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PEDIATRIC
GRAY MATTER DISEASES
Degenerative neurological diseases
presenting in the 1st six years of life
A whirlwind tour of eponyms and other
hard-to-remember minutiae
Steven Leber, M.D., Ph.D.
January 12, 2017
Developmental level
Normal
Delayed
Regression
Age
HOW DO WE CLASSIFY NEUROMETABOLIC
DISORDERS?
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Disorders of lipid metabolism
Disorders of carbohydrate metabolism
Disorders of urea cycle enzymes
Disorders of amino acid metabolism
Disorders of organic acids
Mucopolysaccharidoses
Mucolipidoses
Disorders of trace metal metabolism
Disorders of purine & pyrimidine metabolism
Mitochondrial disorders
Peroxisomal disorders
“GRAY MATTER” vs “WHITE MATTER”
Gray
White
Early seizures
Common
Uncommon
EEG
Sharp
Slow
Dementia
Early
Variable
Motor deficit
Variable early; later
severe
Prominent early
Visual deficit
Early; usually
Later; optic nerve or
retinal; abnormal
usually tract;
ERG
abnormal VER
CLASSIFICATION
• Infantile vs late infantile
• With or without visceral storage
INFANTILE, WITHOUT
VISCERAL STORAGE
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Tay-Sachs
Alper
Menke
Rett
Farber
Pompe
Leigh
Infantile neuroaxonal dystrophy
"Cerebral" GM1 gangliosidosis (type II)
Infantile neuronal ceroid lipofuscinosis (NCL, CLF)
Congenital disorder of glycosylation type Ia
INFANTILE, WITH
VISCERAL STORAGE
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Generalized GM1 gangliosidosis
Gaucher's (infantile)
Niemann Pick, type A
Sandhoff
Wolman
Glycolipid and glycoprotein disorders(fucosidosis,
mannosidosis, sialidosis, I-cell disease)
LATE INFANTILE,
WITHOUT VISCERAL STORAGE
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Neuronal ceroid lipofuscinosis
Juvenile Tay-Sachs
Progressive myoclonus epilepsies
Huntington disease
Xeroderma pigmentosa
LATE INFANTILE,
WITH VISCERAL STORAGE
• Gaucher Type III
• Niemann Pick, type C
• Mucopolysaccharidoses
– Hurler's
– Hunter's
– Sanfilippo's
INFANTILE, WITHOUT
VISCERAL STORAGE
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Tay-Sachs
Alper
Menke
Rett
Farber
Pompe
Leigh
Infantile neuroaxonal dystrophy
"Cerebral" GM1 gangliosidosis (type II)
Infantile neuronal ceroid lipofuscinosis (NCL, CLF)
Congenital disorder of glycosylation type Ia
TAY-SACHS DISEASE
(GM2 GANGLIOSIDOSIS)
• Onset: 0-6 months, usually 1-3
• Early myoclonus (startle, without habituation, especially to
noise [hyperacusis]) and irritability
• Seizures in first six months (infantile spasms, gelastic or other
partial, generalized).
