Autosomal dominant disorder

Episodic ataxia (EA) is an autosomal dominant disorder that brief episodes of ataxia can be triggered by physical or emotional stress. The symptom can occur several times during the day, last for seconds to minutes, and be associated with dysarthria and motor neuron activity, which causes muscle rippling (myokymia) between and during attacks. It is caused by a mutation in a neuronal voltage dependent Ca2+ channel. 

Liddle s syndrome is an autosomal dominant disorder that is caused by persistent hyperactivity of the epithelial Na channel. Its symptoms mimic aldosterone excess, but plasma aldosterone levels are actually reduced (pseudoaldosteronism). The disease is characterized by early onset arterial hypertension, hypokalemia, and metabolic alkalosis. 

Riidel, R., Ricker, R. (1985). The primary periodic paralysis. Trends in Neurosci. 8,467-470, Zeviani, M., Servidei, S., Gellera, C., Bertini, E., Di Mauro, S.. Di Donato, S. (1989). An autosomal dominant disorder with multiple deletions of mitochondrial DNA starting at the D-loop. Nature (Lond.) 339, 309-311. 

HAE is transmitted as an autosomal dominant disorder due, in most instances, to alterations of the Cl INH gene. Its prevalence is 1/50,000 [60] however, there is a high incidence of de novo mutations accounting for close to 25% of cases. Thus there may not be a family history to guide evaluation of such patients and it is therefore reasonable to obtain a C4 and Cl INH determination in any patient presenting with recurrent angioedema in the absence of urticaria. 

Von Willebrand disease (vWD) is the most common inherited bleeding disorder caused by a deficiency or dysfunction of von Willebrand factor. The disease prevalence is estimated at 30 to 100 cases per million. In contrast to hemophilia, vWD is inherited as an autosomal dominant disorder (although autosomal recessive cases exist), ensuing equal frequency in male and females.16... 

Familial hypercholesterolemia (FH), an autosomal dominant disorder of lipoprotein metabolism, is caused by absent or defective LDL receptors. Several studies indicated that Lp(a) levels were approximately doubled in FH heterozygotes, compared to their unaffected family members or non-FH controls (H30, L14, M20, M21, U8, W13, W14). 

Autosomal dominant inheritance A person affected by an autosomal dominant disorder has a 50 percent chance of passing the mutated gene to each child. The chance that a child will not inherit the mutated gene is also 50 percent. 

More than 100 mutations of the COL3A1 gene can cause Ehlers-Danlos syndrome (EDS) type IV, an autosomal dominant disorder characterized by joint and dermal manifestations similar to the other forms of the syndrome, but in addition these individuals are prone to spontaneous ruptures of bowel and large arteries. 

Huntington s disease, an autosomal dominant disorder, has a mean age-of-onset of 43-48 years. Symptoms appear gradually and worsen over a period of about 15 years until death occurs. Mood disturbance, impaired memory, and hyperrefiexia are often the first signs, followed by abnormal gait, chorea (loss of motor control), dystonia, dementia, and dysphagia. Cases of juvenile onset (<10 years old) are more severe and most frequently occur when the defective allele is inherited paternaily. About 25% of cases have late onset, slower progression, and milder symptoms. 

Thi autosomal dominant disorder, which affects approximately 1 in 8,000 individuals, is characterized by progressive muscle deterioration, cardiac arrhythmia, testicular atrophy, frontal baldness, and cataraas. As noted above, most cases are caused by a trinucleotide repeat expansion in the 3 UTR of a gene that encodes a protein kinase. Larger repeat numbers lead to earlier and more severe expression of the disease (anticipation). Especially large expansions sometimes occur in maternal transmission of the trinucleotide repeat, resulting in a severe neonatal form of the disorder. 

A man and woman are both affected by an autosomal dominant disorder that has 80% penetrance in all affected individuals. They are both heterozygotes for the disease-causing mutation. What is the probability that they will produce phenotypically normal of pring ... 

Huntington disease is an autosomal dominant disorder involving degeneration of the striatum and cortex that manifests as motor dysfunction in midlife and leads to progressive loss of cognitive function and death. 

Pedigree charts for an autosomal dominant disorder may show the following features ... 

Figure 13-4. Pedigrees illustrating inheritance of (A) a mitochondrial disorder and (B) an autosomal dominant disorder exhibiting anticipation. In pedigree A note the similarity to the X-linked dominant inheritance pattern (Figure 13-3A), but incomplete penetrance as exemplified by individuals 11-4 and 111-4. In pedigree B, the age of onset, indicated next to the symbols for affected individuals, becomes progressively earlier with each generation.

Type I NFis an autosomal dominant disorder characterized by a wide range of clinical presentations by... 

