Transcript 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
Upper motor
neuron signs
are prominent
early
Convulsions,
intellectual, visual
impairment
 Outcome
 Fatal
 Correct diagnosis
 Genetic counselling
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
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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
 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
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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
 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
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Deficiency of Hexosaminidase A
GM2 gangliosidosis
 Sandoff disease
 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
 Rare AR neurodegenarative
disorder characterized by
Krabbe
Disease
severe myelin loss
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 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
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Excessive irritability, crying
Unexplained episodes of hyperprexia
Feeding problems
Failure to thrive
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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
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Myelin breakdown
 Prenatal diagnosis is possible
 Cresyl violet applied to tissue specimens produces metachromatic staining of
the sulfatide granules
 Late infantile
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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
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Optic atrophy
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CT-MRI
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CSF
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Bone marrow transplantation is a promising experimental therapy
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Diffuse symmetric attenuation of the cerebellar and cerebral white matter
Elevated protein content
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)
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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
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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
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Infantile
Juvenile
Cherry red spots, myoclonus, somatic involvement, coarse facial features
Lymphocytes show vacuoles in the cytoplasm
Liver biopsy
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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
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Measles Ab in CSF
EEG
Typical histological findings in the brain
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
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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
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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
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Meningomyelocele
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Consists of the above in addition to the spinal cord being herniated as
well
Myelocele
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Consists of herniation of both dura and arachnoid through a vertebral
defect
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
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ectopia of cerebellar tonsils
 Type 2
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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
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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
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Such as an island of gray matter in the subcortex
More common in the cerebellum than the cerebrum
 Agyria
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Total absence of gyri (lisencephaly)
 Pachygyria
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A few broad malformed gyri varying in size and number
 Polymicrogyria
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An increased number of gyri some of which may be abnormally small
 Schizencephaly
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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
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 AD
 The characteristic brain lesions conssist of tubers
 Undergo calcification
 Von Hippel Lindau’s Angiomatosis
 AD
 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
 AD
 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)
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Resulting from the obstruction within the ventricular system
 Nonobstructive (communicating)
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Resulting from obliteration of subarachnoid cisterns or
malformation of the arachnoid villi