• Dementing
• Hypotonic at first; progressively weak; later spastic
• Macrocephaly usually begins at ~ 18 months (brain weight
often > 2000 gm)
• Progressive; most die in 2nd or 3rd year
• Milder forms exist
TAY-SACHS DISEASE
• Cherry-red spot
– Usually seen within first few
months
– Accumulation of storage
material, with degeneration
of parafoveal ganglion cells
– Choroid visible and appears
red and is surrounded by
gray ring
– Not specific for TS
• Blindness by 1 year
• Normal pupillary reaction
and ERG; VER abnormal
TAY-SACHS DISEASE - Genetics
• Not only Ashkenazi Jews
• Carrier frequency
– Ashkenazi Jews: 1 in 30
• Those from small area near Lithuania: 1 in 19
• Prior to screening, 1 in 2500-3600 Ashkenazi Jews were
affected; screening has ↓’d by >90%
– Non-Jews 1 in 300
• Pockets of higher incidence
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Western China
French Quebec
Pennsylvania Dutch
Louisiana Cajun
Ceramide
GANGLIOSIDE NOMENCLATURE
• G: ganglioside
• M: how many sialic
acids
– A 0, M 1, D2, T3
• Number: position
on band
– Smaller (few
hexoses) migrate
faster; have
higher numbers
• 4 sugars: 1
(e.g., GM1)
• 3 sugars: 2
• 2 sugars: 3
TAY-SACHS DISEASE
• Hexosamindase A = α β
• Hexosamindase B = β2
• Tay-Sachs: α-subunit mutation
– Chromosome 15
– Hexosaminidase A deficiency
• Cannot breakdown GM2 ganglioside
• Accumulates in lysosomes
• Sandhoff's: β-subunit mutation
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Hexosaminidase A & B
Like Tay-Sachs but with visceromegaly
Rarer than Tay-Sachs
Death usually by age 4
TAY-SACHS DISEASE - Pathology
• Ballooned cells
with swollen
axons
(torpedoes) and
membranous
cytoplasmic
bodies
• If survive long
enough, often
cystic white
matter changes
ALPER
(progressive infantile poliodystrophy)
• Controversial and difficult to define
• Triad of progressive:
– Refractory epilepsy
– Dementia
– Liver failure
• Familial in some
• Onset in neonatal period to 1st few years
• Arrested head growth  microcephaly
• Vegetative after 1-3 years
ALPER
• Severe cortical neuronal degeneration (especially
layers III and IV)
• No visceral or brain storage
• Liver cirrhosis in some
• Pathologic diagnosis, plus one of exclusion and
family hx
• Can be caused by mutation in the nuclear gene
encoding mitochondrial DNA polymerase gamma
(POLG), leading to mitochondrial DNA depletion
• Risk of valproate-induced hepatic failure!
MENKE
• X-linked recessive
– Xq13
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Onset: 1st weeks to months
Prominent seizures and myoclonus at onset
Severe dementia and regression
Hypotonic with brisk DTRs
Hypothermia, hypoglycemia, and prematurity
common
MENKE
• Hair
– “short, sparse, coarse, and
twisted”
– kinky, coarse, unpigmented
– Pili torti: twisted shafts
– Trichorexis nodosa:
fragmentation
– Monilethrix: periodic narrowing
MENKE
• Copper and ceruloplasmin both low
– in brain and liver (high in intestine, kidney, and fibroblasts)
– Intestinal malabsorption
– Cu++ and ceruloplasmin may be nl 1st few weeks of life
• Menkes gene (MNK) product copper-transporting
ATPase
• Copper-dependent enzymes (e.g., cytochrome-coxidase, dopamine ß-hydoxylase) malfunction
– Parenteral copper injections help survival and neurologic
symptoms in pts with certain mutations if treatment started
in the neonatal period
MENKE
• Vasculopathy; tortuous
cerebral vessels
• Pathological fx’s
• Pathology
– Diffuse atrophy plus
focal infarctions
– Subacute inflammatory
meningoencephalitis
– Hemorrhages common
(ddx – abuse)
RETT SYNDROME
• Almost exclusively girls
• Common; one of most common genetic causes of
mental retardation in girls
• Incidence in US: up to 1 in 10,000 female births
RETT SYNDROME: 4 clinical stages
• Normal at birth
• I. At 6-18 months: Developmental arrest
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Development slows and then arrests
Possible decrease in eye contact and communication
Diminished interest in play
Head growth decelerates
• Acquired microcephaly
– Seizures not common but can occur
RETT SYNDROME: 4 clinical stages
• II. 1-4 years (usually 2nd year): rapid regression
– Phase lasts days to months
– Dramatic deterioration; can appear encephalitic or
toxic
• Loss of language skills
• Autistic behavior
• Decreased purposeful use of hands
• Stereotyped hand-wringing, slapping, or hand-to mouth
