-
Frontiers in Endocrinology 2022The diagnosis of neonatal hypocalcemic seizures (HS) in newborns is made based on clinical signs and serum calcium level. Their etiology is broad and diverse, and timely...
BACKGROUND
The diagnosis of neonatal hypocalcemic seizures (HS) in newborns is made based on clinical signs and serum calcium level. Their etiology is broad and diverse, and timely detection and initiation of treatment is essential.
METHODS
We retrospectively reviewed 1029 patients admitted to the neonatal intensive care unit. Neonatal HS were diagnosed in 16 patients, and we compared etiologies and clinical outcomes, including clinical seizures and neurodevelopment at least over 1 year old.
RESULTS
The etiologies can be broadly categorized into 5 syndromic and 11 non-syndromic neonatal HS. Syndromic neonatal HS included 3 Digeorge syndrome, 1 Kleefstra syndrome and 1 Alström syndrome. Non-syndromic neonatal HS included 8 vitamin D deficiency, 1 hypoparathyroidism, and 2 hypoxic-ischemic encephalopathy. Patients with syndromic neonatal HS were found to have worse clinical outcomes than those with nonsyndromic HS. In eight patients with vitamin D deficiency, neurodevelopment was normal. Five of five patients (100%) with syndromic HS used two or more antiseizure drugs. However, among patients with non-syndromic neonatal HS, only one of 11 (9.1%) used more than one drug ( 0.001).
CONCLUSION
This finding highlighted that syndromic hypocalcemic seizures in newborns have worse neurodevelopmental outcomes and are more often difficult to manage, and would benefit from a genetic diagnostic approach.
Topics: Infant; Humans; Infant, Newborn; Retrospective Studies; Seizures; Vitamin D Deficiency
PubMed: 36440223
DOI: 10.3389/fendo.2022.998675 -
American Journal of Ophthalmology Case... Dec 2020We present 3 cases of Alström syndrome (ALMS) that highlight the importance of the ophthalmic exam, as well as the diagnostic challenges and management considerations...
PURPOSE
We present 3 cases of Alström syndrome (ALMS) that highlight the importance of the ophthalmic exam, as well as the diagnostic challenges and management considerations of this ultra-rare disease.
OBSERVATIONS
The first case is of a 2-year-old boy with history of spasmus nutans who presented with head bobbing and nystagmus. The second patient is a 5-year-old boy with history of infantile dilated cardiomyopathy status post heart transplant, Burkitt lymphoma status post chemotherapy, obesity, global developmental delay, and high hyperopia previously thought to have cortical visual impairment secondary to heart surgery/possible ischemic event. This patient presented with nystagmus, photophobia, and reduced vision. The third case involves a 8-year-old boy with history of obesity, bilateral optic nerve atrophy, hyperopic astigmatism, exotropia, and nystagmus. Upon presentation to the consulting pediatric ophthalmologist, none of the patients had yet been diagnosed with ALMS. All 3 cases were subsequently found to have an electroretinogram (ERG) that exhibited severe global depression and to carry pathogenic variants.
CONCLUSIONS AND IMPORTANCE
ALMS is an autosomal recessive disease caused by variations, characterized by cone-rod dystrophy, obesity, progressive sensorineural hearing loss, cardiomyopathy, insulin resistance, and multiorgan dysfunction. Retinal dystrophy diagnosis is critical given clinical criteria and detection rates of genetic testing. Early diagnosis is extremely important because progression to flat ERG leads to the inability to differentiate between rod-cone or cone-rod involvement, either of which have their own differential diagnoses. In our series, the ophthalmic exam and abnormal ERG prompted further genetic testing and the subsequent diagnosis of ALMS. Multidisciplinary care ensures the best possible outcome with the ophthalmologist playing a key role.
PubMed: 32944671
DOI: 10.1016/j.ajoc.2020.100873 -
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 -
Molecular Genetics and Metabolism Sep 2018Alström Syndrome is a ciliopathy associated with obesity, insulin resistance/type 2 diabetes mellitus, cardiomyopathy, retinal degeneration, hearing loss, progressive...
Alström syndrome: Renal findings in correlation with obesity, insulin resistance, dyslipidemia and cardiomyopathy in 38 patients prospectively evaluated at the NIH clinical center.
Alström Syndrome is a ciliopathy associated with obesity, insulin resistance/type 2 diabetes mellitus, cardiomyopathy, retinal degeneration, hearing loss, progressive liver and kidney disease, and normal cognitive function. ALMS1, the protein defective in this disorder, localizes to the cytoskeleton, microtubule organizing center, as well as the centrosomes and ciliary basal bodies and plays roles in formation and maintenance of cilia, cell cycle regulation, and endosomal trafficking. Kidney disease in this disorder has not been well characterized. We performed comprehensive multisystem evaluations on 38 patients. Kidney function decreased progressively; eGFR varied inversely with age (p = 0.002). Eighteen percent met the definition for chronic kidney disease (eGFR < 60 mL/min/1.73 m and proteinuria); all were adults with median age of 32.8 (20.6-37.9) years. After adjusting for age, there were no significant associations of kidney dysfunction with type 2 diabetes mellitus, dyslipidemia, hypertension, cardiomyopathy or portal hypertension suggesting that kidney disease in AS is a primary manifestation of the syndrome due to lack of ALMS1 protein. Approximately one-third of patients had hyperechogenicity of the renal parenchyma on imaging. While strict control of type 2 diabetes mellitus may decrease kidney-related morbidity and mortality in Alström syndrome, identification of novel targeted therapies is needed.
