Genetic Disorders and Neurology
by Samuel G. Carruth, MD, March 2000

There are some key neurological and physical features that pediatric providers as well as neurologists should be aware of that give clues to possible genetic disorders. When children present with a particular pattern of neurological symptoms, unrelated to birth asphyxia/anoxia, infection, trauma or environmental causes, and distinctive physical features, a referral to a geneticist may be indicated for possible diagnostic genetic testing. Correct diagnosis of a genetic disorder is important because it may have implications for treatment, anticipatory guidance and family planning.

The most common of these neurological symptoms include: mental retardation, developmental delay with or without language delay, hypotonia and ataxia. Associated neurological symptoms include: weakness, seizures, feeding difficulties, sensorineural hearing loss, vision loss, coordination abnormalities, decreased reflexes, exercise intolerance, voice changes and abnormal respiratory patterns which may include, but are not limited to, apnea or an acute life threatening event. When a combination of such symptoms are seen along with specific findings on physical exam, a genetic diagnosis can be highly suspected.

Although causes of mental retardation with developmental delay (MR/DD) run the full spectrum of possible medical diagnoses they often will go undiagnosed. The history and physical exam is most helpful in this situation and, when done in combination with a three-generation pedigree, will often point the provider in the right direction. Cytogenetic, metabolic and molecular studies, when indicated, are all useful tools in this situation. As mentioned above, finding a chromosomal abnormality (deletion, duplication, or an extra sex chromosome - e.g. XXY), metabolic disorder (inborn error of metabolism) or molecular disorder (e.g. Fragile X or a mitochondrial disorder such as MELAS or MERFF) has implications for family planning, treatment and anticipatory guidance.

Congenital hypotonia, when not due to birth asphyxia, may also be a clue to a possible genetic diagnosis. There are numerous genetic conditions for which hypotonia is apparent at the time of birth. Among the more common are: Prader-Willi syndrome, trisomy 21, the glycogen storage diseases, oxidative metabolic disorders, the congenital muscular dystrophies (CMD types I-IV) as well as Werdnig-Hoffman or spinal muscular atrophy (SMA type I) and myotonic dystrophy (MD.) As can be inferred from the conditions mentioned, it is the combination of hypotonia along with certain physical characteristics that are the main clues to possible genetic diagnoses. The presence of hypotonia by itself should lead the physician to think of possible genetic conditions.

Hypotonia that becomes apparent early in childhood rather than being present at birth is suggestive of the X-linked muscular dystrophies of Becker and Duchenne. Although hypotonia may be present in these two muscular dystrophies, delayed walking, weakness, easy fatigability, and abnormal gait may be the presenting complaint by the parent to the provider.

Ataxia, when related to a genetic disorder, can present in early or later in childhood and may not be evident at birth. Some such conditions include: ataxia-telangiectasia, Friedreich ataxia, Angelman syndrome, Xeroderma Pigmentosum, Kallman syndrome as well as the gangliosidoses and oxidative metabolic disorders. As with hypotonia, ataxia should alert the provider to a possible genetic diagnosis.

Oxidative metabolic disorders can present in infancy, early childhood, and even later in life. The neurological symptoms due to these inborn errors of metabolism are progressive, they may go unrecognized at the time of birth, and the health care provider's first clue to oxidative metabolic disorders may be respiratory distress, acidosis, seizures or failure to thrive. These disorders are usually inherited in an autosomal recessive pattern although some may be X-linked, so there are often no other affected individuals in prior generations. The symptoms may be progressive in nature, acute, recurrent and/or reversible, with or without exercise intolerance. Worsening of symptoms may also arise from illness or fasting. This variable degree of symptoms can make the diagnosis of an oxidative metabolic disorder more difficult to recognize, but should be highly suspected when myopathy and encephalopathy are present together. The following neurological symptoms common to metabolic disorders are: hypotonia, encephalopathy, myopathy, developmental delay, ataxia, optic neuropathy, stroke-like episodes, exercise intolerance, weakness and/or myoclonic epilepsy. The myopathies may also show evidence of acute muscle breakdown or myoglobinuria. All of these symptoms are usually progressive when the underlying inborn error of metabolism is left untreated, although some may occur episodically with periods of relatively good health in between.

Normal hearing is essential for speech and language development and, therefore, prompt identification and treatment of hearing loss is crucial for pediatric patients. Furthermore, sensorineural hearing loss (SNHL), in particular, can alert the primary care provider to a possible genetic diagnosis. Like the other neurological symptoms, there are numerous disorders that are associated with this type of hearing loss. Some syndromes associated with SNHL are: Velocardiofacial syndrome, DiGeorge syndrome, renal tubular acidosis and primary hypomagnesemia.

The presence of any one of these manifestations must be considered in the context of the evaluation of the entire patient and, alone, these neurological symptoms carry little weight. On the other hand, when they are found in combination with abnormal physical features and/or laboratory findings, the primary care provider's suspicion of a genetic diagnosis should lead to referral. A three-generation family tree may also reveal a particular inheritance pattern such as X-linked recessive, X-linked dominant or autosomal dominant. Autosomal recessive disorders may not be as obvious, but are more highly suspected when there are no other family members affected (except possibly within a sibship) or there is a family history of consanguinity.

Specific neurological signs and symptoms in and of themselves do not always indicate the need for genetic testing, but when these present in combination with additional physical features, a genetic diagnosis should be pursued. Such patients may benefit from a referral for genetic diagnosis, discussion about the diagnosis and the long-term prognosis. The previously mentioned syndromes represent only a handful of the full spectrum of genetic diagnoses related to neurological signs and symptoms, thus some practical guidelines may be helpful. The following table represents a list of neurologic symptoms that are more commonly seen concomitantly with genetic conditions.

Indications for Referral to Genetics by Presenting Symptom ( unrelated to birth asphyxia/anoxia)

• Always

Hypotonia with or without weakness
Ataxia Mental retardation/ Developmental delay
Sensorineural hearing loss/ Visual loss
Loss of milestones

• Sometimes

  Exercise intolerance
  Failure to thrive
  Dysphagia Seizures
  Scoliosis in boys (Marfan syndrome)

• Hardly Ever

  Static encephalopathy
  Specific epilepsy diagnosis (unless there is a family history)
  Abnormal respiratory patterns (ALTE or apnea)