Genetics And The Child With Developmental Delay

Pamela Arn, M.D.
Pamela Arn, M.D. is a Clinical Geneticist with Nemours Children's Clinic, Jacksonville. 

Over the past few years, discoveries in the field of genetics have been explosive. New cytogenetic and molecular techniques have significantly changed the array of tests available for the diagnosis of genetic disorders. In addition, new modes of inheritance have been discovered, further complicating the clinical evaluation and counseling of patients who may have a genetic disorder. In this article, some of the genetic causes of developmental delay and mental retardation will be reviewed.

Mental retardation affects about 3% of the population. The causes of mental retardation vary with the severity; moderate to severe cases (IQ <50) are more likely to be due to a single cause than are mild cases. Chromosomal and genetic disorders account for 30 - 40% of cases of moderate to severe mental retardation, environmental factors explain 10 - 30%, and the cause is unknown in about 40%.^1-4

As in any evaluation, the history, family history and physical exam are essential pieces of information prior to diagnostic testing. Family history should focus on other individuals with developmental or learning problems, mental retardation, stillbirths, birth defects, or deaths occurring during childhood.

Teratogens

In cases of developmental delay, a thorough prenatal history should be obtained. Information regarding smoking, drug and alcohol exposure should be obtained. Known teratogens that can affect fetal neurological development include radiation, infections, maternal diseases such as diabetes and phenylketonuria, alcohol and some medications.⁵ Both genetic and environmental factors influence development, and many influences have both genetic and environmental components. An example of this interaction can be found with neural tube defects. Low folic acid intake during early pregnancy is a risk factor for neural tube defects. A genetic polymorphism in the enzyme methylene tetrahydrofolate reductase also confers an increased risk for neural tube defects. The polymorphism and a low folate status combined convey a higher risk than with either variable alone.⁶ There are probably many other examples of genetic and environmental interaction that can result in developmental delay or birth defects, however, we are only beginning to understand these processes.

Chromosome Abnormalities

Little is known about the factors that cause chromosomal disorders in humans, however, our ability to diagnose chromosomal problems has expanded dramatically over the past 30 years. In the 1970's it became possible to analyze chromosomes using special staining methods which produce banding patterns allowing more detailed analysis of each chromosome. Over the years techniques have been refined so that "high resolution" banding can detect small deletions and duplications in chromosomes that were technically impossible to detect in the past. Newer techniques for screening for subtle chromosome abnormalities have been developed. Fluorescence in situ hybridization (FISH) is a technique that utilizes DNA probes stained with fluorescent dye. (See Figure 1.) The fluorescently tagged probes are placed directly on chromosome preparations, and very small deletions can be detected due to lack of hybridization to one chromosome.⁷ A recent study suggests that up to 7% of patients who have moderate to severe mental retardation with normal conventional chromosome analysis have a subtle chromosome abnormality detected by FISH. A variation of fluorescence in situ hybridization used in this study examines the integrity of the chromosome ends in order to detect subtle rearrangements.⁸

Figure 1. Chromosomes labeled with Fluorescent in situ hybridization probes for chromosome 22. Probe A is a control probe for a distal locus on chromosome 22 (ARSA), Probe B is the TUPLEI of the number 22 chromosome. This deletion can be seen in DiGeorge Syndrome, Velocardiofacial Syndrome, and in some cases of isolated complex congenital heart disease.

Contiguous gene syndromes result when a series of neighboring genes are deleted from a single chromosome. Many of these have consistent phenotypes, however the deletions are not always identical in all patients so that there may be some phenotypic variability. Our ability to detect these small deletions has been enhanced by the technique of FISH, since in most cases probes specific to these deletions are available.^9,10 Examples are shown in Table 1.

