In the group in which the abnormalities are confined to the nervous system, attention is focused on a larger number of diseases, many caused by exogenous factors such as perinatal hypoxia-ischemia, preor postnatal infections, trauma, and so on. There are usually conspicuous neurologic signs. The degree of developmental delay is variable, depending on the location and extent of a demonstrable neuropathology. Usually the family history is negative, but careful questioning of parents regarding the pregnancy, delivery, and early postnatal period and examination of hospital records from birth may disclose the nature of the neurologic insult.
The third category is one in which neither somatic anomalies nor focal neurologic signs are present, or if present, they are minimal. The more severely delayed in cognitive development of this special group are represented by the following disease states: autism (Asperger-Kanner syndrome), the Rett and Williams syndromes, and the fragile X and Renpenning syndromes. All of these but autism are now known to have a genetic basis as noted earlier in the chapter and are described together below.
The practical importance of this clinical approach is that it directs the intelligent use of laboratory procedures for confirmation of the diagnosis. CT and MRI are useful in clarifying maldevelopment and neurologic diseases but are seldom helpful in the third group of cases. EEG confirms seizure discharges when there is uncertainty as to the nature of episodic neural dysfunction. Karyotyping and genetic studies are useful in group 1 (somatic abnormalities with or without obvious neurologic signs) and rarely in group 2 (abnormalities confined to the nervous system). An algorithmic approach to genetic testing for evaluation of a patient with intellectual disability is provided by
Mefford and colleagues.
A major pitfall in this clinical approach is in mistaking a hereditary metabolic disease for a developmental one. Here one is helped by the fact that manifestations of the metabolic diseases are not usually present in the first days of life; they appear later and are progressive and often associated with specific visceral abnormalities. However, some metabolic diseases are of such slow progression that they appear almost stable, especially the late-onset ones, such as one type of metachromatic leukodystrophy, late-onset Krabbe leukodystrophy, adult adrenoleukodystrophy, and adult hexosaminidase deficiency (see Chap. 36).
There has been great interest in this syndrome, which some geneticists hold accountable at least in part for the preponderance of developmentally delayed males in whom an etiology could not be previously established. A large kindred in whom developmental delay was inherited in an X-linked pattern was first reported by Martin and Bell in 1943. It was in such a family, with X-linked developmental delay, that Lubs, in 1969, discovered a fragile site at the distal end of the long arm of the X chromosome; subsequently, it was established that there is an unstable inherited CGG repeating sequence at this site, which leads to breakage, as discussed previously. At first, it was assumed that the fragile X syndrome was only an example of the Renpenning syndrome (an X-linked hereditary developmental delay in males; see below) until it was pointed out that in this latter condition, stature was reduced, as was the cranial circumference, and further that the X chromosomes of the Renpenning patients were normal. The nature of chromosomal breakage that can be attributed to an expanded trinucleotide repeat sequence of the FMR1 gene and a resultant loss of protein function were discussed earlier in “Other Chromosomal Dysgeneses.”