Genetic disorders autosomal dominant

Reduced penetrance and variable expressivity are factors that influence the effects of particular genetic changes. These factors usually affect disorders that have an autosomal dominant pattern of inheritance, although they are occasionally seen in disorders with an autosomal recessive inheritance pattern. 

As noted earlier, there is also a genetic association between OCD and Tourette s disorder, with many Tourette s patients experiencing OCD symptoms ( 183, 184 and 185). Tourette s disorder is thought to be an autosomal dominant disease, and although it has not been localized as yet, studies are actively in process, with at least 50% of the autosomal genome excluded as the locus (186, 187). 

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... 

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. 

Heritable and spontaneous genetic disorders represent additional applications for therapeutic ribozymes targeting cellular genes. These include the beta-amyloid peptide precursor mRNA involved in Alzheimer s disease (Currie et al., 1997 Dolzhanskaya et al., 2000), and an autosomal-dominant point mutation in the rhodopsin mRNA that gives rise to photoreceptor degeneration and retinitis pigmentosa (Hauswirth and Lewin, 2000 LaVail et al., 2000). 

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. 

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. 

The severe perinatal and infantile forms of hypophosphatasia are inherited as autosomal recessive conditions. The patient receives one defective gene from each parent. Some of the more mild childhood and adult cases are also inherited this way. More mild adult cases are inherited in an autosomal dominant pattern where the patient gets just one defective gene from one parent. Individuals with hypophosphatasia and parents of children with this disorder are encouraged to seek genetic counseling to understand the likelihood and severity of hypophosphatasia recurring in their family. 

Although this disorder is not usually expressed in childhood, several affected preadolescents have been described. Clinical presentations in adult patients include eruptive xanthomas, lipemia retinalis, pancreatitis, and abnormal glucose tolerance with hyperinsulinism. Premature atherosclerotic complications are not as commonly seen as with FH. This heterogeneous syndrome appears to be inherited in an autosomal dominant mode, but its genetic basis is yet to be elucidated. 

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