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American Journal of Ophthalmology Case... Sep 2022To illustrate the importance of systemic evaluation in retinal dystrophies through examples of Alstrom syndrome, Bardet Biedl syndrome, and Refsum disease.
PURPOSE
To illustrate the importance of systemic evaluation in retinal dystrophies through examples of Alstrom syndrome, Bardet Biedl syndrome, and Refsum disease.
OBSERVATIONS
Detailed eye evaluations, including visual acuity, visual field, slit lamp examination, and indirect ophthalmoscopy were performed. Retinal imaging included fundus photography and spectral domain optical coherence tomography (SD-OCT). Functional testing of the retina was done using full field electroretinography (ffERG). In addition, molecular genetic testing was performed using a ciliopathy panel, a retinal dystrophy panel, and whole genome sequencing (WGS).We report three individuals who presented with vision concerns first to ophthalmology, noted to have retinal dystrophy, and then referred to genomic medicine for genetic testing. Additional evaluation led to suspicion of specific groups of systemic disorders and guided appropriate genetic testing. The first individual presented with retinal dystrophy, obesity, and short stature with no reported neurocognitive deficits. Genetic testing included a ciliopathy panel that was negative followed by WGS that identified biallelic variants in : a novel frame-shift pathogenic variant c.6525dupT (p.Gln2176Serfs*17) and a rare nonsense pathogenic variant c.2035C > T (p.Arg679Ter) consistent with Alstrom syndrome. The second individual presented with retinal dystrophy, central obesity, and mild neurocognitive deficits. A ciliopathy genetic testing panel identified a homozygous pathogenic variant in : c.389_390del (p.Asn130Thrfs*4), confirming the diagnosis of Bardet Biedl syndrome. The third individual presented with progressive vision loss due to retinitis pigmentosa, anosmia, hearing loss, and shortened metatarsals and digits. Genetic testing identified two variants in : c.375_375del (p.Glu126Argfs*2) a pathogenic variant and c.536A > G (p.His179Arg), a variant of uncertain significance (VUS), suggestive of Refsum disease. Additional biochemical testing revealed markedly elevated phytanic acid with a low concentration of pristanic acid and normal concentrations of very long-chain fatty acids (C22:0, C24:0, C26:0), a pattern consistent with a diagnosis of Refsum disease.
CONCLUSIONS AND IMPORTANCE
In individuals who present with retinal dystrophy to ophthalmologists, additional systemic manifestations such as sensorineural hearing loss, anosmia, or polydactyly, should be sought and a positive history or examination finding should prompt an immediate referral to a clinical geneticist for additional evaluation and appropriate genetic testing. This facilitates pre-test genetic counseling and allows for more accurate diagnosis, prognosis, and management of affected individuals along with better recurrence risk estimates for family members. Identification of an underlying etiology also enhances the understanding of the pathophysiology of disease and expands the genotypic and phenotypic spectrum. Ultimately, successful recognition of these diseases facilitates development of targeted therapies and surveillance of affected individuals.
PubMed: 35756836
DOI: 10.1016/j.ajoc.2022.101613 -
Intractable & Rare Diseases Research May 2022Alström syndrome (AS) is a rare autosomal recessive monogenic disorder caused by mutations of the () gene, located on chromosome 2p13. It is a progressive...
Alström syndrome (AS) is a rare autosomal recessive monogenic disorder caused by mutations of the () gene, located on chromosome 2p13. It is a progressive multisystemic disease characterized mostly by obesity, sensorineural hearing loss, visual impairments, cardiomyopathy, insulin resistance and/or type 2 diabetes mellitus (T2DM), metabolic dysfunctions, non-alcoholic fatty liver disease, and chronic progressive kidney disease. Generally, the first clinical symptoms of the disease appear in the first years of life with a major variation of onset age. In this study, we aimed to examine the molecular diagnosis of a 6-year-old patient with suspected AS clinical symptoms. After applying clinical exome sequencing (CES) in the patient we found a homozygous deletion in exon 8 at the gene (c.2311_2312del). We identified a homozygous frameshift mutation. The reported variant was pathogenic according to the criteria of the American College of Medical Genetics and Genomics (ACMG). Thus, the patient was diagnosed with AS as a result of the combined clinical phenotype and genetic tests results. We hope the variant we found can expand the spectrum of variants in AS.
