distinguishes BBS from Al- tient 2 at age 6 years), the full-field ERG at the first ex- stro¨m syndrome, polydactyly or syndactyly has been ob- amination demonstrated rod responses within normal lim- served in a small number of patients with Alstro¨m its. Follow-up examination in all 3 patients showed a syndrome (2%).8,15 Patient 3 in this study, with genetic diminished rod response by different degrees. The pro- confirmation of Alstro¨m syndrome, had bilateral syn- gression varied from marked reduction to undetectable dactyly of the feet. function at the ages of 5 and 6 years (patients 1 and 3) Alstro¨m syndrome is caused by mutations in ALMS1 to only a minor loss of rod function at the age of 10 years on chromosome 2p13.2-4 Unlike BBS, in which multiple in patient 2 (Figure 3). genes have been implicated in the causation of the syndrome,35,36 no genetic heterogeneity has been reported GENETIC RESULTS for Alstro¨m syndrome.2-8 However, different clinical phenotypes with a wide range of onset and progression have Stop codons predicting a premature truncation of ALMS1 been reported.9,11,13 were identified in all 3 patients. Only 1 mutant allele has With the exception of the possible association between been identified to date in patient 1, a deletion of a cyto- severity of kidney disease and mutations in exon 8, no geno-

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135 70 45 135 70 45 60 Left eye60 Right eye

150 50 30 150 50 30 40 40 30 30 165 15 165 15 20 20 10 10 Age 7 y 180 90 80 70 60 50 40 30 20 10 10 20 30 40 50 60 70 80 90 0 180 90 80 70 60 50 40 30 20 10 10 20 30 40 50 60 70 80 90 0 10 10 V:4e V:4e 20 20 195 345 195 345 30 30 40 40 210 50 330 210 50 330 60 60 225 70 315 225 70 315 240255 270 285 300 240255 270 285 300

135 70 45 135 70 45 60 Left eye60 Right eye

150 50 30 150 50 30 40 40 30 30 165 15 165 15 20 20 10 10 Age 12 y 180 90 80 70 60 50 40 30 20 10 10 20 30 40 50 60 70 80 90 0 180 90 80 70 60 50 40 30 20 10 10 20 30 40 50 60 70 80 90 0 10 10 V:4e 20 20 V:4e 195 345 195 345 30 30 40 40 210 50 330 210 50 330 60 60 225 70 315 225 70 315 240255 270 285 300 240255 270 285 300

Patient 2 135 70 45 135 70 45 60 Left eye60 Right eye 150 50 30 150 50 30 40 40 30 30 165 I:4e 15 165 I:4e 15 20 20 10 10 Age 6 y 180 90 80 70 60 50 40 30 20 10 10 20 30 40 50 60 70 80 90 0 180 90 80 70 60 50 40 30 20 10 10 20 30 40 50 60 70 80 90 0 10 10 20 20 195 345 195 345 30 30 V:4e V:4e 40 40 210 50 330 210 50 330 60 60 225 70 315 225 70 315 240255 270 285 300 240255 270 285 300

135 70 45 135 70 45 60 Left eye60 Right eye 150 50 30 150 50 30 40 40 30 30 165 15 165 I:4e 15 I:4e 20 20 10 10 Age 10 y 180 90 80 70 60 50 40 30 20 10 10 20 30 40 50 60 70 80 90 0 180 90 80 70 60 50 40 30 20 10 10 20 30 40 50 60 70 80 90 0 10 10 20 20 195 345 195 345 30 30 V:4e V:4e 40 40 210 50 330 210 50 330 60 60 225 315 70 225 70 315 240255 270 285 300 240255 270 285 300

Figure 2. Visual fields tested with Goldmann perimetry. Patient 1 (top) with severe constricted peripheral limits at the ages of 7 and 12 years. Patient 2 (bottom) with substantially normal peripheral limits at the ages of 6 and 10 years. V:4e and I:4e indicate standardized targets.

type-phenotype correlations have been reported.9 Variabil- loss in patients (including siblings) carrying the same mu- ity in liver function, dilated cardiomyopathy, and hearing tation suggest the existence of modifier genes.5

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Normal

Patient 1 5 y

12 y

Patient 2 6 y

10 y

Patient 3 4 mo

6 y 50 µV 50 µV 10 µV 1 µV 20 ms 20 ms 10 ms 10 ms

Figure 3. Full-field electroretinogram recordings from the 3 patients at different ages compared with normal response. Left column, Dark-adapted rod response to dim blue light. Second column, Dark-adapted mixed cone-rod response to white flashes. Right 2 columns, Cone-isolated responses to 30-Hz flickering light.

