Maple Syrup Urine Disease

40.1 Clinical Features

and Laboratory Investigations Maple syrup urine disease (MSUD) is a hetero- geneous disorder. Classification is based on clinical presentation and outcome. Five phenotypes can be distinguished: classical, intermediate, intermittent, thiamine-responsive, and dihydrolipoyl dehydroge- nase (E

)-deficient forms of MSUD. All forms have an autosomal recessive mode of inheritance.

Classical MSUD is the most severe and the most common form of the disease. Infants appear normal at birth. By the end of the first week symptoms emerge, with lethargy, poor feeding (but rarely vom- iting), alternating periods of hypertonia and hypoto- nia, opisthotonus, convulsions, bulging fontanel, irregular respiration, and apnea. An odor of maple syrup is frequently noted, but may not initially be pre- sent. If the disease is not treated, rapidly progressive neurological deterioration occurs, with cerebral ede- ma, coma, and death usually within the first month of life. If an untreated patient survives the first few weeks of life, signs of severe brain damage remain, with profound psychomotor retardation, spasticity, generalized dystonia, and cerebral blindness. Early diagnosis and treatment may avert or reverse the neurological abnormalities, but mental and neurolog- ical residua are common in treated patients. It has been shown that the length of time after birth for which the metabolic derangement is not adequately treated, and the quality of long-term metabolic con- trol both have important influences on eventual intel- lectual capacities. If the disease is identified and treat- ed within a few days after birth, IQ scores are higher and may be normal. A problem is that throughout life intercurrent illnesses, even minor illnesses, may lead to severe metabolic derangement, cerebral edema, and possibly death.

The intermediate variant of MSUD is milder and patients do not have catastrophic illness in the neona- tal period. Many patients do not have episodes of acute metabolic decompensation. Progressive mental retardation is the major clinical feature, usually be- coming apparent during the first year of life. General- ized hypotonia and an odor of maple syrup are pre- sent.

Patients with the intermittent form of MSUD show normal early development. They are at risk for acute metabolic decompensation during stressful situa-

tions. Clinical signs may be first seen between the ages of 2 months and 40 years, triggered by infection, vaccination, operation, or sudden increase in dietary protein. The episodic deterioration is characterized by maple syrup odor, cerebellar ataxia, irritability, and progressive lethargy. With supportive care the patient recovers, but will experience repeated similar episodes until the correct diagnosis is established and specific dietary treatment started.

Thiamine-responsive MSUD is not a well-defined subtype of MSUD. In the reported patients, the clini- cal course tends to be relatively mild, even if untreat- ed, although thiamine responders may also have the classical, severe form of the disease. In general, these patients do not have acute neonatal illness and their early clinical course is similar to that of intermediate MSUD. The course of the disease is greatly ameliorat- ed by simultaneous thiamine administration and dietary treatment. Outcome is favorable.

E

-deficient patients have a relatively uneventful first few months of life. Patients develop persistent lactic acidosis between 2 and 6 months of life and a progressive neurological deterioration sets in with hypotonia, developmental delay, and extrapyramidal movement abnormalities.

Laboratory investigations reveal ketoacidosis in episodes of metabolic decompensation. Concentra- tions of branched-chain amino acids (leucine, valine, and isoleucine) and related keto acids (a-ketoiso- caproic acid, a-ketoisovaleric acid, and a-keto-b- methylvaleric acid) are elevated in blood, urine, and CSF. Smaller amounts of the respective 2-hydroxy acids are formed by reduction of the keto acids. An unusual isomer of isoleucine, alloisoleucine, is also found. Diagnosis is confirmed by demonstration of a deficiency of branched-chain keto acid dehydroge- nase in leukocytes or cultured fibroblasts. DNA con- firmation is an option.

In the early stages of untreated classical MSUD, EEG shows characteristic abnormalities, variously called a “comb-like” or “picket fence” rhythm or “cen- tral theta spindle.” The pattern consists of bursts and runs of 5–7 Hz, primarily monophasic, negative, mu-like activity in the central and central–parasagit- tal regions during wakefulness and sleep with the most abundant bursts occurring during quiet, non- REM sleep. The background pattern shows diffuse slowing, loss of reactivity to auditory stimuli, burst- suppression patterns, and spike and sharp wave pat-

Maple Syrup Urine Disease

terns. The abnormalities disappear on treatment. Mo- tor and sensory peripheral nerve conduction velocity is normal.