movements
RETT SYNDROME: 4 clinical stages
• Stage II, continued:
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Ataxia of trunk and extremities
Gait apraxia
Seizures (GTC, complex partial, atypical absence)
Apnea, then hyperventilation, only during wakefulness
Episodes of jerky movements
Insomnia and sleep disturbance
Self-abusive behavior
Bruxism, aerophagia
GI problems (constipation, GER, poor growth)
RETT SYNDROME: 4 clinical stages
• III. 2-10 years of age: pseudostationary
– Lasts months to years
– Apparent stabilization
– Autistic behavior less prominent, improved personality,
eye contact
– Increased rigidity, bruxism
– Continued seizures and gait ataxia/apraxia
– Continued sleep problems
– Poor weight gain
– Prolonged QT
RETT SYNDROME: 4 clinical stages
• IV. Teenage years: late motor deterioration
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Slow deterioration
Ambulation lost
Spasticity plus LMN signs
Dystonia, parkinsonian features may occur
Scoliosis, foot deformities
Reduced seizure frequency
Improved eye contact
Most survive to 5th or 6th decade
RETT SYNDROME - Etiology
• Pathology: Moderate neuronal loss and
cortical/dendritic atrophy
• Despite developmental regression, not felt to be
degenerative
• Gene MeCP2 identified in 1999
– Methyl-CpG binding protein-2
– Affects regulation of other genes (“expression silencer”)
– MeCP2 protein binds to methylated DNA, activating histone
deacetylase
– Mutations allow gene to be inappropriately turned on
• Testing is now 96% sensitive (CDKL5, FOXG1 in ddx)
RETT SYNDROME - Genetics
• Phenotypic severity correlates with proportion nl vs
mutant X-chromosome inactivated
• Spontaneous mutations 99%, familial 1%
• Spontaneous mutations almost always occur in
sperm
• Boys: familial cases or in-ova mutations
RETT SYNDROME- Variants
• Females
– Classic
– Preserved speech variant (Zappella variant)
– Early seizure variant (Hanefeld variant)
– Mental retardation and seizures
– Pure autism
– Angelman-like
– Mild mental retardation
• Boys
– Severe neonatal encephalopathy; usually die in 1st year
– Mild MR, seizure, ataxia
– Bipolar or schizophrenic
• Whom to test????
– Tremor seems to be prominent in most
FARBER LIPOGRANULOMATOSIS
• Extremely rare
• Presents soon after birth
with hoarse cry,
respiratory distress,
hyperesthesia over joints
• Then painful joint
swellings and rigidity,
subcutaneous nodules,
especially around
tendons and joints
FARBER LIPOGRANULOMATOSIS
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Hypotonia
Usually dementing, but some normal
No seizures
↓ acid ceramidase   ceramide with
anterior horn cell storage
• May have cherry-red spots
POMPE DISEASE
(glycogen storage type II disease;
acid maltase deficiency)
• Onset at several weeks to several months of age
• Involves brain and muscle
• Presents with profound hypotonia & weakness, little
spontaneous movement (resembles SMA)
• Later develop dementia
POMPE DISEASE
• Massive cardiomegaly
• Liver firm but usually
not enlarged unless CHF
• Usually die by 1-2 years
of age
• Acid maltase deficiency
 glycogen storage
POMPE DISEASE
• Treatment with alglucosidase alfa approved by FDA
in 2006
• Early treatment (compared to an untreated historical
control group)
– Reduced the risk of death by 99%
– Reduced the risk of death or any type of ventilation by
88%
– Significantly improved motor and cognitive development
• Basis of movie Extraordinary Measures
• Cost: $60-400,000 per year
LEIGH SYNDROME (subacute necrotizing
encephalomyelopathy)
• Onset in early infancy (60% in 1st year) or childhood;
rarely in adulthood
• Neonatal form
– Acidosis
– Severe retardation
– Usually early death
• Other types with variable clinical picture:
– Steadily progressive, saltatory, or episodic
– May progress with intercurrent infections
– Typically associated with lactic acidosis
LEIGH – Symptoms and signs
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Retarded motor and intellectual development
Respiratory disturbances
Ophthalmoplegia
Dysphagia and weight loss
Vomiting
Hypotonia & weakness
Ataxia
LEIGH – Symptoms and signs
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Seizures
Visual loss
Nystagmus
Dystonia
Peripheral neuropathy (often subclinical)
Fevers
LEIGH - Pathology
• Brainstem and basal
ganglia lesions
common
• Necrosis around 4th
ventricle and
aqueduct.
