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Leukoencephalopathies Associated with calcifications Mahvelati, F. MD. Child Neurologist

Introduction: The leukodystrophies are a heterogeneous group of diseases, which primarily affect white matter. A group of leukoencephalopathies are associated with calcifications.

Leukoencephalopathies Associated with Calcifications Aicardi- Goutieres syndrome Naku-Hakola's disease Cerebrotendious Xanthomatosis Cystic leukoencephalopathy without megalencephaly (RNASET 2-deficient cystic leukoencephalopathy) Labrune's syndrome (cerebroretinal microangiopathy with calcifications and cysts, Leukoencephalopathy with calcification and cyst) Cockayne 's syndrome Krabbe Metabolic diorders (Aminoacidopathies, Mitochondrial)

Leukoencephalopathies Associated with Calcifications Aicardi- Goutieres syndrome Naku-Hakola's disease Cerebrotendious Xanthomatosis Cystic leukoencephalopathy without megalencephaly (RNASET 2-deficient cystic leukoencephalopathy) Labrune's syndrome (cerebroretinal microangiopathy with calcifications and cysts, Leukoencephalopathy with calcification and cyst) Cockayne 's syndrome Krabbe Metabolic diorders (Aminoacidopathies, Mitochondrial)

Aicardi-Goutieres Syndrome: AGS is a genetically heterogeneous autosomal recessive group of inherited encephalopathies with 5 subtypes.

Aicardi-Goutieres Syndrome: Classic AGS is characterized by cerebral atrophy, white matter abnormalities, intracranial calcifications, chronic CSF lymphocytosis, and elevated CSF alpha-interferon.

Aicardi-Goutieres Syndrome: 2 clinical presentations have been delineated: an early onset neonatal form, with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development with remarkably preserved neurologic function.

Aicardi-Goutieres Syndrome: Severe neurologic dysfunction in infancy, as progressive microcephaly, spasticity, dystonic posturing, profound psychomotor retardation, and often death in early childhood.

Aicardi-Goutieres Syndrome: Outside the nervous system, thrombocytopenia, hepatosplenomegaly, and elevated hepatic transaminases along with intermittent fever may also erroneously suggest an infective process.

Aicardi-Goutieres Syndrome: AGS subtype 1 is autosomal recessive and is caused by mutations in the TREX1 gene on chromosome 3p21. The other subtypes are caused by mutations in nuclease genes, namely RNASEH2B gene, RNASEH2C gene, RNASEH2A gene and an autosomal dominant TREX1 gene mutation.

Aicardi-Goutieres Syndrome: It is important to exclude of pre-/perinatal infections, in particular the TORCH complex. Genetic screening for mutations in the four genes known to cause AGS allows definitive confirmation of the diagnosis in the majority (83%).

Leukoencephalopathies Associated with Calcifications Aicardi- Goutieres syndrome Naku-Hakola's disease Cerebrotendious Xanthomatosis Cystic leukoencephalopathy without megalencephaly (RNASET 2-deficient cystic leukoencephalopathy) Labrune's syndrome (cerebroretinal microangiopathy with calcifications and cysts, Leukoencephalopathy with calcification and cyst) Cockayne 's syndrome Krabbe Metabolic diorders (Aminoacidopathies, Mitochondrial)

Leukoencephalopathies Associated with Calcifications Aicardi- Goutieres syndrome Naku-Hakola's disease Cerebrotendious Xanthomatosis Cystic leukoencephalopathy without megalencephaly (RNASET 2-deficient cystic leukoencephalopathy) Labrune's syndrome (cerebroretinal microangiopathy with calcifications and cysts, Leukoencephalopathy with calcification and cyst) Cockayne 's syndrome Krabbe Metabolic diorders (Aminoacidopathies, Mitochondrial)

Naku-Hakola's disease: Affected patients had onset in the third decade of pain and swelling following strain of the wrist or ankle; fractures occurred after minor accidents.

Naku-Hakola's disease: Radiographs showed cystic rarefactions in the epiphyseal regions of bones. The cysts contained jelly-like material and microscopically showed membranous and lamellar structures between fatty and collagenous connective tissue.

Naku-Hakola's disease: In the fourth decade, patients developed neuropsychiatric symptoms, including memory impairment, euphoria, loss of social inhibitions, and impotency or frigidity.

