Analysis of the ocular clinical features and pathogenic genes in patients with Alstr?m syndrome_Chinese Journal of Ocular Fundus Diseases

Authors：

Liu Weiwei ¹ , Chu Yingying ¹ , Wang Hui ¹ , Wang Fei ¹ , Chu Ruixue ¹ , Sun Xiantao ¹ , Lu Yuebing ¹ ,  Yu Jifeng ²

1. Department of Ophthalmology, Children's Hospital Affiliated to Zhengzhou University, Children's Hospital of Henan Province, Zhengzhou Children's Hospital, Zhengzhou 450000, China;
2. Department of Ophthalmology, Beijing Children's Hospital Affiliated to Capital Medical University, National Center for Children's Health, Beijing 100045, China;

Corresponding?author：

Yu Jifeng, Email: jeffernyu@126.com

Keywords：

Alstr?m syndrome; Cone-rod dystrophy; ALMS1 mutations

DOI：

10.3760/cma.j.cn511434-20221018-00552

Video：

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Objective To observe and analyze the ocular clinical features and pathogenic genes of Alstr?m syndrome (ALMS). Methods A retrospective clinical study. From October 2020 to July 2022, 3 patients and 5 normal family members from 2 families affected with ALMS who visited in the Ophthalmology Department of Henan Children's Hospital were enrolled in the study. These 2 families were without blood relationship. The medical history and family history were inquired. Best corrected visual acuity (BCVA), fundus color photography, full-field electroretinogram (ERG), frequency domain optical coherence tomography (OCT) and systemic examination were performed. 3 ml peripheral venous blood of patients and their family members were collected, and the whole genomic DNA was extracted. The second generation sequencing analysis was performed on these members. The suspected pathogenic mutation sites were verified by Sanger, and the pathogenicity of the gene mutation sites were determined by bioinformatics analysis. Results Three patients from two families all developed nystagmus and photophobia in infancy. In the family 1, the BCVA of both eyes of the proband was no light perception. The fundus examination revealed vascular attenuation and retinal pigment abnormality. OCT showed retinal thinning, loss of photoreceptor layer and atrophy of the retinal pigment epithelium layer. ERG examination showed extinguished. The BCVA of the proband’s younger brother was 0.04 in the right eye and 0.02 in the left eye. The fundus examination revealed vascular attenuation but the pigment distribution was roughly normal. OCT showed blurred photoreceptor layers in both eyes. ERG examination showed extinguished. Two patients developed sensorineural deafness, obesity, acanthosis nigricans, insulin resistance/diabetes, and abnormal liver function. In addition, the proband also had left heart enlargement, hyperlipidemia and abnormal kidney function. The results of genetic testing showed that the proband and his younger brother had compound heterozygous mutations in exon 8 (c.1894C＞T/p.Gln632*, M1) and exon 10 (c.9148_9149delCT/p.Leu 3050 Leufs*9, M2) of ALMS1, which were both known mutations. The father of the proband was a carrier of M1 and the mother of the proband was a carrier of M2. The proband of the family 2 had a normal fundus at 23 months old. The amplitude of ERG b wave under the stimulation of the dark adaptation 0.01 and a, b wave under the stimulation of dark adaptation 0.3 were all mild reduced. The amplitude of ERG a, b wave under the stimulation of the light adaptation 0.3 was severity decreased. At 4 years old, the BCVA was 0.01 in the right eye and 0.05 in the left eye. The fundus examination revealed vascular attenuation and bilateral blunted foveal reflex. In addition to severely diminished of a, b wave under the stimulation of dark adaptation 0.3, the rest showed extinguished. There were no systemic abnormalities. The results of genetic testing showed that the proband had compound heterozygous mutations in exon 11 (c.9627delT/p.Pro3210Glnfs*22, M3) and exon 5 (c.1089delT/p.Asp364Ilefs*13, M4) of ALMS1, which were both novel mutations. The father of the proband was a carrier of M3 and the mother of the proband was a carrier of M4. Conclusions Nystagmus and photophobia are often the first clinical manifestations of ALMS. In the early stage, the fundus can be basically normal. As the disease progresses, the fundus examination reveals vascular attenuation and retinal pigment abnormality, and the reflection of the fovea is unclear. OCT shows the photoreceptor cell layers are blurred or even lost. The final ERG is extinguished. M1, M2, and M3, M4 compound heterozygous mutations may be the pathogeny for family 1 and family 2, respectively.

