Genetics lecture 3
By dr Rusul Mahdi Abid
• Clinical Presentation of Diseases with molecular defect
• Inborn errors of metabolism• Inborn errors of metabolism (IEM) are caused by mutations that disrupt the normal function of a biochemical pathway. Most IEM are due to autosomal or X-linked recessive loss-of-function mutations in genes encoding specific enzymes or enzymatic co-factors.
• Knowledge of the biochemical pathway involved means that specific blocks have predictable consequences, including deficiency
• of the end product and build-up of intermediary compounds. Many hundreds of different IEM have been identified and. Most IEM are restricted to paediatric practice; however, a growing number may now present during adult life and some of these are discussed below:
Intoxicating IEM
• A subgroup of IEM, termed ‘intoxicating IEM’, can present as a sudden deterioration in a previously well individual. Such deteriorations are usually precipitated by some form of stress, such as infection, pregnancy, exercise or changes in diet. The intoxication is due to the build-up of accumulation of intermediary compounds, which will vary according to the pathway involved. For example, in urea cycle disorders ammonia is the toxic substance
• The intoxication is often associated with derangement of the acid–base balance and, if not recognised and treated, will often proceed to multi-organ failure, coma and death.
• The diagnosis of these disorders requires specialist biochemical analysis of blood and/or urine.
• Treatment relies on removal of the toxic substance using haemodialysis or chemical conjugation, and prevention of further accumulation by restricting intake of the precursors: as total protein restriction in urea cycle disorders
• Mitochondrial disorders
• Disorders of energy production are the most common type of IEM presenting in adult life• The tissues that are most commonly affected in this group of disorders are those with the highest metabolic energy requirements, such as muscle, heart, retina and brain.
• Therapy in this group of disorders is based on giving antioxidants as vitamin C and co-factors that can improve the function of the respiratory chain.
• Storage disorders
• Storage disorders are most commonly caused by loss-of function mutations affecting enzymes involved in lysosomal degradation pathways.• The clinical consequences depend on the specific enzyme involved. For example:
• Niemann–Pick disease type C is caused by autosomal recessive loss-of function mutations in either the NPC1 or NPC2 gene.
• These results in hepatosplenomegaly, dysphagia, loss of speech, early dementia, spasticity, An increasing number of storage disorders are treatable with enzyme replacement therapy, making awareness and diagnosis more important.
• Neurological disorders:
• Progressive neurological deterioration is one of the most common presentations. These diseases are mostly autosomal dominant , examples would be early-onset familial forms of dementia, Parkinson’s disease , Huntington disease The triplet repeat disorders cause an interesting group of syndromes and have specific features• Huntington disease:
• Huntington disease (HD) is triplet repeat disorders. This condition can present with a movement disorder or weight loss or psychiatric symptoms (depression, psychosis, dementia) Or with a combination of all three. The disease is the result of a [CAG] triplet repeat expansion mutation in the HD gene on chromosome 4. Since CAG is a codon for glutamine, the mutation probably leads to gain of function, as deletions of the gene do not cause HD, expansion of the repeat to above the normal range results in neurological disease.
• The severity of disease and age at onset are related to the repeat length. In HD, atrophy of the caudate nuclei is obvious on magnetic resonance imaging (MRI) of the brain, and in later stages cerebral atrophy is also apparent.
• There is currently no therapy that will alter the progression of the disease, which will often be the cause of the patient’s death.
• Within families there is a tendency for disease severity to increase and age at onset to fall due to further expansion of the repeat, a phenomenon known as anticipation. The mutation is more likely to expand through the male germ line than through female.
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