NEURODEGENERATIVE DISORDERS OF CHILDHOOD

Neurodegenerative disorders of childhood A group of heterogenous diseases resulting from Genetic and biochemical defects Chronic viral infection Toxic substances Unknown cause

Neurodegenerative disorders of childhood Modern neuroimaging techniques and spesific biochemical molecular diagnostic tests Diagnosis becomes easier History and physical examination deterioration of neurologic function with loss of speech, vision, hearing or locomotion Seizures, feeding difficulties and impairment of intellect

Neurodegenerative disorders of childhood White and gray matter involvement Outcome Fatal Correct diagnosis Genetic counselling Upper motor neuron signs are prominent early Convulsions, intellectual, visual impairment

Neurodegenerative disorders of childhood For all conditions in which the spesific enzyme defect is known Prevention by prenatal diagnosis ( chorionic vilus sampling or amniocentesis) is possible

The inherited neurodegenerative disorders Sphingolipidosis Neuronal ceroid lipofuscinosis Adrenoleukodystrophy Sialidosis

Sphingolipidosis Niemann-Pick disease Gaucher disease GM1 gangliosidosis GM2 gangliosidosis Krabbe disease Metachromatic leukodystrophy

Niemann-Pick disease Fatal disorder of infancy characterized by Failure to thrive, hepatosplenomegaly and/or rapidly progressive neurodegenerative course that leads to death by 2-3 years of age Six subtypes are described Autosomal recessive Deficient activity of sphingomyelinase (encoded by a gene located on chromosome 11) Pathologic accumulation of sphingomyelin and other lipids in monocyte-macrophage system

Gaucher disease Multisystemic lipidosis characterized by Hematologic problems( trombocytopenia, anemia Organomegaly Skelatal involvement (bone pain, pathologic fractures) 3 clinical subtypes Type 1: adult, non-neuropathic form Type 2: infantile, acute neuropathic form Type 3: juvenile

Gaucher disease Autosomal recessive Deficient activity of acid β-glucosidase (encoded by a gene on chromosome 1) Accumulation of glycolipid substances, particularly glucosyl ceramide in the cells of RES Onset from early childhood to late adulthood The pathologic hallmark Gaucher cell in RES especially in bone marrow

Gangliosidoses Gangliosides Abnormalities in catabolism Glycosphingolipids Normal constituents of the neuronal and synaptic membranes Abnormalities in catabolism An accumulation of the ganglioside within the cell GM1 gangliosidosis GM2 gangliosidosis

Gangliosidoses GM1 gangliosidoses Infantile : Type 1 Juvenile: Type 2 Adult : Type 3 Autosomal recessive Deficiency of acid β-galactosidase Prenatal diagnosis is possible by measurement of acid β-galactosidase in cultured amniotic cells

Gangliosidoses Infantile Presents at birth or during the neonatal period Anorexia, poor sucking, inadequate weight gain, generalized seizures Facial features are coarse Macroglossia, prominent forehead, hepatosplenomegaly Neurologic examination Apathy, progressive blindness, deafness, spastic quadriplegia, decerebrate rigidity Cherry red spot in the macular region is visualized in 50% of cases Rarely survive beyond 2-3 years

Gangliosidoses Juvenile Beginning at about 1 year of age Incoordination, weakness, ataxia, regression of language Convulsions Spasticity Decerebrate rigidity Blindness No hepatosplenomegaly Rarely survive

Gangliosidoses Adult Slowly progressive disease Spasticity Ataxia Disarthria Gradual loss of cognitive function

GM2 gangliosidosis Adult GM2 g. Heterogenous group of AR inherited disorders that consist of several subtypes Tay-Sachs disease (TSD) Sandhoff disease Juvenile GM2 g. Adult GM2 g.

