Autosomal Recessive Disorder

The autosomal recessive disorder proximal spinal muscular atrophy (SMA) is a severe neuromuscular illness characterized past degeneration of blastoff motor neurons in the spinal cord, which results in progressive proximal muscle weakness and paralysis.

From: Spinal Muscular Atrophy , 2017

Bones Genetic Principles

Fred Levine , in Fetal and Neonatal Physiology (Third Edition), 2004

Autosomal Recessive Disorders

AR disorders are those that are clinically apparent but when the patient is homozygous for the disease (i.east., both copies of the gene are mutant). The following pattern of inheritance is feature of AR disorders (run across Fig. one-7 B ):

i.

The parents of afflicted children may be clinically normal (i.e., carriers).

two.

Bold that the carrier frequency in the population is low, but siblings are afflicted, and vertical manual does not occur; the design therefore tends to appear horizontal.

3.

Males and females are afflicted in equal proportions.

4.

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

Every person is a carrier of certain AR mutations. Fortunately, the carrier frequency for near of these mutations is so low that likelihood that carriers will take affected children is low.

Recessive mutations ofttimes involve enzymes, equally opposed to regulatory and structural proteins. This is because 50% of the normal level of enzyme activity is usually sufficient for normal office. Complete enzyme deficiency produces an accumulation of one or more metabolites preceding the enzymatic block, such as the build-upwards of phenylalanine in phenylketonuria, and a deficiency of metabolites distal to the block. Either, or both, of these abnormalities may be responsible for the disease phenotype. Although many recessive disorders involve enzymes, two of the most common AR disorders are cystic fibrosis, resulting from a mutation in a chloride channel, and sickle cell anemia, resulting from a mutation in the β-globin gene.

The terms dominant and recessive refer to phenotypes only and have their greatest awarding at the clinical level. At the gene level, dominance and recessiveness practise not exist. Persons heterozygous for a recessive disorder may exist clinically normal, but the reduced level of functional or immunoreactive protein is normally detectable analytically and may pb to other biochemical abnormalities that have no obvious effect on the person's health. In addition, patients homozygous for dominant mutations are usually more severely affected than are heterozygous patients, every bit is true in familial hypercholesterolemia. In many cases, the homozygous condition results in embryonic lethality and is never seen. Huntington affliction stands out as a major exception in that homozygous patients are not clinically different from heterozygous patients.

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Lysosomal Storage Diseases With Predominantly Histiocytic Storage

In Diagnostic Pathology: Claret and Os Marrow (2nd Edition), 2018

ETIOLOGY/PATHOGENESIS

Gaucher Disease

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Autosomal recessive disease acquired by mutations in GAB

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GAB encodes acid β-glucocerebrosidase (a.one thousand.a. glucosylceramidase), which breaks down glucocerebroside into glucose and ceramide

Niemann-Choice Disease

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Autosomal recessive illness of lipid metabolism

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Types A and B are caused by SMPD1 mutations

○

SMPD1 encodes lysosomal acid sphingomyelinase

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Deficiency of sphingomyelinase leads to aggregating of sphingomyelin

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Type C is caused by mutations in NPC1 or NPC2

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NPC1 and NPC2 both encode proteins involved in intracellular binding and transport of exogenous cholesterol

Mucolipidosis I (Sialidosis)

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Autosomal recessive disease caused by mutations in NEU1

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NEU1 encodes α-N-acetyl neuraminidase-1, which removes sialic acid residues

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In absence of neuraminidase, sialylated glycopeptides and oligosaccharides accrue

Cystinosis

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Autosomal recessive affliction caused by mutations in CTNS

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CTNS encodes cystinosin, send poly peptide involved in export of cystine from lysosomes

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In absenteeism of cystinosin, cystine is trapped in crystallized grade within lysosomes

GM1 Gangliosidosis

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Autosomal recessive disease caused by mutations in GLB1

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GLB1 is same cistron implicated in mucopolysaccharidosis IVB (Morquio B)

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Clinical clarification equally GM1 gangliosidosis vs. mucopolysaccharidosis IVB depends on predominance of sphingolipid or glycosaminoglycan accumulation, respectively

α-Mannosidosis

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Autosomal recessive disease caused by mutations in MAN2B1

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MAN2B1 encodes α-mannosidase

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α-mannosidase assists in degradation of oligosaccharides, which contain mannose

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β-mannosidosis, in dissimilarity, has been reported in only a few individuals and will non be further discussed here

Fucosidosis

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Autosomal recessive disease acquired by mutations in FUCA1

