Autosomal Recessive Disorders

Genetics of Main Allowed Deficiencies

Troy Torgerson , Hans Ochs , in Stiehm's Immune Deficiencies, 2014

Autosomal Recessive Inheritance

Autosomal recessive disorders occur when a person has defects in both copies of an autosomal cistron (a gene that is located on any of the autosomes) ( Figure 3.1B), resulting in "loss of function" (Figure 3.2A). If both copies of the gene have the same deleterious mutation, the defect is termed homozygous. If each copy of the gene has a dissimilar deleterious mutation, the defect is termed compound heterozygous. Each parent of an afflicted patient is typically a heterozygous carrier, and has one normal and one abnormal copy of the gene (Figure 3.1B). In most cases a normal copy of the factor can compensate for the defective copy; thus, heterozygous carriers are generally asymptomatic. When two carrier parents have offspring, statistically, one in four offspring should have the affliction, two should be carriers, and one should be normal. Autosomal recessive disorders occur with increased frequency in offspring of consanguineous marriages or in isolated populations where an original "founder mutation" that occurs in i individual at some betoken in history is afterward propagated throughout the population.

Figure iii.2. (A) Graph comparing the relative amount of poly peptide function in a jail cell containing ii normal copies of a gene (Wild Blazon) vs a cell containing ii mutant copies of a gene (Loss of Role), a cell containing one normal and i mutant re-create of a gene that tin act in a ascendant negative manner (Dominant Negative), a jail cell containing one normal re-create of a factor that has normal function and 1 copy of a factor that has no role (Haploinsufficiency), and a cell containing one normal re-create of a gene and one mutant copy of a factor that has a dominant gain of role (Gain of Function). (B) Machinery of how a mutant protein with dominant negative office tin can decrease total protein function by more than 50% in situations where the poly peptide multimerizes (such as forming dimers, equally shown here). Protein complexes containing i mutant subunit are non-functional.

Read full affiliate

URL:

https://world wide web.sciencedirect.com/science/article/pii/B9780124055469000030

Basic Genetic Principles

Fred Levine , in Fetal and Neonatal Physiology (Fifth Edition), 2017

Autosomal Recessive Disorders

AR disorders are those that are clinically credible just when the patient is homozygous for the disease (i.e., both copies of the gene are mutant). The following full general principles of inheritance are recognized for AR disorders (run across Figure ane-seven, B ):

•

The parents of affected children are clinically normal (i.eastward., carriers).

•

Assuming that the carrier frequency in the population is depression, just siblings are affected, and vertical manual does not occur; the pattern therefore tends to appear horizontal.

•

Consanguinity can be a cistron. This can occur in outbred populations by mating betwixt family members, or in inbred populations (e.yard., the Amish) where the unabridged population is descended from a modest number of ancestors.

•

Males and females are affected in equal proportions.

•

When both parents are heterozygous carriers of the mutation, 25% of their children are affected, 50% are carriers, and 25% are normal.

Every person is a carrier of AR mutations. Fortunately, the carrier frequency for most of these mutations is and then depression that the likelihood that carriers will have affected children is low.

Recessive mutations frequently involve enzymes, as opposed to regulatory and structural proteins. This is because 50% of the normal level of enzyme activeness normally is sufficient for normal function. Complete enzyme deficiency produces an accumulation of one or more than metabolites preceding the enzymatic block, such as the buildup of phenylalanine in phenylketonuria, and a deficiency of metabolites distal to the cake. Either, or both, of these abnormalities may exist responsible for the disease phenotype. Although many recessive disorders involve enzymes, 2 of the most common disorders with AR inheritance are cystic fibrosis, resulting from a mutation in a chloride channel, and sickle jail cell anemia, resulting from a mutation in the β-globin gene.