One mutated copy of the gene in each cell is sufficient for a person to be affected by an autosomal dominant disorder. Each affected person usually has one affected parent. Autosomal dominant disorders tend to occur in every generation of an affected family. 

Familial hypercholesterolemia (FH) is one of the most common genetic disorders in lipoprotein metabolism, and causes elevated cholesterol levels. This autosomal dominant disorder with a prevalence of about 1/500 in Western countries is caused by mutations in the LDLR gene. The LDLR defect impairs the catabolism of LDL and results in elevation of plasma LDL-cholesterol. Untreated heterozygous FH patients have 2-3 times elevated cholesterol levels and have a 100-fold increased risk to die... 

BH4 is an obligatory cofactor for both tyrosine and tryptophan hydroxylase. Consequently, the inborn errors of BH4 metabolism are associated with impaired dopamine and serotonin turnover, which is reflected by decreased concentrations of HVA and 5HIAA in the CSF. Whilst such a pattern is particularly true for the autosomal recessive disorders of BH4 metabolism, an autosomal dominant disorder of BH4 metabolism, (autosomal dominant GTP cyclohydrolase deficiency) is not always associated with marked decreases in the CSF concentration of HVA and 5HIAA [1]. 

Porphyrias are caused by inherited (or occasionally acquired) defects in heme synthesis, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors (see Summary Figure 21.7). With the exception of congenital erythropoietic porphyria, which is a genetically recessive disease, all porphyrias are inherited as autosomal dominant disorders. The mutations that cause the porphyrias are heterogenous (not all are at the same DNA locus), and nearly every affected family has its own mutation. Each porphyria results in the accumulation of a unique pattern of intermediates caused by the deficiency of an enzyme in the heme synthetic pathway. 

Mutations in fibrillin-1 cause the autosomal dominant disorder Marfan syndrome and related disorders, termed fibrillinopathies (Robinson and Booms, 2001). MFS is characterized by life-threatening cardiovascular... 

EA2, similar to FHM1, is an autosomal dominant disorder associated with mutations in the CACNA1A gene, but is clinically quite distinct. EA2 patients experience spontaneous episodes of ataxia (poor muscle coordination) that last for hours to days. In between attacks, patients often experience gaze-evoked or down-beat nystagmus (rapid, involuntary eye oscillations). Approximately 50% of patients experience migraine-like symptoms, and cerebellar atrophy is common (Lorenzon and Beam, 2000). Attacks are often initiated by emotional stress, exercise, or alcohol. Most patients respond well to treatment with acetazolamide (reviewed in (Jen et al., 2004)). EA2 is genetically variable and has been associated with missense, truncation and alternative splice site mutations. 

Darier disease (keratosis follicularis) is an autosomal dominant disorder of keratinization, which usually starts at puberty. Mutations in an endoplasmatic ATPase, which pumps calcium ions across membranes in keratinocytes, have been found to cause the disease.43... 

Of the many disorders of lipoprotein metabolism (Tables 5.2 and 5.3), familial hypercholesterolaemia type II may be the most prevalent in the general population. It is an autosomal dominant disorder that results from mutations affecting the structure and function of the ceU-surface receptor that binds plasma LDLs and removes them from the circulation. The defects in LDL-receptor interaction result in lifelong elevation of LDL cholesterol in the blood. The resultant hypercholesterolaemia leads to premature coronary artery disease and atherosclerotic plaque formation. Familial hypercholesterolaemia was the first inherited disorder recognised as being a cause of myocardial infarction (heart attack). 

PSP is the second most common cause of Parkinsonism typified by early gait instability and difficulty with vertical eye movement. PSP is characterized by neurofibrillary tangles composed almost entirely of sdaight filaments of four repeats of Tau protein. Although most cases of PSP appear to be sporadic, genetic diatheses have been implicated. De Yebenes described a pattern of inheritance consistent with a Mende-lian autosomal dominant disorder (De Yebenes et al., 1995). Difficulty recognizing the variable phenotypic expression of PSP may be one reason fewer familial cases have been identified than expected (Rojo et al., 1999). The HI haplotype of the Tau gene has also been found to have association with increased risk for PSP, as it has been for PD (Conrad et al.. 

Marfan syndrome is genetic disease that involves defects in the connective tissues of the body with the cardinal collection of abnormalities affecting the skeletal, ocular, and cardiovascular systems. It is inherited as an autosomal dominant disorder, meaning that inheriting only one defective gene from either the paternal or maternal side will lead to the disorder. Although the majority of mutations are inherited from one of the parents, approximately 25% of affected individuals develop Marfan syndrome as a result of a new mntation. The prevalence is 1/20,000 and the disorder is inherited with variable expression. This means that each individual may have a different combination of the possible clinical features that characterize the disorder. 

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