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FUCA1 encodes α-Fifty-fucosidase

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α-L-fucosidase cleaves fucose residues from oligosaccharides and glycolipids

Farber Disease

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Autosomal recessive disease caused past mutations in ASAH1

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ASAH1 encodes acrid ceramidase

Acrid Lipase Deficiency (Wolman and Cholesteryl Ester Storage Disease)

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Autosomal recessive disease caused past mutations in LIPA

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LIPA encodes acid lipase

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In absenteeism of acrid lipase, undegraded cholesteryl esters and triglycerides accumulate

Sialic Acid Storage Disease

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Autosomal recessive disease caused by mutations in SLC17A5

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SLC17A5 encodes sialin, which transports gratis sialic acid out of lysosome

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In absence of sialin, free sialic acrid accumulates inside lysosomes

Sandhoff Affliction

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Autosomal recessive illness caused by mutations in HEXB

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HEXB encodes β-subunit essential for formation of both β-hexosaminidase A and B

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Thus, Sandhoff disease is characterized past lack of both β-hexosaminidase A and B activity

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In contrast, HEXA mutations (Tay-Sachs disease) crusade deficiency of β-hexosaminidase A just

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Both Tay-Sachs and Sandhoff affliction lead to accumulation of undegraded GM2 gangliosides within lysosomes

Fabry Disease

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X-linked disease caused past mutations in GLA

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GLA encodes α-galactosidase A, deficiency of which leads to accumulation of globotriaosylceramide in lysosomes

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Genetics of Primary Immune 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 gene (a gene that is located on whatsoever of the autosomes) ( Figure 3.1B), resulting in "loss of function" (Effigy three.2A). If both copies of the factor have the aforementioned deleterious mutation, the defect is termed homozygous. If each copy of the gene has a different deleterious mutation, the defect is termed compound heterozygous. Each parent of an affected patient is typically a heterozygous carrier, and has 1 normal and one abnormal re-create of the gene (Figure 3.1B). In most cases a normal copy of the cistron tin compensate for the lacking copy; thus, heterozygous carriers are generally asymptomatic. When two carrier parents accept offspring, statistically, ane in four offspring should have the disease, two should be carriers, and one should exist 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 ane private at some indicate in history is later on propagated throughout the population.

Figure 3.2. (A) Graph comparing the relative amount of protein function in a jail cell containing ii normal copies of a factor (Wild Type) vs a cell containing two mutant copies of a gene (Loss of Function), a jail cell containing one normal and one mutant copy of a gene that can act in a dominant negative fashion (Ascendant Negative), a jail cell containing one normal re-create of a gene that has normal function and one copy of a gene that has no function (Haploinsufficiency), and a cell containing i normal copy of a gene and one mutant copy of a gene that has a dominant gain of function (Proceeds of Function). (B) Machinery of how a mutant protein with dominant negative function can decrease full protein function by more than 50% in situations where the protein multimerizes (such every bit forming dimers, as shown here). Protein complexes containing one mutant subunit are non-functional.

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Basic Genetic Principles

Fred Levine , in Fetal and Neonatal Physiology (5th Edition), 2017

Autosomal Recessive Disorders

AR disorders are those that are clinically apparent only when the patient is homozygous for the disease (i.e., both copies of the cistron are mutant). The following general principles of inheritance are recognized for AR disorders (see Effigy ane-7, B ):

•

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

•

Bold that the carrier frequency in the population is depression, simply siblings are affected, and vertical transmission does non occur; the pattern therefore tends to announced horizontal.

•

Consanguinity can be a factor. This can occur in outbred populations past mating between family unit members, or in inbred populations (e.one thousand., the Amish) where the entire population is descended from a minor 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 afflicted, 50% are carriers, and 25% are normal.

Every person is a carrier of AR mutations. Fortunately, the carrier frequency for virtually of these mutations is so low that the likelihood that carriers will have affected children is low.

Recessive mutations frequently involve enzymes, equally opposed to regulatory and structural proteins. This is because fifty% of the normal level of enzyme activity ordinarily is sufficient for normal office. Consummate enzyme deficiency produces an accumulation of one or more metabolites preceding the enzymatic block, such every bit the buildup of phenylalanine in phenylketonuria, and a deficiency of metabolites distal to the block. Either, or both, of these abnormalities may be responsible for the disease phenotype. Although many recessive disorders involve enzymes, two of the nigh mutual disorders with AR inheritance are cystic fibrosis, resulting from a mutation in a chloride aqueduct, and sickle cell anemia, resulting from a mutation in the β-globin gene.