Information technology is important to be aware that the terms dominant and recessive refer to clinical phenotypes but. At the gene level, "dominance" and "recessiveness" do not exist. Persons heterozygous for a recessive disorder may be clinically normal, but the reduced level of functional or immunoreactive protein can be detected analytically and may pb to other biochemical abnormalities that have no obvious effect on the person's health. For example, short concatenation acyl-coenzyme A dehydrogenase deficiency, a disorder of short chain fat acrid metabolism, is detected by newborn screening but appears to have no clinical consequences. Patients homozygous for dominant mutations normally are more severely afflicted than are heterozygous patients. This is true in familial hypercholesterolemia. In many cases, the homozygous condition results in embryonic lethality, and then it is never seen clinically. Huntington disease stands out every bit an exception in that homozygous patients are not clinically dissimilar from heterozygous patients, presumably because the gain of function effect of the triplet repeat mutation is not dose responsive.

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780323352147000019

Mechanisms and Morphology of Cellular Injury, Adaptation, and Death1

Margaret A. Miller , James F. Zachary , in Pathologic Basis of Veterinary Affliction (6th Edition), 2017

Autosomal Recessive Disorders.

In autosomal recessive disorders, both alleles at a given gene locus must be mutated for an animal to be afflicted by the disorder. One mutated allele is provided past the sire and the other by the dam. Thus there is a 25% chance that each offspring from heterozygous parents will inherit both mutated alleles. Heterozygotes, with only one mutated allele, are clinically normal carriers of the trait. Homozygous animals usually have clinical disease, and the onset is unremarkably early in life. Many of the mutated genes encode enzymes. Examples of autosomal recessive disorders in animals include lysosomal storage diseases (see E-Fig. 1-27 and Figs. 14-63 and 14-64), glycogen storage diseases (see Fig. 14-63) and mucopolysaccharidoses, and aminoacidopathies that affect organs such every bit the brain, spinal string, skeletal muscle, liver, and kidney.

Read full chapter

URL:

https://www.sciencedirect.com/science/commodity/pii/B9780323357753000011

Congenital Genetic Disorders and Syndromes

Rebecca L. Slayton , ... Rebecca 50. Slayton , in Pediatric Dentistry (Sixth Edition), 2019

Autosomal Recessive

An autosomal recessive disorder becomes manifest only when an private has 2 copies of the mutant cistron. Virtually frequently each parent has one re-create of the defective factor and is a carrier, and there is a 25% gamble that both mutant genes will be passed on to their offspring. Male and female offspring will be equally likely to be affected. Fifty pct of the time the offspring will go one re-create of the mutant gene from ane parent and volition be carriers, and 25% of the time the offspring will get two normal copies of the cistron. Although autosomal recessive disorders are relatively uncommon, the carrier condition in certain populations can be significant. For example, 1 in 25 people of northern European descent are carriers of cystic fibrosis. three Genetic diseases more common amid people of Asian and African descent are beta-thalassemia and sickle cell anemia, respectively. 4,5

Read total chapter

URL:

https://www.sciencedirect.com/scientific discipline/article/pii/B9780323608268000171

Mendelian and Mitochondrial Inheritance, Cistron Identification, and Clinical Testing

VIRGINIA V. MICHELS , ... ERIK C. THORLAND , in Peripheral Neuropathy (Quaternary Edition), 2005

Autosomal Recessive Inheritance

Autosomal recessive disorders are coded for by genes located on the nonsex chromosomes. In dissimilarity to autosomal dominant inheritance, the heterozygote, who has one abnormal allele and one normal allele, does not differ clinically from a person homozygous for the normal gene. Rather, the person must be homozygous for the abnormal allele for the illness or trait to be expressed. In some cases, the person has two aberrant alleles of a certain gene, just each is abnormal in a different way. Such persons are referred to as chemical compound heterozygotes. Equally described to a higher place for autosomal dominant illness, trinucleotide repeat expansions tin can also exist the blazon of mutation causing autosomal recessive disease, such as Friedreich'southward clutter.

For the disease to be nowadays in the offspring, both parents must have i re-create of an abnormal allele, and the risk of disease for each of their offspring, of either sex, is 25%. In autosomal recessive inheritance, the previous generations commonly are not affected with the disease. Although the classic description of pedigrees for autosomal recessive inheritance includes two or more than affected siblings, with today'due south small boilerplate family size of 2.iv children, it is not unusual for the disease to appear sporadically within the family unit. One cannot exclude autosomal recessive disease on the basis of a negative family unit history. In these cases it is sometimes necessary to rely on cognition of the usual manner of inheritance of the disease. Although some diseases, such as CF, are always inherited in an autosomal recessive pattern, other clinically defined diseases may be inherited in one of several means. For example, retinitis pigmentosa tin can be inherited every bit an autosomal dominant, autosomal recessive, or X-linked recessive disease.

