Autosomal Dominant Disorders

In AD inheritance, the presence of a single pathological allele overwhelms the function of the wild-type allele. This can occur through several mechanisms: haploinsufficiency (where 50% of the gene product is insufficient for normal function), dominant-negative effects (where the mutant protein interferes with the normal protein), or gain-of-function mutations (where the mutant protein takes on a new, toxic function). AD conditions are characterized by vertical transmission—that is, the disease appears in parents, children, and grandchildren. However, some cases arise from 'de novo' mutations, where the parents are unaffected. Two key concepts in AD disorders are penetrance and expressivity. Reduced penetrance occurs when an individual carries the mutation but shows no symptoms (e.g., in some cases of BRCA1). Variable expressivity refers to affected individuals showing different symptoms or severities even within the same family (common in Neurofibromatosis). Some AD conditions, like Huntington’s disease, show 'anticipation' where symptoms become more severe or appear at an earlier age in subsequent generations due to triplet repeat expansion. Accurate diagnosis requires clinical assessment, pedigree analysis, and molecular genetic testing.

At the molecular level, AD mutations often occur in genes encoding structural proteins (like fibrillin-1 in Marfan syndrome) or regulatory proteins (like the NF1 tumor suppressor). Unlike recessive disorders, where a 'backup' allele provides enough enzyme activity for normal metabolism, structural proteins often require 100% produced from both alleles to maintain tissue integrity. In Huntington's disease, a CAG repeat expansion in the HTT gene leads to a polyglutamine tract that causes protein misfolding and neuronal toxicity. In Achondroplasia, a gain-of-function mutation in the FGFR3 gene constitutively inhibits bone growth. Understanding the molecular mechanism—whether it is a loss of function of one copy or the creation of a 'bad' protein—is essential for developing targeted therapies.

AD disorders often present later in life, such as Huntington's or Polycystic Kidney Disease (ADPKD), making them relevant to adult medicine and general practice. Identifying an AD pattern is a 'red flag' that requires screening of first-degree relatives. For instance, a family history of sudden cardiac death may suggest AD conditions like Hypertrophic Cardiomyopathy or Long QT Syndrome. In the MLA, recognizing the physical signs (e.g., Lisch nodules in NF1 or arachnodactyly in Marfan's) combined with a positive family history is high-yield for diagnosis.

1. Detailed three-generation pedigree. 2. Targeted genetic testing (e.g., sequencing for specific mutations). 3. Clinical screening of relatives (e.g., echocardiogram for Marfan or ADPKD relatives). 4. Prenatal testing or Pre-implantation Genetic Diagnosis (PGD) for known family mutations.

Management is mostly condition-specific and supportive. Genetic counseling is paramount to discuss the 50% recurrence risk. Long-term surveillance is often required (e.g., annual MRI for NF1, echocardiograms for Marfan's). Predictive testing (testing an asymptomatic person at risk) for late-onset disorders like Huntington's requires intensive psychological support and adherence to international protocols.