Information technology is of import to be aware that the terms ascendant and recessive refer to clinical phenotypes just. At the gene level, "dominance" and "recessiveness" practice not exist. Persons heterozygous for a recessive disorder may exist clinically normal, but the reduced level of functional or immunoreactive protein tin can be detected analytically and may lead to other biochemical abnormalities that have no obvious effect on the person'due south health. For example, brusque chain acyl-coenzyme A dehydrogenase deficiency, a disorder of short chain fatty acid metabolism, is detected by newborn screening but appears to have no clinical consequences. Patients homozygous for dominant mutations usually are more severely affected than are heterozygous patients. This is true in familial hypercholesterolemia. In many cases, the homozygous status results in embryonic lethality, and and then it is never seen clinically. Huntington affliction stands out as an exception in that homozygous patients are not clinically dissimilar from heterozygous patients, presumably because the gain of role consequence of the triplet echo mutation is not dose responsive.

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Mendelian and Mitochondrial Inheritance, Cistron Identification, and Clinical Testing

VIRGINIA Five. MICHELS , ... ERIK C. THORLAND , in Peripheral Neuropathy (4th Edition), 2005

Autosomal Recessive Inheritance

Autosomal recessive disorders are coded for past genes located on the nonsex chromosomes. In contrast to autosomal ascendant inheritance, the heterozygote, who has 1 abnormal allele and one normal allele, does non differ clinically from a person homozygous for the normal cistron. Rather, the person must be homozygous for the abnormal allele for the illness or trait to be expressed. In some cases, the person has ii abnormal alleles of a certain gene, only each is abnormal in a different way. Such persons are referred to as compound heterozygotes. Every bit described above for autosomal dominant illness, trinucleotide repeat expansions tin also be the blazon of mutation causing autosomal recessive affliction, such equally Friedreich's ataxia.

For the disease to exist present in the offspring, both parents must have one re-create of an aberrant allele, and the risk of disease for each of their offspring, of either sex, is 25%. In autosomal recessive inheritance, the previous generations usually are non affected with the disease. Although the classic description of pedigrees for autosomal recessive inheritance includes two or more affected siblings, with today's small average family size of two.4 children, it is not unusual for the illness to appear sporadically inside the family. One cannot exclude autosomal recessive affliction on the ground of a negative family history. In these cases information technology is sometimes necessary to rely on noesis of the usual fashion of inheritance of the disease. Although some diseases, such as CF, are e'er inherited in an autosomal recessive pattern, other clinically defined diseases may exist inherited in ane of several ways. For example, retinitis pigmentosa tin be inherited as an autosomal ascendant, autosomal recessive, or Ten-linked recessive disease.

Even the same factor tin take dissimilar mutations that deed in a dominant or recessive fashion. For example, both autosomal dominant and autosomal recessive retinitis pigmentosa tin be caused by different mutations in the rhodopsin cistron. 7 Furthermore, different mutations in the aforementioned gene can cause unlike clinical disorders. For example, mutations in the peripherin/RDS gene tin can cause autosomal dominant retinitis pigmentosa, as well as several types of macular dystrophy. 5

For autosomal recessive diseases, the run a risk for an affected person to take an afflicted child is low, unless the affliction is very common or the afflicted person marries a blood relative or a person also afflicted with the same autosomal recessive disease. However, even amongst couples who run into neither of these criteria, the risk is greater than the general population hazard. For instance, if one assumes that the carrier frequency of the gene for phenylketonuria (PKU) is 1 in 50 in the general population, the gamble for healthy parents without a positive family history is i/50 × 1/fifty × 1/4 = ane/10,000. Still, if a man has PKU, the adventure for his children is 1 × ane/50 × i/2 = 1/100. The gamble for the affected homo's healthy sister to have a child with PKU is 2/3 × i/l × 1/4 = one/300.

There are some unusual mechanisms by which autosomal disease may occur, in which simply ane parent is a carrier for the gene defect. New mutations may occur, every bit 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 7 and 8 of the SMN1 gene. The mother was a carrier of the deletion, but the father was not. Nonpaternity was excluded, and information technology was ended that the mutation had arisen past new mutation. 52 In another type of situation, 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 1 parent rather than one from each parent. This can occur past various mechanisms, such as trisomic rescue, in which the zygote starts out with trisomy for a given chromosome, only the extra chromosome is lost early in subsequent jail cell divisions. Therefore, caution is always warranted in making presumptions about carrier condition, particularly if prenatal diagnosis may be involved.