GM2 gangliosidosis Tay-Sachs Disease Affected infants appear normal until 6 months of age Except startle reaction to noise soon after birth Early hypotonia Progressive spasticity Convulsions, blindness, deafness, and cherry red spots in almost all patients Deficiency of Hexosaminidase A

GM2 gangliosidosis Sandoff disease Juvenile GM2 G. Adult GM2 G. Similar to TSD May also have hepatosplenomegaly Juvenile GM2 G. midchildhood Ataxia Progressive visual loss with optic atrophy Adult GM2 G. slowly progressive gait ataxia Dysarthria Intellectual function is unimpaired

Krabbe Disease Rare AR neurodegenarative disorder characterized by severe myelin loss and the presence of globoid bodies in the white matter Marked deficiency of the lysosomal enzyme galactocerebroside β-galactosidase Symptoms become evident during the first few months of life Excessive irritability, crying Unexplained episodes of hyperprexia Feeding problems Failure to thrive During the initial stages patients are often treated for colic or milk allergy Generalized seizures Rigidity Opisthotonus Optic atrophy, visual problems

Metachromatic Leukodystrophy (MLD) AR Deficiency of arylsulfatase A activity Accumulation of cerebroside sulfate within the myelin sheath of CNS and peripheral nervous system Myelin breakdown Prenatal diagnosis is possible Cresyl violet applied to tissue specimens produces metachromatic staining of the sulfatide granules Late infantile İnsidious onset of gait disturbances between 1-2 years of age Extremities are hypotonic DTR are absent or diminished Deterioration of intellectual function Visual fixation is diminished Optic atrophy CT-MRI Diffuse symmetric attenuation of the cerebellar and cerebral white matter CSF Elevated protein content Bone marrow transplantation is a promising experimental therapy

Metachromatic Leukodystrophy (MLD) Juvenile MLD 5-10 years of age Deterioration of school performance Incoordination of gait Urinary incontinance Dysarthria Generalized tonic-clonic convulsions Adult MLD From 2nd to 6th decade

Neuronal ceroid lipofuscinosis The most common class of neurodegenerative disease in children and consists of three disorders inherited as autosomal recessive traits Characterized by the storage of an autoflorescent substance within neurons and other tissues Infantile type Begins toward the end of first year with myoclonic seizures, intellectual deterioration, blindness Death occurs at approximately 10 years of age

Neuronal ceroid lipofuscinosis Late infantile The most common type Presenting manifestation Myoclonic seizures between 2-4 years of age in a previously normal child dementia, ataxia Blindness Microcephaly Juvenile Progressive visual loss and intellectual impairment between 5-10 years of age

Adrenoleukodystrophy Often associated with adrenal cortical insufficiency X-linked recessive Classic adrenoleukodystrophy (ALD) 5-15 years of age Academic deterioration Behavioral disturbances Gait abnormalities Generalized seizures Spastic quadriplegia Hypoadrenalism (%50)

Adrenoleukodystrophy Adrenomyeloneuropathy Slowly progressive Spastic paraparesis, urinary incontinance and onset of impotance during the 3rd or 4th decade One of the most difficult problems in the management of X-linked ALD is the common observation that affected individuals in the same family may have quite different clinical coarses Neonatal ALD Marked hypotonia Early onset of seizures AR Adrenal atrophy is evident post mortem Correction of adrenal insufficiency is ineffective in halting neurological deterioration

Sialidosis AR Accumulation of a sialic acid oligosaccharide complex secondary to a deficiency in the lysosomal enzyme neuraminidase Urinary excretion of sialic acid containing oligosaccharides is increased Sialydosis type 1 Cherry red spot-myoclonus syndrome Visual deterioration Myoclonus Sialydosis type 2 Infantile Juvenile Cherry red spots, myoclonus, somatic involvement, coarse facial features Lymphocytes show vacuoles in the cytoplasm Liver biopsy Cytoplasmic vacuoles

Miscellaneous disorders Multiple sclerosis (MS) Multiple white lesions in the CNS Rare in the pediatric population Cause is unknown Genetic, immunologic, infectious factors Unilateral weakness, ataxia Headache Paresthesias Sudden visual loss Optic neuritis Pathology Demyelination with the formation of plaques

Miscellaneous disorders Subacute Sclerosing Panencephalitis Personality changes Aggressive behaviour Impaired cognitive function Myoclonic seizures Diagnosis Measles Ab in CSF EEG Typical histological findings in the brain

CONGENITAL ABNORMALITIES OF CENTRAL NERVOUS SYSTEM

Congenital abnormalities of Central Nervous System (1) The incidence of malformations is higher in children with IUGR and multiple pregnancies The same anomaly may occur as a result of genetic or environmental causes Etiology Genetic factors Forms of microcephaly inherited as AR Sex-linked variety of hydrocephalus Hereditary congenital facial paralysis AD Some anomalies have a high risk of recurrence within families Some anomalies are associated wiyh inborn errors of metabolism Cytogenetic abnormalities Most important group are the trisomies( e.g Down Syndrome) Translocations, deletions Maternal age Maternal infections (rubella, CMV)

