What are the genetic changes related to Miller syndrome ?
Mutations in the DHODH gene cause Miller syndrome. This gene provides instructions for making an enzyme called dihydroorotate dehydrogenase. This enzyme is involved in producing pyrimidines, which are building blocks of DNA, its chemical cousin RNA, and molecules such as ATP and GTP that serve as energy sources in the cell. Specifically, dihydroorotate dehydrogenase converts a molecule called dihydroorotate to a molecule called orotic acid. In subsequent steps, other enzymes modify orotic acid to produce pyrimidines.  Miller syndrome disrupts the development of structures called the first and second pharyngeal arches. The pharyngeal arches are five paired structures that form on each side of the head and neck during embryonic development. These structures develop into the bones, skin, nerves, and muscles of the head and neck. In particular, the first and second pharyngeal arches develop into the jaw, the nerves and muscles for chewing and facial expressions, the bones in the middle ear, and the outer ear. It remains unclear exactly how DHODH gene mutations lead to abnormal development of the pharyngeal arches in people with Miller syndrome.  Development of the arms and legs is also affected by Miller syndrome. Each limb starts out as a small mound of tissue called a limb bud, which grows outward. Many different proteins are involved in the normal shaping (patterning) of each limb. Once the overall pattern of a limb is formed, detailed shaping can take place. For example, to create individual fingers and toes, certain cells self-destruct (undergo apoptosis) to remove the webbing between each digit. The role dihydroorotate dehydrogenase plays in limb development is not known. It is also unknown how mutations in the DHODH gene cause bone abnormalities in the arms and legs of people with Miller syndrome.