Canavan Spongiform Leukodystrophy: Aspartoacylase Deficiency

Kvittingen et al. first described patients with cerebral atrophy and leukodystrophy with N-acetylaspartic aciduria. It was the merit of Matalon et al and divry et al. to link this disorder with Canavan disease.

Clinical Presentation Canavan Spongiform Leukodystrophy: Aspartoacylase Deficiency

The diagnosis of Canavan disease can be suggested by clinical features including leukodystrophy, megaloencephaly, mental retardation, and optic atrophy. Death usually occurs in the first decade of life. Computed Tomography (CT) scan or magnetic resonance imaging (MRI) show white matter attenuation. Brain histopathology shows spongy degeneration of the myelin, astrocytic swelling, and elongated mitochondria; neurons are normal. Three clinical variants of the disease have been described:

• A congenital form in which the disease is apparent from birth

• An infantile form, which is the most common and which becomes manifest after the first 6 months of life (this form is frequently seen among Jewish patients)

• A juvenile form in which symptoms appear after the first 5 years of life.

Metabolic Derangement Canavan Spongiform Leukodystrophy: Aspartoacylase Deficiency

The key feature is accumulation of N-acetylaspartic acid in the body fluids, levels in the CSF being much higher than in the serum. The enzymatic defect can be confirmed by assay of aspartoacylase in fibroblasts. Aspartoacylase is also deficient in Brain, liver, and kidney.

N-acetylaspartic acid is abundant in Brain, where its concentration is second only to glutamic acid in the free amino acid pool and is higher than that of GABA Brain is the only organ where biosynthesis of N-acetylaspartic acid has been demonstrated. Its normal function is not well understood. It has been reffered to as an essential component in a series of reactions required for the conversion of lignoceric acid to cerebronic acid, a component of myelin, and the formation of glutamic acid and has been assigned a possible role in neurotransmission and in the production of N-acetylaspartylglutamate. It may also serve as a chemical compartment so that aspartate is released only by the action of aspartoacylase and the released aspartate may be channeled to form arginine.

Diagnostic Tests Canavan Spongiform Leukodystrophy: Aspartoacylase Deficiency

The diagnosis is based on gas chromatography mass spectrometry (GCMS) of urine or other body fluids showing increased N-acetylaspartic acid levels and is confirmed by aspartoacylase assay on cultured fibroblasts and/or by restriction fragment length polymorphism (RFLP) or mutation analysis of DNA. For prenatal diagnosis the measurement of aspartoacylase in fresh chorionic villi samples or the quantitation of N-acetylaspartic acid in amniotic fluid supernatant are the methods of choice. Obviously, molecular diagnosis using RFLP or mutation analysis within given families will provide prenatal diagnostic facilities and carrier detection in at risk populations in the near future.

Treatment and Prognosis Canavan Spongiform Leukodystrophy: Aspartoacylase Deficiency

It has been proposed that N-acetylaspartic acid serves as a transporter of acetyl groups from mitochondria to the cytosol for lipogenesis. Therefore, in an attempt to supply alternative substrate for lipogenesis in the brain, a ketogenic diet was given to one patient for 5 months. No improvement was seen. No other treatment is available. Progressive deterioration leads to a decorticate condition and death within a few years.

Genetics Canavan Spongiform Leukodystrophy:Aspartoacylase Deficiency

Genetic transmission is autosomal recessive. The human aspartoacylase gene is localized on chromosome 17 p13-ter. A full-length human cDNA for aspartoacylase has been isolated and a predominant point mutation 856 A>C was identified in Jewish patients.

Monoamine Oxidase-A (MAO-A) Deficiency

MAO-A has been identified very recently in five generations of a large Dutch kindred.

Clinical Presentation Monoamine Oxidase-A Deficiency

Only males were affected. They showed borderline mental retardation (IQ scores around 85) with prominent behavioral disturbances including aggressive and sometimes violent behavior, arson, attempted rape, and exhibitionism. Aggressive behavior was usually triggered by anger and tended to cluster in periods of 1-3 days. During this time the affected male would experience frequent night terror. Several affected males were reported to suddenly grasp or hold female relatives. All patients displayed a tendency toward stereotyped hand movements such as hand wringing, plucking, or fiddling. Growth and morphology were normal. All of the females functioned normally.

Metabolic Derangement Monoamine Oxidase-A Deficiency

Marked elevations were noted in the MAO substrates such as serotonin, normetanephrine, 3-methoxytyramine, and tyramine in the urine. Levels of the MAO products vanillylmandelic acid, homovanilic, 5-hydroxyindoleacetic acid, and 3-methoxy-4-hydroxyphenylglycol, however, were reduced. As platelet MAO-B activity was found to be normal, these results are consistent with a deficiency of MAO-A, the isozyme found in neural tissue.