Citation： Liu Weiwei, Chu Yingying, Wang Hui, Wang Fei, Chu Ruixue, Sun Xiantao, Lu Yuebing, Yu Jifeng. Analysis of the ocular clinical features and pathogenic genes in patients with Alstr?m syndrome. Chinese Journal of Ocular Fundus Diseases, 2023, 39(7): 530-537. doi: 10.3760/cma.j.cn511434-20221018-00552 Copy

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14.	Leitch CC, Lodh S, Prieto-Echagüe V, et alBasal body proteins regulate Notch signaling through endosomal trafficking[J]. J Cell Sci2014127Pt1124072419. DOI: 10.1242/jcs.130344.
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17.	Waldman M, Han JC, Reyes-Capo DP, et alAlstr?m syndrome: Renal findings in correlation with obesity, insulin resistance, dyslipidemia and cardiomyopathy in 38 patients prospectively evaluated at the NIH clinical center[J]. Mol Genet Metab20181251-2181191. DOI:10.1016/j.ymgme. 2018.07.010. doi:10.1016/j.ymgme.2018.07.010.
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19.	Zhang Q, Ding Y, Feng B, et al. Molecular and phenotypic expansion of Alstr?m syndrome in Chinese patients[J/OL]. Front Genet, 2022, 13: 808919[2022-02-08]. https://europepmc.org/article/MED/35211159. DOI: 10.3389/fgene. 2022.808919.
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22.	Torkamandi S, Rezaei S, Mirfakhraei R, et al. Whole exome sequencing identified two homozygous ALMS1 mutations in an Iranian family with Alstr?m syndrome[J/OL]. Gene, 2020, 727: 144228[2020-02-15]. https://linkinghub.elsevier.com/retrieve/pii/S0378-1119(19)30887-X. DOI: 10.1016/j.gene.2019.144228.
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24.	Liang X, Li H, Li H, et alNovel ALMS1 mutations in Chinese patients with Alstr?m syndrome[J]. Mol Vis20131918851891. DOI:http://www.molvis.org/molvis /v19/1885.
25.	Weiss S, Cohen L, Ben-Yosef T, et alLate diagnosis of Alstrom syndrome in a Yemenite-Jewish child[J]. Ophthalmic Genet2019401711. DOI: 10.1080/13816810.2018.1561900.
26.	Shurygina MF, Parker MA, Schlechter CL, et alA case report of two siblings with Alstrom syndrome without hearing loss associated with two new ALMS1 variants[J]. BMC Ophthalmol2019191246. DOI: 10.1186/s12886-019-1259-y.
27.	Russell-Eggitt IM, Clayton PT, Coffey R, et alAlstr?m syndrome. Report of 22 cases and literature review[J]. Ophthalmology1998105712741280. DOI: 10.1016/S0161-6420(98)97033-6.
28.	Bronson SC, Anand Moses CR, Periyandavar I, et alDiabetes in the young: a case of Alstr?m syndrome with myopathy[J]. J R Coll Physicians Edinb20154513337. DOI:10.4997/JRCPE.2015.108.
29.	Chakroun A, Ben Said M, Ennouri A, et alLong-term clinical follow-up and molecular testing for diagnosis of the first tunisian family with Alstr?m syndrome[J]. Eur J Med Genet2016599444451. DOI: 10.1016/j.ejmg.2016.08. 004. doi:10.1016/j.ejmg.2016.08.004.
30.	Mauring L, Porter LF, Pelletier V, et alAtypical retinal phenotype in a patient with Alstr?m syndrome and biallelic novel pathogenic variants in ALMS1, including a de novo variation[J]. Front Genet202011938. DOI:10.3389/fgene.2020.00938.
31.	Chang MY, Borchert MS, Schmidt R, et al. Neovascularization of the optic disc and peripheral retinal ischemia in a child with a novel variant in ALMS1 (Alstrom syndrome)[J/OL]. Am J Ophthalmol Case Rep, 2022, 26: 101506[2022-03-25]. https://linkinghub.elsevier.com/retrieve/pii/S2451-9936(22)00252-3. DOI:10.1016/j.ajoc. 2022.101506.
32.	Wang Y, Huang L, Sun L, et al. Ocular findings and genetic test in Alstr?m syndrome in childhood[J/OL]. Exp Eye Res, 2022, 225: 109277[2022-10-04]. https://linkinghub.elsevier.com/retrieve/pii/S0014-4835(22)00358-X. DOI:10.1016/j.exer.2022.109277.
33.	Dotan G, Khetan V, Marshall JD, et alSpectral-domain optical coherence tomography findings in Alstr?m syndrome[J]. Ophthalmic Genet2017385440445. DOI:10.1080/13816810.2016.1257029.
34.	Baig S, Veeranna V, Bolton S, et alTreatment with PBI-4050 in patients with Alstr?m syndrome: study protocol for a phase 2, single-centre, single-arm, open-label trial[J]. BMC Endocr Disord201818188. DOI:10.1186/s12902- 018-0315-6. doi:10.1186/s12902-018-0315-6.