Fifty-fifty the same cistron tin have different mutations that act in a dominant or recessive manner. For case, both autosomal dominant and autosomal recessive retinitis pigmentosa can exist acquired by different mutations in the rhodopsin gene. seven Furthermore, unlike mutations in the same gene can cause different clinical disorders. For instance, mutations in the peripherin/RDS cistron tin can cause autosomal ascendant retinitis pigmentosa, as well every bit several types of macular dystrophy. 5

For autosomal recessive diseases, the risk for an affected person to have an affected child is low, unless the disease is very common or the afflicted person marries a blood relative or a person too afflicted with the same autosomal recessive disease. Yet, even among couples who meet neither of these criteria, the gamble is greater than the full general population adventure. For example, if one assumes that the carrier frequency of the gene for phenylketonuria (PKU) is 1 in 50 in the full general population, the risk for healthy parents without a positive family history is i/fifty × 1/fifty × one/four = one/x,000. Still, if a man has PKU, the risk for his children is 1 × 1/50 × 1/two = ane/100. The take chances for the affected man's healthy sister to have a kid with PKU is 2/3 × 1/50 × 1/4 = 1/300.

There are some unusual mechanisms by which autosomal disease may occur, in which but one parent is a carrier for the gene defect. New mutations may occur, as has been documented at the molecular level. For example, a patient with spinal muscular atrophy type I was shown to be homozygous for the common deletion of exons seven and 8 of the SMN1 gene. The mother was a carrier of the deletion, just the begetter was non. Nonpaternity was excluded, and it was ended that the mutation had arisen past new mutation. 52 In another type of state of affairs, uniparental disomy for a chromosomal segment with an autosomal recessive gene defect was shown to cause "homoallelic" disease in a patient with a retinal dystrophy. 40 Uniparental disomy refers to the inheritance of both of a pair of chromosomes or chromosomal segments from one parent rather than i from each parent. This tin can occur by various mechanisms, such equally trisomic rescue, in which the zygote starts out with trisomy for a given chromosome, but the actress chromosome is lost early in subsequent prison cell divisions. Therefore, caution is ever warranted in making presumptions about carrier status, particularly if prenatal diagnosis may be involved.

Read total chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780721694917500673

Main Disorders of Connective Tissue

William Thou. Cole , Outi Mäkitie , in Textbook of Pediatric Rheumatology (7th Edition), 2016

Progressive Pseudorheumatoid Arthropathy

This autosomal recessive disorder (OMIM #208230) presents between the ages of 3 and viii years in healthy appearing children, and is acquired by mutation in WISP3 (WNT1 inducible signaling pathway protein 3, felt to play a part in BMP and WNT signaling). 93 Information technology is a progressive disorder manifesting with stiffness, swelling, weakness with waddling gait, joint space narrowing, and periarticular osteopenia, and progresses to metaphyseal enlargement, contractures, and kyphoscoliosis with platyspondyly (Fig. 54-7). This disorder is sometimes labeled "rheumatoid arthritis with Scheuermann affliction" only has none of the laboratory abnormalities of JIA.

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780323241458000545

Odour and Taste

Richard 50. Doty , Christopher H. Hawkes , in Handbook of Clinical Neurology, 2019