Disorders of Neurotransmitters Diseases

Diagnostic Tests Monoamine Oxidase-A Deficiency

The discovery of this disorder suggests that it might be worthwhile to perform systematic urinary monoamine analysis in unexplained significant behavior disturbances, particularly when occurring in several male family members.

Treatment and Prognosis Monoamine Oxidase-A Deficiency

No efficient treatment is known at the present time. Both the borderline mental retardation and the behavior abnormalities seem to have a stable evolution. No patient has been institutionalized because of mental retardation.

Genetics Monoamine Oxidase-A Deficiency

The locus for this disease has been assigned to the Xp11-21 region. A point mutation was identified in the eight exon of the MAO-A structural gene which changes a glutamine to a termination codon.

Aromatic L-Amino Acid Decarboxylase Deficiency

Aromatic L-amino acid decarboxylase deficiency was reported in 1990 in one family (male twins).

Disorders of Neurotransmitters Diseases

Clinical Presentation Aromatic L-Amino Acid Decarboxylase Deficiency

Generalized hypotonia, developmental delay, and paroxysmal movements with oculogyric crises were noted at 2 months of age. At 9 months there was also a fine chorea of the distal limbs and temperature instability with excessive sweating. The electroencephalogram (EEG) was normal, but brain imaging showed cerebral atrophy.

Disorders of Neurotransmitters Diseases

Metabolic Derangement Aromatic L-Amino Acid Decarboxylase Deficiency

Deficiency of aromatic L-amino acid decarboxylase leads to accumulation of L-dopa, its metabolite 3-methoxytyrosine, and of 5-hydroxytryptophan in CSF, plasma, and urine, as L-amino acid decarboxylase has both L-dopa decarboxylase and 5- hydroxytryptophan decarboxylase activities. In urine, there is also a gross elevation of vanillactic acid, a metabolite of 3-methoxytyrosine.

On the other hand, blood concentrations of serotonin and catecholamines, and CSF concentrations of their metabolites 5-hydroxyindoleacetic acid and homovanillic acid, are decreased. Very low activity of L-dopa decarboxylase in plasma and
of 5-hydroxytryptophan decarboxylase in
a liver biopsy sample confirmed the diagnosis. The parents of the affected index patient had plasma aromatic L-amino acid decarboxylase activity of 16% and 19% of control values, respectively, and yet they had a totally normal phenotype.

Disorders of Neurotransmitters Diseases

Diagnostic Tests Aromatic L-Amino Acid Decarboxylase Deficiency

The diagnosis can be made by finding the characteristic profile in CSF or very high levels of 3-methoxytyrosine and very low levels of 5-hydroxyindoleacetic acid and homovanillic acid. This suggests a systematic investigation of monoamine metabolism in unexplained neurological disease. Very low activity of aromatic L-amino acid decarboxylase in plasma and/or liver tissue confirms the diagnosis. The feasibility of prenatal diagnosis is not yet known.

Disorders of Neurotransmitters Diseases

Treatment and Prognosis Aromatic L-Amino Acid Decarboxylase Deficiency

The index patients were treated with pyridoxine (cofactor of the defective enzyme), bromocriptine (dopamine agonist), and tranylcypromine (monoamine oxidase inhibitor). Pyridoxine (50 mg b.d) caused a drop in CSF 3-methoxytyrosine and L-dopa and an increase in homovanillic acid. However, there was no clinical effect. Bromocripine alone stopped the oculogyric crises, while tranylcypromine improved muscle tone, increased spontaneous movements, and reduced sweating. Growth, which had stopped, resumed during treatment. Anti convulsants were ineffective.

Disorders of Neurotransmitters Diseases

Genetics Aromatic L-Amino Acid Decarboxylase Deficiency

Inheritance is most probably autosomal recessive.

Disorders of Neurotransmitters Diseases

Dopa-Responsive Dystonia

The following disorders are discussed: dopa-responsive dystonia, aromatic L-amino acid decarboxylase deficiency, and monoamine oxidase A deficiency (MAO-A). Dopamine β-hydroxylase deficiency is not dealt with because it has only been diagnosed in adults (orthostatic hypotension), and defects of tetrahydrobiopterin are discussed in the chapter by Smith and Brenton. Dopa-responsive dystonia was first reported in 1976. At least 130 patients are presently known. Nygaard at al, have reported 66 personally examined patients.

