Organic Aciduria

2.4.1. Canavan Disease

Canvan disease is also known as Canavan-Van Bogaert-Bertrand disease; spongy degeneration of CNS; aspartoacylase deficiency; ASP deficiency; aminoacylase 2 deficiency; and ACY2 deficiency.

Canavan's disease is an autosomal-recessive disorder caused by aspartoacylase deficiency. The deficiency of aspartoacylase leads to increased concentration of NAA acid in the brain and body fluids. This causes disruption of myelin, resulting in spongy degeneration of the white matter of the brain. The clinical features of the disease are hypotonia in early life, which evolves to spasticity, macrocephaly, head lag, and progressive severe mental retardation. Like Tay-Sachs and Nieman Pick disease, it is most prevalent in the Ashkenazi Jewish population. Research at the molecular level led to the cloning of the gene for aspartoacylase and the possibility of genetic diagnosis, the creation of animal models and continued research into the patho-physiology of this still poorly understood disorder.

2.4.1.2. Clinical Features

There are at least three different phenotypes of Canavan disease. A congenital form has been described, with marked hypotonia, feeding difficulties, lethargy and a rapid decline with death within months.

The infantile form of Canavan disease is the most common. Patients have an unremarkable gestation and appear normal at birth. Hypotonia becomes evident by 6 mo of life. Affected infants have poor head control, decerebrate posturing, irritability, poor feeding, and limited spontaneous motor activity.

By the second year of life, hypotonia has given way to spas-ticity with tonic extensor spasms. Cortical blindness and optic atrophy develop. Sensorineural hearing loss may be present with developmental malformations of the organ of Corti (116). Macrocephaly is a prominent finding at this stage. The patient may have myoclonic or other seizures and choreoathetosis. Autonomic crises may occur with vomiting, temperature instability and vasomotor disturbances. A vegetative state develops and affected infants generally die in early childhood.

The juvenile form is less common. Symptoms develop often after 5 yr of life. Visual loss, progressive cerebellar ataxia, regression of cognitive function, and spasticity are present. Macrocephaly is not an obligate feature. Some of these patients have had long-term survival, even into adulthood (117).

2.4.1.3. Biochemical Features

The first reported cases of NAA aciduria in patients with leukodystrophy occurred nearly 40 yr ago (118-120); however, it is not until much later that the association with Canavan disease was made (121). Since that time, the measurement of NAA in urine, plasma, and amniotic fluid has proved to be a valuable diagnostic tool. Aspartoacylase can be assayed in cultured skin fibroblasts and cultured amniotic cells and chorionic villi.

2.4.1.4. Genetic Features

Gene Locus: 17pter-p13. The gene for aspartoacylase has been cloned (122), and more than 40 mutations have been described, with two founder mutations among Ashkenazi Jewish patients (E285A and Y231X). Programs for carrier testing are currently in practice for the screening of Ashkenazi Jews for these two common mutations. Mutations in the aspartoacylase gene among non-Jewish patients are different and more diverse.

2.4.1.5. Imaging Features

Since diagnosis is available biochemically, there are limited recent studies on the MRI findings of Canavan disease. Conventional magnetic resonance imaging classically reveals early involvement of the arcuate fibers (U fibers). In most cases, the entirety of the cerebral white matter is then progressively affected, with relative sparing of the putamen (123). There also may be early involvement of the lentiform nuclei and the heads of the caudate nuclei apparent on T2-weighted images (124).

Magnetic resonance proton spectroscopy reveals an increase of the NAA/choline ratio and an overall increase of the NAA concentration (125).

2.4.1.6. Pathology

Classical descriptions of the pathology of Canavan disease include spongy degeneration (vacuolization) of cortical and subcortical tissues and extensive demyelination, with preservation of axons and oligodendroglia. Demyelination is accompanied by a moderate astrocytosis. Optic pathways manifest significant demyelination

2.4.1.7. Treatment

No effective treatment currently exists for Canavan disease. Virus-based gene transfer by recombinant adeno-associated virus containing the aspartoacylase gene is a possible therapeutic option in the future (126).

2.4.2. Glutaric Aciduria Type 1

Glutaric aciduria type 1 is also known as Glutaricaciduria I; GA I; and glutaryl-CoA dehydrogenase deficiency.

Glutaric aciduria is an inherited biochemical disorder caused by a deficiency of the enzyme glutaryl CoA dehydrogenase, which is in the mitochondrial biochemical pathway for degradation of the lysine and tryptophan. It is characterized by progressive dystonia and athetosis as the result of gliosis and neuronal loss in the basal ganglia. If not treated, episodes of biochemical intoxication cause degeneration of the basal ganglia of the brain and progressive extrapyramidal features. Children who have glutaric aciduria and have suffered significant brain damage often mistakenly are given a diagnosis cerebral palsy.

2.4.2.2. Clinical Features

Glutaric aciduria type 1 is manifested in infancy by macro-cephaly, hypotonia, choreoathetosis, dystonia, and encephalo-pathic crisis associated with an intercurrent illness or surgery. Rare adult onset cases are described.

2.4.2.3. Biochemical Features

GA1 is caused by a deficiency of glutaryl-CoA dehydrogenase.

2.4.2.4. Genetic Features

Gene map locus: 19p13.2. The GCDH gene contains 11 exons and spans approx 7 kb (127). A single mutation was found as the cause of glutaric acidemia in the Old Order Amish of Lancaster County, Pennsylvania. Mutation analysis is more heterogeneous in nonAmish patients.

2.4.2.5. Imaging Features

Marked widening of the operculae is found on MRI in patients with glutaric acidemia type 1. White matter changes have been reported in approx half of patients with organic acidurias (128). Abnormal high signal intensity on T2-weighted images is seen in the basal ganglia and periventricular white matter in approx two thirds of children. Abnormal high signal on T2-weighted images may be seen in the dentate nucleus, substantia nigra, and the pontine medial lemniscus (129). Features seen on MRI in adult-onset cases have been described as a diffuse leu-koencephalopathy.

Strauss et al. (130) suggests that micrencephalic macroceph-aly is a distinctive radiological feature of GA I. He studied a group of Old Order Amish, in which the disease has increased prevalence. In most neonates, an enlarged head circumference is the only presenting sign of the disorder. The authors pointed to radiologic signs of large fluid collections in the middle cranial fossae. Veins can be seen stretching tenuously across this space, where they are subject to distortion and rupture. Acute subdural hemorrhage can occur after minor head trauma and in some instances is accompanied by retinal hemorrhages. Investigation of child abuse preceded a correct metabolic diagnosis in some non-Amish children.

2.4.2.6. Pathology

Neuropathology in Glutaric aciduria type 1 may demonstrate temporal and frontal lobe hypoplasia, degeneration and necrosis of the putamen and the globus pallidus, status spongiosus of the cerebral white matter and, occasionally, heterotopic neurons in the cerebellum. There may be hypoplasia of the cerebral white matter (130).

2.4.2.7. Treatment

Specific management includes pharmacological doses of l-carnitine and dietary protein restriction. Metabolic decompen sation must be treated aggressively to avoid permanent brain damage.

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