Clinical genetics has become increasingly more important in the practice of clinical medicine. Clinical genetics has historically been confined to a relatively rare number of diseases that were encountered by only a few specialists. However, we now know there is a genetic component not only to a majority of pediatric diseases but also to adult disorders such as heart disease, diabetes, and other late onset, disabling conditions. With recent advances in genetics, it is becoming increasingly important that all medical specialties be aware of the role of genetics in the clinical arena.
OVERVIEW OF GENE STRUCTURE AND FUNCTION
Genetic diseases involve defects at the cellular level. These defects result in errors in both the replication of genetic material and the production of proteins by the genes. Figure 1 illustrates the relationship between chromosomes, DNA, genes, and proteins.
Somatic cells of the body contain 23 pairs of chromosomes, one pair of sex chromosomes and 22 pairs of autosomes. A chromosome consists in part of DNA, which is a combination of the four nucleotide bases (cytosine, thymine, adenine, and guanine) formed into a double-helix structure. Triplets of these bases, known as codons, provide the genetic code to develop the proteins of the body. Genes are the blueprint for all proteins in the body, which in turn influence all aspects of body structure and function. The human is reported to have between 50,000 and 100,000 genes that code proteins, and an error in translation of the genes is what leads to genetic disease. 1
TYPES OF GENETIC DISEASES
It has now been established that there are approximately 30,000 different and clinically relevant genes in the human genome that, when altered, will lead to genetic disease. An alteration of one or a combination of these genes or other rearrangements can result in genetic conditions that lead to the need for physical therapy. Some of these disorders are described in this section.
Numerical chromosome abnormalities occur when an entire chromosome is missing (monosomy) or extra chromosome is present (trisomy). Common syndromes include Down syndrome, Klinefelter syndrome, and Turner syndrome. Figure 2 shows an example of trisomy 21, which is diagnostic of a nonhereditary form of Down syndrome. The absence of an entire chromosome (monosomy) or the presence of an extra chromosome (trisomy) is generally due to a meiotic error during gametogenesis and is generally genetic but not hereditary. In other words, the risk of recurrence is low. However, there are exceptions in which these syndromes are inherited, and input from a genetics professional is necessary to assess and resolve risks.
Common examples of structural chromosome abnormalities include Wolf-Hirschhorn syndrome (deletion of the short arm of chromosome 4), Cri-du-Chat syndrome (deletion of the short arm of chromosome 5), and DiGeorge syndrome (interstitial deletion of chromosome 22), and there are many other syndromes that involve deletion, translocation, inversion, duplication, or other rearrangement of chromosomes. More than 2000 of these syndromes have been described, and although each is rare, most are associated with a balanced chromosome rearrangement in a parent. Figure 3 illustrates a translocation (hereditary) form of Down syndrome. Input from a genetics professional is necessary to assist in the assessment of medical needs as well as to deal with parents’ concerns about the risk of recurrence.
There are several to several hundred genes residing in each individual chromosome band. Gene abnormalities are often referred to as mendelian conditions, in which single genes are altered in either the homozygous or heterozygous state. These conditions can be further classified as follows.
Autosomal dominant condition.
Autosomal dominant disorders result from a single gene being mutated or abnormal. The abnormal gene overrides the effect of the other normal allele inherited from the other parent. The condition can be exhibited as an autosomal dominant trait that typically follows a familial pattern in which a parent is also affected. Currently more than 1000 autosomal dominant conditions have been described. Some common examples are achondroplasia, Huntington’s disease, Waardenburg syndrome, and Marfan syndrome.
Autosomal recessive diseases.
Autosomal recessive disorders are characterized by the same abnormal allele being inherited from each parent, thereby resulting in a disease state. Typically neither parent is affected, and there is usually no family history of this specific condition. Examples of this type of condition include cystic fibrosis, sickle cell disease, and the majority of metabolic diseases.
X-linked recessive inheritance.
Characteristically, in X-linked recessive diseases only males are affected and females are carriers. A classic family history would include normal females and affected males. Examples include hemophilia, Duchenne muscular dystrophy, and fragile X syndrome.
Multifactorial disorders result from a combination of genetic and environmental factors. A complex interaction occurs between genetic and environmental factors, and these interactions can result in birth defects such as cleft lip, cleft palate, and spina bifida, as well as many adult disorders, including heart disease, diabetes, and other conditions.
Mitochondrial diseases are due to alterations of small mitochondrial DNA fragments that are typically inherited from the mother. This condition is responsible for a relatively small number of genetic diseases, but it is responsible for such disorders as Leber’s optic atrophy and some of the ataxias.
Overall, most specific genetic diseases are rare, so the average healthcare practitioner will seldom encounter most of them. However, genetic diseases, as a group, result in conditions that will be seen by physical therapists in clinical practice almost daily. Physical therapists can play a major role not only in the management and treatment of individuals with genetic syndromes, but also in the recognition of individuals who would benefit from a genetic evaluation.
