Mutations were mainly found in exons 12-22 of the intracellular TKD, including 10 missense mutations that have a single nucleotide deletion and a single codon deletion that consists of a triplet of nucleotides that have been removed causing a whole amino acid to not be coded. Additionally, three splice site mutations were identified that caused an in-frame deletion of an exon, an expressed nucleotide sequence, leading to the removal of more than 40 amino acids in the TKD.This determination has based upon genetic studies of 14 HDLS families confirming mutations in this gene. The CSF1 receptor protein primarily functions in regulation, survival, proliferation, and differentiation of microglial cells. The mechanism of microglial dysfunction due to mutations in CSF1R to the myelin loss and axonal spheroid formation remains unknown. Further research is needed to better understand disease pathogenesis. Pathology
In HDLS, there is enlargement of the lateral ventricles and marked thinning or weakening of cerebral white matter. The loss of white matter is caused by myelin loss. These changes are associated with diffuse gliosis, moderate loss of axons and many axonal spheroids.Activated or ameboid microglia and macrophages that contain myelin debris, lipid droplets and brown autofluorescent pigment granules are found in the areas with demyelination and axonal spheroids. In severely degenerated areas there are many large, reactive astrocytes filled with glial fibrils.In autopsy cases, it has been shown that white matter abnormalities are relatively confined to the cerebrum while avoiding the cerebellum and many of the major fiber tracts of the nervous system.
Tetrasomy X and pentasomy X syndrome affect a small number of girls worldwide, while boys may be affected by 49, XXXXY, or 49, XYYYY. 47, XYY is not associated with significantly lowered IQ though affected individuals may have slightly lower IQs than non-affected siblings on average. Problems during pregnancy. Intellectual disability can result when the fetus does not develop properly. For example, there may be a problem with the way the fetuss cells divide as it grows. A pregnant woman who drinks alcohol (see fetal alcohol spectrum disorder) or gets an infection like rubella during pregnancy may also have a baby with an intellectual disability. Problems at birth. If a baby has problems during labor and birth, such as not getting enough oxygen, he or she may have a developmental disability due to brain damage. The group of proteins known as histones have an essential part in gene regulation, and sometimes these proteins becomes modified and are prevented from working properly. When the genes responsible for the development of neurons are affected, it affects the brain and behavior in the individual. Exposure to certain types of disease or toxins. Diseases like whooping cough, measles, or meningitis can cause intellectual disability if medical care is delayed or inadequate. Exposure to poisons like lead or mercury may also affect mental ability. Iodine deficiency, affecting approximately 2 billion people worldwide, is the leading preventable cause of intellectual disability in areas of the developing world where iodine deficiency is endemic.