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 Convulsions,

neuron signs intellectual, visual
are prominent impairment
early

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
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 -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 -galactosidase
Prenatal diagnosis is possible by measurement of
acid -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
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
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
severe myelin loss
disorder characterized by

and the presence of globoid bodies in the white matter

Marked deficiency of the lysosomal enzyme
galactocerebroside -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
nsidious 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 (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
Tuberous sclerosis
syndromes
AD
The characteristic brain lesions conssist of tubers
Undergo calcification

Von Hippel Lindaus 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 Recklinghauses 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)
Resulting from the obstruction within the ventricular system
Nonobstructive (communicating)
Resulting from obliteration of subarachnoid cisterns or
malformation of the arachnoid villi