• Distribution resembles
Wernicke's without
mammilary bodies and
without hemorrhage
Figure 1. Sequential FLAIR (fluid-attenuated inversion recovery) MR images of the brain
Goldenberg, P. C. et al. Neurology 2003;60:865-868
LEIGH - Multiple specific causes
• Generally defects in
energy metabolism
• Lactate elevated in
most patients in some
phase of illness, CSF >
blood
LEIGH - Genetics
• Usually due to
nuclear gene
mutation (autosomal
recessive)
• Minority due to
mitochondrial DNA
abnormality
(maternal)
INFANTILE NEUROAXONAL DYSTROPHY (INAD)
• Onset age 6 months-3 years (classic form)
• Slowly progressive
• Combination of lower, then upper
motoneuron signs:
– Falling, clumsiness
– Hypotonia, hyporeflexia with normal NCV's
– Later, spasticity
INFANTILE NEUROAXONAL DYSTROPHY
• Also later
– Optic atrophy, blindness
– Involuntary movements, dystonia, decerebrate
rigidity
– Dementia
– Seizures occur in a minority of pts
• NCV's normal; EMG's suggest denervation
• Autosomal recessive
INFANTILE NEUROAXONAL DYSTROPHY
• Iron in globus pallidus in 40-50%
• Cerebellar atrophy
INFANTILE NEUROAXONAL DYSTROPHY
• Pathology
– Axonal spheroids in medulla
(cuneate, gracilis), pons,
thalamus, and peripheral
nerve
INFANTILE NEUROAXONAL DYSTROPHY
• Optic atrophy and MRI are helpful in suspecting
diagnosis
• Resembles PKAN (pantothenate kinase-associated
neurodegeneration; Hallervorden-Spatz) but no “eye
of the tiger” sign
• Diagnosis in the past: skin or conjunctival biopsy;
spheroids in nerves
• PLA2G6 mutations found in 95% of patients (gene
found 2006)
– Calcium-independent phospholipase A2, catalyzing the
hydrolysis of glycerophospholipids, probably causing membrane
pathology
"CEREBRAL" GM1 GANGLIOSIDOSIS (TYPE II)
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Normal until 6-14 months, then regress
Hyperacusis, ataxia, dysarthria, strabismus
Then mental regression, spasticity, and seizures
No organomegaly or macular degeneration
ß-galactosidase deficiency
INFANTILE NEURONAL CEROID LIPOFUSCINOSIS
(Santavuori-Haltia)
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Onset 2nd year of life; occasionally by 8 months
Rapid deterioration (weeks to months)
Myoclonus
Visual loss; retinal degeneration; blind by age 2-3
Dementia
Loss of motor skills
INFANTILE NEURONAL CEROID LIPOFUSCINOSIS
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Acquired microcephaly and severe cerebral atrophy
Vegetative state, with death usually by 5-10 years
Seizures occur, but not prominent
Leukocytes, skin, conjunctiva, rectum: granular
inclusions
CASE
INFANTILE, WITH
VISCERAL STORAGE
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Generalized GM1 gangliosidosis
Gaucher's (infantile)
Niemann Pick, type A
Sandhoff
Wolman's
Glycolipid and glycoprotein disorders (fucosidosis,
mannosidosis, sialidosis, I-cell disease)
GENERALIZED GM1 GANGLIOSIDOSIS (TYPE I)
• Feeding difficulty plus failure to thrive noted soon
after birth
• Poorly responsive
• Hypoactive
• Hypotonic
• Hyperacusis
• Cherry-red spot in about half
GENERALIZED GM1 GANGLIOSIDOSIS (TYPE I)
• Edema of face and extremities
• Bone changes
– Long bones wide in center, tapered at end
– Vertebral hypoplasia and beaking
• Hepatosplenomegaly
• Corneas clear
• Store ganglioside in brain and mucopolysaccharide
in viscera and bone
• ß-galactosidase deficiency
• Usually die in first 1-2 years
GAUCHER DISEASE
(TYPE II; Acute Neuronopathic)
• Rapid (1-3 year) course