PubMed: 35702577
DOI: 10.5582/irdr.2022.01024 -
Translational Pediatrics Apr 2022Alstrom syndrome (ALMS) is a rare genetic disorder. ALMS is characterized by progressive bilateral sensorineural hearing impairment, cone-rod dystrophy, infantile-onset...
BACKGROUND
Alstrom syndrome (ALMS) is a rare genetic disorder. ALMS is characterized by progressive bilateral sensorineural hearing impairment, cone-rod dystrophy, infantile-onset cardiomyopathy, hypertriglyceridemia, accelerated non-alcoholic fatty liver disease, renal dysfunction and insulin-resistant diabetes mellitus (DM). DM typically develop in childhood or adolescence. Dilated cardiomyopathy may arise in infancy. Clinical symptoms appear with great variability and severity. Several cases have been reported worldwide; however, diagnosis remains challenging.
CASE DESCRIPTION
We report an 8-year-and-11-month-old female diagnosed with ALMS who had a long history of obesity and amblyopia from infancy. We found high levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in this patient. She showed no hearing disfunction. Recently, she presented with sudden-onset insulin-resistant DM. Genetic analysis revealed the heterozygous mutations c.8366delT, p.L2789* and c.6829C>T, p.R2277*. c.8366delT, which results in premature protein termination, has not been reported previously in . Although the patient's two sisters died of acute heart failure following infection at 4 and 14 months respectively, she showed no signs of cardiomyopathy until now.
CONCLUSIONS
This case provides an unusual cause of genetic syndrome associated with diabetes. A detailed medical history, physical examination and appropriate gene analysis are critical for diagnosis. Our case identifies a novel mutation and reaffirms the great clinical variation of this disease even within families.
PubMed: 35558979
DOI: 10.21037/tp-21-623 -
Translational Pediatrics Apr 2022Alstrom syndrome (ALMS) is an ultra-rare multisystem genetic disorder caused by autosomal recessive inheritance of the ALMS1 gene. It manifests as multisystem...
BACKGROUND
Alstrom syndrome (ALMS) is an ultra-rare multisystem genetic disorder caused by autosomal recessive inheritance of the ALMS1 gene. It manifests as multisystem dysfunction, displaying unique clinical signs and symptoms and various severity, which may lead to delayed prognosis or misdiagnosis in medical practice. Although almost 300 pathogenic variants have been reported, there are some variant sites that have not been recognized yet.
CASE DESCRIPTION
We report a case of a 14-year-old boy with manifestations, including binocular vision loss, acanthosis nigricans, type 2 diabetes, insulin resistance, elevated transaminase, hepatic fibrosis, and proteinuria. Compound heterozygous variants in the gene have been discovered by whole exon sequencing. One of his variant sites was C. 8158C>T, which was from his father. And the other variant site was C. 3575C>A, which was from his mother. To the great of our knowledge, this site has not been reported before. Both of the variants make the synthesis of the peptide chain terminated in advance and an incomplete polypeptide chain is formed.
CONCLUSIONS
The clinical presentations of ALMS are complicated and varied. Although early diagnosis can be made according to typical clinical symptoms, whole exon sequencing is necessary for the diagnosis of ALMS, as indicated by our study.
PubMed: 35558973
DOI: 10.21037/tp-21-535 -
Orphanet Journal of Rare Diseases Apr 2022Improving care coordination is particularly important for individuals with rare conditions (who may experience multiple inputs into their care, across different...
