In the latest Case Record of the Massachusetts General Hospital, an 11-month-old girl was seen in the neurology clinic because of developmental delay. Development to 6 months was normal; by 11 months, she had difficulty sitting and had stopped reaching for objects and feeding herself. An examination and diagnostic tests were performed.
In general, infants with nonprogressive disorders show signs of developmental delay but maintain their trajectory on the developmental curve; infants with progressive neurologic disorders reach a plateau and then lose their developmental skills.
• What is the definition of cerebral palsy, as well as causes and associated findings on imaging studies?
Cerebral palsy is a controversial term that includes motor-impairment syndromes caused by lesions in the brain in the early stages of development. The classification of spastic cerebral palsy, the common subtype, is made according to the topography of the lesions; the topography varies depending on whether the cause is spastic diplegia (e.g., cystic periventricular leukomalacia), spastic quadriplegia (e.g., hypoxic-ischemic injury), or spastic hemiplegia (e.g., perinatal stroke and malformations). Causes of cerebral palsy are prenatal (60% of cases), perinatal (15 to 20%), or postnatal (10%).
Both chorioamnionitis and fetal thrombotic vasculopathy have been implicated as causes of cerebral palsy. In one study, 70 to 90% of cases of cerebral palsy were associated with abnormal MRI scans. In another study, predominant abnormalities associated with cerebral palsy included white-matter lesions on MRI in 43% of cases, although 12% of cases were normal.
• How does the age of onset differ between various neurometabolic disorders?
Age at the onset of various metabolic and degenerative disorders differs. Most amino acid and organic acid disorders, urea-cycle disorders, and peroxisomal disorders are manifested in the neonatal period. Disorders that become apparent in early and late infancy include lysosomal storage disorders (e.g., Tay-Sachs disease, Krabbe’s disease, Canavan’s disease, and metachromatic leukodystrophy), mitochondrial disorders (e.g., Leigh’s disease), glucose transporter 1 (GLUT-1) deficiency, and congenital glycosylation disorders.
Morning Report Questions
Q: What is the pathophysiologic mechanism in Tay-Sachs disease?
A: The lack of hexosaminidase A in persons with Tay-Sachs disease impairs degradation of the ganglioside GM2, leading to excessive storage in neurons. In infancy, normal myelin development is also impaired. This leads to progressive weakness and loss of motor skills in the first year of life. Only one half of the patients learn to sit independently, and those that acquire this ability, such as this patient, lose it within 1 year. Early excessive startle was a pathognomonic sign. Once the diagnosis of Tay-Sachs disease was made in this case, pupillary dilatation to assess for a cherry-red spot was deferred. The median survival in infants with Tay-Sachs disease is 47 months, and no treatment, including bone marrow transplantation, has been shown to favorably alter the natural history of the disease.
Q: What is the nature of the startle response in infants with Tay-Sachs disease?
A: Among the lysosomal disorders, a characteristic startle response occurs in infants with Tay-Sachs disease (GM2 gangliosidosis or hexosaminidase A deficiency). In 1887, Bernard Sachs wrote, “Hearing seemed to be very acute, there was unusual hyperexcitability to auditory and tactile impressions; the slightest touch and every sound were apt to startle the child.” Clinically, these startle responses appear spontaneously or as an extension response triggered by auditory stimuli (hyperacusis) and often begin before a patient is 4 months of age.