1. Tahani N, Maffei P, Dollfus H, et alConsensus clinical management guidelines for Alstr?m syndrome[J]. Orphanet J Rare Dis2020151253. DOI: 10.1186/s13023-020-01468-8.
2. Macari F, Lautier C, Girardet A, et alRefinement of genetic localization of the Alstr?m syndrome on chromosome 2p12-13 by linkage analysis in a North African family[J]. Hum Genet19981036658661. DOI: 10.1007/s004390050887.
3. Torimitsu T, Yoshida T, Nishi S, et alAmiodarone-induced multiple organ damage in an Alstr?m syndrome patient with end-stage renal disease and hepatic cirrhosis[J]. CEN Case Rep20221111116. DOI: 10.1007/s13730-021-00621-x.
4. Nasser F, Weisschuh N, Maffei P, et alOphthalmic features of cone-rod dystrophy caused by pathogenic variants in the ALMS1 gene[J]. Acta Ophthalmol2018964e445e454. DOI:10.1111/aos.13612.
5. Khan AO, Bifari IN, Bolz HJOphthalmic features of children not yet diagnosed with Alstrom syndrome[J]. Ophthalmology2015122817261727. DOI: 10.1016/j.ophtha.2015.03.001.
6. Marshall JD, Maffei P, Collin GB, et alAlstr?m syndrome: genetics and clinical overview[J]. Curr Genomics2011123225235. DOI: 10.2174/138920211795677912.
7. Marshall JD, Beck S, Maffei P, et alAlstr?m syndrome[J]. Eur J Hum Genet2007151211931202. DOI: 10.1038/sj.ejhg.5201933.
8. Richards S, Aziz N, Bale S, et alStandards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med2015175405424. DOI: 10.1038/gim.2015.30.
9. Wang L, Zhang J, Chen N, et alApplication of whole exome and targeted panel sequencing in the clinical molecular diagnosis of 319 Chinese families with inherited retinal dystrophy and comparison study[J]. Genes (Basel)201897360. DOI:10.3390/genes9070360.
10. Shenje LT, Andersen P, Halushka MK, et alMutations in Alstr?m protein impair terminal differentiation of cardiomyocytes[J]. Nat Commun201453416. DOI: 10.1038/ncomms4416.
11. Marshall JD, Bronson RT, Collin GB, et alNew Alstr?m syndrome phenotypes based on the evaluation of 182 cases[J]. Arch Intern Med20051656675683. DOI: 10.1001/archinte.165.6.675.
12. Marshall JD, Muller J, Collin GB, et alAlstr?m syndrome: mutation spectrum of ALMS1[J]. Hum Mutat2015367660668. DOI:10.1002/humu.22796.
13. Etheridge T, Kellom ER, Sullivan RO, et al. Ocular evaluation and genetic test for an early Alstr?m Syndrome diagnosis[J/OL]. Am J Ophthalmol Case Rep, 2020, 20: 100873[2020-08-12]. https://linkinghub.elsevier.com/retrieve/pii/S2451-9936(20)30188-2. DOI: 10.1016/j.ajoc.2020.100873.
14. Leitch CC, Lodh S, Prieto-Echagüe V, et alBasal body proteins regulate Notch signaling through endosomal trafficking[J]. J Cell Sci2014127Pt1124072419. DOI: 10.1242/jcs.130344.
15. Joy T, Cao H, Black G, et alAlstrom syndrome (OMIM 203800): a case report and literature review[J]. Orphanet J Rare Dis2007249. DOI:10.1186/1750-1172-2- 49. doi:10.1186/1750-1172-2-49.
16. Collin GB, Marshall JD, Ikeda A, et alMutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alstr?m syndrome[J]. Nat Genet20023117478. DOI: 10.1038/ng867.
17. Waldman M, Han JC, Reyes-Capo DP, et alAlstr?m syndrome: Renal findings in correlation with obesity, insulin resistance, dyslipidemia and cardiomyopathy in 38 patients prospectively evaluated at the NIH clinical center[J]. Mol Genet Metab20181251-2181191. DOI:10.1016/j.ymgme. 2018.07.010. doi:10.1016/j.ymgme.2018.07.010.
18. Xu R, Zhou H, Fang F, et alA novel variant site of Alstrom syndrome in a Chinese child: a case report[J]. Transl Pediatr2022114595600. DOI: 10.21037/tp-21-535.
19. Zhang Q, Ding Y, Feng B, et al. Molecular and phenotypic expansion of Alstr?m syndrome in Chinese patients[J/OL]. Front Genet, 2022, 13: 808919[2022-02-08]. https://europepmc.org/article/MED/35211159. DOI: 10.3389/fgene. 2022.808919.
