MedGen

PMM2-CDG, the most common of a group of disorders of abnormal glycosylation of N-linked oligosaccharides, is divided into three clinical stages: infantile multisystem, late-infantile and childhood ataxia–intellectual disability, and adult stable disability. The clinical manifestations and course are highly variable, ranging from infants who die in the first year of life to mildly affected adults. Clinical findings tend to be similar in sibs. In the infantile multisystem presentation, infants show axial hypotonia, hyporeflexia, esotropia, and developmental delay. Feeding problems, vomiting, faltering growth, and developmental delay are frequently seen. Subcutaneous fat may be excessive over the buttocks and suprapubic region. Two distinct clinical courses are observed: (1) a nonfatal neurologic course with faltering growth, strabismus, developmental delay, cerebellar hypoplasia, and hepatopathy in infancy followed by neuropathy and retinitis pigmentosa in the first or second decade; and (2) a more severe neurologic-multivisceral course with approximately 20% mortality in the first year of life. The late-infantile and childhood ataxia–intellectual disability stage, which begins between ages three and ten years, is characterized by hypotonia, ataxia, severely delayed language and motor development, inability to walk, and IQ of 40 to 70; other findings include seizures, stroke-like episodes or transient unilateral loss of function, coagulopathy, retinitis pigmentosa, joint contractures, and skeletal deformities. In the adult stable disability stage, intellectual ability is stable; peripheral neuropathy is variable, progressive retinitis pigmentosa and myopia are seen, thoracic and spinal deformities with osteoporosis worsen, and premature aging is observed; females may lack secondary sexual development and males may exhibit decreased testicular volume. Hypogonadotropic hypogonadism and coagulopathy may occur. The risk for deep venous thrombosis is increased. [from GeneReviews]

Alpha-mannosidosis encompasses a continuum of clinical findings from mild to severe. Three major clinical subtypes have been suggested: A mild form recognized after age ten years with absence of skeletal abnormalities, myopathy, and slow progression (type 1). A moderate form recognized before age ten years with presence of skeletal abnormalities, myopathy, and slow progression (type 2). A severe form manifested as prenatal loss or early death from progressive central nervous system involvement or infection (type 3). Individuals with a milder phenotype have mild-to-moderate intellectual disability, impaired hearing, characteristic coarse features, clinical or radiographic skeletal abnormalities, immunodeficiency, and primary central nervous system disease – mainly cerebellar involvement causing ataxia. Periods of psychiatric symptoms are common. Associated medical problems can include corneal opacities, hepatosplenomegaly, aseptic destructive arthritis, and metabolic myopathy. Alpha-mannosidosis is insidiously progressive; some individuals may live into the sixth decade. [from GeneReviews]

Osteoarthritis (OA) is a degenerative disease of the joints characterized by degradation of the hyaline articular cartilage and remodeling of the subchondral bone with sclerosis (Meulenbelt et al., 2006). Clinical problems include pain and joint stiffness often leading to significant disability and joint replacement. Osteoarthritis exhibits a clear predilection for specific joints; it appears most commonly in the hip and knee joints and lumbar and cervical spine, as well as in the distal interphalangeal and the first carpometacarpal (base of thumb) and proximal interphalangeal joints of the hand; however, patients with osteoarthritis may have 1, a few, or all of these sites affected (Stefansson et al., 2003). According to a conservative estimate, greater than 70% of the population of the United States at age 65 years is affected by the disease, reflecting its age dependence. Genetic Heterogeneity of Susceptibility to Osteoarthritis Susceptibility to osteoarthritis has been associated with variation in other genes: OS2 (140600) with variation in the MATN3 gene (602109) on chromosome 2p24; OS3 (607850) with variation in the ASPN gene (608135) on chromosome 9q22; and OS5 (612400) with variation in the GDF5 gene (601146) on chromosome 20q11. Other susceptibility loci for osteoarthritis have been mapped to chromosomes 2q33 (OS4; 610839) and 3p24 (OS6; 612401). [from OMIM]

