Evaluation of the Adult with Learning Disabilities
by Beth A. Pletcher, MD, September 1998

Physicians caring for adult patients may be less likely to order diagnostic tests in an attempt to uncover an underlying cause for learning difficulties or mild mental retardation. However, making a specific diagnosis can be very important in the life of the patient, may provide insight into potential problems for offspring of the affected individual and certainly may be useful information for close relatives who may be thinking about having children of their own. A consensus conference held in October of 1995 attempted to shed some light on this very difficult subject. The group reviewed recent literature, sought expert opinion and used evidence-based data to draw some conclusions about a reasonable approach to such patients. While the provider's decision making for such patients must be individualized, here are a few ideas resulting from the consensus meeting as well as a few of my own:

• Evaluations need to be thoughtfully done to avoid unnecessary, often expensive tests (the SHOTGUN approach to patient care) and subspecialty referrals should also be carefully selected. There are many example of patients who have been seen by 5 or more specialists in an attempt to make a diagnosis. These medical odysseys submit patients to a terrible strain and provide very little useful information.

• The initial step in evaluating a patient with learning disabilities (LD) is to obtain prenatal, perinatal and birth histories to rule out teratogens, perinatal complications or neonatal problems. Significant prematurity, for example, increases risks for intracranial hemorrhage and frequently results in asymmetric neurologic symptoms or CP. A brief family history may also be important and should include questions about other individuals with LD or mental retardation (MR), miscarriages, stillbirths, neonatal deaths, individuals with birth defects and a history of consanguinity (parental relatedness).

• Chromosome studies are the mainstay of genetic testing and should be considered in any patient with LD or MR. Sex chromosome variations such as XXY, XYY or XXX may present with LD in the absence of physical features. Only XXY has the more obvious finding of post-pubertal testicular atrophy whereas individuals with the other sex chromosome variations rarely have physical stigmata. LD and psychiatric or psychological problems are often seen in individuals with sex chromosome aneuploidies as well as micro deletions on chromosome 22. The evolving phenotype or abnormalities seen in people with 22q- run the gamut from mild LD, hyper nasal voice +/- cleft palate and psychiatric difficulties in late adolescence (the velocardiofacial phenotype) to congenital cardiac defects such as a VSD or Tetralogy of Fallot to a full DiGeorge syndrome picture including congenital conotruncal defects with or without T-cell deficiency or hypocalcemia secondary to parathyroid hypoplasia.

• Routine chromosome studies should be done for those individuals with unexplained LD or MR. They should also be considered in adults with unusual or dysmorphic facial features, short stature, microcephaly and one major or several minor birth defects that are not part of a recognized pattern of malformations or secondary to a known prenatal or postnatal insult. Specialized molecular cytogenetic testing by FISH for micro deletions such as 22q- should only be done when there is increased suspicion based on clinical features.

• DNA or molecular testing for Fragile X syndrome should be considered in any male with unexplained MR and females with LD who have a suggestive family history maternally inherited MR in males). Many young adults with Fragile X are the only person in their family with MR. Post-adolescent males should be carefully evaluated for macro-orchidism since this is one of the few consistent physical findings in this condition. Making a correct diagnosis even in an adult with Fragile X is potentially beneficial to siblings and other family members who may unknowingly be at risk for having affected children. Cytogenetic testing for Fragile X should NEVER be done! This test is outmoded and much, much less accurate than molecular testing. Unless there is a very clear reason to do Fragile X testing alone, each patient screened for Fragile X should also have a routine chromosome analysis done simultaneously. The pick up rate for Fragile X in a male with MR is about 4% and for a chromosome abnormality also about 4%.

• Mendelian disorders or syndromes are much more difficult to ascertain because there are so many and frequently the diagnostic findings are varied and somewhat subjective. Such disorders should be considered in individuals with: Multiple congenital anomalies, normal chromosome studies, similarly affected relative(s) or if there is parental consanguinity.

• Targeted metabolic screening should be considered in individuals with: seizures, ataxia, developmental regression, cyclic vomiting/recurrent illnesses, intermittent somnolence, eye abnormalities such as cataracts/corneal clouding/ophthalmoplegia/retinopathy, coarse facial features, hepatosplenomegaly or abnormal sexual differentiation. Cardiomyopathy and/or myopathy may be associated with mitochondrial disorders and should be promptly evaluated.

• Neuroimaging studies may augment the clinical evaluation in some cases but need not be done in all individuals with LD or MR. They should be considered in any patient with asymmetric neurologic signs, unusual or progressive neurologic findings, microcephaly, macrocephaly or abnormal cranial contour. MRI is generally better than CT except when ruling out intracranial calcifications, tuberous sclerosis or craniosynostosis.

• For many patients with genetic disorders, the physical features or phenotype evolves over many years. For this reason, adults who were previously evaluated in infancy or early childhood who still have no diagnosis, should be reseen from a genetic perspective. Furthermore, advances in genetic testing including sophisticated cytogenetic and molecular methodologies now permit diagnoses to be made that could not be made even five years ago. Recent studies suggest that reevaluation of patients with MR increases diagnostic coverage in as many as 5-20% of patients.

• Mendelian disorders that have a slowly evolving phenotype include: neurofibromatosis, tuberous sclerosis, Noonan syndrome, Fragile X syndrome and Williams syndrome. Metabolic disorder that may rarely present with progressive deterioration in adulthood include: lysosomal storage disorders, some forms of leukodystrophy and Wilsons disease.

In summary, the clinical evaluation should be the primary assessment tool for adults with LD or MR and should be supplemented by appropriate historical information and cytogenetic studies. The evolution of physical features in certain syndromes may occasionally necessitate a reevaluation in adulthood. Fragile X testing should be considered in all males with MR and focused metabolic testing should be done under specific clinical circumstances. Neuroimaging studies are tools that can be helpful in selected patients. However, one should never substitute good clinical judgement for sophisticated laboratory or radiographic studies.