Autosomal dominant inheritance

Mutations in GK (Hx IV) causes maturity-onset diabetes of the young (MOD Y), a form of non-insulin-dependent diabetes mellitus (NIDDM) characterized by onset before 25 years of age and an autosomal dominant inheritance (PI 2). This suggests that the mutations in other forms of Hx may also contribute to the development of NIDDM. Among them, Hx II is a particularly attractive candidate, although this isozyme is not expressed in red blood cells. Hx II has been analyzed extensively in the muscle of prediabetic insulin-resistant individuals. But studies have shown that Hx II mutation alone is unlikely to have a significant role in the development of peripheral insulin resistance and NIDDM (L6). 

Familial hypercholesterolemia (FH) is an autosomal dominantly inherited disease caused by mutations in the gene for the LDL receptor. Up to now more than 680 distinct mutations, distributed over the entire gene, have been described [42]. Heterozygous FH individuals express only half the number of functional LDL-r and, therefore, have a markedly raised plasma cholesterol and usually present with premature coronary artery disease. Homozygous FH individuals are more severely affected and may succumb before the age of maturity. The prevalence of heterozygous FH is approximately 1 in 500 in Caucasians. 

Lewy bodies, neurofibrillary lesions and Pick bodies are intracellular filamentous inclusions. It is now well established that Lewy bodies are made of the protein a-synuclein and both neurofibrillary lesions and Pick bodies of the microtubule-associated protein tau. Mutations in the a-synuclein gene or an increase in its copy number cause autosomal-dominantly inherited forms of Parkinson s disease and dementia with Lewy bodies. Mutations in the tau gene cause a familial form of frontotemporal dementia. Here we review the evidence implicating a-synuclein and tau in these inherited and a number of sporadic neurodegenerative diseases. Collectively, a-synucleinopathies and tauopathies account for the vast majority of cases of late-onset neurodegenerative disease (Tables 45-1 and 45-2). 

FIGURE 45-2 Missense mutations in the a-synuclein gene and multiplication of the chromosomal region containing the a-synuclein gene cause autosomal-dominantly inherited forms of Parkinson s disease and dementia with Lewy bodies. The a-synuclein gene is shown schematically in green. 

Frontotemporal dementias occur as familial forms and, more commonly, as sporadic diseases. They are characterized by a remarkably circumscribed atrophy of the frontal and temporal lobes of the cerebral cortex, often with additional, subcortical changes. In 1994, an autosomal-dominantly inherited form of frontotemporal dementia with parkinsonism was linked to chromosome 17q21.2. Subsequently, other forms of frontotemporal dementia were linked to this region, resulting in the denomination frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) for this class of disease. All cases of FTDP-17 have so far shown a filamentous pathology made of hyperphosphorylated tau protein (Fig. 45-7). In 1998, mutations in tau were reported in FTDP-17 patients [29-31]. Since then, more than 30 different mutations have been described in over 80 families with FTDP-17 (Fig. 45-6). 

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. 

A number of features in a pedigree help to identify autosomal dominant inheritance ... 

As in autosomal dominant inheritance, the disease phenotype is seen in multiple generations of a pedigree skipped generations are relatively unusual. 

B. In autosomal dominant inheritance, the condition is expressed even if a single... 

The answer is B. The presence of many affected persons in multiple generations of this family suggests autosomal dominant inheritance. Male-to-male transmission of the condition in several generations would rule out both X-linked and mitochondrial disorders. Each affected person has an affected parent and there are multiple affected persons in several successive generations. 

Essential tremor is a postural tremor, sometimes familial with autosomal dominant inheritance, which is clinically similar to physiologic tremor. At least three gene loci (ETM1 on 3ql3, ETM2 on 2p24.1, and a locus on 6p23) have been described. Dysfunction of receptors has been implicated in some instances, since the tremor may respond dramatically... 

Huntington s disease is an autosomal dominant inherited disorder caused by an abnormality (expansion of a CAG trinucleotide repeat that codes for a polyglutamine tract) of the huntingtin gene on chromosome 4. An autosomal... 

A series of point mutations as well as expansion of the octapeptide repeatss account for the various diseases, which have an autosomal dominant inheritance. At least 23 pathogenic mutations have been... 

Autosomal dominant-inherited cancer syndromes provide direct evidence for a genetic component in the origin of cancer. 

Frontotemporal dementia Approximately 10% of dementias. Initial complaint is often personality changes. Disinhibition withdrawal apathy hyperoral behavior (including weight gain) compulsions memory problems speech and language difficulty. Familial cases have approximately 40% autosomal dominant inheritance and may develop signs of Parkinson s disease. 

The most direct link (125) between genetic events predisposing to cancer and the HIF system occurs in von Hippel-Lindau (VHL) disease, which is an autosomal dominant inherited cancer... 

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