Prenatal diagnosis can be performed by assessing branched-chain keto acid dehydrogenase in cultured amniocytes or chorionic villus cells. In families with known mutations, DNA analysis can replace the enzyme assay.

40.2 Pathology

In young infants who die in the acute stage of the dis- ease, the brain is enlarged due to generalized edema.

Brain weight is increased. Gyri may be broadened and flattened. Microscopic examination reveals a status spongiosus of myelinated areas. Unmyelinated re- gions are not affected. Thus, in neonates the areas involved are the spinal cord, medulla oblongata, dorsal part of pons, midbrain, cerebellar white mat- ter, cerebellar peduncles, posterior limb of the inter- nal capsule, and central part of the corona radiata.

Sponginess may also be present in the basal ganglia, in particular in the globus pallidus due to its density of myelinated fibers. The sponginess is caused by myelin splitting at the intraperiod line and in- tramyelinic vacuole formation. No signs of active myelin breakdown are seen and no sudanophilic breakdown products. In the spongy white matter marked astrocytic gliosis is present.

In older, untreated infants neuropathological find- ings may also be characterized by edema if the patient died during an acute metabolic decompensation.

Further findings consist of a delay in myelination and a status spongiosus and astrogliosis of the myelinated white matter. Myelin stains reveal myelin paucity, but there is no evidence of active myelin breakdown.

Oligodendrocytes are decreased in numbers. There are no phagocytic cells and no or little deposition of sudanophilic breakdown products. The myelin ab- normalities occur in all regions; no areas are spared.

Gray matter is essentially normal. In treated infants and children myelination is normal and white matter sponginess is minimal.

The neuropathology in E

deficiency resembles that of Leigh syndrome with lesions in the basal gan- glia, thalami, and brain stem.

40.3 Chemical Pathology

In neonates the lipid composition of the brain is nor- mal or near-normal. In older, untreated infants the findings of chemical analysis of the brain are in con- formity with delayed myelination without active myelin breakdown. Major myelin components, in- cluding sulfatide, cerebroside, and proteolipid pro-

tein, are significantly reduced. Cholesterol esters are not elevated. Free amino acids in the brain are not altered with the exception of the branched-chain amino acids, which are markedly increased. Gluta- mine, glutamate, and GABA are significantly reduced.

In older, treated patients, the lipid composition of the brain is normal.

40.4 Pathogenetic Considerations

MSUD is caused by a deficiency in activity of the branched-chain a-keto acid dehydrogenase complex.

This is a mitochondrial multienzyme complex cat- alyzing the oxidative decarboxylation of branched- chain a-keto acids, which are derived branched-chain amino acids such as valine, leucine, and isoleucine by transamination. The multienzyme complex consists of three catalytic components: branched-chain a-ke- to acid decarboxylase (E

), dihydrolipoyl acyltrans- ferase (E

), and dihydrolipoyl dehydrogenase (E

).

E

is a heterotetramer composed of two a and two b subunits. The complex also contains two specific reg- ulatory enzymes, a kinase and a phosphatase, com- pounds that are responsible for regulating the catalyt- ic activity through phosphorylation and dephospho- rylation. E

is phosphorylated at two serine residues and hence responsible for regulation of the catalytic activity of the complex. Phosphorylation inactivates the complex and dephosphorylation activates it.

E

binds thiamine diphosphate to create the active site for decarboxylation of the branched-chain a-keto acid substrate. E

catalyzes transfer of the acyl group from the lipoyl moiety to coenzyme A to give rise to a branched-chain acyl-CoA. It forms the structural core of the enzyme complex to which E

, E

, kinase and phosphatase are bound. E

is identical to the dehydrogenases associated with pyruvate de- hydrogenase and a-ketoglutarate dehydrogenase complexes.

