Autosomal Recessive Disorder

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

From: Spinal Muscular Atrophy, 2017

Chapters and Articles

Ataxic Disorders

Alessandro Filla, Giuseppe De Michele, in Handbook of Clinical Neurology, 2012

Diagnosis

Patients with autosomal recessive diseases frequently present as sporadic cases. The presence of consanguinity suggests a diagnosis of autosomal recessive disorder. Biochemical tests are available for A-T, AVED, and several metabolic or mitochondrial ataxias (cerebrotendinous xanthomatosis, muscle CoQ10 deficiency). A direct molecular test is available for FRDA. Genetic testing is possible for MIRAS, IOSCA, AVED, A-T, AOA1, AOA2, SCAN1, XP and CS, ARSACS, and MSS, and some of these tests are available from commercial laboratories in some countries.

Read full chapter
URL: https://www.sciencedirect.com/science/article/pii/B9780444518927000164

Volume 1

Fred Levine, in Fetal and Neonatal Physiology (Fourth Edition), 2011

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 gene are mutant). The following general principles of inheritance are recognized for AR disorders (see Figure 1-7, B):

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

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

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 certain AR mutations. Fortunately, the carrier frequency for most of these mutations is so low 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 activity usually is sufficient for normal function. Complete enzyme deficiency produces an accumulation of one or more metabolites preceding the enzymatic block, such as 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 most common disorders with AR inheritance 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 application at the clinical level. 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 usually is detectable analytically and may lead to other biochemical abnormalities that have no obvious effect on the person’s health. In addition, patients homozygous for dominant mutations usually are more severely affected than are heterozygous patients, as is true in familial hypercholesterolemia. In many cases, the homozygous condition results in embryonic lethality, so the clinical disorder is never seen. Huntington disease stands out as a major exception in that homozygous patients are not clinically different from heterozygous patients.

Read full chapter
URL: https://www.sciencedirect.com/science/article/pii/B9781416034797100011

Basic Genetic Principles

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

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 gene are mutant). The following pattern of inheritance is characteristic of AR disorders (see Fig. 1-7 B):

1.

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

2.

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

3.

Males and females are affected in equal proportions.

4.

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 certain AR mutations. Fortunately, the carrier frequency for most of these mutations is so low that 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 activity is usually sufficient for normal function. Complete enzyme deficiency produces an accumulation of one or more metabolites preceding the enzymatic block, such as the build-up 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 application at the clinical level. 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 is usually detectable analytically and may lead 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, as is true in familial hypercholesterolemia. In many cases, the homozygous condition results in embryonic lethality and is never seen. Huntington disease stands out as a major exception in that homozygous patients are not clinically different from heterozygous patients.

Read full chapter
URL: https://www.sciencedirect.com/science/article/pii/B9780721696546500047

Lipids and disorders of lipoprotein metabolism

Graham R. Bayly, in Clinical Biochemistry: Metabolic and Clinical Aspects (Third Edition), 2014

Lysosomal acid lipase

Lysosomal acid lipase (LAL) is secreted as a 399-amino acid precursor, which includes a 27-amino acid signal peptide for transport across the membrane of the endoplasmic reticulum. Further processing, including N-glycosylation in the endoplasmic reticulum and the attachment of mannose 6-phosphate residues in the Golgi, leads to lysosomal targeting. LAL is responsible for the breakdown of cholesteryl esters and triglycerides that are delivered to lysosomes as a result of receptor-mediated uptake of lipoproteins.

Wolman disease

is an autosomal recessive disease that presents in the neonate and is characterized by hepatosplenomegaly, steatorrhoea and abdominal distention, results from complete lack of LAL activity, causing massive accumulation of both cholesteryl esters and triglycerides in macrophages throughout the body. Affected children usually die before their first birthday. Enzyme replacement therapy has now been developed but its efficacy remains to be fully established.

Cholesteryl ester storage disease

is caused by partial deficiency of LAL. It is a rare autosomal recessive disorder, characterized by hepatomegaly, abnormal liver function tests, hypercholesterolaemia and premature atherosclerosis. The hepatomegaly is a consequence of accumulation of cholesteryl esters and triglycerides in both hepatocytes and Kupffer cells.