20. Malm E, Ponjavic V, Nishina PM, et alFull-field electroretinography and marked variability in clinical phenotype of Alstr?m syndrome[J]. Arch Ophthalmol200812615157. DOI:10.1001/archophthalmol.2007.28.
21. Michaud JL, Héon E, Guilbert F, et alNatural history of Alstr?m syndrome in early childhood: onset with dilated cardiomyopathy[J]. J Pediatr19961282225229. DOI: 10.1016/s0022-3476(96)70394-3.
22. Torkamandi S, Rezaei S, Mirfakhraei R, et al. Whole exome sequencing identified two homozygous ALMS1 mutations in an Iranian family with Alstr?m syndrome[J/OL]. Gene, 2020, 727: 144228[2020-02-15]. https://linkinghub.elsevier.com/retrieve/pii/S0378-1119(19)30887-X. DOI: 10.1016/j.gene.2019.144228.
23. Yang L, Li Z, Mei M, et alWhole genome sequencing identifies a novel ALMS1 gene mutation in two Chinese siblings with Alstr?m syndrome[J]. BMC Med Genet201718175. DOI: 10.1186/s12881-017-0418-3.
24. Liang X, Li H, Li H, et alNovel ALMS1 mutations in Chinese patients with Alstr?m syndrome[J]. Mol Vis20131918851891. DOI:http://www.molvis.org/molvis /v19/1885.
25. Weiss S, Cohen L, Ben-Yosef T, et alLate diagnosis of Alstrom syndrome in a Yemenite-Jewish child[J]. Ophthalmic Genet2019401711. DOI: 10.1080/13816810.2018.1561900.
26. Shurygina MF, Parker MA, Schlechter CL, et alA case report of two siblings with Alstrom syndrome without hearing loss associated with two new ALMS1 variants[J]. BMC Ophthalmol2019191246. DOI: 10.1186/s12886-019-1259-y.
27. Russell-Eggitt IM, Clayton PT, Coffey R, et alAlstr?m syndrome. Report of 22 cases and literature review[J]. Ophthalmology1998105712741280. DOI: 10.1016/S0161-6420(98)97033-6.
28. Bronson SC, Anand Moses CR, Periyandavar I, et alDiabetes in the young: a case of Alstr?m syndrome with myopathy[J]. J R Coll Physicians Edinb20154513337. DOI:10.4997/JRCPE.2015.108.
29. Chakroun A, Ben Said M, Ennouri A, et alLong-term clinical follow-up and molecular testing for diagnosis of the first tunisian family with Alstr?m syndrome[J]. Eur J Med Genet2016599444451. DOI: 10.1016/j.ejmg.2016.08. 004. doi:10.1016/j.ejmg.2016.08.004.
30. Mauring L, Porter LF, Pelletier V, et alAtypical retinal phenotype in a patient with Alstr?m syndrome and biallelic novel pathogenic variants in ALMS1, including a de novo variation[J]. Front Genet202011938. DOI:10.3389/fgene.2020.00938.
31. Chang MY, Borchert MS, Schmidt R, et al. Neovascularization of the optic disc and peripheral retinal ischemia in a child with a novel variant in ALMS1 (Alstrom syndrome)[J/OL]. Am J Ophthalmol Case Rep, 2022, 26: 101506[2022-03-25]. https://linkinghub.elsevier.com/retrieve/pii/S2451-9936(22)00252-3. DOI:10.1016/j.ajoc. 2022.101506.
32. Wang Y, Huang L, Sun L, et al. Ocular findings and genetic test in Alstr?m syndrome in childhood[J/OL]. Exp Eye Res, 2022, 225: 109277[2022-10-04]. https://linkinghub.elsevier.com/retrieve/pii/S0014-4835(22)00358-X. DOI:10.1016/j.exer.2022.109277.
33. Dotan G, Khetan V, Marshall JD, et alSpectral-domain optical coherence tomography findings in Alstr?m syndrome[J]. Ophthalmic Genet2017385440445. DOI:10.1080/13816810.2016.1257029.
34. Baig S, Veeranna V, Bolton S, et alTreatment with PBI-4050 in patients with Alstr?m syndrome: study protocol for a phase 2, single-centre, single-arm, open-label trial[J]. BMC Endocr Disord201818188. DOI:10.1186/s12902- 018-0315-6. doi:10.1186/s12902-018-0315-6.

Chinese Journal of Ocular Fundus Diseases

Analysis of the ocular clinical features and pathogenic genes in patients with Alstr?m syndrome

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