Atrial fibrillation (AF) is the most common sustained cardiac rhythm disturbance, affecting more than 2 million Americans, with an overall prevalence of 0.89%. The prevalence increases rapidly with age, to 2.3% between the ages of 40 and 60 years, and to 5.9% over the age of 65. The most dreaded complication is thromboembolic stroke (Brugada et al., 1997). Genetic Heterogeneity of Familial Atrial Fibrillation ATFB1 shows linkage to chromosome 10q22-q24. ATFB2 (608988) maps to chromosome 6q. ATFB3 (607554) is caused by mutation in the KCNQ1 gene (607542) on chromosome 11. ATFB4 (611493) is caused by mutation in the KCNE2 gene (603796) on chromosome 21. Variants in a region of chromosome 4q25 are associated with ATFB5 (611494). ATFB6 (612201) is caused by mutation in the NPPA gene (108780) on chromosome 1p36. ATFB7 (612240) is caused by mutation in the KCNA5 gene (176267) on chromosome 12p13. ATFB8 (613055) maps to chromosome 16q22. ATFB9 (613980) is caused by mutation in the KCNJ2 gene (600681) on chromosome 17q24.3. ATFB10 (614022) is caused by mutation in the SCN5A gene (600163) on chromosome 3p21. ATFB11 (614049) is caused by mutation in the GJA5 (121013) gene on chromosome 1q21.1. ATFB12 (614050) is caused by mutation in the ABCC9 gene (601439) on chromosome 12p12.1. ATFB13 (615377) is caused by mutation in the SCN1B gene (600235) on chromosome 19q13. ATFB14 (615378) is caused by mutation in the SCN2B gene (601327) on chromosome 11q23. ATFB15 (615770) is caused by mutation in the NUP155 gene (606694) on chromosome 5p13. ATFB16 (see 613120) is caused by mutation in the SCN3B gene (608214) on chromosome 11q24. ATFB17 (see 611819) is caused by mutation in the SCN4B gene (608256) on chromosome 11q23. ATFB18 (617280) is caused by mutation in the MYL4 gene (160770) on chromosome 17q21. Olesen et al. (2014) analyzed 192 Danish Caucasian patients with onset of lone atrial fibrillation before the age of 40 years for the presence of rare variants in 14 AF-associated genes and found that 29 (7.6%) alleles harbored a very rare variant (minor allele frequency less than 1%), a significantly higher percentage than that found in 6,503 individuals in the NHLBI Exome Variant Server database (4.1%; p = 0.0012). Twenty-four of the 29 rare variants found in the lone AF patient cohort had previously been studied, with 23 (96%) showing abnormal ion channel function by patch-clamp analysis. Olesen et al. (2014) suggested that rare variants in AF susceptibility genes may play a role in the pathophysiology of AF. [from OMIM]

The essential features of X-linked sideroblastic anemia include the following: (1) a hypochromic microcytic anemia and 2 discrete populations of red blood cells, one microcytic and the other normocytic; (2) marrow ringed sideroblasts, particularly prominent in the late erythroid precursors; (3) a variable hematologic response to pharmacologic doses of pyridoxine; and (4) systemic iron overload secondary to chronic ineffective erythropoiesis. The age of clinical onset of the disorder can vary from in utero to the ninth decade. Whereas males are preferentially affected, females may present with clinically severe anemia. More commonly, female carriers of the disease have an increased red blood cell distribution width and sometimes erythrocyte dimorphism (Fleming, 2002). Genetic Heterogeneity of Sideroblastic Anemia See also SIDBA2 (205950), caused by mutation in the SLC25A38 gene (610819) on chromosome 3p22; SIDBA3 (616860), caused by mutation in the GLRX5 gene (609588) on chromosome 14q32; SIDBA4 (182170), caused by mutation in the HSPA9 gene (600548) on chromosome 5q31; and SIDBA5 (619523), caused by mutation in the HSCB gene (608142) on chromosome 22q12. [from OMIM]