Mutation in any of the four genes encoding E

, E

, and E

may result in MSUD through dysfunction of the branched-chain a-keto acid dehydrogenase com- plex. The gene encoding E

, BCKDHA, is located on chromosome 19 at position q13.1–13.2. The gene en- coding E

, BCKDHB, is located on chromosome 6 at position p21–22. The gene encoding E

, DBT, is locat- ed on chromosome 1 at position p21–31. The gene encoding E

, DLD, is located on chromosome 7 at position q31–32. Patients with a deficiency of E

activity have combined deficiency of branched-chain

a-keto acid dehydrogenase, pyruvate dehydrogenase,

and a-ketoglutarate dehydrogenase complexes. So

far, no clear relationship between genotype and phe-

notype has emerged. There is some relationship

between clinical phenotype and residual enzyme

activity.

Mechanisms for toxic effects of increased branched-chain amino acids and keto acids remain largely unelucidated. The toxic effects may be related to disturbance of neurotransmission, energy deple- tion, and direct myelin damage. Branched-chain keto acids and their hydroxy derivatives compete with glutamate for decarboxylation and so reduce GABA production. Excess leucine may reduce cerebral sero- tonin. a-Ketoisocaproic acid inhibits pyruvate dehy- drogenase and a-ketoglutarate dehydrogenase, two important enzymes in mitochondrial energy pro- duction. The mechanism of myelin vacuolation and myelin damage is unknown. Hexachlorophene and triethyltin are toxins which also lead to myelin vacuo- lation. These substances are inhibitors of mitochon- drial oxidative phosphorylation. From experimental studies it is known that lasting effects only follow chronic exposure and that early discontinuation of exposure is followed by repair. This course of events is similar to that observed in MSUD: early treatment leads to resolution of abnormalities. Only in untreat- ed cases are lasting effects seen. The precise patho- physiological mechanisms of myelin splitting are unknown, either in exogenous intoxications or in MSUD. Evidence has been found that MSUD metabo- lites, in particular a-isocaproic acid, induce apoptosis in glial and neuronal cells, but the relationship with the in vivo pathology of MSUD is unclear.

40.5 Therapy

In cases of acute metabolic decompensation with very high blood and tissue levels of branched-chain amino acids and keto acids, emergency treatment is neces- sary. Exchange transfusions, peritoneal dialysis, he- modialysis, and hemofiltration are effective in acute- ly ill patients. These therapeutic measures must be supplemented by high-energy intake to reverse the catabolic condition caused by infection or fasting. For this purpose intravenous glucose, intravenous lipids, or a special formula containing a mixture of complete nutrients lacking only branched-chain amino acids can be used. Concomitant administration of insulin is very effective in achieving an anabolic situation. In acutely ill but not comatose patients, nutritional ther- apy may be sufficient. During the course of therapy, isoleucine and valine should be added to the regimen to prevent depletion of these essential amino acids and thus ensure effective protein synthesis.

Minor illnesses may lead to catabolic conditions with release of amino acids from body tissues. Toxic levels of branched-chain amino acids may be reached within a few hours with onset of as yet mild clinical symptoms. Immediate high-energy intake and tem- porary removal of all natural protein from the diet in such situations may prevent a full-blown metabolic

decompensation. Catabolic conditions after surgery can be prevented by administration of insulin and a branched-chain amino-acid-free parenteral nutrition regimen.

All patients with classical MSUD require life-long dietary treatment. The long-term treatment aims at maintaining the whole-body content of branched- chain amino acids close to the minimum requirement for normal body function. The amount of branched- chain amino acids necessary for adequate protein synthesis is given in the form of natural proteins in a protein-restricted diet. A branched-chain amino- acid-free mixture of amino acids is used to supple- ment the diet. The levels of branched-chain amino acids in blood are measured regularly to monitor treatment. Deficiency of branch-chain amino acids leads to growth failure, skin rash, exfoliative dermati- tis, diarrhea, and de-epithelialization of the cornea.

Patients with milder forms of MSUD tolerate a high- er protein intake. In thiamine-responsive MSUD, use of thiamine increases protein tolerance. However, a protein-restricted diet should still be used and the plasma levels of branched-chain amino acids moni- tored. In order to test for thiamin-responsiveness, all patients should receive trial therapy with thiamin.

If onset of dietary treatment leads to lowering of blood levels of branched-chain amino acids within a few days after birth, and if adequate dietary control is maintained over the years, prognosis is excellent and intellectual capacities may be normal. Later onset of treatment or poor dietary control contribute to men- tal deficiency. With adequate dietary treatment and careful monitoring, female patients with MSUD may enjoy successful pregnancies.