Naku-Hakola's disease: Neurologic examination showed exaggerated deep tendon reflexes, pathologic reflexes, and dysplasia.

Naku-Hakola's disease: Patients usually die between ages 35 and 45, and the later features of the disorder resemble those of Alzheimer disease.

Leukoencephalopathies Associated with Calcifications Aicardi- Goutieres syndrome Naku-Hakola's disease Cerebrotendious Xanthomatosis Cystic leukoencephalopathy without megalencephaly (RNASET 2-deficient cystic leukoencephalopathy) Labrune's syndrome (cerebroretinal microangiopathy with calcifications and cysts, Leukoencephalopathy with calcification and cyst) Cockayne 's syndrome Krabbe Metabolic diorders (Aminoacidopathies, Mitochondrial)

Leukoencephalopathies Associated with Calcifications Aicardi- Goutieres syndrome Naku-Hakola's disease Cerebrotendious Xanthomatosis Cystic leukoencephalopathy without megalencephaly (RNASET 2-deficient cystic leukoencephalopathy) Labrune's syndrome (cerebroretinal microangiopathy with calcifications and cysts, Leukoencephalopathy with calcification and cyst) Cockayne 's syndrome Krabbe Metabolic diorders (Aminoacidopathies, Mitochondrial)

Cerebrotendinous xanthomatosis: Also called cerebral cholesterosis, is an autosomal recessive form of xanthomatosis. Associated with the deposition of a form of cholesterol (cholestanol) in the brain and other tissue.

Cerebrotendinous xanthomatosis: The initial clinical manifestation may be neonatal cholestasis or chronic diarrhea from infancy. In 75% of cases, cataract is the first finding, often appearing in childhood. Infants may present with cholestasis and liver dysfunction.

Cerebrotendinous xanthomatosis: Xanthomata may appear in the 2nd or 3rd decade of life, in the Achilles and other tendons (elbow, hand, patella, neck). Some patients show intellectual impairment from infancy, but most have normal or subnormal intellectual function until puberty.

Cerebrotendinous xanthomatosis: Adult-onset progressive neurologic dysfunction includes dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, seizures, and neuropathy. Dementia occurs in the 20s in over 50% of cases. Neuropsychiatric symptoms such as behavioral changes, hallucinations, agitation, aggression, depression, and suicidal tendencies may be prominent.

Cerebrotendinous xanthomatosis: Pyramidal signs and/or cerebellar ataxia are present in the 20s or 30s. Patients may experience extrapyramidal manifestations (dystonia and atypical parkinsonism), and peripheral neuropathy. MRI shows bilateral hyperintensity of the dentate nuclei and cerebral and cerebellar white matter.

Leukoencephalopathies Associated with Calcifications Aicardi- Goutieres syndrome Naku-Hakola's disease Cerebrotendious Xanthomatosis Cystic leukoencephalopathy without megalencephaly (RNASET 2-deficient cystic leukoencephalopathy) Labrune's syndrome (cerebroretinal microangiopathy with calcifications and cysts, Leukoencephalopathy with calcification and cyst) Cockayne 's syndrome Krabbe Metabolic diorders (Aminoacidopathies, Mitochondrial)

Leukoencephalopathies Associated with Calcifications Aicardi- Goutieres syndrome Naku-Hakola's disease Cerebrotendious Xanthomatosis Cystic leukoencephalopathy without megalencephaly (RNASET 2-deficient cystic leukoencephalopathy) Labrune's syndrome (cerebroretinal microangiopathy with calcifications and cysts, Leukoencephalopathy with calcification and cyst) Cockayne 's syndrome Krabbe Metabolic diorders (Aminoacidopathies, Mitochondrial)

Leukoencephalopathies Associated with Calcifications Aicardi- Goutieres syndrome Naku-Hakola's disease Cerebrotendious Xanthomatosis Cystic leukoencephalopathy without megalencephaly (RNASET 2-deficient cystic leukoencephalopathy) Labrune's syndrome (cerebroretinal microangiopathy with calcifications and cysts, Leukoencephalopathy with calcification and cyst) Cockayne 's syndrome Krabbe Metabolic diorders (Aminoacidopathies, Mitochondrial)

Aminoacidopathies and organic acidurias: Untreated aminoacidopathies and organic acidurias may be associated with white matter changes and irregular hypomyelination.