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Genetic Approaches to Cardiovascular Disease

Carl J. Vaughan , Craig T. Basson , in Molecular Footing of Cardiovascular Disease (2d Edition), 2004

Autosomal Recessive

In autosomal recessive disorders ( Figure 8-oneB ), individuals must accept ii illness alleles. Thus, both parents must either be affected or unaffected heterozygotes. If both parents are afflicted, all children will be afflicted. If both parents are unaffected heterozygotes, each child has a 25% chance of existence afflicted and a fifty% take chances of being an unaffected heterozygous carrier of the disorder. Therefore, one fourth of the offspring of two unaffected heterozygotes volition carry two defective copies of the gene and will be afflicted. Half of the offspring will exist heterozygous carriers of the disorder. Because heterozygotes are non affected, clinical manifestations of affliction are not seen in every generation. As in autosomal dominant disorders, males and females are as affected by autosomal recessive disorders. Inborn errors of metabolism, cystic fibrosis, and sickle jail cell anemia are examples of autosomal recessive disorders. Common examples of cardiovascular diseases that are transmitted in an autosomal recessive mode include dilated cardiomyopathy, arrhythmogenic correct-ventricular dysplasia, and homocysteinuria (Table viii-ane).

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Mechanisms and Morphology of Cellular Injury, Adaptation, and Death1

Margaret A. Miller , James F. Zachary , in Pathologic Basis of Veterinarian Disease (Sixth Edition), 2017

Autosomal Recessive Disorders.

In autosomal recessive disorders, both alleles at a given gene locus must be mutated for an beast to be affected by the disorder. I 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 just i mutated allele, are clinically normal carriers of the trait. Homozygous animals normally have clinical disease, and the onset is usually early in life. Many of the mutated genes encode enzymes. Examples of autosomal recessive disorders in animals include lysosomal storage diseases (encounter E-Fig. 1-27 and Figs. 14-63 and 14-64), glycogen storage diseases (run into Fig. 14-63) and mucopolysaccharidoses, and aminoacidopathies that affect organs such equally the encephalon, spinal cord, skeletal muscle, liver, and kidney.

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Congenital Genetic Disorders and Syndromes

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

Autosomal Recessive

An autosomal recessive disorder becomes manifest only when an private has ii copies of the mutant gene. Most frequently each parent has one copy of the defective gene and is a carrier, and there is a 25% hazard that both mutant genes will be passed on to their offspring. Male person and female offspring volition be as likely to be affected. Fifty percentage of the time the offspring will get i copy 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 status in certain populations can exist meaning. For example, 1 in 25 people of northern European descent are carriers of cystic fibrosis. iii Genetic diseases more common among people of Asian and African descent are beta-thalassemia and sickle jail cell anemia, respectively. 4,5

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Parkinson's Disease: Genetics

R.A. Corriveau , ... K. Gwinn , in Encyclopedia of Move Disorders, 2010

Wilson's Affliction

This AR affliction results in systemic copper deposition, peculiarly in brain and liver. Classic PD or parkinsonism with atypical features may occur. The presence of hepatic, extrapyramidal, or mood disorders in relatives of a patient with PD should pb to evaluation for Wilson'southward disease, since treatment is highly effective. The causal factor a copper-transporting P-type adenosine triphosphatase (ATPase). Many mutations are responsible for disease, making genetic testing impractical. However, screening with serum ceruloplasmin, 24-h urinary copper, and slit lamp examination are straightforward.

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Neurometabolic disease and the eye

Jane Fifty Ashworth , ... J Edmond Wraith , in Pediatric Ophthalmology and Strabismus (Quaternary Edition), 2013

Tyrosinemia type two (Richner-Hanhart syndrome)

This autosomal recessive disorder is acquired by deficiency of tyrosine aminotransferase. Information technology may present with ocular signs and symptoms every bit the initial manifestation in the first years of life with photophobia, pain, and conjunctival injection. There is a bilateral pseudodendritic keratitis which may lead to neovascularization and corneal scarring. 77 Patients may take painful erosions and hyperkeratosis of the palms and soles, and cognitive damage. Plasma tyrosine concentrations are extremely loftier and the eye and peel lesions probably upshot from the intracellular atmospheric precipitation of tyrosine crystals. Dietary restriction of tyrosine and phenylalanine leads to resolution of these lesions.

Tyrosine concentrations are lower in tyrosinemia types ane and 3. Type 1 patients treated with nitisinone sometimes complain of sore optics.

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