Dominant autosomal disease

The number of affected individuals in subsequent generations should be higher than in autosomal dominant disease, again were it not for the threshold effect (see below). 

Autosomal dominant diseases are more likely to show late onset of symptoms. The genes involved often encode noncatalytic proteins, and may occasionally show incomplete penetrance or variable expression in a pedigree. 

Answer B. The findings are indicative of heterozygous TVpe 11a familial hypercholesterolemia, an autosomal dominant disease. Deficient CETP, LCAT or fatty acid CoA synthetase would not elevate LDL cholesterol. VLDL are not produced from LDL. 

This late-onset autosomal dominant disease exhibits variable expression. Many heterozygotes remain symptom-free throughout their lives. Signs and symptoms, when present, include ... 

In contrast to autosomal dominant diseases, autosomal recessive diseases are typically seen in only one generation of a pedigree (Fig II-1-5). 

Figure IM-12. Incomplete Penetrance for an Autosomal Dominant Disease...

B. The couple has an increased risk of producing a child with an autosomal dominant disease. 

Adult polycystic kidney disease (APKD) is one of the most common autosomal dominant diseases, affecting about 1/1,000 whites. The key feature of this disease is the progressive accumulation of renal cysts, which ultimately culminate in kidney failure. APKD is responsible for approximately 10% of end-stage renal disease in North America. Patients may also have hypertension, cerebral aneurysms, liver cysts, and cardiac valvular defects. 

Indirect diagnosis can also be performed in a two-generation fomily if there are multiple affected individuals [e.g., an affected parent and an affected offspring for an autosomal dominant disease). 

The homozygous mutant state usually produces a more severe clinical condition than the heterozygous condition in autosomal dominant diseases. 

Table 13-1. Molecular phenotypes of autosomal dominant disease. ...

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). 

Darier s disease (DD)(MIM 124200) or Darier-White s disease (also referred as keratosis follicularis) is a rare autosomal dominant disease, first described by Darier and White in 1889. DD affects both sexes and all ethnic groups, with a prevalence estimated between 1 in 26 300 and 1 in 100,000 in different countries (Godic et at., 2005), (Tavadia et al., 2002), (Wilkinson, 1977) (Cooper and Burge, 2003 Svendsen and Albrecten, 1959). Penetrance of the disease is complete, and expression is highly variable between and within affected families. 

Additionally, patients with familial adenomatous polyposis, an autosomal-dominant disease characterized by numerous small intestinal and colonic polyps with a nearly universal progression to colon cancer, have a favorable response to NSAIDs. Administration of NSAID (usually sulindac) to patients with this disorder reduces the number and size of polyps (DuBois et al., 1996). Recent biochemical evidence indicates that colon polyps and colon cancer are frequendy associated with induction of Cox-2 in the lesion as assessed by expression of Cox-2 mRNA and protein. Such induction appears to correlate with growth of the lesion, and inhibition of Cox-2 correlates with apoptosis of the involved cells (Gupta and DuBois, 1998). 

A second rare, but potentially fatal, condition associated with acute inhalational anesthetic exposure is malignant hypothermia. This is an autosomal dominant disease in which there is excessive sarcoplasmic release of intracellular Ca " " in skeletal muscles during exposure to inhalational anesthetics. This produces a hypermetabolic state that is manifested as increased muscle rigidity and contracture, tachycardia and metabolic acidosis. Extreme hyperthermia is also present. There are currently a number of worldwide registries for tracking this disease and an ex vivo testing paradigm exists to determine a potentially susceptible persons phenotype. 

Osteogenesis imperfecta (166200) is an autosomal dominant disorder that causes thin, bluish scleras (whites of the eyes), deafness, and multiple bone fractures. Parents have two children with osteogenesis imperfecta, but themselves exhibit no signs of the disease. Which of the following genetic mechanisms is the most likely explanation for two offspring of normal parents to have an autosomal dominant disease ... 

The answer is e. (Murray, pp 812-828. Scriver, pp 3-45. Sack, pp 97-158. Wilson, pp 23-39.) If two individuals in a sibship are affected with an autosomal dominant disease, then the usual implication is that one of the parents has the abnormal allele. Parents with one normal and one abnormal allele have a 50% chance of transmitting the abnormal allele with each pregnancy. Complicating the recognition of autosomal dominant inheritance are incomplete penetrance, where there are no signs of the disease phenotype after all relevant medical evaluations, and variable expressivity, where a parent may have more subtle disease than the offspring. 

The risk factors for renal carcinoma include cigarette smoke, obesity, prolonged estrogens (male, Syrian hamsters), lead phosphate, aflatoxin Bl, and strepto-zotocin. Familial factors are seen with Von Hippel-Lindau (VHL) disease, an autosomal dominant disease with retinal angiomas and hemangioblastoma of the central nervous system long-term dialysis patients develop acquired cysts in 30%-50% and 6% with acquired cysts will develop RCC (Richie et al. 2000). 

The more frequent porphyrias (Table 31.1) begin only after puberty except for erythropoietic protoporphyria (31.7). Symptoms in the latter may be seen from infancy or early childhood. These frequent porphyrias are all autosomal dominant diseases with incomplete penetrance. That means that although the enzymatic defect can be traced among 50% of direct relatives, only a minority of them become symptomatic and the overt diseases often appear to be sporadic. 

The three autosomal dominant diseases, acute intermittent porphyria (31.2) [1, 4], variegate porphyria (31.6) and hereditary coproporphyria (31.5) share a common symptomatology (Tables 31.3.1/31.3.2). Affected individuals suffer from acute attacks of severe, colicky, abdominal pain, mostly of several days duration and combined with nausea, vomiting, obstipation and subileus. Tachycardia and hypertension is often present too. Within a few days these symptoms may spontaneously subside or they may progress as well to a predominant motor neuropathy, disturbance of electrolyte balance (hyponatremia, hypomagnesemia), seizures, confusion and coma. 

Family screening As mentioned above, all three acute porphyrias are autosomal dominant diseases. 50% of direct relatives are also carrier of the defect allele and are prone to symptoms, if exposed to drugs and other stressors. Family screening and instruction of all affected individuals to avoid precipitating factors is therefore strongly recommended. Different laboratory tests are used for family screening in the three acute porphyrias ... 

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