early onset neurodegenerative diseases
TRANSCRIPT
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Early Onset Neurodegenerative Diseases
Dr. Kish Mankad MRCP, FRCR
Consultant Pediatric Neuroradiologist & Associate Professor
Great Ormond Street Hospital for Children, London, UK
@drmankad No disclosures
What is a Neurodegenerative disorder?
‘The hallmark of neurodegenerative disease is regression and progressive deterioration of neurologic function with loss of speech, vision, hearing or locomotion, and associated with seizure, feeding difficulties and impairment of intellect.’
When to suspect it early?
• Stormy unexplained neonatal course
• Early Infantile Epileptic Encephalopathy [EIEE]- several genes
• Rapid clinical deterioration with triggers (like infection)
Baby 1: 30 weeks, PROM, poor Apgar's, hypotonic at birth
Baby 2: 40 weeks, uterine rupture , poor Apgar's, jittery at birth
Baby 3: 37 weeks, poor feeding, returns 3d later with seizures
Baby 4: 40 weeks, maternal GBS, flat at birth with odd eye movts
Baby 5: 37 weeks, planned CS, returns 2/52 later with hypotonia
Microcephaly with seizures
Macrocephaly with seizures
Microcephaly with seizures
Macrocephaly with seizures
Clinical Clues
• Tone
• Organomegaly - liver, spleen
• Systemic dysfunction
• Coarse facies
• Eyes- pigmentary retinopathy, cataract
• And…..a movement disorder
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9 month old boy with yes-yes head bobbing, no nystagmus, mild global delay
Head bobbing DD
• Spasmus nutans (with nystagmus)
• Rhombencephalosynapsis
• 3rd ventricular lesion (bobble head doll syndrome)
Cluster 1 Neuronal
• Alpers-Huttenlocher Syndrome
• Epileptic Encephalopathies
• Neuronal Brain Iron Accumulation Disorders (axonal dystrophies)
• Rett Syndrome
45 week old girl with epilepsia partialis continuaAlpers syndrome: Progressive neuronal degeneration of childhood with liver disease [PNDC]
Greenfields Neuropathology
• Hepatorenal syndrome• Nuclear gene that encodes for mitochondrial DNA polymerase gamma POLG• First 2 years of life, seizures and developmental stagnation, followed by spasticity, dementia • Selective involvement of the medial occipital lobe, especially the calcarine cortex• Vacuolation, neuronal loss, astrocytosis- progressive scarring
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Cluster 2 Leukodystrophies/Leukoencephalopathies• Alexander Disease
• Megalencephalic Leukoencephalopathy with Subcortical Cysts
• Pelizaeus-Merzbacher Disease
• Spongy Leukodystrophy (Canavan Disease)
• Vanishing White Matter Disease
• Aicardi-Goutieres Leukoencephalopathy
• Cockayne Syndrome
9 month old boy with spasticity, dysphagia
23 months later after trauma Cluster 3 Disorders of Amino Acid Metabolism
• Hyperphenylalaninaemic Syndromes
• Non-ketotic Hyperglycinaemia
• The Homocystinurias
• Propionic Acidaemia
• Methylmalonic Acidaemia
• Maple Syrup Urine Disease
• Glutaric Aciduria Type 1
• Urea Cycle Disorders
Cluster 4 Neurometabolic
• Congenital Disorders of Glycosylation
• Molybdenum cofactor deficiency
• Menkes disease
• Succinic semialdehyde dehydrogenase deficiency [SSADHD]
• Pyridoxine-dependent epilepsy
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1 day old girl
Molybdenum Cofactor Deficiency
Neuroradiology tips: Which central system is primarily affected?
•Cerebellum
•Pyramidal/Extrapyramidal system
•Mitochondrial? Lysosomal? Peroxisomal?
10 m
22 m
Respiratory Chain Disorders- ‘energy dependant parts’
Courtesy: Dr Kling Chong
F13m; Floppy, cherry-red spot macula
Infantile Tay-Sachs diseaseGM2 gangliosidosis a.k.a.