Congenital abnormalities of Central Nervous System (2) Neural tube defects Anencephaly Complete absence of the cerebral hemispheres Females>males Most common anomaly in humans Encephalocele and cranial meningocele Protrusion of brain or meninges through a cranial defect Most frequent in the occipital region Genetic and environmental factors may be of etiologic importance

encephalocele

Congenital abnormalities of Central Nervous System (3) Neural tube defects Spinal meningocele, myelomeningocele and myelocele All are associated with spina bifida Meningocele Consists of herniation of both dura and arachnoid through a vertebral defect Meningomyelocele Consists of the above in addition to the spinal cord being herniated as well Myelocele Consists of all the above but the spinal cord is open and flat with CSF leaking on to the exposed surface Hydrocephaly commonly occurs in association with all of the above

myelomeningocele

Arnold Chiari Malformation (ACM)(1) Complex deformity of the brain and cerebellum Type 1 ectopia of cerebellar tonsils Type 2 the most common type in neonates and usually associated with lumbar myelomeningocele Consists of lengthening of the vermis and tonsils of the cerebellum and their downward displacement through the foramen magnum in the spinal canal

Arnold Chiari Malformation (ACM)(2) Type 3 Consists of a cervical spinal bifida, the entire cerebellum being herniated through the foramen magnum Type 4 Cerebellar hypoplasia The malformation develops early in gestation at the age of 10 weeks

Malformations of the cerebellum Agenesis of the cerebellum Very uncommon Hypoplasia Dandy Walker malformation Occlusion of the foramina of Lushka and Magendie of 4th ventricle early in cerebral development Small hypoplastic cerebellum with a greatly distended 4th ventricle Obstructive hydrocephalus and cerebellar ataxia are the clinical presentation

Anomalies of cell migration and abnormal surface configurations of the brain (1) Ectopias and heterotopias Misplaced groups of neurons Such as an island of gray matter in the subcortex More common in the cerebellum than the cerebrum Agyria Total absence of gyri (lisencephaly) Pachygyria A few broad malformed gyri varying in size and number Polymicrogyria An increased number of gyri some of which may be abnormally small Schizencephaly Presence of unilateral or bilateral clefts within the cerebral hemispheres. The borders of the cleft are surrounded by abnormal brain particularly microgyria

Cortical heterotopia

pachygyria

lisencephaly

polymicrogyria

schizencephaly

Anomalies of cell migration and abnormal surface configurations of the brain (2) Porencephaly Presence of cysts or cavities within brain communicating with the subarachnoid space Holoprosencephaly Defective cleavage of prosencephalon Facial anomalies are common Alobar Single ventricle+absent falx+fused basal ganglia Semilobar Lobar

Anomalies of cell migration and abnormal surface configurations of the brain (3) Holoprosencephaly In the most severe form there is an anterior holosphere with no interhemispheric fissure and a single ventricle The brain is often smaller than normal and olfactory bulbs and tracts are absent Optic nerves are absent and gyri are broad and have an abnormal pattern Brain stem and cranial nerve structures may be normal

Microcephaly Small brain usually associated with a small head

Megalencephaly Proportionate enlargement of the whole brain, usually associated with the presence of a variable mental aberration Primary Secondary

Agenesis of corpus callosum May be part of a complex malformation or be totally or partially absent in an otherwise normal brain It develops between the 12 and 22 weeks of gestation Mental retardation, mild to moderate, epilepsy and cerebral palsy are common Dignosis can be confirmed with a CT or MRI

Corpus callosum agenesis

Neurocutaneous syndromes Tuberous sclerosis AD The characteristic brain lesions conssist of tubers Undergo calcification Von Hippel Lindau’s Angiomatosis Cerebellar hemangioblastomas and retinal angiomata are major neurologic features Spinal cord, cerebellum, retina, kidney, pancreas and epididymis are affected Sturge Weber Syndrome Facial nevus, seizures, hemiparesis Intracranial calcification Mental retardation Von Recklinghause’s disease Abnormality of neural crest diferrantiation and migration during the early stages of embryogenesis

Hydrocephalus Group of conditions that result from impaired circulation and absorbtion of CSF Obstructive (noncommunicating) Resulting from the obstruction within the ventricular system Nonobstructive (communicating) Resulting from obliteration of subarachnoid cisterns or malformation of the arachnoid villi