Liver transplantation has been shown to increase whole-body branched-chain a-keto acid dehydroge- nase activity to at least the level of very mild MSUD variants (Wendel et al. 1999). After liver transplanta- tion, patients no longer need protein-restricted diets and the risk of metabolic decompensation during catabolic events is apparently abolished. However, liv- er transplantation comes with considerable risks and the benefits may not be significantly different from those of strict dietary treatment.

40.6 Magnetic Resonance Imaging

In MSUD with neonatal presentation, CT shows a very characteristic pattern with profound hypodensity and swelling of the cerebellar hemispheres, dorsal part of the pons, midbrain, posterior limb of the internal capsule, the globus pallidus, and often the thalamus. In addition, milder, generalized cerebral white matter hypodensity is seen.

MRI confirms the pattern. In MSUD with neonatal

presentation, T

-weighted images show marked

Fig. 40.1.

swelling and high signal intensity in the posterior part of the pons, in the midbrain, cerebellar white matter, posterior limb of the internal capsule, thala- mus, globus pallidus, and central part of the corona radiata (Fig. 40.1). Besides, mild diffuse cerebral white matter edema may be present. Without treat- ment, the edema gradually decreases and atrophy en- sues. Edema is most pronounced between the third week and the end of the second month. With treat- ment edema resolves more rapidly.

Remaining abnormalities in treated patients are variable, depending on the severity and duration of the initial episode of metabolic derangement and the subsequent metabolic control (Figs. 40.2–40.4). In some patients MRI becomes normal. In others some signs of atrophy, delay in myelination, and white matter abnormalities are found. Many patients have remaining signal abnormalities in the midbrain, thalamus, and globus pallidus.

If MRI is performed during a later episode of metabolic decompensation in otherwise adequately treated and normally developing children with classi- cal MSUD, it shows brain swelling and abnormally increased signal intensity on T

-weighted images in the deep white matter and U fibers, internal capsule, basal ganglia, thalamus, hypothalamus, dentate nu- cleus, and brain stem. In deep coma, all white matter may be abnormal in signal and seriously swollen. If adequate treatment is initiated immediately, most or all abnormalities disappear.

Milder variants of MSUD usually come to medical attention in the second year of life because of retard-

ed development or signs of metabolic decompensa- tion. MRI at that time (Figs. 40.5 and 40.6) shows more diffuse abnormality of the white matter of the cerebral hemispheres. The cerebral white matter may have a striking stripe-like appearance, the stripes be- ing partly related to enlarged perivascular spaces and partly to myelination in stripes, probably reflecting perivascular myelin deposition (Figs. 40.5 and 40.6).

The brain stem is also involved. Both the thalamus and globus pallidus are affected, whereas the puta- men and caudate nucleus are normal. The cortex is normal. Improvement after treatment has been re- ported. In adequately treated patients with milder variants of MSUD, CT and MRI may be normal.

Diffusion-weighted imaging shows restricted dif- fusion in the areas of acute myelin vacuolation with low ADC values (Fig. 40.1). In neonates, this results in a pattern of very high signal intensity in the medulla, dorsal part of the pons, the midbrain, cerebellar white matter, posterior limb of the internal capsule, thala- mus, globus pallidus, and central part of the corona radiata. The restricted diffusion is probably related to decrease of the extracellular space because of the vacuoles within the myelin sheaths. Diffusion tensor imaging reveals decreased anisotropy in the same regions. In the unmyelinated white matter ADC val- ues are increased, reflecting white matter edema.

Proton MRS is helpful in establishing a diagnosis in acute metabolic decompensation by revealing res- onances related to branched chain amino acids and keto acids at 0.9 ppm. Lactate may also be elevated.

These peaks disappear with treatment.

