Developmental Disorders Introduction

I. INTRODUCTION

A. General considerations

Developmental defects have sometimes been defined as those defects induced by some agent acting in the embryonic period. However, the differentiation of the nervous system continues for a very long period of time. In fact, differentiating cells are still present in the cerebellum at approximately one year post-natal age. This long period of differentiation provides the justification for considering "developmental defects" as disorders of growth resulting from interruption of the orderly sequence of development at any stage by any agent or disease category. In other words, developmental defects are not only "developmental" in origin, but can arise from a vascular, traumatic, metabolic, toxic, nutritional, neoplastic or infectious etiology.

B. Public health considerations

Developmental disorders are public and social problems of large proportions.

1. 2.5 to 5% live births occur with congenital anomalies; 3% quoted in prenatal counseling

2. Up to 50% of patients with serious malformations show involvement of the central nervous system

3. Many central nervous system malformations are accompanied by mental retardation with its attendant management problems.

C. Etiology

All of the disease categories are associated with the etiology of developmental disorders; however, the etiology is actually unknown in 80-90% of cases. Disorders known to be associated with central nervous system malformations include:

1. Chromosomal defects: (trisomies 21, 18 and 13-15 ; partial trisomies, monosomies, translocations and deletions). The severity of malformations with the various chromosomal defects varies from case to case. In no instance is it really clear why specific abnormalities are associated with mental retardation. Specific chromosomal defects which may be accompanied by CNS malformations include:

a. Trisomy 13-15 - associated with holoprosencephaly; survival 2 yrs.

b. Trisomy 21 (Down's syndrome) - associated with slow postnatal growth, abnormal cortical architecture

c. Trisomy 18 - 20% of those affected have CNS malformations of various types

d. Partial trisomies, monosomies, translocations and delections. Variable CNS defects.

2. Certain infectious diseases are associated with specific sets of central nervous system malformations or disordered development. These include AIDS, rubella, toxoplasmosis, syphilis, and cytomegalic inclusion virus. Intrauterine infections occurring between the 7th & 9th months can be detected by measuring IgM levels in fetal blood from the umbilical cord, but earlier infections cannot be ascertained from fetal examination.

3. Teratogenic drugs which induce developmental disorders include chemotherapeutic agents, medications such as anticonvulsant, and drugs of abuse (particularly alcohol - fetal alcohol syndrome).

4. Deficiency states have long been associated experimentally with production of certain malformations, but definite connections between specific deficiency states and well-defined malformations in humans are not clear.

5. Irradiation produces severe anomalies which depend on the developmental stage at the time of injury. In general, rapidly proliferating cell populations sustain the greatest damage. Fertile women should have x-rays of the abdomen only in the first ten days after the last menstrual period.

6. Obstetrical complications in the perinatal period can arise from several sources, including trauma, vascular insufficiency, and infection. Varied CNS and PNS lesions result, depending on the location affected and other factors.

7. Single gene inherited disorders

8. Hereditary "predisposition": Individual differences in dilantin response; ethnic differences in neural tube defects.

9. Preexisting maternal disease especially diabetes mellitus which is poorly controlled.

E. Pathogenesis

1. Rapidly dividing or differentiating populations of cells are most susceptible to chemical and physical agents that disrupt DNA synthesis, e.g. x-rays.

2. Many agents produce similar effects; the time of onset and extent of repair, rather than the nature of the insult, are the most crucial factors in determining the characteristics of the malformation.

3. It is difficult to date malformations for several reasons: the immature brain possesses great powers of recovery, no inflammatory response exists before 6 months gestation and the affected brain region may show only a disorder of normal architecture.

4. Characteristics of the developing brain which make it especially vulnerable to tissue destruction with resulting cavity formation include: high water content, low lipid content, limited numbers of glial cells which provide tissue support.