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Several inherited defects are known in the conversion of the sulfur-containing amino acid methionine to cys teine and the ultimate oxidation of cysteine to inorganic sulfate (Fig. 21.1). Cystathionine β-synthase (CBS) deficiency is the most important. It is associated with severe abnormalities of four organs or organ systems: the eye (dislocation of the lens), the skeleton (dolichostenomelia and arachnodactyly), the vascular system (thromboembolism), and the central nervous system (mental retardation, cerebro-vascular accidents). A low-methionine, high-cystine diet, pyridoxine, folate, and betaine in various combinations, and antithrombotic treatment may halt the otherwise unfavourable course of the disease. Methionine S-adenosyltransferase deficiency and γ-cystathionase deficiency usually do not require treatment. Isolated sulfite oxidase deficiency leads (in its severe form) to refractory convulsions, lens dislocation, and early death. No effective treatment exists. Combined deficiency of sulfite oxidase and xanthine oxidase is discussed in Chap. 35. Deficiencies of glycine N-methyltransferase and S-adenosylhomocysteine hydrolase have been described in a few patients.

is associated with gyrate atrophy of the choroid and retina. Patients usually become virtually blind by age 55. Treatment includes a low arginine diet and pharmacological doses of pyridoxine (vitamin B). Long term compliance to an arginine-restricted diet, especially when started at a young age, can slow the progression of the chorioretinal lesions and loss of vision. Rarely, neonates can present with hyperammonemic encephalopathy, hypoargininemia, and hypoornithinemia and require arginine supplementation. In the there is a wide spectrum of clinical manifestations, most of which are related to the toxicity of hyperammonemia. Progressive spastic paraparesis is often a late complication. Patients have a marked elevation of plasma ornithine associated with hyperammonemia and increased urinary excretion of homocitrulline. HHH results from a defect in the import of ornithine into the mitochondrion and consequent urea synthesis malfunction. Treatment is similar to that for patients with urea cycle disorders.

A newly recognized disorder, -, has been described in two siblings with progressive neurodegeneration and peripheral neuropathy, joint laxity, skin hyperelasticity and bilateral subcapsular cataracts. Their metabolic phenotype includes mild hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and hypoprolinemia. This disorder underscores the importance of low levels of amino acids as markers of metabolic disease.

Seven inborn errors are described in this chapter: may all have no clinical significance, but some patients are retarded and show variable neurological abnormalities.

causes severe neurometabolic disease. The first months may be uneventful with only subtle neurological abnormalities and/or macrocephaly, but progressive cerebral atrophy or subdural hemorrhages on neuroimaging. Between age 6 to 18 months most untreated patients suffer an acute encephalo pathy resulting in irreversible destruction of suscep tible brain regions, in particular the striatum, a dystonic-dyskinetic syndrome and, ultimately, often early death. Restriction of lysine, administration of L-carnitine and timely vigorous treatment during intercurrent illness is able to completely prevent or at least halt the disease.

shows an insidious onset with delay of unsupported walking and speech, febrile convulsions, and macrocephaly. Over the years, severe mental retardation and cerebellar ataxia develop with or without dystonia, pyramidal signs, and seizures.

causes severe earlyonset epileptic encephalopathy with neonatal seizures, lack of psychomotor development and early death. Some patients exhibit milder neurological symptoms such as mild developmental delay, delayed speech and febrile convulsions.

is an infantile degenerative disease primarily affecting the cerebral white matter. It commonly manifests with poor head control and hypotonia at 2–4 months, macrocephaly, marked developmental delay, optic nerve atrophy, progressive spasticity, opisthotonic posturing, seizures and death in childhood.

Nonketotic hyperglycinemia (NKH) or glycine encephalopathy is an autosomal recessive disorder characterized by a rapidly progressive course in the neonatal period or early infancy. Symptoms include muscular hypotonia, seizures, apneic attacks, lethargy and coma. Most patients die within a few weeks, whereas survivors show severe psychomotor retardation. Increased glycine concentrations in plasma, urine, and cerebrospinal fluid are biochemical features of the disorder. The primary lesion is a defect in the glycine cleavage system (GCS) (Fig. 24.1). Although this was first demonstrated in the liver, involvement within the brain is responsible for the clinical expression. No specific treatment is available. Prenatal diagnosis is possible by determining the activity of GCS in chorionic villi.

Three disorders of metabolism are known: two in its catabolism (hyperprolinemia type I due to proline oxidase deficiency and hyperprolinemia type II due to Δ1-pyrroline 5-carboxylate dehydrogenase deficiency) and one in its synthesis (Δ1-pyrroline 5-carboxylate synthase deficiency). Hyperprolinemia type I is mostly considered a non-disease, while hyperprolinemia type II seems to be associated with a disposition to recurrent seizures. The deficiency of the proline-synthesizing enzyme, Δ-pyrroline 5-carboxylate synthase, which also intervenes in ornithine synthesis, is described in ▸ Chap. 22.

Three disorders of metabolism are known. Two are in its biosynthesis: namely, 3-phosphoglycerate dehydrogenase deficiency and phosphoserine phosphatase deficiency. Patients with 3-phosphoglycerate dehydrogenase deficiency are affected with congenital microcephaly, psychomotor retardation and intractable seizures and partially respond to L-serine or L-serine and glycine. One patient with an association of Williams syndrome and phosphoserine phosphatase deficiency has been reported. Another, unexplained serine disorder has been reported in a patient with decreased serine in body fluids, ichthyosis and polyneuropathy but no central nervous system manifestations. There was a spectacular response to L-serine.