• Onset usually by 3-6
months
• Retrocollis
• EOM defects
• Bulbar signs
– Sucking, swallowing
dysfunction
– Facial palsy
GAUCHER DISEASE (TYPE II)
• Irritability
• Later signs and symptoms
– Dementia
– Spasticity
– Ataxia
– Rare seizures
– Trismus and stridor
• Normal fundi
GAUCHER DISEASE (TYPE II)
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Splenomegaly > hepatomegaly
Bones thinned; pathologic fractures common
Pulmonary infiltrates
Do not have Hurler phenotype
Glucocerebrosidase deficiency
GAUCHER DISEASE (TYPE II)
• Can diagnosed by
Gaucher cells in bone
marrow
• Neuropathology:
– Little lipid storage
– Neuron loss,
especially in
brainstem
GAUCHER DISEASE (Type I; Adult)
• Most common
• Nervous system not involved
• Treatment with
– Replacement enzyme
– Miglustat (Zavesca)
• Inhibitor of glucosylceramide synthase, needed for
synthesis of most glycospingolipids
• Prevents accumulation of glucosylceramide
• Also used in other forms of Gaucher, NP-C, GM1, and
Tay Sachs
NIEMANN-PICK DISEASE, TYPE A (ACUTE
NEUROPATHIC)
• Like Gaucher's, plus cherry-red spot in ~25-50%
• Onset 3-9 months of life
• Hepatomegaly > splenomegaly (often initial
presentation)
• Progressive intellectual and motor deterioration
• Feeding difficulty and failure to thrive
• Seizures infrequent
NIEMANN-PICK DISEASE, TYPE A (ACUTE
NEUROPATHIC)
• Pathology
– Ballooned neurons
– Vacuolated histiocytes and
lymphocytes (NiemannPick cells)
• Sphinomyelinase
deficiency
• Autosomal recessive
• Frequently Jewish
CASE
• Visceromegaly
• Hexosaminidase A & B deficiency
LATE INFANTILE,
WITHOUT VISCERAL STORAGE
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Neuronal ceroid lipofuscinosis
Juvenile Tay-Sachs
Progressive myoclonus epilepsies
Huntington's chorea
Xeroderma pigmentosa
NEURONAL CEROID LIPOFUSCINOSIS
• Usually autosomal recessive
• Numerous eponyms, mixed features
• Enzyme and genetic testing has generally
replaced biopsies
• Defects in lysosomal function
NEURONAL CEROID LIPOFUSCINOSIS
Type
Infantile:
INCL, CLN1
Late-infantile: LINCL,
CLN2
Juvenile:
JNCL, CNL3
Adult:
ANCL, CNL4, 5
Eponyms
Santavuori-Haltia
Jansky-Bielschowsky
Spielmeyer-Sjögren;
Spielmeyer-Vogt;
Batten
Kufs (AR)
Parry (AD)
Usual age of onset
6-24 months
2-4 years
4-10 years
Variable; usually 2nd-3rd
decade
Course
Rapid
Rapid
Slower
Slow
Age at death
5-10 years
8-12 years
15-25 years
Variable
Manifesting symptoms
Myoclonus, visual loss
Seizures, particularly
myoclonic
Visual loss, dementia
Extrapyramidal signs, ataxia
Other symptoms
Dementia, seizures,
ataxia, acquired
microcephaly
Ataxia, dementia, late
visual loss
Seizures (less
prominent),
dysarthria,
extrapyramidal signs
Myoclonus, dysarthria,
seizures, personality changes,
neuropathy
Retina
Nonpigmentary
degeneration
Pigmentary
degeneration
Pigmentary
degeneration
Normal*
ERG
Decreased
Decreased
Absent
VER
Decreased
Increased
Absent
Membranous inclusions
Granular
Curvilinear or
rectilinear
Fingerprints; vacuolated lymphocytes
Granular
NEURONAL CEROID LIPOFUSCINOSIS
Type
Infantile:
INCL, CLN1
Late-infantile:
LINCL, CLN2
Juvenile:
JNCL, CNL3
Adult:
ANCL, CNL4, 5
Eponyms
Santavuori-Haltia
JanskyBielschowsky
SpielmeyerSjögren;
Spielmeyer-Vogt;
Batten
Kufs (AR)
Parry (AD)
Enzymatic defect
Palmitoyl protein
thioesterase
(PPT)
Pepstatininsensitive
lysosomal
peptidase—
tripeptyidyl
peptidase 1
(some pts)
CLN3 protein;
trans-membrane
chaparone,
involved in
folding of other
proteins
?
