ABSTRACT
Short telomeres are a principal defining feature of telomere biology disorders, such as dyskeratosis congenita (DC), for which there are no effective treatments. Here, we report that primary fibroblasts from DC patients and late generation telomerase knockout mice display lower nicotinamide adenine dinucleotide (NAD) levels, and an imbalance in the NAD metabolome that includes elevated CD38 NADase and reduced poly(ADP-ribose) polymerase and SIRT1 activities, respectively, affecting many associated biological pathways. Supplementation with the NAD precursor, nicotinamide riboside, and CD38 inhibition improved NAD homeostasis, thereby alleviating telomere damage, defective mitochondrial biosynthesis and clearance, cell growth retardation, and cellular senescence of DC fibroblasts. These findings reveal a direct, underlying role of NAD dysregulation when telomeres are short and underscore its relevance to the pathophysiology and interventions of human telomere-driven diseases.
Subject(s)
Dyskeratosis Congenita/genetics , Dyskeratosis Congenita/metabolism , Fibroblasts/metabolism , NAD/metabolism , Telomerase/genetics , Telomere/metabolism , ADP-ribosyl Cyclase 1/genetics , Animals , Brain/pathology , Cell Line , Cellular Senescence , Dyskeratosis Congenita/pathology , Female , Homeostasis , Humans , Membrane Glycoproteins/genetics , Mice , Mice, Knockout , Mitochondria/metabolism , Niacinamide/analogs & derivatives , Niacinamide/metabolism , Phenotype , Poly (ADP-Ribose) Polymerase-1/metabolism , Pyridinium Compounds/metabolism , Telomerase/metabolismABSTRACT
CONTEXT: Endocrine problems are common in patients with Fanconi anemia (FA). About 80% of children and adults with FA have at least one endocrine abnormality, including short stature, GH deficiency, abnormal glucose or insulin metabolism, dyslipidemia, hypothyroidism, pubertal delay, hypogonadism, or impaired fertility. The goal of this report is to provide an overview of endocrine abnormalities and guidelines for routine screening and treatment to allow early diagnosis and timely intervention. EVIDENCE ACQUISITION: This work is based on a comprehensive literature review, including relevant articles published between 1971 and 2014, and proceedings of a Consensus Conference held by the Fanconi Anemia Research Fund in 2013. EVIDENCE SYNTHESIS: The panel of experts collected published evidence and discussed its relevance to reflect current information about the endocrine care of children and adults with FA before the Consensus Conference and through subsequent deliberations that led to the consensus. CONCLUSIONS: Individuals with FA should be routinely screened for endocrine abnormalities, including evaluation of growth; glucose, insulin, and lipid metabolism; thyroid function; puberty; gonadal function; and bone mineral metabolism. Inclusion of an endocrinologist as part of the multidisciplinary patient care team is key to providing comprehensive care for patients with FA.
Subject(s)
Endocrine System Diseases/diagnosis , Endocrine System Diseases/therapy , Fanconi Anemia/diagnosis , Fanconi Anemia/therapy , Mass Screening/standards , Practice Guidelines as Topic , Adult , Child , Endocrine System Diseases/etiology , Fanconi Anemia/complications , Glucose Metabolism Disorders/diagnosis , Glucose Metabolism Disorders/etiology , Glucose Metabolism Disorders/therapy , Growth Disorders/diagnosis , Growth Disorders/etiology , Growth Disorders/therapy , Human Growth Hormone/deficiency , Human Growth Hormone/therapeutic use , Humans , Malnutrition/diagnosis , Malnutrition/etiology , Malnutrition/therapy , Mass Screening/methods , Thinness/diagnosis , Thinness/etiology , Thinness/therapyABSTRACT
BACKGROUND: Dyskeratosis congenita (DC), an inherited bone marrow failure syndrome (IBMFS), is caused by defects in telomere biology, which result in very short germline telomeres. Telomeres, long nucleotide repeats and a protein complex at chromosome ends, are essential for chromosomal stability. Several association studies suggest that short telomeres are associated with certain psychiatric disorders, including mood disorders and schizophrenia. There are two cases in the literature of schizophrenia and DC occurring as co-morbid conditions. We noted that many patients with DC in our cohort had neuropsychiatric conditions. METHODS: Subjects were participants in NCI's IBMFS prospective cohort study. Psychiatric evaluation was incorporated into our clinical assessment in January 2009. Fourteen DC or DC-like patients, including six children, were evaluated in this study through in person interview by either a psychiatrist specialized in psychosomatic medicine or a child and adolescent psychiatrist. RESULTS: Three of the six pediatric subjects and five of the eight adults had a neuropsychiatric condition such as a mood, anxiety, or adjustment disorder, intellectual disability, attention deficit hyperactivity disorder, or pervasive developmental disorders. The lifetime occurrence of any of these disorders in our study was 83% in pediatric subjects and 88% in adults. Notably, the literature reports neuropsychiatric conditions in 25% and 38% in chronically ill children and adults, respectively. CONCLUSION: This pilot study suggests that patients with DC may have higher rates of neuropsychiatric conditions than the general population or other chronically ill individuals. This potential link between very short telomeres and neuropsychiatric conditions warrants further study.