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