Hexosaminidase A deficiency,
HEXA gene mutation
CLN2
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M8m severe delay, irritable, tone; calcified WM tracts
Leukodystrophy; dark thalamus ; large optic nerves
Krabbe disease: a.k.a. globoid cell leukodystrophy
or galactosylceramide lipidosis, GALC gene mutation End-stage Krabbe disease
Peroxisomal Biogenesis Disorders
Zellweger Syndrome Adrenoleukodystrophy
Key messages
•Mitochondrial / Respiratory chain• Brainstem; cerebellum; deep grey nuclei
• Lysosomal• Thalamus; Hypomyelination-Dysmyelination
• Peroxisomal• Cerebellum; posterior WM; malformations
Reflection piece
Group 1: Disorders which give rise to intoxication
Group 2: Disorders involving energy
metabolism
Group 3: Disorders involving complex
molecules
Amino acidOrganic aciduria
UCD
MitochondrialCCDS
LSDPeroxisomal
CDG
Treatable entities- where you must add value
• Cerebral folate deficiency [FOLR1]
• Thiamine deficiency syndromes [SLC19A3]
• Pyruvate dehydrogenase complex deficiency [PDHA1, DLAT..]
• Biotinidase deficiency [BTD]
• Coenzyme Q10 deficiency [COQ8A, PDSS2..]
• Creatine deficiency [GAMT]
• Wilsons disease [ATP7B]
• Hypermanganesemia [SCL30A10, SLC39A14]
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2 year old boy, unspecified motor abnormality, hypotonia, epileptic spasms in clusters.
EEG: Generalized interictal epileptiform discharges with bilateral occipital slowing.
Case
Short TE (30 msec) Long TE (270 msec)
Cerebral Creatine Deficiency Syndrome
11 years old girl with acute encephalopathy and dystonic movements
Biotin Thiamine Responsive Basal Ganglia DiseaseSCL19A3 mutation
9y, girl with neuropsychiatric manifestations and dystonia
Wilson’s Disease
17 year old girl
Manganese transporter defect
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Pyruvate Dehydrogenase Deficiency
Biotinidase deficiency
19 month old boy with developmental delay, ataxia and high blood lactate level.
The common thread
Canavan's GA-1 MLC L2-OH
Large head & leukodystrophy
•Alexander disease
•Canavan’s disease
•MLC (Megalencephalic Leukodystrophy with Cysts)
•Glutaric Aciduria Type 1
•GM2 gangliosidosis (Tay Sach, Sandhoff)
• L-2-hydroxyglutaric aciduria
Treatable entities- a kind reminder
• Cerebral folate deficiency [FOLR1]
• Thiamine deficiency syndromes [SLC19A3]
• Pyruvate dehydrogenase complex deficiency [PDHA1, DLAT..]
• Biotinidase deficiency [BTD]
• Coenzyme Q10 deficiency [COQ8A, PDSS2..]
• Creatine deficiency [GAMT]
• Wilsons disease [ATP7B]
• Hypermanganesemia [SCL30A10, SLC39A14]
Treatable, but scans normal..
• Monoamine neurotransmitters
• Glucose Transporter type 1 (GLUT 1) deficiency syndrome
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Beware the evolving motor disorder
•Progressive spasticity
•Progressive dystonia
•Progressive ataxia
Dystonia: sustained involuntary contractions
•Hyperkinetic
•Non-progressive
• Progressive
Courtesy: Dr Nagi Barakat
Primary Dystonia
PKAN
PLAN
5 year old girl- seizures, spasms, dystonia, chorea, ADHD, ASD, oppositional defiant disorder.
Juvenile Huntington’s Disease
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Ataxia: impaired voluntary coordination
• +Eye• +Speech• +Gait• +Tremor• +Spasticity
• Acute- Toxic/ Autoimmune/ Trauma/ Neoplasm• Intermittent- IEM/ Genetic• Chronic nonprogressive- Malformations/ Genetic• Chronic progressive- Neurodegenerative
TIGROID PONS
Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay
SACS
Piecing the imaging and patient together
Child A Child BCourtesy: Dr Biju Hameed Under review
Periventricular Leukomalcia
SPG 11: HSP
Selective Dorsal Rhizotomy
Thank you.
[email protected]+44 7861639010Tweet @drmankad