Topics: Adult; Alstrom Syndrome; Cardiomyopathies; Cell Cycle Proteins; Dyslipidemias; Female; Humans; Insulin Resistance; Kidney; Kidney Diseases; Male; Mutation; Obesity; Proteins; Retinal Degeneration
PubMed: 30064963
DOI: 10.1016/j.ymgme.2018.07.010 -
Clinical Case Reports Feb 2023Alstrom syndrome is a rare genetic disorder with an autosomal recessive mutation in the ALMS1 gene. The disease's manifestations include ophthalmic problems, hearing...
Alstrom syndrome is a rare genetic disorder with an autosomal recessive mutation in the ALMS1 gene. The disease's manifestations include ophthalmic problems, hearing loss, obesity, and cardiovascular disorders. In addition, medical cases include other organ complications. However, the overlapping variety of such symptoms with other diseases may delay the diagnosis. In this article, we describe the case of a 7-year-old female patient with Alstrom syndrome, and cardiovascular and hyperphenylalaninemia diseases since birth. Other symptoms included diabetes and ophthalmologic problems with skeletal disability. Blindness and hearing impairment were diagnosed, along with recurrence of respiratory problems at the age of 7 years. The patient's obesity-induced snoring predisposed her to uncontrolled blood glucose. In fact, respiratory tract problems and sleep disorders had occurred as a degraded cycle and left her with a severe disability for years. The similarity of the symptoms with other diseases had misled the physician in diagnosis. However, a polysomnography test (because of complaints of short sleep duration) recognized the source of the patient's sleep disorders and breathing problems. Eventually, we delivered a portable ventilator to the child for continuous positive airway pressure (CPAP) therapy. The child's breathing and oxygenation conditions improved. Using the ventilator and the CPAP system, we discharged her from the hospital without requiring oxygenation, in a stable condition. The procedure could prevent the patient from hypoxia and retinal problem.
PubMed: 36777792
DOI: 10.1002/ccr3.6894 -
Contemporary Clinical Trials... Jun 2021A phase 2 trial has suggested that treatment with the melanocortin-4 receptor (MC4R) agonist setmelanotide is associated with a decrease in hunger and weight-related...
BACKGROUND
A phase 2 trial has suggested that treatment with the melanocortin-4 receptor (MC4R) agonist setmelanotide is associated with a decrease in hunger and weight-related outcomes in participants with Bardet-Biedl syndrome (BBS) and Alström syndrome. Here, we present the study design of an ongoing, randomized, double-blind, placebo-controlled, phase 3 trial to assess the long-term efficacy and safety of setmelanotide for the treatment of obesity and hyperphagia in individuals with BBS or Alström syndrome (ClinicalTrials.gov identifier: NCT03746522).
METHODS
It was initially planned that ~30 participants aged ≥6 years with a clinical diagnosis of BBS or Alström syndrome would be enrolled. Participants with obesity as defined by a body mass index ≥30 kg/m (in those aged ≥16 years) or a weight >97th percentile (in those aged 6-15 years) are included. Participants are initially randomized in a 1:1 ratio to receive setmelanotide or placebo for 14 weeks (period 1). Following period 1, all participants receive 38 weeks of open-label treatment with setmelanotide (period 2). In each treatment period, setmelanotide is administered at 3 mg once a day following completion of dose escalation. The primary endpoint is the proportion of participants aged ≥12 years achieving a clinically meaningful reduction from baseline (≥10%) in body weight after ~52 weeks (eg, following period 2). Safety and tolerability are assessed by frequency of adverse events.
CONCLUSIONS
This pivotal trial is designed to evaluate the efficacy and safety of setmelanotide for the treatment of obesity and hyperphagia in individuals with BBS and Alström syndrome.
SUBMISSION CATEGORY
Study Design, Statistical Design, Study Protocols.
PubMed: 34013094
DOI: 10.1016/j.conctc.2021.100780 -
Nephron 2020Alström syndrome is a rare recessive genetic disease caused by mutations in ALMS1, which encodes a protein that is related to cilia function and intracellular endosome...
INTRODUCTION
Alström syndrome is a rare recessive genetic disease caused by mutations in ALMS1, which encodes a protein that is related to cilia function and intracellular endosome trafficking. The syndrome has been linked to impaired glucose metabolism and CKD. Polymorphisms in Alms1 have likewise been linked to CKD, but little is known about the modification of the phenotype by environmental factors.