Also PPT in one
family
Lysosomal
accumulation
Sapsosin A, B
Subunit C of
mitochondrial
ATP
Subunit C of
mitochondrial
ATP
Subunit C of
mitochondrial
ATP
Genetic defect
CLN1/PPT1
1p32
CLN2/TPP1
11p15.5
CLN3
16p12.1
CLN4
Mixed findings
From
Genetests.org
Epilepsy
gene panel!
NEURONAL CEROID LIPOFUSCINOSIS
Pathology
• Atrophy of both gray and white matter
– Cerebral > cerebellar
– Cerebellar prominent in CLN2
– Almost complete loss of cortical neurons in CLN1
• Lipopigments in neurons, glia, endothelial cells, liver,
skin, WBCs, etc.
• Retinal necrosis; almost complete loss of
photoreceptors
NEURONAL CEROID LIPOFUSCINOSIS Pathology
• Vacuolated
lymphocytes in CLN3
Bovine model of NCL
Retina atrophy
Granular osmophilic deposits
Curvilinear inclusions
Fingerprint inclusions
NEURONAL CEROID LIPOFUSCINOSIS
Imaging
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•
•
Atrophy
Hypointense thalami on T2
Progressive WM signal on T2
↓ ↓ N-acetylaspartate on MRS
Now 14 NCL variants
JUVENILE TAY-SACHS
(PARTIAL GM2 GANGLIOSIDOSIS)
• Variant 1
– Typical "gray matter disease“
• Seizures and dementia
• Cerebellar and basal ganglia dysfunction
• No cherry-red spot
• Onset 5-10+ years, with 5-10 year course
• Variant 2
– More like spinocerebellar degeneration
– Onset between age 2 and adulthood
CASE
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•
•
•
5 y.o.
Visual loss
Starts losing cognition
Age 8: a few seizures
LATE INFANTILE,
WITH VISCERAL STORAGE
• Gaucher Type III
• Niemann Pick, type C
• Mucopolysaccharidoses
– Hurler's
– Hunter's
– Sanfilippo's
GAUCHER DISEASE
(Type III; Chronic Neuronopathic)
• Slower course
– Onset early childhood to adult
– Mild to severe mental retardation
– Seizures and myoclonus (progressive myoclonus epilepsy)
– Spasticity
– Cranial nerve dysfunction
– Eye movment abnormalities (e.g., oculomotor apraxia with
failure of saccadic initiation, supranuclear gaze palsy)
– Splenomegaly
NIEMANN-PICK, TYPE C
(CHRONIC NEUROPATHIC)
• Similar to type A but onset later (> 2 years) and
slower progression
• Can have hepatic disease due to cholestasis even in
neonatal period
• Mild splenomegaly
• Dementia
• Marked spasticity
• Apraxia of vertical gaze
NIEMANN-PICK, TYPE C
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•
•
•
•
•
Ataxia
Cataplexy
Generalized tonic-clonic and myoclonic seizures
Some with cherry-red spot
Most die before age 10-15
Sphinomyelinase deficiency
1. Cherry red spots can be seen in all but which
of the following disorders?
A.
B.
C.
D.
E.
Tay Sachs
Generalized GM1 Gangliosidosis
Infantile Neuroaxonal Dystrophy
Niemann Pick type A
Farber lipogranulomatosis
2. A 3-month-old boy comes in with seizures,
subdural hemorrhages, and rib fractures.
What metabolic disorder should be
suspected?
A.
B.
C.
D.
Leigh
Niemann-Pick type A
Alper
Menke
3. Match the disorder with other organ involvement:
Alper
Retina
Pompe
Heart
Neuronal ceroid
lipofuscinosis
Blood vessels
Gaucher
Liver
Farber
lipogranulomatosis
Joints
Menke
Spleen
4. Which symptom is not common in girls with
Rett syndrome?