Wilson's affliction

This autosomal recessive disorder of copper metabolism, also known equally hepatolenticular degeneration, is an autosomal recessive disorder caused by an ATP7B factor mutation on the long arm of chromosome 13. Copper accumulation occurs in the liver and basal ganglia and can lead, if not treated, to progressively severe dystonia and parkinsonism. Mueller et al. (2006), used the SS test battery to assess olfactory function in 24 Wilson's disease patients. There were 11 with just liver disease and a further 13 with additional neurologic symptoms. Those in the neurologic group were compared to the hepatic group and found to have mild to moderate olfactory impairment. Olfactory function was unrelated to long-term penicillamine handling. The olfactory scores correlated with neither MRI nor fluorodeoxyglucose PET scans. The authors suggested that the microsmia related to "specific functions of the basal ganglia in the processing of odorous stimuli." Although pathologic studies of the OB in Wilson's disease announced to be lacking, there is evidence of amygdala pathology, suggesting a potential limbic cause of the disorder (Shimoji et al., 1987). At that place is 1 report of "olfactory paranoid syndrome" (maybe similar to the olfactory reference syndrome) in a Japanese patient with Wilson's disease associated with idiopathic thrombocytopenic purpura. The psychiatric and concrete symptoms recovered afterwards handling with penicillamine (Sagawa et al., 2003).

Read full chapter

URL:

https://world wide web.sciencedirect.com/science/article/pii/B9780444638557000204

Identifying and Managing the High-Gamble Patient

Michael S. Sabel Md, FACS , in Essentials of Breast Surgery, 2009

ATM (Ataxia Telangiectasia)

An autosomal recessive disorder, ataxia telangiectasia (AT) results from a mutation in the ATM cistron, mapped to chromosome 11q22.3. It is quite rare (between 1 in 20,000 and one in 100,000 live births) and is characterized by progressive cerebellar ataxia and other neurologic abnormalities, oculocutaneous telangiectasias, immune deficiencies, diabetes mellitus, and a predisposition to malignancy, including chest cancer Although the affliction is rare, it is estimated that equally many as 1% to two% of Caucasians in the The states may bear one defective gene. Several studies support an increased gamble of breast cancer in AT carriers (as high as 4 times that of noncarriers).

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780323037587000089

Strategy for the Molecular Testing of Spinal Muscular Cloudburst

T.W. Prior , in Spinal Muscular Cloudburst, 2017

Abstract

The autosomal recessive disorder proximal spinal muscular atrophy (SMA) is a severe neuromuscular affliction characterized by degeneration of blastoff motor neurons in the spinal cord, which results in progressive proximal musculus weakness and paralysis. SMA is the most common fatal autosomal recessive disorder, with an estimated incidence of 1 in 6000 to one in 10,000 live births. Two almost identical survival motor neuron (SMN) genes are present on 5q13: the SMN1 factor, which is the SMA-determining factor, and the SMN2 factor, which is the modifying gene. The homozygous absence of the SMN1 exon seven has been observed in the majority of patients and is being utilized as a reliable and sensitive SMA diagnostic test. Although SMN2 produces less total-length transcript than SMN1, the number of SMN2 copies has been shown to modulate the clinical phenotype and is an important prognostic indicator. The goal of population-based SMA carrier screening is to place couples at risk of having a child with SMA, thus assuasive carriers to brand informed reproductive choices. Since there is no constructive cure for SMA as of 2016, prevention through the identification of carriers becomes an important alternative and has recently been initiated. New treatments are being investigated in clinical trials and may exist dependent upon early detection of the disorder, before the irreversible loss of motor neurons. This could potentially be accomplished through a newborn screening program for SMA.

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780128036853000045

Disorders of Sex Development

Valerie A. Arboleda and , Eric Vilain , in Yen & Jaffe'due south Reproductive Endocrinology (Sixth Edition), 2009

Management

The autosomal recessive disorder SRD5A2 has been described in a number of consanguineous families in Turkey, New Republic of guinea, Saudi Arabia, and the Dominican Commonwealth. Many XY patients with this disorder are raised every bit female during childhood, but at the onset of puberty, identify with the male gender.102-104 It is unclear why individuals with this disorder take a high prevalence of gender identity change. However, given the geographic clustering of this disorder, the gender switch may be attributed in part to cultural and societal beliefs. Topical application of DHT foam in the pubic area promotes phallic growth before puberty, and local application results in increases in both facial and body hair. Fertility is possible with surgical correction of the male person ductal organisation or through assisted reproductive technology.

Read full affiliate

URL:

https://www.sciencedirect.com/science/article/pii/B9781416049074000164