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KK Paediatric Neurology study > Neurodegenerative and movement disorders > Flashcards

Neurodegenerative and movement disorders Flashcards

1
Q

Describe the development of the neural tube

A
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2
Q

Describe the physiology of the parasympathetic and sympathetic nerves (pre and post ganglionic neurons)

A
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3
Q

Describe T1/T2/FLAIR/SWI/DWI - what are they useful to see?

A
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4
Q

Describe (draw) the progression of :

  1. early onset, non-progressive
  2. acute onset, non-progressive
  3. progressive disorders
A
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5
Q

Differential diagnosis of neurodegenerative conditions?

A

Frequent Seizures (epileptic encephalopathy)

Drug toxicity

Infection

Psychological/emotional

Autism

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6
Q

What are some treatable DDx of neurodegenerative conditions that should be rigorously excluded?

A

Inborn errors (PKU, Wilson’s, Pyridoxine dependency)

Neoplasms

Infections: TB

Intoxications: Lead

Deficiency: B12

Hydrocephalus

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7
Q

What are the two major groups of neurodenerative conditions?

A

Leukoencephalopathies

  • Problems of Myelin

Others:

  • Metabolic, genetic
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8
Q

What are the differentiating features of white matter vs. gray matter disorders?

A
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9
Q

What are some clues/alarm bells when it comes to neurodegenerative conditions?

A

Prior normal development followed by regression/cognitive decline

Sensorineural deafness

Pigmentary retinopathy

Myoclonus

Epilepsy

Movement disorder

Poor recovery from viral illness, general anaesthesia (energy disorder)

Ptosis, myopathy, cardiomyopathy

Decompensation after fasting

Food aversions – protein, sugars

  • Eg: minor urea cycle disorders

Multi-organ system involvement

Deterioration in school performance, personality or new-onset hyperactivity in adolescent male

Rule out: inflammatory diseases, brain tumours, obstructive hydrocephalus, vascular disorders (moyamoya, sickle cell, arteriovenous malformations)

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10
Q

What are some differentiating exam features of neurodegenerative disorders on eye exam?

A

Eyes:

Cherry red spot

  • ¨Tay Sachs
  • ¨Neimann Pick
  • ¨GM 1 gangliosidosis

Cataracts

  • ¨Galactosemia
  • ¨Lower Syndrome

Corneal clouding

  • ¨MPS

Retinal dystrophy

  • ¨Peroxisomal disorders
  • ¨Mitochondrial diorders
  • ¨Neuroceroid lipfuscinosis

Eye movement disorder

  • ¨Neimann-pick type c (chaotic eye movements)
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11
Q

What are some differentiating exam features with head size/visceral enlargement and skeletal abn in neurodegenerative disorders?

A

Head Size

  • ¨Macrocephaly
    • ¨Alexanders
    • ¨Canavans
    • ¨MPS
  • ¨Microcephaly

Visceral enlargement

  • ¨Gauchers
  • ¨Neimann-Pick
  • ¨Hurlers
  • ¨GSD
  • ¨GM gangliosidosis

Skeletal Abnormality

  • ¨Hurlers
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12
Q

What are some of the abnormal myelination patterns with leukoencephalopathies?

A
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13
Q

What is the pathological classification of leukoencephalopathies?

A

Pathological Classification

Demyelinating (broken down)

  • Eg: Adrenoleukodystrophy

Dysmyelinating (Abnormally formed)

  • Eg: Metachromatic leukodystrophy

Hypomyelinating (never formed)

  • Eg: Pelizaeus Merzbacher Disease

Spongioform (Cystic degeneration)

  • Eg: Canavan’s Disease
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14
Q

Describe the biochemical classification of leukoencephalopathies

A

Biochemical Classification

Lipid disorders

  • ALD, Krabbe, MLD

Myelin protein disorders

  • Pelizaeus Merzbacher, Myelin basic protein deficiency

Organic Acid disorders

  • Canavan’s

Defects of energy metabolism

  • MELAS, Leber, Complex 1, III, COX

Other

  • CADASIL, Merosin deficiency, Alexanders
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15
Q

What is the genetics and classification of Krabbe disease?

A

Autosomal recessive, Lysosomal storage disorder

Deficiency of galactocerebrosidase

  • mt in Glycosylceramidase gene (GALC)
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16
Q

What is the clinical progression of Krabbe disease

A

Clinically:

Rapidly progressive

  • Infantile form: 3-4mo old with irritability, psychomotor deteriorations, seizures, spasticity and myoclonus.
  • Absent deep tendon reflexes
  • Death 4-5 years
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17
Q

What are imaging findings in Krabbe disease?