Disorders of Neurotransmitters Diseases

Clinical Presentation Dopa-Responsive Dystonia

Age at onset of the dystonia is mostly between 1 and 10 years. There is a great variability in the severity of the disorder. The dystonia starts in the lower extremities, mostly with gait difficulties, and often remains limited to the extremities (e.g., writer’s cramp) with no or minimal axial dystonia. About 25% of affected children have clinical signs suggestive of spastic diplegia. In most patients there is a marked diurnal fluctuation of symptoms characterized by worsening of symptoms and increasing fatigue throughout the day and marked benefit of sleep. Symptoms noted in

a minority of patients are scoliosis, opisthotonus, dysarthria, dysphagia, postural tremor, and/or

intermittent abnormal eye movements. The disorder may be expressed as pure ‘parkinsonism’ in some adults without any dystonia in childhood.

Disorders of Neurotransmitters Diseases

Metabolic Derangement Dopa-Responsive Dystonia

The precise biochemical defect is still unknown. Most evidence points to a defect in striatal dopamine production. CSF levels of homovanillic acid, a dopamine metabolite, tend to be reduced. Levels of neopterin and its metabolite biopterin (a cofactor for tyrosine hydroxylase, the rate-limiting enzyme in dopamine production) are reduced.

Disorders of Neurotransmitters Diseases

Diagnostic Tests Dopa-Responsive Dystonia

The only diagnostic test is the dramatic responsiveness to levodopa which distinguishes dopa-responsive dystonia from other causes of childhood-onset dystonia-parkinsonism.

Disorders of Neurotransmitters Diseases

Treatment and Prognosis Dopa-Responsive Dystonia

Low doses of L-dopa (5-30 mg/kg per day), associated with a decarboxylase inhibitor such as in prolopa or sinemet, cause a marked improvement with complete or almost complete remission of symptoms usually within days or weeks. Progressive improvement continues to occur for months in some cases without increase in dosage. On withdrawal of L-dopa, there is immediate recurrence of symptoms. The effect of levodopa is sustained and free from the complications which occur in Parkinson disease, such as wearing off and unpredictable dose response.

Disorders of Neurotransmitters Diseases

Genetics Dopa-Responsive Dystonia

Available data strongly suggest autosomal dominant inheritance with sex-related reduced penetrance. Girls are more frequently and severely affected than boys. Moreover, it seems that the age of onset is earlier in girls. The disorder occurs worldwide. Recently, the gene for dopa-responsive dystonia has been mapped to chromosome 14q by linkage analysis.

Disorders of Neurotransmitters Diseases

Succinic Semialdehyde Dehydrogenase (SSDH) Deficiency

SSADH deficiency was first reported as ᵞ-hydroxybutyric aciduria in 1981. It has been documented in at least 32 patients.

Clinical Presentataion Succinic Semialdehyde Dehydrogenase Deficiency 

The clinical presentation varies from mild to severe and comprises psychomotor retardation, delayed speech development, hypotonia, ataxia and less frequently, hyporeflexia, convulsions, aggressive behavior, hyperkinesis, oculomotor apraxia, choreoathetosis, and nystagmus. Ataxia, when present, may resolve with age.

Disorders of Neurotransmitters Diseases

Metabolic Derangement Succinic Semialdehyde Dehydrogenase Deficiency

The key feature is an accumulation of ᵞ-hydroxybutyric in urine, plasma, and CSF. ᵞ-hydroxybutyric is a neuropharmacologically active compound. Its accumulation in the body fluids tends to decrease with age. Metabolites indicative of the β and α- oxidation of ᵞ-hydroxybutyric acid may be variably detected in the urine of SSADH-deficient patients. The identification of other metabolites in the urine of SSADH-deficient patients related to pathways of fatty acid, pyruvate, and
glycine metabolism suggests that the deficiency has metabolic consequences beyond the pathway of GABA metabolism.

Disorders of Neurotransmitters Diseases

Diagnostic Tests Succinic Semialdehyde Dehydrogenase Deficiency

Diagnosis is made by organic acid analysismof urine, plasma, and/or CSF. ᵞ-hydroxybutyrate can be higher in CSF than in plasma and even be extremely increased. The enzyme deficiency can be demonstrated in lymphocytes and lymphoblasts. Patients typically show 0%-19% of residual activity in isolated lymphocytes or 0%-12% in cultured lymphocytes (0%-6% in lymphoblasts and 4%-12% in intact lymphoblasts), and parents have intermediate levels of enzyme activity.

SSADH activity is expressed in normal human liver, kidney and brain, and SSADH deficiency in these tissues was recently demonstrated. The prenatal diagnosis of an affected fetus has been reported: ᵞ-hydroxybutyrate was elevated in amniotic fluid, and SSADH activity was absent from cultured amniocytes and autopsied fetal brain, liver, and kidney.