Prader-Willi syndrome and Angelman syndrome share a common deletion but manifest a dramatically different phenotype. This is explained by uniparental disomy and genomic imprinting. Normally each parent contributes one chromosome to each chromosome pair of their children. Occasionally, both chromosomes or a section of a chromosome are inherited from the same parent; a condition termed uniparental disomy. There are a number of regions in the human genome in which gene expression is modified during meiosis depending on whether the gene was inherited from the mother or from the father. Gene expression is therefore exclusively from only one of the two alleles; this is the process of genomic imprinting. In cases where uniparental disomy has occurred in one of these regions, gene expression is abnormal. Prader-Willi syndrome occurs when there is a deletion of the paternal chromosome 15 or when both copies of chromosome 15 are of maternal origin. Similarly, Angelman syndrome results when the deletion arises on the maternal chromosome 15.¹¹ Some of the genes that are known to be imprinted have been described, however, there are probably many more examples yet to be described.

DNA Expansion

Fragile X mental retardation is the most common causes of inherited mental retardation in males. The unusual features of Fragile X have included variability in penetrance and cytogenetic expression. About 1/3 of female carriers of Fragile X have a significant learning disability or mental retardation. The molecular basis for Fragile X is the result of an unusual mutational mechanism, known as a "dynamic" mutation. This type of mutation results due to the amplification of a simple repeated DNA sequence. In the case of Fragile X, the sequence (CGG)_n is expanded from the normal number of repeats (which is usually less than 60) to 200 or more copies. A direct analysis of the number of copies of the repeat has now replaced traditional cytogenetics in the diagnosis of Fragile X mental retardation. Several other neurological diseases including Huntington's Disease and myotonic dystrophy also share this disease mechanism.¹²

Inborn Errors Of Metabolism

There is considerable evidence that many inherited metabolic disorders remain undiagnosed or misdiagnosed. Acutely, inborn errors of metabolism often present with vomiting and central nervous system depression shortly after feedings or during intercurrent illness. There are an ever-increasing number of inborn errors, however, in which affected children manifest developmental delay as one of the major manifestations with or without episodes of acute decompensation. It is beyond the scope of this article to review all inborn errors that can cause developmental delay, however, review articles and textbook chapters will offer more comprehensive information.^13,14

Diseases of mitochondrial metabolism exhibit a wide range of clinical manifestations, and physicians in all subspecialties of pediatric and adult medicine may encounter these patients. This category of disease has been described relatively recently, and new discoveries in this field are frequent. The respiratory chain of the mitochondria consists of sub-units responsible for electron transport and oxidative phosphorylation. It is here that most of the cellular ATP is generated. Organs with high energy requirements are frequently most affected, with the central nervous system showing the most frequent and diverse manifestations. Other organ systems often involved include the heart, skeletal muscle, endocrine systems, kidney and liver. In many cases, symptoms seen in organ systems other than the central nervous system provide helpful clues in making a diagnosis. Defects in these pathways can result from mutations in the mitochondrial genome or from nuclear encoded genes, making inheritance patterns seem unorthodox in some cases. Examples of these disorders include Leigh Disease (subacute necrotizing encephalomyopathy), infantile and adult cardiomyopathies, and many others.¹⁵

Specific diagnosis of these disorders often requires mitochondrial DNA analysis and muscle biopsy and should be guided by clinicians experienced in workup and diagnosis of these diseases.

Summary

Because of the complexities associated with the different categories of genetic disease, it is no longer adequate to refer only patients with birth defects or overt dysmorphic features with developmental delay for a genetic evaluation. Children with persistent global developmental delay with or without other birth defects or organ system involvement, children with mental retardation, and children with unexplained persistent or intermittent neurological symptoms should be considered for evaluation.

A specific diagnosis will provide parents and caregivers with a clear understanding of the nature of the disease, the expected natural history, and the recurrence risk in subsequent pregnancies. While many diseases that we are able to identify do not have specific treatments, advances in therapies of some disorders have led to improvements in prognosis.

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Jacksonville Medicine / March, 2000