Read full chapter
URL: https://www.sciencedirect.com/science/article/pii/B9780702051401000377

Lysosomal Storage Diseases With Predominantly Histiocytic Storage

In Diagnostic Pathology: Blood and Bone Marrow (Second Edition), 2018

ETIOLOGY/PATHOGENESIS

Gaucher Disease

Autosomal recessive disease caused by mutations in GAB

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

Niemann-Pick Disease

Autosomal recessive disease of lipid metabolism

Types A and B are caused by SMPD1 mutations

SMPD1 encodes lysosomal acid sphingomyelinase

Deficiency of sphingomyelinase leads to accumulation of sphingomyelin

Type C is caused by mutations in NPC1 or NPC2

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

Mucolipidosis I (Sialidosis)

Autosomal recessive disease caused by mutations in NEU1

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

In absence of neuraminidase, sialylated glycopeptides and oligosaccharides accumulate

Cystinosis

Autosomal recessive disease caused by mutations in CTNS

CTNS encodes cystinosin, transport protein involved in export of cystine from lysosomes

In absence of cystinosin, cystine is trapped in crystallized form within lysosomes

GM1 Gangliosidosis

Autosomal recessive disease caused by mutations in GLB1

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

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

α-Mannosidosis

Autosomal recessive disease caused by mutations in MAN2B1

MAN2B1 encodes α-mannosidase

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

β-mannosidosis, in contrast, has been reported in only a few individuals and will not be further discussed here

Fucosidosis

Autosomal recessive disease caused by mutations in FUCA1

FUCA1 encodes α-L-fucosidase

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

Farber Disease

Autosomal recessive disease caused by mutations in ASAH1

ASAH1 encodes acid ceramidase

Acid Lipase Deficiency (Wolman and Cholesteryl Ester Storage Disease)

Autosomal recessive disease caused by mutations in LIPA

LIPA encodes acid lipase

In absence of acid lipase, undegraded cholesteryl esters and triglycerides accumulate

Sialic Acid Storage Disease

Autosomal recessive disease caused by mutations in SLC17A5

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

In absence of sialin, free sialic acid accumulates within lysosomes

Sandhoff Disease

Autosomal recessive disease caused by mutations in HEXB

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

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

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

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

Fabry Disease

X-linked disease caused by mutations in GLA

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

Read full chapter
URL: https://www.sciencedirect.com/science/article/pii/B9780323392549500854

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 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 different deleterious mutation, the defect is termed compound heterozygous. Each parent of an affected 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 gene 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 disease, 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 one individual at some point in history is subsequently propagated throughout the population.

Figure 3.2. (A) Graph comparing the relative amount of protein function in a cell containing two normal copies of a gene (Wild Type) vs a cell containing two mutant copies of a gene (Loss of Function), a cell containing one normal and one mutant copy of a gene that can act in a dominant negative manner (Dominant Negative), a cell containing one normal copy of a gene that has normal function and one copy of a gene that has no function (Haploinsufficiency), and a cell containing one normal copy of a gene and one mutant copy of a gene that has a dominant gain of function (Gain of Function). (B) Mechanism of how a mutant protein with dominant negative function can decrease total protein function by more than 50% in situations where the protein multimerizes (such as forming dimers, as shown here). Protein complexes containing one mutant subunit are non-functional.

Read full chapter
URL: https://www.sciencedirect.com/science/article/pii/B9780124055469000030

Parkinson’s Disease: Genetics

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

Wilson’s Disease

This AR disease results in systemic copper deposition, especially 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 lead to evaluation for Wilson’s disease, since treatment is highly effective. The causal gene 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.

Read full chapter
URL: https://www.sciencedirect.com/science/article/pii/B9780123741059000629

Primary Disorders of Connective Tissue

William G. Cole, Outi Mäkitie, in Textbook of Pediatric Rheumatology (Seventh Edition), 2016

Progressive Pseudorheumatoid Arthropathy

This autosomal recessive disorder (OMIM #208230) presents between the ages of 3 and 8 years in healthy appearing children, and is caused by mutation in WISP3 (WNT1 inducible signaling pathway protein 3, felt to play a role in BMP and WNT signaling).93 It 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 disease” but has none of the laboratory abnormalities of JIA.