A.
B.
C.
D.
E.
Perseverative speech
Hand wringing
Bruxism
Hyperventilation
Aerophagia
5. Match the disease and the gene or enzyme:
Rett
Hexosamindase A
Alper
PLA2G6
Tay Sachs
Acid maltase
Niemann Pick
Mitochondrial DNA
polymerase gamma
(POLG)
MeCP2
Pompe
Infantile neuroaxonal
dystrophy
Sphingomyelinase
6. Which of the following is considered a
mitochondrial disorder?
A.
B.
C.
D.
E.
Pompe
Leigh
Tay Sachs
Gaucher
Neuronal ceroid lipofuscinosis
7. For each of the neuronal ceroid lipofuscinoses,
check off the most prominent initial symptoms.
Seizures
Infantile
Late infantile
Juvenile
Adult
Visual loss
Myoclonus
Dementia
Extrapyramidal sx’s,
ataxia
7. For each of the neuronal ceroid lipofuscinoses,
check off the most prominent initial symptoms.
Seizures
Infantile
Late infantile
Juvenile
Adult
Visual loss
Myoclonus


Dementia
Extrapyramidal sx’s,
ataxia
7. For each of the neuronal ceroid lipofuscinoses,
check off the most prominent initial symptoms.
Seizures
Infantile
Late infantile
Juvenile
Adult

Visual loss
Myoclonus


Dementia
Extrapyramidal sx’s,
ataxia
7. For each of the neuronal ceroid lipofuscinoses,
check off the most prominent initial symptoms.
Seizures
Infantile
Late infantile
Juvenile
Adult
Visual loss
Myoclonus


Dementia



Extrapyramidal sx’s,
ataxia
7. For each of the neuronal ceroid lipofuscinoses,
check off the most prominent initial symptoms.
Seizures
Infantile
Late infantile
Juvenile
Adult
Visual loss
Myoclonus


Dementia
Extrapyramidal sx’s,
ataxia




8. Name the metal associated with the disease:
A. Menke:
Copper
B. Infantile Neuroaxonal Dystrophy:
Iron
9. Match the disease and pathological finding:
Infantile neuroaxonal dystrophy
Glycogen storage
Alper
Pili torti
Tay Sachs
Ballooned cells with “torpedoed”
axons
Neuronal ceroid lipofuscinosis
Spheroids
Pompe
Curvilinear, fingerprint, and
granular osmophilic inclusions
Menke
Laminar cortical degeneration
Case #1: girl with slow regression
• Normal motor and cognitive development until age 2
• Then gradually lost ability to verbalize, with slower loss of
comprehension
• Progressive ataxia and weakness. Using walker by age 3.
Stopped crawling by age 4.
• Exam: No HSM. Followed a few commands. Nonverbal.
Hypotonic but with spastic catch. Weak. Hyporeflexic. Ataxic.
• Later, visual loss, seizures, hypertonicity, hyperreflexia
• MRI: cerebellar and brainstem atrophy
• EMG and nerve bx: mild axonopathy
• Died age 10
• Dx: infantile neuroaxonal dystrophy
INFANTILE NEUROAXONAL DYSTROPHY (INAD)
• Onset age 6 months-3 years (classic form)
• Slowly progressive
• Combination of lower, then upper
motoneuron signs:
– Falling, clumsiness
– Hypotonia, hyporeflexia with normal NCV's
– Later, spasticity
INFANTILE NEUROAXONAL DYSTROPHY
• Also later
– Optic atrophy, blindness
– Involuntary movements, dystonia, decerebrate
rigidity
– Dementia
– Seizures occur in a minority of pts
• NCV's normal; EMG's suggest denervation
• Autosomal recessive
INFANTILE NEUROAXONAL DYSTROPHY
• Iron in globus pallidus in 40-50%
• Cerebellar atrophy
Case #2: girl with slow regression
• History of 32-week prematurity and neonatal hepatitis, HSM that
resolved.
• Started walking at 17 months, always a toe-walker. Delayed but could
ride a bike at age 5.
• Seizures starting at 18 months.