BACKGROUND
Improving care coordination is particularly important for individuals with rare conditions (who may experience multiple inputs into their care, across different providers and settings). To develop and evaluate strategies to potentially improve care coordination, it is necessary to develop a method for organising different ways of coordinating care for rare conditions. Developing a taxonomy would help to describe different ways of coordinating care and in turn facilitate development and evaluation of pre-existing and new models of care coordination for rare conditions. To the authors' knowledge, no studies have previously developed taxonomies of care coordination for rare conditions. This research aimed to develop and refine a care coordination taxonomy for people with rare conditions.
METHODS
This study had a qualitative design and was conducted in the United Kingdom. To develop a taxonomy, six stages of taxonomy development were followed. We conducted interviews (n = 30 health care professionals/charity representatives/commissioners) and focus groups (n = 4 focus groups, 22 patients/carers with rare/ultra-rare/undiagnosed conditions). Interviews and focus groups were audio-recorded with consent, and professionally transcribed. Findings were analysed using thematic analysis. Themes were used to develop a taxonomy, and to identify which types of coordination may work best in which situations. To refine the taxonomy, we conducted two workshops (n = 12 patients and carers group; n = 15 professional stakeholder group).
RESULTS
Our taxonomy has six domains, each with different options. The six domains are: (1) Ways of organising care (local, hybrid, national), (2) Ways of organising those involved in care (collaboration between many or all individuals, collaboration between some individuals, a lack of collaborative approach), (3) Responsibility for coordination (administrative support, formal roles and responsibilities, supportive roles and no responsibility), (4) How often appointments and coordination take place (regular, on demand, hybrid), (5) Access to records (full or filtered access), and (6) Mode of care coordination (face-to-face, digital, telephone).
CONCLUSIONS
Findings indicate that there are different ways of coordinating care across the six domains outlined in our taxonomy. This may help to facilitate the development and evaluation of existing and new models of care coordination for people living with rare conditions.
Topics: Caregivers; Focus Groups; Humans; Qualitative Research; Rare Diseases; Telephone; United Kingdom
PubMed: 35443702
DOI: 10.1186/s13023-022-02321-w -
Molecules and Cells Apr 2022A primary cilium, a hair-like protrusion of the plasma membrane, is a pivotal organelle for sensing external environmental signals and transducing intracellular... (Review)
Review
A primary cilium, a hair-like protrusion of the plasma membrane, is a pivotal organelle for sensing external environmental signals and transducing intracellular signaling. An interesting linkage between cilia and obesity has been revealed by studies of the human genetic ciliopathies Bardet-Biedl syndrome and Alström syndrome, in which obesity is a principal manifestation. Mouse models of cell type-specific cilia dysgenesis have subsequently demonstrated that ciliary defects restricted to specific hypothalamic neurons are sufficient to induce obesity and hyperphagia. A potential mechanism underlying hypothalamic neuron cilia-related obesity is impaired ciliary localization of G protein-coupled receptors involved in the regulation of appetite and energy metabolism. A well-studied example of this is melanocortin 4 receptor (MC4R), mutations in which are the most common cause of human monogenic obesity. In the paraventricular hypothalamus neurons, a blockade of ciliary trafficking of MC4R as well as its downstream ciliary signaling leads to hyperphagia and weight gain. Another potential mechanism is reduced leptin signaling in hypothalamic neurons with defective cilia. Leptin receptors traffic to the periciliary area upon leptin stimulation. Moreover, defects in cilia formation hamper leptin signaling and actions in both developing and differentiated hypothalamic neurons. The list of obesity-linked ciliary proteins is expending and this supports a tight association between cilia and obesity. This article provides a brief review on the mechanism of how ciliary defects in hypothalamic neurons facilitate obesity.
Topics: Animals; Cilia; Humans; Hyperphagia; Hypothalamus; Leptin; Mice; Obesity
PubMed: 35387896
DOI: 10.14348/molcells.2022.2046 -
American Journal of Ophthalmology Case... Jun 2022The ophthalmologic findings in Alström syndrome include cone-rod dystrophy, optic atrophy, optic disc drusen, and retinal telangiectasias with exudative retinopathy....