Read full chapter
URL: https://www.sciencedirect.com/science/article/pii/B9780323241458000545

Mendelian and Mitochondrial Inheritance, Gene Identification, and Clinical Testing

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

Autosomal Recessive Inheritance

Autosomal recessive disorders are coded for by genes located on the nonsex chromosomes. In contrast 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 disease or trait to be expressed. In some cases, the person has two abnormal alleles of a certain gene, but each is abnormal in a different way. Such persons are referred to as compound heterozygotes. As described above for autosomal dominant disease, trinucleotide repeat expansions can also be the type of mutation causing autosomal recessive disease, such as Friedreich's ataxia.

For the disease to be present in the offspring, both parents must have one copy 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 usually are not 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 2.4 children, it is not unusual for the disease to appear sporadically within the family. One cannot exclude autosomal recessive disease on the basis of a negative family history. In these cases it is sometimes necessary to rely on knowledge of the usual mode 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 ways. For example, retinitis pigmentosa can be inherited as an autosomal dominant, autosomal recessive, or X-linked recessive disease.

Even the same gene can have different mutations that act in a dominant or recessive fashion. For example, both autosomal dominant and autosomal recessive retinitis pigmentosa can be caused by different mutations in the rhodopsin gene.7 Furthermore, different mutations in the same gene can cause different clinical disorders. For example, mutations in the peripherin/RDS gene can cause autosomal dominant retinitis pigmentosa, as well as 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 affected person marries a blood relative or a person also afflicted with the same autosomal recessive disease. However, even among couples who meet neither of these criteria, the risk is greater than the general population risk. For example, if one assumes that the carrier frequency of the gene for phenylketonuria (PKU) is 1 in 50 in the general population, the risk for healthy parents without a positive family history is 1/50 × 1/50 × 1/4 = 1/10,000. However, if a man has PKU, the risk for his children is 1 × 1/50 × 1/2 = 1/100. The risk for the affected man's healthy sister to have a child with PKU is 2/3 × 1/50 × 1/4 = 1/300.

There are some unusual mechanisms by which autosomal disease may occur, in which only 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 7 and 8 of the SMN1 gene. The mother was a carrier of the deletion, but the father was not. Nonpaternity was excluded, and it was concluded that the mutation had arisen by 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 one parent rather than one from each parent. This can occur by various mechanisms, such as trisomic rescue, in which the zygote starts out with trisomy for a given chromosome, but the extra chromosome is lost early in subsequent cell divisions. Therefore, caution is always warranted in making presumptions about carrier status, particularly if prenatal diagnosis may be involved.

Read full chapter
URL: https://www.sciencedirect.com/science/article/pii/B9780721694917500673

Genetic Approaches to Cardiovascular Disease

Carl J. Vaughan, Craig T. Basson, in Molecular Basis of Cardiovascular Disease (Second Edition), 2004

Autosomal Recessive

In autosomal recessive disorders (Figure 8-1B), individuals must have two disease alleles. Thus, both parents must either be affected or unaffected heterozygotes. If both parents are affected, all children will be affected. If both parents are unaffected heterozygotes, each child has a 25% chance of being affected and a 50% chance of being an unaffected heterozygous carrier of the disorder. Therefore, one fourth of the offspring of two unaffected heterozygotes will carry two defective copies of the gene and will be affected. Half of the offspring will be heterozygous carriers of the disorder. Because heterozygotes are not affected, clinical manifestations of disease are not seen in every generation. As in autosomal dominant disorders, males and females are equally affected by autosomal recessive disorders. Inborn errors of metabolism, cystic fibrosis, and sickle cell anemia are examples of autosomal recessive disorders. Common examples of cardiovascular diseases that are transmitted in an autosomal recessive manner include dilated cardiomyopathy, arrhythmogenic right-ventricular dysplasia, and homocysteinuria (Table 8-1).

Read full chapter
URL: https://www.sciencedirect.com/science/article/pii/B9780721694283500135