METHODS
To gain further insights, the fat aussie (foz) mouse strain, a genetic murine model of Alström syndrome, was exposed to a normal chow (NC) or to a Western diet (WD, 20% fat, 34% sucrose by weight, and 0.2% cholesterol) and renal outcomes were measured.
RESULTS
Body weight and albuminuria were higher in foz than in wild-type (WT) mice on both diets but WD significantly increased the difference. Measurement of plasma creatinine and cystatin C indicated that glomerular filtration rate was preserved in foz versus WT independent of diet. Renal markers of injury, inflammation, and fibrosis were similar in both genotypes on NC but significantly greater in foz than in WT mice on WD. A glucose tolerance test performed in foz and WT mice on WD revealed similar basal blood glucose levels and subsequent blood glucose profiles.
CONCLUSIONS
WD sensitizes a murine model of Alström syndrome to kidney injury, inflammation, and fibrosis, an effect that may not be solely due to effects on glucose metabolism. Polymorphisms in Alms1 may induce CKD in part by modulating the deleterious effects of high dietary fat and sucrose on kidney outcome.
Topics: Alstrom Syndrome; Animals; Blood Glucose; Cell Cycle Proteins; Cilia; Diet, Western; Disease Models, Animal; Fibrosis; Glomerular Filtration Rate; Glycosuria; Kidney; Kidney Tubules; Leptin; Male; Mice; Nephritis; Obesity; Organ Size; Renin
PubMed: 32629454
DOI: 10.1159/000508636 -
Disease Models & Mechanisms May 2012The ciliopathies are an apparently disparate group of human diseases that all result from defects in the formation and/or function of cilia. They include disorders such... (Review)
Review
The ciliopathies are an apparently disparate group of human diseases that all result from defects in the formation and/or function of cilia. They include disorders such as Meckel-Grüber syndrome (MKS), Joubert syndrome (JBTS), Bardet-Biedl syndrome (BBS) and Alström syndrome (ALS). Reflecting the manifold requirements for cilia in signalling, sensation and motility, different ciliopathies exhibit common elements. The mouse has been used widely as a model organism for the study of ciliopathies. Although many mutant alleles have proved lethal, continued investigations have led to the development of better models. Here, we review current mouse models of a core set of ciliopathies, their utility and future prospects.
Topics: Abnormalities, Multiple; Animals; Cilia; Disease Models, Animal; Humans; Mice; Sense Organs; Signal Transduction; Translational Research, Biomedical
PubMed: 22566558
DOI: 10.1242/dmm.009340 -
Journal of Medicine and Life 2008Over the past ten years, several studies demonstrated the connections between cilia, basal bodies and human diseases with a wide phenotypic spectrum, including... (Review)
Review
Over the past ten years, several studies demonstrated the connections between cilia, basal bodies and human diseases with a wide phenotypic spectrum, including randomization of body symmetry, obesity, cystic kidney diseases and retinal degeneration. Alström syndrome (OMIM 203800) first described in 1959, is a rare autosomal recessive disorder caused by mutations in a novel gene of unknown function, ALMS1, located on the short arm of chromosome 2. Central features of Alström syndrome include obesity, insulin resistance, and type 2 diabetes. About 500 individuals with Alström syndrome are known worldwide. ALMS1 is widely expressed and localizes to centrosomes and to the base of cilia. We discuss the possible molecular mechanisms, clinical features, and future therapeutic options in a patient diagnosed with this rare disease. Monogenic defects causing human obesity actually disrupt hypothalamic pathways with a profound effect on satiety and food intake. A potential contributor to obesity- cilia with impaired function or abnormal structure, creates a new link to be studied in the future, between these organelles and the genetics of obesity.
Topics: Abnormalities, Multiple; Adult; Alstrom Syndrome; Blindness; Body Mass Index; Cell Cycle Proteins; Chromosomes, Human, Pair 2; Cilia; Diabetes Mellitus, Type 2; Female; Genetic Markers; Genotype; Hearing Loss; Human Growth Hormone; Humans; Insulin Resistance; Mutation; Obesity; Phenotype; Proteins; Retinitis Pigmentosa; Treatment Outcome
PubMed: 20108502
DOI: No ID Found -
Archivum Immunologiae Et Therapiae... Dec 2016Monogenic diabetes is a rare genetic type of diabetes caused by pancreatic β-cells dysfunction. All subtypes of monogenic diabetes are recognized in the pediatric... (Review)
Review
Monogenic diabetes is a rare genetic type of diabetes caused by pancreatic β-cells dysfunction. All subtypes of monogenic diabetes are recognized in the pediatric population. They include maturity onset diabetes of the young, permanent neonatal diabetes mellitus and rare syndromic forms of diabetes. An early and proper diagnosis allows to implement an optimal treatment, leads to improved metabolic control and amelioration of related disabilities as well as increases the quality of life of the patients.
Topics: Adult; Alstrom Syndrome; Bardet-Biedl Syndrome; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucokinase; Humans; Insulin-Secreting Cells; Mutation; Poland; Quality of Life; United Kingdom; Wolfram Syndrome
PubMed: 28083605
DOI: 10.1007/s00005-016-0432-8