Disorders of Neurotransmitters Diseases

Treatment and Prognosis Succinic Semialdehyde Dehydrogenase Deficiency

In an attempt to reduce the accumulation of ᵞ-hydroxybutyrate, we introduced a novel treatment principle, namely inhibition of the preceding enzymatic step GABA transaminase. This was realized by giving ᵞ-vinyl GABA (Vigabatrin), an irreversible inhibitor of this enzyme, in doses of 50-100 mg/kg per day.

This treatment was shown to reduce CSF ᵞ-hydroxybutyrate levels and improved cerebellar signs in five out of six patients. However longterm administration of vigabatrin should be monitored closely because this drug increases CSF (and probably also brain) GABA levels.

As for the prognosis, this disease can manifest a mild to severe neurological course. Some patients have died, although there was no evidence for metabolic acidosis or decompensation.

Disorders of Neurotransmitters Diseases

Genetics Succinic Semialdehyde Dehydrogenase Deficiency

The mode of inheritance is autosomal recessive.

Disorders of Neurotransmitters Diseases

Gamma Aminobutyric Acid Transminase Deficiency

Gamma aminobutyric acid transminase deficiency was first reported in 1984 in a brother and sister from a Flemish family. No other patients seem to have been described since.

Clinical Presentation Gamma Aminobutyric Acid Transminase Deficiency

Both patients showed feeding difficulties from birth, often necessitating gavage feeding. They had a pronounced axial hypotonia and generalized convulsions. A high-pitched cry and hyperreflexia were present during the first 6-8 months. Furgher evolution was characterized by leghargy and psychomotor retardation (the developmental level of 4 weeks was never attained). Corneal reflexes and reaction of the pupils to light remained normal. A remarkable, continued acceleration of length-growth was noted from birth to death. This was explained by increased fasting plasma growth hormone levels (8-39 ng/ml;normal, <5); these could be suppressed by oral glucose. In one of the patients, head circumference showed a rapid increase during the last 6 weeks (from the 50th to the 97th percentiles). Postmortem examination of the brain showed a spongiform leukodystrophy.

Metabolic Derangement Gamma Aminobutyric Acid Transminase Deficiency

The CSF and plasma concentrations of GABA, GABA conjugates, β-alanine. Liver GABA and β-alanine concentration were normal. This metabolite pattern could be explained by a decrease in GABA transaminase activity in the liver (and lymphocytes). Intermediate levels were found in the healthy sibling, the father, and the mother. It can be assumed that the same enzymatic defect exists in the brain, since GABA transaminases of human brain and of peripheral tissues have the same kinetic and molecular properties. β-alanine seems to be an alternative substrate for GABA transaminase , hence its increase in this disease.

In this context it can be mentioned that the antiepileptic drug γ-vinyl GABAGABA transaminase (vigabratin) causes an irreversible inhibition of , leading to two-to threefold increases in CSF free GABA. Interestingly, we have noted that this drug also constantly and
significantly but not glutamic oxaloacetic transaminase activity.

Disorders of Neurotransmitters Diseases

Diagnostic Test Gamma Aminobutyric Acid Transminase Deficiency

The diagnosis requires amino acid analysis of the CSF. Due to enzymatic homocarnosine degradation, free GABA levels in the CSF show artifactual increases unless samples are deep-frozen (at-200C) within a few minutes if analysis is performed within a few weeks and at-700C if time until analysis is longer. Control CSF free GABA levels range from about 40 to 150 nmol/l after the age of 1 year and are lower in younger children. Because of these low levels, sensitive techniques have to be used such as ion-exchange chromatography and fluorescence detection or a stable isotope dilution technique.

Enzymatic confirmation can be obtained on lymphocytes, lymphoblasts, and liver. As for prenatal diagnosis, GABA transaminase activity is not expressed in fibroblasts, but activity is present in chorionic villus tissue.

Disorders of Neurotransmitters Diseases

Treatment and Prognosis Gamma Aminobutyric Acid Transminase Deficiency

We obtained no clinical or biochemical response after administration of pharmacological doses of pyridoxine, the precursor of the coenzyme of GABA transaminase, nor with picrotoxin, a potent noncompetitive GABA antagonist. Both children died at the ages of 1 year and 2 year and 7 months, respectively.

Disorders of Neurotransmitters Diseases

Genetics Gamma Aminobutyric Acid Transminase Deficiency

Inheritance is autosomal recessive.

Disorders of Neurotransmitters Diseases

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