A
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18
Q

What is the genetics and classification of metachromatic leukodystrophy?

A

Autosomal recessive – Lysosomal storage dysorder

mt in Arylsulfatase A

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19
Q

What is the clinical presentation and progression of metachromatic leukodystrophy?

A

Infantile type (80%)

  • Onset 2nd year
  • Regression, ataxia, optic atrophy
  • Death months-years

Late Infantile type

  • Early dev normal
    • By 30mo – regression, neuropathy, optic atrophy, death by 5-10yrs
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20
Q

How to diagnose Metachromatic leukodystrophy?

A

Dx: Clinical, imaging, CSF, EEG, deficient arylsulftase A

  • decreased arylsulftase A Plasma / Urine
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21
Q

What are the classic imaging features of metachromatic leukodystrophy?

A
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22
Q

What are the different leukoencephalopathies?

A

Peroxisomal disorders

  • Disorders of lipid metabolism

Adrenoleukodystrophy

Adrenomyeloneuropathy

Zellweger syndrome

Refsums disease

Rhizomelic chondrodysplasa punctata

Pipecolic acidaemia

Actalasia

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23
Q

What is the genetics and overall progression of adrenoleukodystrophy?

A

X-linked recessive peroxisomal disorder

  • Progressive CNS dysfunction
  • Adrenal cortical failure
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24
Q

What are the clinical features of Adrenoleukodystrophy?

A

Clinical features – variable

  • Neurological deterioration precedes adrenal unsufficiency (85%)
    • Onset 5-10yrs (childhood)
    • Behaviour change most common first sign
    • Then poor school performance
    • Gait disturbance, poor coordination, loss of vision, hearing and progression to vegetative state
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25
Q

What are the different forms/presentations of adrenoleukodystrophy?

A

Forms/presentations:

  • Childhood cerebral (48%)
  • Adolescent cerebral (5%)
  • Adult Cerebral (3%)
  • Adrenomyeloneuropathy (25%)
  • Addisons only (8%)
  • Symptomatic heterozygote female carriers (10-15%)
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26
Q

How is adrenoleukodystrophy diagnosed?

A

Diagnosis:

  • Clinical history
  • Presence of adrenal insufficiency
  • Laboratory evidence of demyelination
    • CSF protein elevated
    • CT or MRI evidence white matter abnormalities
    • Elevated serum VLCFAs (C26:C22) ratio
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27
Q

What is the genetics cause of Adrenoleukodystrophy?

A

Cause: Mutations in ATP-binding cassette, subfamily D, member 1 (ABSD1) located in peroxisomal membrane protein (ALDP)

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28
Q

What are characteristic features of adrenoleukodystrophy on imaging

A
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29
Q

What are different treatment options for adrenoleukodystrophy?

A

Adrenal sufficiency: Steroids

Lower VLCFAs

  • Dietary restriction
  • Erucic Acid (Lorenzo’s Oil)
    • 4:1 mix of triglyceride forms Oleic acid + Erucic Acid
    • Film ‘’lorenzos oil’
    • Competitive inhibition to decrease VLCFAs (variable effect

Immune modulation

Anti-oxidants (N-acetylcysteine)

Gene Therapy

  • Bone Marrow Transplant (Doesn’t reverse damage / pre symptomatic)
  • Gene replacement therapy
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30
Q

What is the genetics and inheritence of Zellweger Syndrome?

A

Autosomal recessive peroxisomal disorder

  • Mutations in any PEX genes (perixisomal biogenesis)
  • Thus no peroxisomal formation > multi-system disorder
    • Wide spectrum
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31
Q

What are the clinical features of Zellweger syndrome?

A
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32
Q

What are some of the neurological features of Zellweger syndrome?

A

Severe mental retardation / GDD then regression

Hypotonia

Seizures

Sensorineural deafness

Brain malformations

  • Polymicrogyria
  • Abnormal white matter
  • Callosal dysgenesis
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33
Q

Clinical features of Zellweger syndrome?

A
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34
Q

Imaging findings in Zellweger syndrome?

A
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35
Q

Describe the clinical progression of Alexander disease

A

Progressive neurodegenerative diosorder

Early megalencephaly, psychomotor retardation, spasticity, seizures

Death by 6years

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36
Q

How to diagnose Alexander disease?

A

Diagnosis:

  • Clinical history and exam
  • Brain biopsy with rosenthal fibres in perivascular position
  • Cause: Mutation in GFAP – Glial fibrillary acidic protein
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37
Q

Imaging features of Alexander disease?

A
38
Q

Describe the clinical progression of Canavan disease?

A

Developmental regression as infant

Visual loss, progressive macrocephaly

Seizures, spasticity, optic atrophy

Death in childhood

39
Q

How to diagnose Canavan disease?

A

Diagnosis:

  • Clinical hx + macrocephaly
  • Imaging with macrocephaly and diffuse subcortical and periventricular white matter abnormalities
  • Increased NAA peak on MRS (N-acetyl Aspartate)
  • Aspartoacylase deficiency with N-acetylaspartic aciduria
  • Mutations in Aspartoacylase gene (ASPA)
40
Q

What is the genetics and classification of Pelizaeus-Merzbacher disease?

A

Myelin protein disorder

Hypomyelinating leukoencephalopathy

Genetics

  • X-linked mutations in Proteolipid protein 1 gene (PLP1)
  • A related disease “Peliaeus-Merzbacher-like disease
    • Gap junction alpha 12 gene (GJA12)
41
Q

What is the clinical progression of Pelizaeus-Merzbacher Disease?

A

Clinical

  • Progress psychomotor retardation
  • Nystagmus, choreoathetosis with ataxia
  • Death in 2nd decade
  • Co-natal form: shortly after birth
    • Aggresive course: severe hypotonia and feeding difficulties
42
Q

What are classic imaging findings for Pelizaeus-Merzbacher disease?

A
43
Q

Describe the clinical presentation of Neimann-Pick Disease?

A

Clinical:

  • Acute forms (IA and IIA) – rapid progression of hepatospleenomegaly and neurological deterioration with death by 6yrs
  • Subacute forms (1S and IIS) slowly progressive
  • If neurologically deteriorating, death in 2-3rd decade
    • Autosomal recessive
    • Sphingomyelinase deficiency
    • Cherry red spot macula may be seen
  • Type C (for chronic) is usually adult onset but may present with neonatal hepatitis and oculomotor apraxia
44
Q

How to diagnose Neimann-Pick Disease?

A

Diagnosis: Clinical findings, vacuolated histiocytes and demonstration of sphingomyelinase deficiency

Genetics testing available now

45
Q

Describe the clinical presentation of Tay-Sachs disease

A

Clinical:

  • Onset between 3-6mo, higher incidence in jewish
  • An abnormal / excessive startle to noise/light is characteristic first symptom
  • Regression between 4-6 months
  • Cherry red spot is universal
  • Macrocephaly and seizures in second year
  • Death in early years
46
Q

How to diagnose Tay-Sachs disease

A

Dx: hexosaminadase A deficiency

Mutations in hexosaminadase A, alpha polypeptide gene (HEXA)

47
Q

Describe the genetics and pathogenesis in Wilson disease

A

Autosomal recessive disorder of copper metabolism

Mutation in an ATPase – Cu++ transporting beta polypeptide gene (ATP7B) *transports copper accross cell membrane

48
Q

Describe the epidemiology of Wilson disease

A

Prevalence = 30 / million

Carrier frequency = 1 in 90

49
Q

What clinical manifestations occur with Wilson disease?

A

Heterogenous clinical manifestations

Hepatic:

  • Acute liver failure with haemolysis
  • Chronic liver failure with varices

Neurological:

  • Parkinsonism
  • MS-like (but without radiological features)
  • Dystonia
  • Chorea
  • Kayser-fleischer rings usually present when neurological involvement
50
Q

In Wilsons, there is increased T2 signal of:

A

Basal ganglia

  • Caudate
  • Putamen
  • Ventrolateral thalami
51
Q

Describe the overall treatment of Wilson’s disease

A
52
Q

What is Menkes disease?

A

X-linked Defect of copper transport/metabolism with abnormal intracellular utilisation

53
Q

What are the symptoms of Menkes disease?

A

Symptoms secondary to deficiency of copper-dependent enzymes

  • Temperature instability and feeding difficulties as neonate
    • Prematurity is common
  • 1st 3mo: Developmental Regression, seizures, ataxia, slow growth
  • Hypopigmented, sparse, stubby and twisted hair with hypopigmented and hyperextensible skin and hypermobile joints
  • Cerebral neuronal AND arterial degeneration
  • Survival >3yrs rare (but milder variants have lived to 20s
54
Q

How to diagnose Menkes disease?

A

Diagnosis:

  • Clinical hx
  • Sex
  • Decreased Serum copper and cerulosplasmin
  • Gene: ATP7A (copper transporter) Xq13.2-q13.3
55
Q

How to treat Menkes disease?

A

Supportive although IM copper also used

Variable response, better early and for missense (rather than nonsense) mutations

56
Q

Classic MRI findings in Menkes disease?

A
57
Q

What is Neuronal Ceroid Lipofuscinosis?

A

Group of genetic disorders

Lipopigment deposited in neurons and some visceral tissues

Classified by age onset and speed of progression

Most after 2yrs

Most characterised by: dementia + blindness

  • Seizures common
58
Q

How to diagnose Neuronal Ceroid Lipofuscinosis?

A

Dx

  • Characteristic clinical hx
  • Opthalmologic findings
  • Cerebral atrophy
  • Electron microscopy findings on skin, conjunctiva or rectum
  • Genetic testing available for some forms
59
Q

Eye findings in Neuronal Ceroid Lipofuscinosis?

A
60
Q

Describe NCL 1

A

}NCL1: Infantile form (Santavuori type)

}Onset from 2yrs > visual impairment, myoclonus

}Rapid regression, hypotonia, ataxia

61
Q

Describe NCL 2

A

}NCL2: Late Infantile form (Bielschowsky-jansky)

}Later onset 2-4yrs

}Most common form

}Seizure primary initial symptoms (myoclonic)

}Followed by regression. Relentlessly progressive

}Enzyme replacement therapy available

62
Q

Describe NCL 3

A

}NCL3: Juvenile form (Spielmeyer-Vogt-Sjogren)

}Mean onset 6yrs

}Inital: decreasing vision > dementia > seizures

63
Q

What are mitochondrial disorders? How might they present?

A

Disorders of main energy producing organelles

  • Mutations in either mtDNA or nuclear DNA
  • Can be recessive or X-linked or maternal inheritance

Highly variable presentation

  • Any organ system
  • Different manifestations at different ages
  • CNS and PNS often involved
64
Q

When to suspect mitochondrial disorders?

A

Suspect when:

  • Multisystem involvement
  • Multiple-neurological involvement
    • Vision/hearing/ataxia/seizures/neuropathy
  • Signs and symptoms that come and go
  • MRI lesions that change over time
    • Grey + White matter
65
Q

What investigations are needed in suspected mitochondrial disorders?

A

Once needed liver and muscle biopsies for Dx

Blood and CSF lactate may be normal !

Now investigations are genetic – exome/genone/mtDNA

66
Q

What are some mitochondrial diseases with neurological involvement?

A

Leber’s hereditary optic neuropathy (LHON)

Leigh Syndrome = subacute sclerosing encephalopathy

Neuropathy, ataxia, retinitis pigmentosa and ptosis (NARP)

Myoneurogenic gastrointestinal enephalopathy (MNGIE)

Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS)

Myoclonus Epilepsy with Ragged-Red Fibers (MMERF)

Kearns Sayre Syndrome

67
Q

How does Leigh’s disease present?

A

Psychomotor delay / hypotonia in first year

Subsequently:

Abnormal extra-ocular movements

Optic atrophy

Cerebellar dysfunction

Respiratory disturbances

Peripheral neuropathy

Cardiomyopathy

Movement disorder

68
Q

What are the causes of Leigh disease? What might suggest it? What is the typical MRI findings?

A
69
Q

How does Alper’s disease present? What defects are there?

A

Heterogenous group of disorders

  • Characterised by grey matter degeneration > Atrophy
  • Onset <2yrs

Clinically

  • Seizures (myoclonic, epilepsy partialis continua)
  • Bilateral spasticity, blindness, regression
  • +/- hepatic involvement > cirrhosis, liver failure

Many cases genetic with AR inheritance

Defects: Pyruvate metabolism, kreb’s cycle

70
Q

Describe Congenital disorders of glycosylation

A

Deficient or disordered N-glycosylation (sugar attachment) – post translational protein processing

Type 1 Disorders:

Disrupted synthesis of lipid-linked oligosacharide precursor

12 Type 1 variants

Type II Disorders:

Malfunctioning of Trimming/processing of protein-bound oligosacharide chain

6 Type II variants known

71
Q

How might congenital disorder of glycosylation present and how do we test for them?

A

Multiorgan and multisystem

  • Nervous system / intestines / skin / muscles / eyes

Neurological manifestations

  • “malformations”- Cerebellar hypoplasia
  • Ataxia
  • Seizures
  • Retinopathy and optic atrophy

Psychomotor retardation

Behavioural abnormalities

Ataxia

Strokes

Epilepsy

Abnormal eye movements (mainly strabismus, roving eye movements)

Hypotonia

Hyporeflexia

Peripheral neuropathy

Test: Transferrin Isoforms

72
Q

What structural CNS abnormalities might be seen in congenital disorders of glycosylation?