ROLE OF THE PEDIATRIC PHYSICAL THERAPIST IN THE REFERRAL AND IDENTIFICATION OF GENETIC DISEASES
Although many genetic diseases may already be identified in children referred for physical therapy services, there are perhaps equally as many who are not diagnosed. For these children, the physical therapist will have a role not only in medical management but also in facilitating diagnosis. In considering the five elements of patient/client management from the “Guide to Physical Therapist Practice,”2 the examination and evaluation processes are key in assisting the medical team with undiagnosed genetic diseases. During the examination, history-taking, tests, and measures are critical factors, and during evaluation, the practitioner should render clinical judgment about the need for consultation with or referral to another provider.
When taking the history, the therapist should inquire about any family background related to the chief complaint or condition. Genetic diseases are inherited, so clues to a possible genetic origin may be identified in the family history. The lack of a positive family history, however, does not rule out a genetic basis, because many diseases arise from spontaneous mutations. For example, up to 30% of all cases of Duchenne muscular dystrophy are due to spontaneous mutations.
During the test and measures process of the examination, the therapist must specifically look for any evidence of dysmorphism related to abnormal physical development. Dysmorphism is frequently seen in chromosome, single-gene, and multifactorial disorders. It is not as common in mitochondrial disorders, and it is not present in metabolic disorders. When looking for dysmorphic features and classifying findings, it is recommended that the following definitions, developed by Jorde et al, 1 be used:
- Malformation: a defect of an organ or body part resulting from an abnormal developmental process (eg, cleft lip).
- Dysplasia: a defect involving abnormal organization of cells into tissues (eg, hemangioma).
- Sequence: a defect with secondary structural changes (eg, Pierre Robin sequence with primary defect of mandibular development that produces a small jaw and cleft palate).
- Syndrome: a pattern of multiple malformations due to a single cause (eg, trisomy 13 syndrome)
- Deformation: an alteration of the form, shape, or position of normally formed body parts by mechanical forces (eg, clubfoot due to abnormal intrauterine positioning secondary to oligohydramnios).
- The presence of any of these features is a diagnostic clue used by the geneticist in making clinical diagnoses. For example, individuals with impairments of two or more major organ systems should be suspected of having a genetic syndrome. Also, an unusual facial appearance, unusual ears, cleft lip/palate, or other unusual features might trigger the physical therapist to request a genetic consultation. The pediatric physical therapist is uniquely qualified to identify abnormal developmental aspects of the musculoskeletal and integumentary systems as part of routine examination, providing diagnostic information to the geneticist or other member of the diagnostic team. It is important for the practitioner to understand genetic diseases to appropriately treat the patient and discuss these disorders with the family.
- If the pathogenesis of a specific genetic disease is known and the genetic disease is understood, the disease can be better treated and addressed with appropriate therapy. This is specifically important when we know that certain disabilities might be more common in certain genetic diseases than in others and that appropriate attention can be directed to preventive strategies before disabilities develop.
A number of resources are available to interested readers. The resources listed in this section are intended to be only selected resources; others are available to further inform and educate professionals about various types of genetic conditions and genetics facilities.
Several textbooks in the area of genetics have been written for medical professionals. The reader should consult the texts by Jorde et al 1 or Sack, 3 both of which are entitled Medical Genetics, for additional information on the topic. A recent chapter by Stuberg et al, 4 entitled “Genetic Disorders: A Pediatric Prospective,” also will provide the pediatric physical therapist with greater detail and examples of frequently encountered genetic conditions.
Online resources have also been developed to provide detailed clinical information and links to indexed medical references on genetics. One primary resource is the Online Mendelian Inheritance of Man (OMIM) database, 5 which was designed from a catalog of human genetic diseases and genetic disorders authored and edited by McKusick and colleagues. GeneTests 6 (http://www.genetests.org) is a helpful database that includes listings of facilities that perform genetic testing for specific diseases, detailed descriptions of clinical presentations of individual conditions, listings of genetics and multidisciplinary clinics, as well as names of professionals who conduct clinics for specific genetic disorders. GeneTests, which is funded by the National Library of Medicine of the National Institutes of Health and the Maternal and Child Health Bureau of the Health Resources and Services Administration, also provides a set of references for each condition.
CONCLUSIONS AND RECOMMENDATIONS
The value of having an accurate diagnosis in the development of a prognosis and appropriate intervention plan cannot be overemphasized. This is important because, unless a disease has been verified by a laboratory test or specifically documented as a diagnosis by a clinical geneticist, there can be some very misleading approaches taken in addressing the needs of a specific patient. In our practice, we have repeatedly seen patients treated for an alleged diagnosis that health professionals had assumed was correct but that was later determined to be incorrect. Consequently, inappropriate plans for medical management had been developed.
A correct diagnosis and information on the natural history of genetic disorders allow the therapist to avoid unrealistic expectations for the intervention program and thus less than optimal outcomes. It is very important that the physical therapist develop and maintain a very close relationship with genetics services, including the clinical geneticist, genetics counselor, and, if appropriate, the laboratory. Close relationships with these resources are important not only for accurate diagnosis, but also because they can provide assistance to physical therapists in their management approaches for particular patients. Overall, it should be strongly emphasized that the physical therapist plays a major role addressing the management of the more than 4000 known genetic diseases that occur in humans.