It will be recognized from the foregoing synopses that many of the neurologic manifestations of the inherited metabolic diseases of infancy are nonspecific and are common to most or all of the diseases in this group. In general, in the early stages of all these diseases, there is a loss of postural tone and a paucity of movement without paralysis or loss of reflexes; later there is spasticity with hyperreflexia and Babinski signs. Equally nonspecific are features such as irritability and prolonged crying; poor feeding, difficulty in swallowing, inanition, and retarded growth; failure of fixation of gaze and following movements of the eyes (often misinterpreted as blindness); and tonic spasms, clonic jerks, and focal and generalized seizures.
The differentiation of the inherited metabolic diseases of infancy rests essentially upon four types of data: (1) a few highly characteristic neurologic and ophthalmic signs; (2) the presence of an enlarged liver and/or spleen; (3) dysmorphic features of the face; and (4) the results of several relatively simple laboratory tests, such as images of the thoracolumbar spine, hips, and long bones; smears of the peripheral blood and bone marrow; CSF examination; and certain urinary tests and other biochemical estimations (serum lactate, glucose, ammonia, and urinary ketones, amino acids, and organic acids). For purposes of differential diagnosis, we have found the flowcharts constructed by our colleague, E.H. Kolodny, to be very useful. One such schematic, illustrated in Fig. 36-4, is based on the subdivision of patients into three groups: (1) dysmorphic, (2) visceromegalic, and (3) purely neurologic. Only rarely does an inherited metabolic disease fall into more than one of these categories. There is also considerable value in beginning the diagnostic process by classifying the syndrome as a leukodystrophy or a poliodystrophy (disease predominantly affecting neurons, see further on), although this distinction is easier to make in the older child.
Once the major category of disease has been identified, correct diagnosis depends on particular clinical and laboratory features tabulated below (Tables 36-5 and 36-6).
Of course, in the current era genetic testing discloses the diagnosis of most of these disorders but unless whole exome screening is planned to be undertaken, the clinician must have some idea of the likely diagnosis. Panels of over 100 genes pertaining to nuclear and mitochondrial causes of leukodystrophy are available.
Neurologic signs that are more or less specific for certain metabolic diseases are as follows: 1. Acousticomotor obligatory startle: Tay-Sachs disease 2. Abolished tendon reflexes with definite Babinski signs: globoid cell (Krabbe) leukodystrophy, occasionally Leigh disease, and (beyond infancy) metachromatic leukodystrophy 3. Peculiar eye movements, pendular nystagmus, and head rolling: Pelizaeus-Merzbacher disease, Leigh disease; later, hyperbilirubinemia and Lesch-Nyhan hyperuricemia (see below) 4. Marked rigidity, opisthotonos, and tonic spasms: Krabbe, Alpers disease, or infantile Gaucher disease (classic triad: trismus, strabismus, opisthotonos) 5. Intractable seizures and generalized or multifocal myoclonus: Alpers disease 6. Intermittent hyperventilation: Leigh disease and congenital lactic acidosis (also nonprogressive familial agenesis of vermis) 7. Strabismus, hypotonia, seizures, lipodystrophy: