Progressive Diseases of Infancy and Childhood

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A large number of amino and organic acid disorders appear primarily with neurological symptoms. Only four disorders, phenylketonuria (classic form and biopterin-dependent variant) homocystinuria, type 1 glutaricaciduria, and biotinidase deficiency are presented here.


Pathogenesis and Pathophysiology. Although phenylalanine hydroxylase (PAH) is a liver enzyme, the clinical manifestations of classic phenylketonuria (PKU) relate to the CNS. There are no abnormal metabolites formed in classic PKU but only excessive amounts of normal compounds. Therefore, it is logical to assume that elevated levels of blood phenylalanine are responsible for the toxicity. Both animal models and magnetic spectroscopic studies in human brain indicate that phenylalanine levels exceeding 1.3 mM affect the brain metabolism adversely and account for acute phenylalanine toxicity. The threshold for chronic toxicity may be much lower. Acute and chronic adverse effects of high blood phenylalanine on brain can be prevented by high doses of BCAAs. Because both phenylalanine and BCAA share the same transport system, it is conceivable that mutual competition of neutral amino acids at the L-transport system may account for some of these toxic effects. Some patients diagnosed to have mild hyperphenylalaninemia in the past might have had carbinolamine dehydratase deficiency. Fair features and hypopigmentation are caused by the inhibition of tyrosinase by hyperphenylalaninemia. Location of the PHA gene is given in Tablei31i:2 , and its complementary DNA is available.

Epidemiology and Risk Factors. The disease occurs at varying frequency. The highest frequency is in Turkey with 1 in 2,600 births; it is lower among Japanese at 1 in 140,000. Ashkenazic Jews and Finns each have an incidence of 1 in 200,000 births.

Clinical Features and Associated Disorders. PKU usually manifests after 1 year of age as mental retardation. The late emergence of physical findings is the rationale for screening tests in all newborns. The safety window is approximately 6 weeks; and by 1 year of age, the untreated child might lose 50 percent on IQ measurements. The infant is usually born prematurely and has a fair complexion and eczematoid lesions. Myoclonic seizures might occur as

early as 4 months of age, and developmental delay appears between 6 and 18 months of age. Some patients develop normally until 1 year but then lose the milestones. Despite severe CNS involvement, no pyramidal or extrapyramidal signs are usually detected.

Children with untreated or poorly managed PKU usually end up in institutions. A review of 51 never-treated patients followed for more than 20 years indicated 25 percent had seizures disorders, half were profoundly retarded, and about half were moderately impaired. y Approximately two thirds of untreated patients develop microcephaly. Autistic behavior may also emerge. Aggressive, hyperactive behavior is common in poorly managed patients, which becomes less noticeable on lowering the blood phenylalanine level. In well-controlled patients, ingestion of food with high phenylalanine content, at any time during life, will cause confusion and a clear-cut fall in school performance.

Differential Diagnosis. In neonates with severe liver disease, levels of most plasma amino acids, notably tyrosine and methionine, are elevated; and at times that of phenylalanine may also be moderately high. Occasionally, isolated elevation of the blood phenylalanine level (up to 250 pM) will occur transiently in a normal neonate. In such infants, a repeat study at 4 to 6 weeks usually indicates normal phenylalanine, and the infant will not develop any signs of PKU later in life. The reasons for this transient hyperphenylalaninemia remain obscure.

Other common causes of childhood mental retardation include hyperprolinemia, homocystinuria, and fragile X- syndrome. Clinically, hyperprolinemia cannot be distinguished from mild PKU except by the amino acid analysis. Patients with a missed diagnosis of homocystinuria will have its classic phenotype, which is not observed in classic PKU. Patients with fragile X-syndrome are mostly males with typical facial features of the disease, severe autism, or mental retardation; molecular genetic studies identify the disease.

Many developing countries do not have a neonatal PKU screening program. Therefore, any infant with seizures, developmental delay, or fair features in a community with dark complexion, and any child with mental retardation, hyperactivity, and aggressive behavior should be evaluated for classic PKU.

Evaluation. The blood phenylalanine level is elevated (>120 pM), usually more than 1 mM, and the blood phenylalanine/tyrosine ratio is higher than 2, as determined by high-protein liquid chromatography or tandem mass spectrometry techniques. The green color produced by acidic ferric chloride in the urine of PKU patients is caused by the presence of phenylpyruvic acid. This compound is labile, disappearing from urine stored cold or frozen in 1 to 2 days. This test must be done on freshly collected urine. Computed tomography (CT) or magnetic resonance imaging (MRI) reveals demyelination or dysmyelination in central white matter, disappearing on treatment and reappearing if treatment is discontinued.

Prognosis and Prevention. Well-controlled studies indicate that prognosis is extremely rewarding if treatment is started in the first month of life. The North American Collaborative Study of patients to 12 years of age indicates that the longest treated patients who had phenylalanine values less than 900 pM had the best IQ and psychological test scores.y Numerous studies indicated deterioration of IQ, deviant electroencephalographic findings, and emergence of demyelination on MRI if the treatment is discontinued at or about school age. It is prudent to continue the treatment as long as possible, well into adolescence. Parents should be warned that a well-treated patient will function normally in daily life but may show significant deficits in conceptual, visuospatial, and language-related tasks, in reading and arithmetic skills, in attention span, and in problem-solving abilities.

Classic PKU was one of the first inborn errors of metabolism for which neonatal screening was applied. y Hyperphenylalaninemia and disturbed ratio of phenylalanine/tyrosine in a neonate with classic PKU may be apparent as early as 24 hours but definitely by 3 to 7 days of life. Given the 6-week safety window, neonatal screening for PKU may be done during the first month. Any positive screening result should be rechecked within 1 month. The conventional procedure for PKU screening is the Guthrie test. The problem of false-positive results and the anxiety created in the family recalled for repeat testing led to the exploration of other techniques. More recently, tandem mass spectrometry-based screening procedures have been described that have less problems with false-negative and false-positive results, because, in addition to phenylalanine estimation, they provide an accurate phenylalanine/tyrosine ratio. ^ , y

The principle of treatment is to restrict dietary intake of phenylalanine. There are numerous formulas for this purpose that have been in use since the mid-1950s. Treatment should be monitored by monthly or bimonthly measurement of plasma amino acids, to ensure that phenylalanine and other essential amino acids are not lower than normal. Given the beneficial effects of BCAAs in preventing the adverse CNS manifestations of hyperphenylalaninemia, they may be used to supplement the diet. Patients with PKU should avoid consuming food or drinks that contain aspartame, an artifical sweetener ( W-aspartylphenylalanine), because intestinal hydrolysis liberates phenylalanine.

Successful management of many females with PKU has resulted in normal lifestyle, marriages, and child bearing. Infants born to mothers with PKU, however, have numerous congenital defects, such as microcephaly, impaired somatic growth, and heart disease. y Because similar defects are not seen among offspring of fathers with PKU, it is apparent that high blood phenylalanine levels in the mother are the cause. Although no threshold is agreed on, fetal outcome is satisfactory if the maternal blood phenylalanine levels are maintained at less than 600 pM throughout the pregnancy.


Pathogenesis and Pathophysiology. Defective synthesis of biopterin (BH4 ) causes disruption in several biochemical functions. Deficiencies of the first two steps, that is, guanosine triphosphate cyclohydrolase (GTP-CH) and 6- pyruvoyltetra-hydropterin synthase (6PTS), are known as synthetic defects. The hydroxylase reacts with BH4 , converting it to its hydroxy form 4alpha-carbinolamine, which is then dehydrated by primapterin carbinolamine dehydratase

(PCD) to quininoid dihydrobiopterin, which is labile and must be reduced back to BH 4 through a reaction that uses reduced nicotinamide adenine dinucleotide (NADH) and is catalyzed by dihydropteridine reductase (DHPR). The deficiencies of the latter two enzymes are known as recycling defects. Because primapterin is excreted in PCD deficiency, the disease is also called primapterinuria. BH 4 is a cofactor for enzymes of the initial step in dopamine and serotonin synthesis; when it is not available, neurotransmitter and autonomic function, both in the CNS and periphery, are disturbed. In addition, BH 4 is a cofactor for the generation of nitric oxide in CNS, which is a neurotransmitter/modulator. Deficiency of BH4 causes severe autonomic irregularities and mental retardation and, ultimately, is not compatible with life. Severe cardiopulmonary dysrhythmia, fluctuating blood pressure, sleep irregularities, and early unexpected death may be explained by these considerations. Because 4alpha-carbinolamine can be spontaneously dehydrated, PCD deficiency does not cause a severe disease. In BH 4 -dependent PKU, neurological manifestations are severe in the presence of mild hyperphenylalaninemia, suggesting that trace BH 4 levels are sufficient to promote the phenylalanine hydroxylase reaction in liver but not high enough for adequate hydroxylation of tyrosine and tryptophan in the CNS. All four diseases are inherited as autosomal recessive. The location of their genes is shownin IabJe,3:.1.-.2 .

Epidemiology and Risk Factors. Hyperphenylalaninemia due to BH4 deficiency is rare and accounts for 2 percent of all PKU cases. An international database in 1995 for abnormal BH4 metabolism indicated the followingy : 12 patients with GTP-CH deficiency, 182 with 6PTS deficiency, 87 with DHPR deficiency, and 12 with

PCD deficiency. The overall frequency is estimated to be 1 in 106 births. In some parts of the world these defects occur more frequently (e.g., 10 percent in Italy, 15 percent in Turkey, 19 percent in Taiwan, and 68 percent in Saudi Arabia).

Clinical Features and Associated Disorders. The signs seen in this disorder are remarkably similar except for PCD deficiency. y The classic presentation is an infant, usually of low birth weight, who develops normally for 2 to 3 months. Then myoclonic seizures appear approximately at 3 months, probably due to serotonin depletion. Bradykinesia is apparent particularly when the infant is naked. The infant lies expressionless. Initially, there may be hypotonia, but soon after "lead pipe" or

"cogwheel" rigidity appears (..Fig, 31-3 ). These are parkinsonian features caused by deficient dopamine. In fact, extensor posturing of the extremities, opisthotonic arching of the back, and pronation of hands are common. Oculogyric crisis, involuntary dystonic movements, and tremors may be observed. Feeding is difficult owing to difficulties in swallowing, and the patient drools because of inability to manage secretions. Early failure to thrive and fair features of PKU are observed. Development arrests at 2 to 3 months, unless the disorder is treated. The patient suffers from severe bronchopneumonia from respiratory irregularities and is often admitted to an intensive care unit for cardiorespiratory difficulties, usually dying before 5 years of age. Those children who survive remain profoundly

Figure 31-3 Glutaricaciduria, biotinidase deficiency and biopterin-dependent phenylketonuria. Clockwise from left upper corner. Infant with glutaricaciduria type I (GAT I) showing dystonic posture and rigidity in flexion. MRI of the brain showing open operculum sign and frontotemporal atrophy in infant with GAT I. Alopecia in a biotinidase-deficient 9-month-old infant with frequent myoclonic seizures from age 3 months. Infant with biopterin-dependent phenylketonuria due to 6-pyruvoyl tetrahydropterin synthase (6-PTS) deficiency showing dystonic grimacing and fisting of hands and hypotonic pithed frog posture of legs.

retarded. Episodes of hyperthermia without infection, fluctuating high blood pressure, and reversed diurnal rhythm of sleep have been described. Deficiency of DHPR, in general, shows a more severe progression of the disease, whereas GTP-CH deficiency might be milder and missed in some instances. The clinical picture of PCD deficiency is essentially that of a mild PKU, and it is not unusual for such a patient to be classified as having transient hyperphenylalaninemia.

Differential Diagnosis. All infants with parkinsonian signs, myoclonic seizures, unexpected fair features, unexplained failure to thrive, unexplained severe bronchopneumonia or cardiopulmonary arrest, unexplained hyperthermia, and fluctuating blood pressure should be studied for the presence of 6PTS and DHPR deficiencies. Blood amino acids, particularly phenylalanine, should be determined in all children with mental retardation. Even when mild hyperphenylalaninemia is found, BH4 loading, DHPR activity in red blood cells, and pterin measurement in urine should be performed.

Evaluation. Hyperphenylalaninemia is usually not as severe as in classic PKU. The end products of catecholamine and serotonin metabolism in cerebrospinal fluid and urine, such as 5-hydroxyindoleacetic, homovanillic, and vanillylmandelic acids, are considerably lower than normal. The characteristic findings are in the urinary pterin metabolites. In GTP-CH deficiency both neopterin and biopterin are low in the urine. In 6PTS deficiency the urine neopterin level is very high and that of biopterin is very low or undetectable, leading to a greatly elevated neopterin/ biopterin ratio. The urinary excretion of pterins may range from normal to massively elevated in DHPR deficiency. In PCD, an unusual pterin, primapterin, is detected in the urine. The pterin assay has been adapted to be used with dried urine spots on filter paper.y

Another option is to perform a BH4 loading dose, given 2 mg/kg IV or 7.5 to 20 mg/kg orally in divided doses. This will lower plasma phenylalanine to within normal limits within 8 to 12 hours if a patient has BH 4 -dependent PKU. In 6PTS deficiency the excretion of neopterin will rapidly decrease on BH 4 loading. The BH4 loading must be done while the patient is on a normal diet. An occasional patient with 6PTS deficiency with normal CSF finding but abnormal plasma and urine phenylalanine and pterin values has been described. This milder form of the disease is called the peripheral type. It is important to measure the red blood cell DHPR activity to rule out DHPR deficiency, because a BH4 loading test might miss an occasional patient. Levels of prolactin are elevated in various forms of BH 4 deficiency and might provide a rapid clue to the presence of these diseases.

Management. The patients with BH4 deficiency should be treated with BH4 , which is available from either Milupa, Hillington, Middlesex, UK, or Schirks Laboratories, Jona, Switzerland. The standard therapy is 20 mg/kg/day BH4 given in three to four equal doses. All patients with proven diagnosis should be immediately placed on neurotransmitter precursors, which do not require hydroxylation. These are levodopa, 15 mg/kg/day and i_5-hydroxytryptophan, 4 mg/kg/day, together with 2- to 4-mg/kg/day carbidopa. The best results are obtained when neurotransmitter therapy is combined with BH 4 . Therapeutic results should be followed by plasma phenylalanine, by prolactin, and, when possible, by urine pterins. Additional supplementation of folate is given in DHRP deficiency because it results in reduction of synthesis of tetrahydrofolate.

Prognosis and Prevention. Certainly the majority of the patients with 6PTS deficiency will respond well to the therapy and will grow as normal children. However, prognosis in all BH4 -dependent PKU is guarded, particularly in DHPR deficiency, because many patients have neurological impairment despite vigorous and early therapy. The hyperphenylalaninemia of various forms of BH 4 deficiency can be identified in routine screening tests: however, the diagnosis in a patient with GTP-CH deficiency was missed in the neonatal screening. Prenatal diagnosis has been achieved in DHPR and 6-PTS deficiencies.


Pathogenesis and Pathophysiology. Two important groups of diseases involving methionine metabolism are (1) homocystinuria due to the deficiency of cystathionine beta- synthase (CBS) and (2) homocystinuric syndromes with abnormalities of folate or vitamin B 12 metabolism with or without methylmalonic aciduria.y CBS deficiency, commonly known as homocystinuria, was reported in 1962.y The recognition of homocystinuric syndromes is more recent. y

The primary metabolic consequence of CBS deficiency is intracellular homocysteine accumulation. The cells then excrete the compound to plasma where the elevated levels exist either as free or as oxidized to homocystine, to mixed disulfides with cysteine, or with other sulfhydryl groups in proteins. When homocysteine is elevated in plasma, homocystine is excreted through the urine. Homocysteine is located at the crossroads of important biochemical reactions.

Homocysteine is an end product of biochemical reactions that utilize methylation. Biological methylations are achieved by activated methionine, S-adenosylmethionine. Once the methyl group is transferred, remaining S-adenosylhomocysteine is hydrolyzed into homocysteine and adenosine. Homocysteine must then either be reconverted into methionine or condensed with serine by CBS into cystathionine and excreted. These two paths are catalyzed by several different enzymes. The cystathionine synthesis is catalyzed by CBS, whereas the remethylation through the use of methyltetrahydrofolate is catalyzed by 5-methyltetrahydrofolate-homocysteine S-methyltransferase (methionine synthetase) or through other enzymes from betaine if the latter compound is used as a therapeutic agent. When CBS is deficient, homocysteine is elevated and thus hypermethioninemia and homocystinuria ensue; urine contains no cystathionine. Hypermethioninemia is due to increased methylation of homocysteine in liver by folate-dependent methylating enzymes. Numerous physiological disturbances account for the symptoms of CBS deficiency.

High homocysteine may cause undesirable disulfide cross-linkages, disrupting fibrillin. Among other vasoactive properties, homocysteine impairs the protein C-activating cofactor activity of thrombomodulin, and this feature may be involved in thrombotic events. In addition, both l- homocysteic acid and homocysteine-sulfinic acids derived from homocysteine are present in the urine of CBS-deficient patients. These two compounds are potent agonists

for N-methyl-D-aspartate (NMDA) receptors and might cause neuronal damage as a result of excessive stimulation of NMDA receptors. Two primary groups of patients are identified, based on their response to pyridoxine. In pyridoxine-responsive patients, a small residual activity of CBS is present that is enhanced by large doses of pyridoxine. Although the control activity does not attain control levels, it becomes sufficient to maintain a low level of the homocysteine pool. The CBS gene is mapped (see Table. .31-2 ).

In 1967, it was shown that the biochemical abnormalities in some patients with CBS deficiency could be corrected by administering large doses of pyridoxine. y Large international surveys indicate that approximately half of the patients are pyridoxine responsive. These patients are clinically heterogeneous, with some showing a clear-cut response and others a less dramatic response. Even the most responsive patient will have elevated plasma methionine and homocystinuria when loaded with methionine; therefore they should be kept under continuous treatment.

Because of interactions between folate and vitamin B12 with homocysteine metabolism, homocystinuria occurs in acquired or inherited disorders of folate or vitamin B12 .

Epidemiology and Risk Factors. The cumulative frequency of CBS deficiency for countries with screening programs is 1 in 344,000. In parts of New South Wales in Australia this might be as high as 1 in 65,000 to 75,000. The disease is common in the Middle East, possibly occurring in 1 in 1,000 to 2,000 births. Approximately 75 patients with cblC and 30 with methylenetetrahydrofolate reductase deficiency are known.

Clinical Features and Associated Disorders. The phenotype of few diseases is as impressive as that of CBS deficiency, because numerous organs are involved. The main systems affected are the eye, the vascular system, the CNS, and the skeletal system.

Eye. Dislocation of the lens, ectopia lentis, is a constant feature but occurs usually after 2 years. The rate of lens dislocation is higher among patients who do not respond to pyridoxine. Marked myopia is associated with the loosened or subluxated lens. Cataracts, acute pupillary block glaucoma, and retinal degeneration may be additional complications.

Vascular System. Thromboembolic phenomena are dreaded complications of the disease, accounting for morbidity and mortality (see Fig 31-1 ). They can occur at any age and in any vessel. Thrombosis in CNS causes neurological signs, such as hemiplegia, dystonia, or seizures; in the eye, optic atrophy; and in the kidney, severe hypertension. The risk of thrombosis is less in pyridoxine- responsive patients.

Central Nervous System. Mental retardation and neurological abnormalities are the main features. The developmental delay is usually apparent by the second year of life. Patients with pyridoxine-responsive disease are less affected. The degree of mental retardation varies between severe to normal, and it is not unusual to encounter an occasional pyridoxine-unresponsive child with normal or high IQ. Besides the neurological findings related to thrombotic events in the CNS, approximately 20 percent of the patients will suffer from seizures, mainly generalized convulsions. It is common for these individuals later in life to suffer from episodic depression, behavior disorders, and other personality disorders.

Skeletal Findings. Osteoporosis is a common late complication, and half of the patients will show some evidence of it by 20 years of age. It is more severe and appears earlier in pyridoxine-nonresponsive patients. Biconcave vertebrae are seen. The maturation of the skeleton is abnormal and leads to lengthening of the long bones (dolichostenomelia), which accounts for the marfanoid appearance of patients.

Other Features. Females with CBS deficiency experience frequent fetal loss. The offspring of men with CBS deficiency are normal. The risk factors for early vascular disease among heterozygotes and those individuals with mild homocystinemia have been investigated in detail. Since the pioneering publication by Wilcken and Wilcken,y numerous reports and reviews support that preceding homocystinemia in normal subjects with mild homocystinemia may be responsible for vascular disease. However, most obligate heterozygotes do not have overt clinical atherosclerotic disease, and more studies are needed to conclude the risk factor for carriers.

Differential Diagnosis. Several symptoms of CBS are shared by other disorders. Lens abnormalities are encountered in a number of ophthalmological diseases. Another abnormality of sulfur metabolism, sulfite oxidase deficiency, also causes ectopia lentis. Thromboembolic phenomena and mental retardation are encountered in a large number of clinical conditions and are not detailed. The neurological symptoms of folate or vitamin B 12 metabolic abnormalities are not specific. Their presence is first suspected either by macrocytic anemia or by a positive urine homocystine test.

All children with lens, vascular, and CNS signs of CBS deficiency should be evaluated for homocystinuria. Any child with macrocytic anemia or neurological symptoms associated with a positive urine homocystine test should be evaluated for a possible defect in folate or vitamin B 12 metabolism.

Evaluation. The most consistent laboratory feature is homocystinuria. An easy test is urinary sodium nitroprusside reaction. If positive, homocystine should be identified by other procedures because most sulfur amino acids will yield a positive test. Some patients with pyridoxine-responsive disease will show marked responses to low doses of pyridoxine and the urine in such patients might give false- negative results. In most patients, blood methionine levels will be significantly elevated, which is a clue to CBS deficiency, unless a liver pathological process exists. Whereas in CBS deficiency homocystinuria is accompanied by elevated blood levels of methionine, other diseases associated with homocystinuria have accompanied hypomethioninemia and cystathioninuria. Some of these disorders show other laboratory findings, such as methylmalonicaciduria and megaloblastic anemia.

Management. The medical management of CBS deficiency requires correction of biochemical abnormalities, with the goal of preventing or halting the disease or improving the reversible clinical manifestations. This is best achieved in a newborn before any complication of the disease becomes apparent. Patients who are pyridoxine responsive require the administration of large amounts of pyridoxine. A patient should not be considered unresponsive until a dose of 500 to 1000 mg/day is given for several

weeks. The dose of pyridoxine recommended varies from as little as 25 mg/day to as large as 1200 mg/day. The neuropathy and ataxia resulting from the toxic effect of pyridoxine is not encountered in doses of 500 mg/day for at least as long as 2 years. Although it is not uniformly agreed on, pyridoxine-responsive patients should be given a methionine-restricted, cystine-supplemented diet, since they have reduced tolerance for high doses of methionine. Folate repletion may be necessary for pyridoxine responsiveness and folate, 5 to 10 mg/day, should be provided. The preventive use of anticoagulants such as aspirin is also controversial; and if used they should be given in small quantities, such as 325 mg/day or less to an adolescent.

Patients who are not pyridoxine responsive and who are diagnosed later during childhood should be treated with large doses of betaine, 50 to 100 mg/kg/day. The compound increases the rate of homocysteine methylation by the action of a liver enzyme, betaine homocysteine methyltransferase. It reduces plasma homocystine and increases methionine. In conjunction with diet therapy, it usually improves the clinical condition and retards the progression of disease. The best results are obtained in newborns detected to have the disease by providing a diet restricted in methionine and supplemented with cystine. At least four such formulas are commercially available and, when used together with betaine, ensure normal growth and psychological development. Experience is limited for the outlook of pyridoxine-responsive infants identified neonatally.

Prognosis and Prevention. Untreated patients with CBS deficiency die as a result of thromboembolic phenomena; mortality is much less in pyridoxine-responsive patients. The outcome is excellent in early-diagnosed and treated pyridoxine-responsive children. The mental development is normal, and thromboembolic phenomena are minimal or absent. The best one can hope for in a pyridoxine-unresponsive patient diagnosed late is to arrest the progression of the disease by treatment. By strict adherence to the therapy outlined, it is possible to normalize mental development in neonatally diagnosed pyridoxine- unresponsive patients.

In other syndromes associated with homocystinuria, the prognosis depends on early detection, early treatment, and the degree of the responsiveness of the disease to treatment. The neurological prognosis for the cblG and methylenetetrahydrofolate reductase deficient group is not as good as the others. Approximately 50 million newborns in the world, mainly in Japan and the United States, have been screened for CBS deficiency. The disease may be screened through blood methionine or urine homocystine tests. The drawback of methionine-based screening is that only a few patients with the pyridoxine-responsive variant have so far been identified, whereas these are the patients that will benefit most from early detection. Screening based on homocystine detection in urine has also been disappointing. The efficiency and false-positive and false-negative results of screening tests for CBS deficiency have not yet been settled.


Pathogenesis and Pathophysiology. Glutaricaciduria type 1 (GAT1) was first described in 1975 y and is caused by the deficiency of glutaryl-CoA dehydrogenase (GCDH), which is on the catabolic pathways of L-lysine and l- tryptophan. The presence of glutaric, 3-hydroxyglutaric, and glutaconic acids in urine is pathognomonic for the disease. Excess glutaryl-CoA leads to the formation of glutarylcarnitine, which can be detected both in blood and urine. The concentration of acids in the blood is not high enough to disturb the acid-base balance; and because there is no inhibition of ketone body and lactate utilization, or of urea formation, the disease does not usually cause acidosis or hyperammonemia. Its significant metabolic sequel is solely in the CNS. Chromosome location of GCDH is shownin TabJe,.31:2. .

The mechanism of toxicity of glutaric acid in the CNS, particularly to the striatal system, is not well understood. Neither the degree of GCDH deficiency nor the amount of glutaric aciduria correlates with the severity of the disease. Glutaric acid is toxic toward striatal cells in culture. Glutaric, glutaconic, and 3-hydroxyglutaric acids are competitive inhibitors of glutamate decarboxylase (GAD), the enzyme responsible for gamma-aminobutyric acid (GABA) formation. Whether inhibition of GAD by itself accounts for neuronal death is uncertain. The block in GCDH might shift trytophan metabolism to quinolinic acid which is a potent neurotoxin. y Autopsy of brain in advanced cases shows severe neuronal loss and fibrous gliosis in basal ganglia, with some spongy degeneration of cortical white matter, indicating these as the target areas.

Epidemiology and Risk Factors. The disease is not rare but might be underdiagnosed. Over 100 patients have been described, 20 of whom are from the Middle East. It is estimated to affect 1 in 30,000 persons in Sweden. It is especially common in consanguineous communities, such as in Saudi Arabia, among the Saulteaux/Ojibway Indians in Canada, and in the United States among the Amish community in Pennsylvania.

Clinical Features and Associated Disorders. The infant is normal at birth, and the only detectable symptom might be macrocephaly. A typical history is rapid neurological deterioration and loss of developmental milestones after an infectious episode, which is usually mistaken for meningitis or encephalitis because a slight increased CSF protein level is usual. Seizures, dystonia (see Fig, 31.-3 ), and choreoathetosis appear soon after and worsen, leading to a diagnosis of choreoathetoid cerebral palsy or postencephalitic cerebral palsy. Repeated viral infections each cause further deterioration, and the patient will eventually be severely crippled. Almost all patients show absolute or relative macrocephaly. In some patients, the clinical picture will be mild and no further deterioration will occur, particularly if no intercurrent viral infection takes place. An occasional infant identified through screening will show no or minimal neurological signs and will have macrocephaly and neuroradiological findings of GAT1, suggesting prenatal onset of the disease.

Evaluation. All infants with acute or chronic extrapyramidal signs should be investigated for GAT1. Results of routine blood cell counts, blood chemistries, and amino acid determinations are normal even in the most advanced patient; and unless the neurologist suspects and orders special tests, the disease remains undiagnosed. The characteristic biochemical findings are the presence of glutaric,

3-hydroxyglutaric, and glutaconic acids in the urine and of glutarylcarnitine in blood and urine. Use of tandem mass spectrometry to detect glutarylcarnitine in blood and urine has proved to be an unfailingly rewarding means of diagnosis.