The first abnormality usually observed in affected chil- tions in age at onset, progression rate, and degree of vi- dren is nystagmus and photophobia developing into se- sual dysfunction were also reflected in the rod function. vere cone-rod dysfunction.21-23 On fundus examination, The extent and progression rate of the cone-rod de- a pigmentary retinal dystrophy with narrowing of ves- generation are important prognostic features for pa- sels and pallor of the optic disc is often detected in in- tients with Alstro¨m syndrome because of the conse- fancy, with profound visual impairment in the second quences in their daily life and their future. To improve decade of life.15,20-24 Two studies of patients have re- medical and educational support, early diagnosis is es- ported comparable results describing a similar clinical sential for children with this disease, since most of them phenotype, including early cone dysfunction followed by are blind in their teens. Molecular diagnosis is not yet a rapid deterioration of the rod responses.21,22 readily available for Alstro¨m syndrome; therefore, the In contrast to these reports, this study demonstrates diagnosis relies on ophthalmologic, auditory, and so- a variability in retinal function as assessed by full-field matic findings. Full-field ERG is important both for dis- ERG in Alstro¨m syndrome, which to our knowledge has tinguishing Alstro¨m syndrome from other syndromes not been described previously. Ophthalmologic variabil- and for evaluating the severity of the visual handicap. ity was also observed in fundus appearance, color vi- Repeated full-field ERG of patients in this study con- sion, visual fields, refraction, and visual acuity among these firms the course of the retinal degeneration in Alstro¨m patients. Two patients (patients 1 and 3) had all of the syndrome as an early cone dysfunction, prior to a sub- typical features but differed in disease progression and sequent rod dysfunction but with different rates of final visual outcome. Patient 1 had some remaining cone progression. function at the age of 5 years. Patient 2 had a more be- Our study demonstrates that the final visual out- nign clinical phenotype with no signs of nystagmus, an come in Alstro¨m syndrome can vary considerably, which almost normal fundus appearance, and stable visual acu- has not been fully appreciated in previous studies. ity (20/100) up to the age of 10 years with preserved visual fields. Cone responses were only slightly reduced Submitted for Publication: April 11, 2007; final revi- at 10 years of age. Patient 3, who demonstrated severe sion received June 20, 2007; accepted June 26, 2007. dysfunction with no cone responses at the age of 4 months, Correspondence: Eva Malm, MD, Department of Oph- had a more aggressive disease course with classic clini- thalmology, Lund University Hospital, SE-221 85 Lund, cal features characteristic of Alstro¨m syndrome. The varia- Sweden ([email protected]).

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Author Contributions: Dr Malm had full access to all the 15. Millay RH, Weleber RG, Heckenlively JR. Ophthalmologic and systemic mani- data in the study and takes responsibility for the integ- festations of Alstro¨m’s disease. Am J Ophthalmol. 1986;102(4):482-490. 16. Alter CA, Moshang T. Growth hormone deficiency in two siblings with Alstro¨m rity of the data and the accuracy of the data analysis. syndrome. Am J Dis Child. 1993;147(1):97-99. Financial Disclosure: None reported. 17. Hearn T, Spalluto C, Phillips VJ, et al. Subcellular localization of ALMS1 sup- Funding/Support: This study was supported by grants ports involvement of centrosome and basal body dysfunction in the pathogen- from the Swedish Medical Research Council (projects 73X esis of obesity, insulin resistance, and type 2 diabetes. Diabetes. 2005;54(5): 12597-04B and 73P-12964-05B), the Swedish Associa- 1581-1587. 18. Li G, Vega R, Nelms K, et al. A role for Alstro¨m syndrome protein, Alms1, in kid- tion of the Visually Impaired, grants EY08683 and ney ciliogenesis and cellular quiescence. PLoS Genet. 2007;3(1):e8. HD036878 (Drs Nishina and Naggert and Mss Hinman, doi:10.1371/journal.pgen.0030008. and Marshall) from the National Institutes of Health, and 19. Badano JL, Mitsuma N, Beales P, Katsanas N. The ciliopathies: an emerging class the Foundation Fighting Blindness. of human genetic disorders. Annu Rev Genomics Hum Genet. 2006;22(7): 125-148. Additional Contributions: Ying Liu, MD, and Kristina 20. Sebag J, Albert DM, Craft JL. The Alstro¨m syndrome: ophthalmic histopathol- Eriksson, MD, performed prior examinations of the pa- ogy and retinal ultrastructure. Br J Ophthalmol. 1984;68(7):494-501. tients, and Ing-Marie Holst and Boel Nilsson provided 21. Tremblay F, LaRoche RG, Shea SE, et al. Longitudinal study of the early electro- skillful technical assistance. retinographic changes in Alstro¨m syndrome. Am J Ophthalmol. 1993;115(5): 657-665. 22. Russell-Eggitt IM, Clayton PT, Coffey R, et al. Alstro¨m syndrome: report of 22 REFERENCES cases and literature review. Ophthalmology. 1998;105(7):1274-1280. 23. Van den Abeele K, Craen M, Schuil J, Meire FM. Ophthalmological and systemic 1. Alstro¨m CH, Hallgren B, Nilsson LB, A˚ sander A. Retinal degeneration combined features of the Alstro¨m syndrome: report of 9 cases. Bull Soc Belge Ophtalmol. with obesity, diabetes mellitus and neurogenous deafness: a specific syndrome 2001;281(281):67-72. (not hitherto described) distinct from the Laurence-Moon-Bardet-Biedl syn- 24. Sadowski B, Baumeister FAM, Schmitz T, Rudolph G. Onset of bilateral blind- drome: a clinical, endocrinological and genetic examination based on a large ness in the first year of life: Alstro¨m syndrome [in German]. Ophthalmologe. 2004; pedigree. 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