Aminoacidopathies and organic acidurias: L -2-Hydroxyglutaric aciduria is an autosomal recessive disorder with unknown metabolic defect.

Aminoacidopathies and organic acidurias: The onset is during the first year of life with macrocephaly, slowly progressive deterioration of motor functions with pyramidal signs and ataxia.

Aminoacidopathies and organic acidurias: Mental abilities are relatively spared. Seizures, easily controlled with AEDs, occur in most patients.

Mitochondrial disorders: Mitochondrial diseases are a heterogeneous group of disorders caused by impairment of the mitochondrial oxidative phosphorylation system.

Mitochondrial disorders: The clinical phenotypes are variable. The presence of significant basal nuclei or brainstem abnormalities has been described in the majority of cases.

Mitochondrial disorders: In a few cases, diffuse white matter abnormality without other MRI findings has been reported.

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Cystic leukoencephalopathy without megalencephaly (RNASET 2-deficient cystic leukoencephalopathy) It is caused by homozygous or compound heterozygous mutation in the RNASET2 gene on chromosome 6q27.

Cystic leukoencephalopathy without megalencephaly (RNASET 2-deficient cystic leukoencephalopathy) Neurologic deficits were noted within the first months of life, and included severe intellectual impairment, motor retardation, and spasticity.

Cystic leukoencephalopathy without megalencephaly (RNASET 2-deficient cystic leukoencephalopathy) Brain MRI showed extensive cysts within the anterior temporal lobes, ventricular enlargement, and white matter disease. The signal intensities of the cysts were identical to CSF.

Cystic leukoencephalopathy without megalencephaly (RNASET 2-deficient cystic leukoencephalopathy) CT scans showed intracranial calcifications in some subjects.

Leukoencephalopathies Associated with Calcifications Aicardi- Goutieres syndrome Naku-Hakola's disease Cerebrotendious Xanthomatosis Cystic leukoencephalopathy without megalencephaly (RNASET 2-deficient cystic leukoencephalopathy) Labrune's syndrome (cerebroretinal microangiopathy with calcifications and cysts, Leukoencephalopathy with calcification and cyst) Cockayne 's syndrome Krabbe Metabolic diorders (Aminoacidopathies, Mitochondrial)

Leukoencephalopathies Associated with Calcifications Aicardi- Goutieres syndrome Naku-Hakola's disease Cerebrotendious Xanthomatosis Cystic leukoencephalopathy without megalencephaly (RNASET 2-deficient cystic leukoencephalopathy) Labrune's syndrome (cerebroretinal microangiopathy with calcifications and cysts, Leukoencephalopathy with calcification and cyst) Cockayne 's syndrome Krabbe Metabolic diorders (Aminoacidopathies, Mitochondrial)

Labrune's syndrome (cerebroretinal microangiopathy with calcifications and cysts, Leukoencephalopathy with calcification and cyst) Triad of leukoencephalopathy, cerebral calcifications and cysts (LCC) is a recently reported rare disease named ‘Labrune syndrome.

The clinical presentation is insidious and variable. Labrune's syndrome (cerebroretinal microangiopathy with calcifications and cysts, Leukoencephalopathy with calcification and cyst) The clinical presentation is insidious and variable. Initial symptoms are of raised ICP and then spasticity, dystonia, seizures, and cognitive decline.

Labrune's syndrome (cerebroretinal microangiopathy with calcifications and cysts, Leukoencephalopathy with calcification and cyst) All the reported patients have a characteristic triad of calcification in the deep cerebral nuclei and white matter, diffuse leukoencephalopathy, and multiple cystic brain lesions on brain imaging.

Labrune's syndrome (cerebroretinal microangiopathy with calcifications and cysts, Leukoencephalopathy with calcification and cyst) Cerebroretinal microangiopathy with calcifications and cysts is an autosomal recessive disorder which caused by mutation in the CTC1 gene and shows phenotypic similarities to Labrune syndrome.

Labrune's syndrome (cerebroretinal microangiopathy with calcifications and cysts, Leukoencephalopathy with calcification and cyst) CRMCC includes the neurologic findings of intracranial calcifications, leukodystrophy, and brain cysts, but also includes retinal vascular abnormalities and other systemic manifestations, such as osteopenia with poor bone healing, a high risk of gastrointestinal bleeding, hair, skin, and nail changes, and anemia and thrombocytopenia.