• Age 6 began to have spells of becoming limp and falling when she was
excited.
• When she presented to us at age 5, she was microcephalic, and had
oculomotor apraxia, truncal hypotonia but tight heel cords, dysmetria
and ataxia.
• Progressive ataxia, dysphagia, loss of speech, and loss of ability to
voluntarily look up, then down (but could be “dolled”).
• Died age 10
• Dx: Niemann-Pick, type C
NIEMANN-PICK, TYPE C
(CHRONIC NEUROPATHIC)
• Similar to type A but onset later (> 2 years) and
slower progression
• Can have hepatic disease due to cholestasis even in
neonatal period
• Mild splenomegaly
• Dementia
• Marked spasticity
• Apraxia of vertical gaze
NIEMANN-PICK, TYPE C
•
•
•
•
•
•
Ataxia
Cataplexy
Generalized tonic-clonic and myoclonic seizures
Some with cherry-red spot
Most die before age 10-15
Sphinomyelinase deficiency
Case #3 – boy with rapid regression
• Normal until 7 months
• Then low grade fever without source, fussy, and
regressed
• Stopped rolling, scooting; lost head control. Weaker
on left.
• Initially very floppy but progressively hypertonic.
• Regressed episodically. Frequent fevers.
• Progressive dysphagia, and stopped feeding.
Hyperventilation.
• Infantile spasms
• Brother with same problem but slower
progression
• No known consanguinity but from “very stable
community”
• Exam: truncal hypotonia, limb hypertonia,
brisk DTRs
• Lactate 29 (up to 2.2); pyruvate 1.2
• MRI: high T2 signal in basal ganglia
• Brother had similar MRI
• Died age 2-1/2
• Brother died age 14 years
• Dx: Leigh syndrome
LEIGH SYNDROME (subacute necrotizing
encephalomyelopathy)
• Onset in early infancy (60% in 1st year) or childhood;
rarely in adulthood
• Neonatal form
– Acidosis
– Severe retardation
– Usually early death
• Other types with variable clinical picture:
– Steadily progressive, saltatory, or episodic
– May progress with intercurrent infections
– Typically associated with lactic acidosis
LEIGH – Symptoms and signs
•
•
•
•
•
•
•
Retarded motor and intellectual development
Respiratory disturbances
Ophthalmoplegia
Dysphagia and weight loss
Vomiting
Hypotonia & weakness
Ataxia
LEIGH – Symptoms and signs
•
•
•
•
•
•
Seizures
Visual loss
Nystagmus
Dystonia
Peripheral neuropathy (often subclinical)
Fevers
LEIGH - Pathology
• Brainstem and basal
ganglia lesions
common
• Necrosis around 4th
ventricle and
aqueduct.
• Distribution resembles
Wernicke's without
mammilary bodies and
without hemorrhage
Figure 1. Sequential FLAIR (fluid-attenuated inversion recovery) MR images of the brain
Goldenberg, P. C. et al. Neurology 2003;60:865-868
Case #4 – a true unknown!
How would you work him up?
• 11 y.o. boy seen in clinic for developmental
decline and myoclonus
• PLD normal
• Early development normal; “riding twowheeler at age 2”
• Age 4: began to be rigid in his routines;
sensitive to a variety of stimuli
• KG: reading 10 words, c/w 20-word average;
not counting as high
Age 6: 1st seizure; clonic; focal EEG (posterior)
Development plateaued
Seizure-free on oxcarb until age 10
Then recurrent clonic seizures, affecting either
or both sides of body
• Frequent generalized myoclonic jerks
• Starting at age 10, progressive ataxia,
cognitive loss, dysarthria
•
•
•
•
– Now crawls to ambulate
– Comprehension ok and good sense of humor;
difficulty thinking of words
Work-up?
• Whole exome analysis
•News since the 2014 talk!
• Late infantile NCL (Epi gene panel)
Case #2
• GM1 37117055
Case #4
• Juvenile TS
Tips for next talk
• Add CDG? 33051487 – no; do as clinic 10:00 case.
• Timing was fine. A little dry in the middle. Cases are good
idea.
• Perhaps add a brief case at the end of each of the 4 sections.