Later Infancy And Childhood Disorders With Prominent Neurologic Manifestations

Classic and biopterin-dependent hyperphenylalaninemia Homocystinuria due to cystathionine beta-synthase deficiency Disorders of folate and vitamin B12 metabolism with homocystinuria

4-Hydroxybutyricaciduria Glutaricaciduria type 1

Certain phenotypes of 3-methylglutaconicacidurias Carmitine palmitoyl transferase (CPT) I and II deficiencies Adenosine triphosphate synthetase deficiency Certain phenotypes of MCAD and LCAD deficiencies Biotinidase deficiency in body fluids. The branched-chain alpha-ketoacid dehydrogenase (BCKAD) is deficient, and the disorder is inherited as an autosomal recessive trait. It is a multienzyme complex that contains three major subunits: E1, a decarboxylase; E2, an acyltransferase; and E3, a lipoamide dehydrogenase (dihydrolipoic dehydrogenase). The activity of BCKAD is regulated either by inhibition of reaction products or substrate analogues by reversible phosphorylation/ dephosphorylation of the E1 subunit or by the regulation of gene expression through such hormones as insulin and corticosteroids, or L-carnitine or by glucose. The chromosome location of the genes of the subunits and of complementary DNAs is established (...Ja,bie.3.1:2. ). Mutations of the subunits from different ethnic groups have been identified.

The severe CNS symptoms of the disease have been attributed to brain edema, caused by elevated BCAAs, particularly L-leucine. The neuropathological finding in patients who die is generalized spongy CNS degeneration, similar to other disorders such as nonketotic hyperglycin- emia.

Epidemiology and Risk Factors. The worldwide frequency based on routine screening data from 26.8 million newborns is about 1 in 185,000. [4 The disease is common in consanguineous communities; for example, among the Mennonites of Pennsylvania the incidence is 1 in 176. It is encountered frequently in the Middle East, particularly in the Arabian peninsula, where its frequency may be as high as 1 in 2,000.

Clinical Features and Associated Disorders. The classical form of MSUD usually presents within the first 2 weeks of life and rarely beyond 1 month of age. The prodromal symptoms include refusal to feed, vomiting, increasing lethargy, and seizures, with eventual coma. Because the cerebral peduncles and the dorsal part of the brain stem are the earliest parts of the CNS involved, the patient develops opisthotonus and primitive reflexes are usually absent. The initial clinical diagnosis is commonly meningitis or sepsis; and because such patients frequently have associated sepsis, the primary diagnosis may be missed for many days. Cerebral edema leads to tone disturbances, alternating between increased tone and hypotonia. Seizure activity is usually clonic or myoclonic with eyes rolling upward. Early optic atrophy is usual and recedes only if the therapeutic intervention is prompt. When the presence of disease is not recognized at this stage, or the neonate is not managed appropriately, the infant becomes blind and has severe spastic quadriplegia (see Fig, 31-1 ). Undiagnosed patients usually develop apnea and die. When treated appropriately, the symptoms will gradually disappear. In well-managed patients, mild to moderate hypotonia (particularly axial hypotonia) persists during the first year of life; eventually, mild to moderate cerebellar ataxia will remain as the only neurological sequela.


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