Labrune's syndrome (cerebroretinal microangiopathy with calcifications and cysts, Leukoencephalopathy with calcification and cyst) Although CRMCC and Labrune syndrome were initially thought to be manifestations of the same disorder, molecular evidence has excluded mutations in the CTC1 gene in patients with Labrune syndrome, suggesting that the 2 disorders are not allelic.

Leukoencephalopathies Associated with Calcifications Aicardi- Goutieres syndrome Naku-Hakola's disease Cerebrotendious Xanthomatosis Cystic leukoencephalopathy without megalencephaly (RNASET 2-deficient cystic leukoencephalopathy) Labrune's syndrome (cerebroretinal microangiopathy with calcifications and cysts, Leukoencephalopathy with calcification and cyst) Cockayne 's syndrome Krabbe Metabolic diorders (Aminoacidopathies, Mitochondrial)

Leukoencephalopathies Associated with Calcifications Aicardi- Goutieres syndrome Naku-Hakola's disease Cerebrotendious Xanthomatosis Cystic leukoencephalopathy without megalencephaly (RNASET 2-deficient cystic leukoencephalopathy) Labrune's syndrome (cerebroretinal microangiopathy with calcifications and cysts, Leukoencephalopathy with calcification and cyst) Cockayne 's syndrome Krabbe Metabolic diorders (Aminoacidopathies, Mitochondrial)

Cockayne 's syndrome: Cockayne syndrome is an autosomal recessive disease due to a DNA repair defect.

Cockayne 's syndrome: Patients show psychomotor developmental delay, dwarfism, progeroid appearance, microcephaly, deafness, pigmentary retinal degeneration, optic atrophy, and photosensitivity.

Cockayne 's syndrome: Abnormal peripheral nerve conduction is due to a demyelinating polyneuropathy.

Cockayne 's syndrome: Neuroimaging shows brain atrophy of variable degree, namely in brainstem and cerebellum; abnormally high signal intensity on T2- weighted images throughout the hemispherical white matter.

Cockayne 's syndrome: late involvement of the subcortical fibers; abnormal hyperintensity on T1- weighted images in the basal ganglia corresponding to calcification.

Leukoencephalopathies Associated with Calcifications Aicardi- Goutieres syndrome Naku-Hakola's disease Cerebrotendious Xanthomatosis Cystic leukoencephalopathy without megalencephaly (RNASET 2-deficient cystic leukoencephalopathy) Labrune's syndrome (cerebroretinal microangiopathy with calcifications and cysts, Leukoencephalopathy with calcification and cyst) Cockayne 's syndrome Krabbe Metabolic diorders (Aminoacidopathies, Mitochondrial)

Leukoencephalopathies Associated with Calcifications Aicardi- Goutieres syndrome Naku-Hakola's disease Cerebrotendious Xanthomatosis Cystic leukoencephalopathy without megalencephaly (RNASET 2-deficient cystic leukoencephalopathy) Labrune's syndrome (cerebroretinal microangiopathy with calcifications and cysts, Leukoencephalopathy with calcification and cyst) Cockayne 's syndrome Krabbe Metabolic diorders (Aminoacidopathies, Mitochondrial)

Globoid Cell Leukodystrophy (Krabbe Disease): Krabbe disease is caused by a deficiency in the lysosomal enzyme cerebroside  - galactocerebrosidase.

Globoid Cell Leukodystrophy (Krabbe Disease): Infantile Krabbe disease presents in the first 6 months of life as hyperirritability, increased muscular tone, fever, and developmental arrest.

Globoid Cell Leukodystrophy (Krabbe Disease): As the disease progresses, there is further cognitive decline, myoclonus, opisthotonus, nystagmus, and optic atrophy. Patients diagnosed in infancy rarely survive beyond 2 years.

Globoid Cell Leukodystrophy (Krabbe Disease): In an estimated 10% of cases, symptoms begin after the patient has begun to walk; these are considered “late- onset.” Central motor signs include spasticity, ataxia, and weakness.

Globoid Cell Leukodystrophy (Krabbe Disease): 20% of late-onset patients have abnormal peripheral nerve conduction studies with uniform slowing of conduction velocities.

Globoid Cell Leukodystrophy (Krabbe Disease): Demyelination of the deep WM, progressively involving the subcortical WM. Calcifications within the thalami, basal ganglia, and corona radiata shown by CT scan.