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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.

drmankad@gmail.com+44 7861639010Tweet @drmankad