بسم الله الرحمن الرحیم

Alexander & canavan Leukodystrophies Dr Bita Shalbafan Neurologist Labafi nejad Hospital

Alexander disease

Definition Alexander disease is a rare genetic disorder that predominantly affects infants and children and is associated with cerebral white matter disease.

Pathophysiology Sporadic mutations in the GFAP gene are the cause of most cases of Alexander disease.

Pathology Intracytoplasmic astrocytic inclusions known as Rosenthal fibers are the hallmark of Alexander GFAP is the intermediate filament peculiar to the astrocytes, where it contributes to cytoskeletal formation and maintenance, cell communication, and may affect functioning of the blood–brain barrier. disease.

The diagnosis The diagnosis of Alexander disease can be established based upon clinical and radiographic (MRI) features. The diagnosis is usually confirmed by demonstrating a GFAP gene mutation. Although genetic testing is not necessarily required for the diagnosis, genetic confirmation should always be attempted due to the heterogeneity of the disease and its presentation.

Differential diagnosis The differential diagnosis of Alexander disease involves consideration of other disorders that present with macrocephaly and/or cerebral white matter changes.

subtypes of Alexander disease Four subtypes of Alexander disease — neonatal, infantile, juvenile, and adult — are traditionally recognized But a revised classification of Alexander disease proposes two subtypes – types I and II – based upon statistical analyses:

Prevalence Prevalence of various forms of AxD was determined as 27.3% (infantile), 24.2% (juvenile), and 48.5% (adult).

type I The main characteristics of infantile and juvenile AxD include delayed psychomotor development or mental retardation, convulsions, macrocephaly, and predominant cerebral white matter abnormalities in the frontal lobe on brain MRI.

Type II Type II onset may occur across the lifespan, The main characteristics of adult AxD include bulbar signs, muscle weakness with hyperreflexia, autonomic dysfunction, eye movement abnormalities, bulbar symptoms, and atypical neuroimaging signal abnormalities (and/or atrophy of medulla oblongata and cervical spinal cord on MRI features)

why in some patients GFAP mutations lead to late onset ? In particular, it is not clear why in some patients GFAP mutations lead to late onset and prevalent localization of pathological, neuroradiological and clinical changes in the lower brainstem, while in other patients AD onset occurs early and supratentorial abnormalities dominate the picture. The explanation for these different phenotypes may reside in the affected mutation sites and their effects on the GFAP protein, as confirmed for a few mutations observed in adults, which displayed an effect milder than severe mutations associated with . In addition, other genetic or still unknown environmental factors have been hypothesized to influence the phenotype These modifiers might explain the variable disease expressivity and the reduced penetrance of some variants, which may also be detected in healthy parents infantile AD

Typical MRI features of Alexander disease 1-Extensive cerebral white matter changes with frontal predominance, 2-Periventricular rim of high T1 signal and low T2 signal, Subependymal cysts 3-Basal ganglia and thalamic abnormalities, 4-Contrast enhancement of selected gray and white matter structures

5-Brainstem abnormalities The clinical picture is not specific, but AOAD must be considered in patients of any age with lower brainstem signs. When present, palatal myoclonus is strongly suggestive of AOAD. Pyramidal involvement, cerebellar ataxia, urinary disturbances and sleep disorders are common. Infrequent findings include scoliosis and dysautonomia. Fluctuations may occur. The course is variable, usually slowly progressive and less severe than the AD forms with earlier onset.

Less common MRI features 1-Multifocal brainstem lesions resembling multiple tumors, 2-Medullary and cervical spinal cord signal abnormalities or 3-atrophy 4-Ventricular garlands

Prevalence of AxD in Japan was estimated to be approximately 1 case per 2.7 million individuals

Treatment Treatment of Alexander disease remains supportive.