Inherited defects in amino acid transport at the cell membrane are usually expressed as selective renal aminoaciduria, i.e., the concentration of the affected amino acids is high in the urine while it is normal or low in plasma. Intestinal absorption of the affected amino acids is also almost always impaired. The clinical symptoms thus result from excess amounts of certain amino acids in the urine or lack of them in the tissues. Consequently, in renal stones may be formed because of high urinary concentration of poorly soluble cystine. In (LPI), the transporter defect for the dibasic cationic amino acids leads to poor intestinal absorption and urinary loss of arginine, ornithine and, particularly, lysine. Deficiencies of arginine and ornithine, intermediates of the urea cycle, lead to hyperammonemia and protein intolerance, and insufficient supply of lysine probably plays a major role in the growth retardation and skeletal and immunological manifestations of LPI. The pellagra-like dermatitis and ataxia in are attributed to deficiency of tryptophan, the precursor of niacin synthesis.

Two inherited defects in biotin metabolism are known: (HCS) and . Both lead to deficiency of all biotindependent carboxylases, i.e. to (MCD). In HCS deficiency, the binding of biotin to apocarboxylases is impaired. In biotinidase deficiency, biotin depletion ensues from the inability to recycle endogenous biotin and to utilize protein-bound biotin from the diet. As the carboxylases play an essential role in the catabolism of several amino acids, in gluconeogenesis and in fatty-acid synthesis, their deficiency provokes multiple, life-threatening metabolic derangements, eliciting characteristic organic aciduria and neurological symptoms. The clinical presentation is extremely variable in both disorders. Characteristic symptoms include metabolic acidosis, hypotonia, seizures, ataxia, impaired consciousness and cutaneous symptoms, such as skin rash and alopecia. All patients with biotinidase and a majority of patients with HCS deficiency respond dramatically to oral therapy with pharmacological doses of biotin. Delayed diagnosis and treatment in biotinidase deficiency may result in irreversible neurological damage. A few patients with HCS deficiency show a partial or even no response to biotin and seem to have an impaired long-term outcome. , which also causes MCD, is extremely rare. A defect in has been reported in a single child; however the genetic defect remains unresolved to date. (BRBGD) is a recently described subacute encephalopathy which disappears within a few days without neurological sequelae if biotin is administered early.

For patients with inherited disorders affecting cobalamin (Cbl) absorption, the main clinical finding is megaloblastic anemia. Except for transcobalamin (TC) deficiency, the serum Cbl level will usually be low. Patients with disorders of intracellular Cbl metabolism show elevations of homocysteine or methylmalonic acid, either alone or in combination. The serum Cbl level is not usually low. For those disorders that affect methylcobalamin (MeCbl) formation, the major manifestations include megaloblastic anemia secondary to folate deficiency and neurological abnormalities presumably secondary to methionine deficiency or homocysteine elevation. The main findings in those disorders that affect adenosylcobalamin (AdoCbl) formation, are secondary to elevated methylmalonic acid and resultant acidosis.

This chapter deals mainly with inborn errors of neurotransmitter metabolism. Defects of their receptors and transporters, and disorders involving pyridoxine (vitamin B) and its derivative, pyridoxal phosphate, a cofactor required for the synthesis of several neurotransmitters, are also discussed.

Two defects of GABA metabolism are known: the very rare, severe, and untreatable , and the much more frequent which, to some extent, responds to GABA transaminase inhibition. is a dominantly inherited defect of the α1 subunit of the glycine receptor which causes excessive startle responses, and is treatable with clo nazepam. Mutations in the γ-subunit of the GABA receptor are a cause of dominantly inherited epilepsy. Disorders of the metabolism of glycine are discusssed in ▸ Chap. 24.

Five disorders of monoamine metabolism are discussed: impairs synthesis of dihydroxyphenylalanine (L-dopa), and causes an extrapyramidal disorder which responds to the latter compound. The clinical hallmark of is severe orthostatic hypotension with sympathetic failure. The other disorders of monoamine metabolism involve both catecholamine and serotonin metabolism. is located upstream of these intermediates. Treatment of its deficiency is more difficult and less effective. , located downstream, mainly causes behavioral disturbances; no effective treatment is known. is a defect upstream of L-dopa and 5-hydroxytryptophan (5-HTP) and, therefore, can be effectively treated with these compounds.

, a rare form of early or late infantile seizures, has been recently found to be caused by mutations of antiquitin, an enzyme intervening in the degradation of lysine (Fig. 23.1). Recently also, defective conversion of pyridoxine to pyridoxal phosphate, due to pyridox(am)ine 5′-phosphate oxidase (PNPO) deficiency, has been identified as a cause of neonatal epilepsy.

Genetic defects have been described in four of the six steps of the γ-glutamyl cycle. is the most frequently recognized disorder and, in its severe form, it is associated with hemolytic anemia, metabolic acidosis, 5-oxoprolinuria (pyroglutamic aciduria), central nervous system (CNS) damage and recurrent bacterial infections. γ- is also associated with hemolytic anemia, and some patients with this disorder show defects of neuromuscular function and generalized aminoaciduria. γ- has been found in patients with CNS involvement and glutathionuria. 5- is associated with 5-oxoprolinuria but without a clear association with other symptoms.

are probably the same disorder. It is uncertain whether there is a relationship between the biochemical abnormalities and clinical symptoms. causes skin lesions and recalcitrant ulceration (particularly on the lower legs) in addition to other features, such as impaired psychomotor development and recurrent infections. The severity of clinical expression is highly variable.