PURPOSE
The ophthalmologic findings in Alström syndrome include cone-rod dystrophy, optic atrophy, optic disc drusen, and retinal telangiectasias with exudative retinopathy. Here we describe peripheral retinal non-perfusion with neovascularization of the disc (NVD) in a child with Alström syndrome-related cone-rod dystrophy.
OBSERVATIONS
A six-year-old girl with a diagnosis of Alström syndrome based on a homozygous nonsense likely pathogenic variant in (NM_015120.4:c.4746C > G; p.Tyr1582Ter) was seen in the ophthalmology clinic for nystagmus, photophobia, and poor vision with non-recordable scotopic and photopic electroretinography (ERG) responses. On routine follow-up exam, she was found to have optic disc hyperermia and apparent swelling. Brain and orbital magnetic resonance imaging (MRI) and lumbar puncture with opening pressure measurement were unremarkable. Because the optic disc findings were persistent, she underwent examination under anesthesia with fluorescein angiography, which revealed bilateral neovascularization of the optic disc (NVD) with peripheral retinal non-perfusion. Systemic workup including hemoglobin A1C measurement was normal. She underwent four sessions of bilateral panretinal photocoagulation and three intravitreal injections of anti-vascular endothelial growth factor (VEGF) with subsequent improvement of the NVD in both eyes.
CONCLUSIONS AND IMPORTANCE
Neovascularization of the optic disc may arise in Alström syndrome as a sequela of peripheral retinal ischemia. This finding may be partially responsive to panretinal photocoagulation and intravitreal anti-VEGF therapy.
PubMed: 35355858
DOI: 10.1016/j.ajoc.2022.101506 -
World Journal of Clinical Cases Mar 2022Alström syndrome (AS) is a rare autosomal recessive disease that is generally induced by mutations of the Alström syndrome 1 gene. We report a case of AS, extend the...
BACKGROUND
Alström syndrome (AS) is a rare autosomal recessive disease that is generally induced by mutations of the Alström syndrome 1 gene. We report a case of AS, extend the spectrum of mutations and highlight the biological role of to explore the relationship between dilated cardiomyopathy (DCM) and mutations in .
CASE SUMMARY
We present the case of an infant with AS mainly manifesting with DCM that was caused by a novel mutation of the gene. Whole-exome sequencing revealed a simultaneous large deletion and point mutation in leading to frameshift and missense mutations, respectively, rather than nonsense or frameshift mutations, which have been reported previously. Upon optimized anti-remodeling therapy, biohumoral exams and arrhythmic burden of the infant were alleviated at follow-up after 6 mo.
CONCLUSION
We identified novel mutations of and extended the spectrum of mutations in an infant with AS.
PubMed: 35321175
DOI: 10.12998/wjcc.v10.i7.2330 -
Frontiers in Genetics 2022Alström syndrome (ALMS) is a rare inherited metabolic disease and ciliopathy. Large cohorts of ALMS are lacking around the world. Detailed genetic and phenotypic data...
Alström syndrome (ALMS) is a rare inherited metabolic disease and ciliopathy. Large cohorts of ALMS are lacking around the world. Detailed genetic and phenotypic data were obtained from all affected individuals. Olfactory function was evaluated by the Chinese Smell Identification Test and facial pattern was analyzed with Face2gene. Fifty ALMS patients were included in this study, aged from 0.3 to 21.7 years old. Sixty-one variants in 50 patients from 47 different families were confirmed, including 59 truncating and two exon deletions. Twenty-four of those variants were novel. We also summarized all previously reported cases of Chinese ALMS patients (69 patients) and identified specific and common variants within the Chinese population. Besides, the Chinese Smell Identification Test scores in patients was lower than that in controls (11.97 Vs. 10.44, < .05), indicating olfactory identification impairments in ALMS patients. The facial pattern in ALMS patients was also distinctive from that of the controls ( < .05). In conclusion, this is the largest cohort of Chinese ALMS patients. We have successfully identified both specific and common variants in our cohort. We found a new phenotype of olfactory impairments in ALMS patients through a case-control study.
PubMed: 35211159
DOI: 10.3389/fgene.2022.808919