Canavan disease

History Canavan disease, also called Canavan-Van Bogaert-Bertrand disease, aspartoacylase deficiency or aminoacylase 2 deficiency, degenerative disorder that causes progressive damage to nerve cells in the brain

Canavan disease has an autosomal recessive pattern of inheritance

Pathophysiology Aspartoacylase deficiency is caused by mutations in the ASPA gene that encodes the enzyme aspartoacylase. The resulting deficiency of aspartoacylase leads to accumulation of N-acetylaspartic acid (NAA)

Pathology The resulting deficiency of aspartoacylase leads to accumulation of N-acetylaspartic acid (NAA) in brain and to oligodendrocyte dysfunction, spongiform changes, and absence of myelin. However, the precise mechanisms causing to spongiform degeneration are uncertain.

Symptoms Aspartoacylase deficiency typically presents at about age three months with lethargy and listlessness, weak cry and suck, poor head control, and hypotonia with a paucity of extremity movement. Macrocephaly becomes prominent by three to six months. Thereafter hypotonia progresses to spasticity and tonic extensor spasms. By age six months, neurologic abnormalities are invariant. Little subsequent development is noted. Blindness from optic atrophy occurs between 6 and 18 months. Seizures are noted in about 50 percent of patients. Pseudobulbar signs and decerebrate posturing dominate the end stage.

Brain imaging Brain imaging by CT and MRI reveals diffuse and symmetrical white matter involvement

pathologic findings The gross pathologic findings are dominated by spongy degeneration of deep cortex, subcortical white matter, and cerebellum. The spongiform changes reflect vacuolated astrocytes in deeper cortical layers and in adjacent subcortical white matter.

Diagnosis the diagnosis of aspartoacylase deficiency is supported by 1- elevated levels of urine N-acetylaspartic acid (NAA) and 2-deficient aspartoacylase activity in cultured skin fibroblasts. 3-Genetic testing may be obtained for purposes of genetic counseling.

Differential diagnosis The differential diagnosis of aspartoacylase deficiency includes other progressive white matter diseases of infancy, particularly -Krabbe disease, -metachromatic leukodystrophy, -early-onset adrenoleukodystrophy, -Alexander disease, -and demyelinating disorders.  

Prevalence Although Canavan disease may occur in any ethnic group, it affects people of Eastern European Jewish ancestry more frequently. About 1 in 40 individuals of Eastern European (Ashkenazi) Jewish ancestry are carriers.

Pathophysiology Canavan disease is caused by a defective ASPA gene which is responsible for the production of the enzyme aspartoacylase. Decreased aspartoacylase activity prevents the normal breakdown of N-acetyl aspartate, wherein the accumulation of N-acetylaspartate, or lack of its further metabolism interferes with growth of the myelin sheath of the nerve fibers in the brain.

Treatment No effective treatment is available for aspartoacylase deficiency. Management is supportive and aimed at maintaining nutrition and hydration, protecting the airway, preventing seizures, minimizing contractures, and treating infections.

Current research  1-Triacetin supplementation has shown promise in a rat model.(Triacetin, which can be enzymatically cleaved to form acetate, enters the brain more readily than the negatively charged acetate.) The defective enzyme in Canavan disease, aspartoacylase, converts N-acetylaspartate into aspartate and acetate. Mutations in the gene for aspartoacylase prevent the breakdown of N-acetylaspartate, and reduce brain acetate availability during brain development. Acetate supplementation using Triacetin is meant to provide the missing acetate so that brain development can continue normally.

Current research  2-A team of researchers headed by Paola Leone are currently at the University of Medicine and Dentistry of New Jersey, in Stratford, New Jersey. The brain gene therapy is conducted at Cooper University Hospital. The procedure involves the insertion of six catheters into the brain that deliver a solution containing 600 billion to 900 billion engineered virus particles. The virus, a modified version of AAV, is designed to replace the aspartoacylase enzyme.[7] Children treated with this procedure to date have shown marked improvements, including the growth of myelin with decreased levels of the n-acetyl-aspartate toxin

Current research  3-AAV-MBP-GFP was administered to the striatum of ASPA-deficient mice at P10 and brains analysed three weeks later to determine spread and selectivity of transgene expression.

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