The neuroradiological studies reveal a widened sylvian fissure or the "open opercular" sign (see Fig, 31-3 ), dense basal ganglia, total atrophy of the caudate heads in advanced disease, and evidence of mild white matter disease in the centrum ovale. y These occur before the emergence of neurological deterioration. Findings on MRI or CT of the brain are characteristic of GAT1, and an experienced neuroradiologist will report the presence of the disease before the results of biochemical tests become available.

Differential Diagnosis. Among infants and young children with striatal necrosis, some have other definable causes, such as 3-methylglutaconicaciduria, propionicacidemia, or oxidative phosphorylation disease. Their clinical and laboratory presentations are different, and macrocephaly and the wide opercular signs are absent. Other causes of macrocephaly in infancy include Canavan's disease, Alexander's disease, and l-2 hydroxyglutaricaciduria. These conditions are progressive pyramidal tract diseases and should not be confused with GAT1.

Management. Treatment may be rewarding if initiated before the clinical manifestations of the disease. The treatment of choice is reducing lysine and tryptophan intake. Such formulas are available. The medications used are l- carnitine orally, 100 to 200 mg/kg/day; riboflavin, 50 mg/ kg/day; and baclofen, 5 to 10 mg three times daily. The exact mechanism of action of baclofen is not known, but it has been effective in some instances. In one patient, vigabatrin caused significant clinical improvement. All intercurrent infections, particularly those with viral etiology, demand immediate intervention by administering L-carnitine intravenously (50 to 100 mg/kg repeated every 6 hours) and providing adequate calories through glucose and insulin drip. These treatments will be of little value in patients who have already suffered significant damage to striatum.

Prognosis and Prevention. Prognosis is poor for patients who have been diagnosed late, although the treatment might slow the progression of the disease. Limited information is available for patients diagnosed early. Prenatal diagnosis of the disease is made through study of organic acids in amniotic fluid or by measuring GCDH in cultured amniotic cells. Tandem mass spectrometry-based neonatal screening identifies GAT1.


Biotinidase deficiency was first recognized in 1983, among patients with late-onset multiple carboxylase deficiency. y The worldwide frequency among 8 million newborns is 1 in 112,000. y Biotin is the cofactor for such carboxylases as propionyl-CoA, 3-methylcrotonyl-CoA, acetyl-CoA, and pyruvate carboxylase. The most important source of biotin is through biotinidase; hence, when biotinidase is absent, a state of biotin deficiency gradually emerges. Biotinidase activity in brain is very low,y and the brain totally depends on the transfer of biotin across the blood-brain barrier. When biotin is deficient, pyruvate carboxylase in the CNS might decrease, leading to localized lactic acidosis. Biotinidase-deficient patients suffer from central deafness before treatment, and hearing usually does not improve after treatment.

The reason for selective targeting of the auditory center is unknown. Alopecia (see Fig, 31 -3 ) and dermatitis in these patients are possible owing to depletion of fatty acids as a result of deficient acetyl-CoA carboxylase activity. Approximately 55 percent of patients develop clonic or myoclonic seizures, hypotonia, and developmental delay between 3 and 6 months of age. Hearing abnormality coincides with the emergence of seizures. Dermatitis, visual problems, and ataxia are the final events. The changes in acylcarnitines and organic acids appear only during acute decompensation, and the disease cannot be identified through these compounds. Individuals with partial deficiency might be at risk only for cutaneous symptoms. Immunological dysfunction manifests as candidal dermatitis as described for propionicacidemia and methylmalonicacidemia.

Colorimetric and fluorometric procedures are available for measurement in serum. Prenatal diagnosis has not yet been reported. During acute decompensation the blood acylcarnitine and urine organic acid profiles are the same as seen in holocarboxylase synthetase (HCS) deficiency.

Biotin-responsive mild forms of HCS deficiency and milder forms of propionicacidemia must be ruled out by clinical and laboratory observations. Alopecia and rash can be encountered in deficiency of zinc or essential fatty acids. Biotinidase deficiency might be confused with severe combined immune deficiency.

Deafness persists even in a well-treated patient, but alopecia and other symptoms disappear with treatment. As little as 5 to 30 mg of biotin will be curative.


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