Fig. 40.1. (continued). Baby boy with MSUD. The T

-weighted images (first three rows) show an elevated signal intensity and swelling of the cerebellar white matter, the medulla, dorsal part of the pons, pyramidal tracts in the basis of the pons, mid- brain, the posterior limb of the internal capsule, and central part of the corona radiata. The thalamus, too, has a slightly ab- normal signal. The diffusion-weighted images (trace images, b = 1000, fourth and fifth rows) show restricted diffusion in the

cerebellar white matter, the medulla, dorsal part of the pons,

pyramidal tracts in the basis of the pons, midbrain, posterior

limb of the internal capsule, and central part of the corona

radiata.The thalamus,anterior limb of the internal capsule,cor-

pus callosum, and hippocampus display less severely restrict-

ed diffusion. Courtesy of Dr. Z. Patay, Department of Radiology,

and Dr. P.T. Ozand, Department of Pediatrics, King Faisal Spe-

cialist Hospital and Research Center, Riyadh, Saudi Arabia

The images of patients with classical MSUD during the neonatal period are diagnostic. All areas which are normally myelinated at that age have an abnormal signal intensity and are swollen. This pattern is exclu- sively seen in vacuolating myelinopathies of neonatal

onset. The images of patients with milder variants of MSUD during the second year of life are very similar to those of Canavan disease. However, clinical history and laboratory findings differentiate between the two.

Fig. 40.2. A 4-month-old girl with neonatal-onset MSUD. She was diagnosed at 3 weeks and has been receiving treatment since that time. Diffuse signal abnormalities are still seen in the cerebral and cerebellar white matter, and brain stem at all lev- els. There is, however, much less swelling than in the neonatal stage.The thalamus and globus pallidus are abnormal, where-

as the putamen and caudate nucleus are spared.These abnor- malities are very similar to those seen in Canavan disease.

Courtesy of Dr. Z. Patay, Department of Radiology, and Dr. P.T.

Ozand, Department of Pediatrics, King Faisal Specialist Hospi-

tal and Research Center, Riyadh, Saudi Arabia

Fig. 40.3. The same girl as in Fig. 40.2, now at the age of 2 years. Under treatment most abnormalities disappeared.

Myelination is mildly delayed. There are slight signal abnor- malities in the globus pallidus. Courtesy of Dr. Z. Patay, Depart-

ment of Radiology, and Dr. P.T. Ozand, Department of Pedi-

atrics, King Faisal Specialist Hospital and Research Center,

Riyadh, Saudi Arabia

Fig. 40.4. Boy with neonatal presentation of MSUD. He has re- sponded well to treatment and is now 6 years old. The MRI shows signal abnormalities in the periventricular white matter, globus pallidus, midbrain (especially the dorsal part), the dor-

sal pons, and the dentate nucleus. Courtesy of Dr. Z. Patay,

Department of Radiology, King Faisal Specialist Hospital and

Research Center, Riyadh, Saudi Arabia

Fig. 40.5. An 18-month-old boy with intermittent MSUD. He experienced metabolic coma at 12 and 18 months. MRI shows extensive cerebral white matter abnormalities, in some areas with a stripe-like aspect.The thalamus and globus pallidus are abnormal, while the putamen and caudate nucleus are spared.

The posterior limb of the internal capsule is spared.In addition,

there are signal abnormalities in the midbrain, pons, medulla, and dentate nucleus. He responded well to treatment and had a full clinical recovery. Courtesy of Dr. Z. Patay, Department of Radiology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

Fig. 40.6. A 4-year-old boy recently diagnosed with MSUD.

The T

-weighted images (first and second rows) show extensive cerebral white matter abnormalities, which have a stripe-like aspect. The stripes are partly related to enlarged perivascular spaces and partly to myelin deposition in a stripe-like pattern, probably perivascular myelin deposition. The thalamus and globus pallidus are abnormal, while the putamen and caudate nucleus are spared.The posterior limb of the internal capsule is spared. There are signal abnormalities in the midbrain, pons, medulla, dentate nucleus, and cerebellar white matter. The

T

-weighted images (third row) demonstrate mild diffuse hyper- intensity of the white matter, consistent with diffuse hypomyeli- nation. Within the white matter the enlarged perivascular spaces are beautifully seen. The sagittal (fourth row, left and middle) and coronal (fourth row, right) images confirm the pres- ence of the enlarged perivascular spaces and the stripe-like pattern of myelin deposition. Courtesy of Dr. I. Verma, Depart- ment of Genetic Medicine, Sir Ganga Ram Hospital, New Delhi, India. (Fig. 40.6 see next page)

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Fig. 40.6.