A

Cerebellar hypoplasia

Corpus callosum hypotrophy (underdeveloped)

Dandy Walker Malformation

Brain demyelination

Eye abnormalities

  • Retinopathy
  • Optic atrophy
  • Corneal dystrophy
  • Iris and retinal coloboma
73
Q

What are some genetic disorders that affect synthesis/metabolism of neurotransmitters?

A

There are lots of neurotransmitter systems

  • Each overlap but can have specific problems

Genetic disorders that affect synthesis/metabolism of NTs:

  • GABA:
    • Succinic Semilaldehyde Dehydrogenase Deficiency (SSADH)
  • Dopamine
    • Tyrosine hydroxylase deficiency (TH)
    • Aromatic-L-Amino Acid Decarboxylase Deficiency (AADC)
    • Guanosine Triphosphate Cyclohydrolase I Deficiency (GTPCH)
    • Sepiapterin reductase deficiency (SR)
  • All:
    • Aromatic amino acid decarboxylase deficiency
74
Q

How might neurotransmitter defects present?

A

Dystonia or tremor

Hypotonia or rigidity

Diurnal variation of movement disorder (fluctuation)

Oculogyric crises

Excessive sweating

Temperature instability

Hypoglycaemia

75
Q

What are some neurodegenerative testing options?

A

Urine metabolic screen (screens only a few things)

Plasma amino acids

Urine amino and organic acids

CSF amino acids

CSF neurotransmitters (‘pterin kit’’)

CSF lactate and pyruvate

Paired CSF and blood glucose

Very long chain fatty acids (VLCFAs)

Lysosomal enzymes

Biopsies: Skin/muscle/liver

Opthalmology consult

Metabolic consult

Genetics (Single gene / panel / exome / genome / mtDNA)

76
Q

What disorders might be linked with pathology associated with very long chain fatty acids? (VLCFAs)

A

X-linked adrenoleukodystrophy (ALD)

X-linked adrenmyeloneuropathy (AMN)

Peroxisomal biogenesis disorders (Zellweger spectrum)

Isolated disorders of peroxisomal b-oxidation

77
Q

What are examples of diseases associated with disorders of lysosomal enzymes?

A

Disorders of Lysosomal Enzymes

  • Lysosome: Cytoplasmic vesicles with enzymes that degrade products of cellular catabolism (trash disposal)
  • Deficient: abnormal storage of materials in multiple organs
  • Eg:
    • Mucopolysaccharidoses
    • Krabbe disease
    • Metachromatic leukodystrophy (MLD)
    • Niemann-Pick Disease
    • Tay-Sachs
    • Sandhoff disease
78
Q

How do glucose transporter deficiency present?

A

Seizures: Classically first onset 1-4mo

  • Usually normal EEG unless fasted
  • Expanding phenotype: EOCAE (early onset childhood absence ep)
  • Not known to cause epileptic spasms

Other episodic / paroxysmal non-epileptic events/phenomena

  • Can precede, coincide with or follow seizure onset. Often fatigue related or pre-meals
    • Abnormal episodic eye movements: simulating opsoclonus / chaotic eye movements
    • Intermittent ataxia, dystonia, dysarthria, alternating hemiparesis, headaches, mental confusional episodes, sleep disturbance

Cognitive Impairment moderate learning disability to severe mental retardation

Acquired microcephaly: or more often – deceleration of head growth (not always)

NO dysmorphism

Neurological exam: Variable with pyramidal, extrapyramidal and cerebellar signs. Spasticity/dystonia. Hypotonia/ataxia

79
Q

Describe the diversity of phenotype with glucose transporter deficiency

A

Diversity of Phenotype:

  • No seizures with choreo-athetosis + dystonia
  • No seizures / paroxysmal events with:
    • Mental retardation, ataxia, dystonia +/- microcephaly
80
Q

How is glucose transporter deficiency diagnosed?

A

1) CSF Glucose measurement

  • Fast 4-6hrs for CSF steady-state
  • Blood first (Stress reponse)
  • CSF:blood ratio >0.6 = normal <0.46 suggestive 0.33 typical
    • CSF BLS <2.2 without cause is suspect
    • CSF lactate normal or low

2) MRI Brain – usually normal or non-specific (exclude other)
3) Mutational analysis of GLUT1 gene (SLC2A1)

81
Q

How do we treat glucose transporter deficiency?

A

Provide alternative fuel

  • Ketogenic diet
    • Controls seizures and improves paroxysmal events
    • No evidence improves developmental delay / cognition

Avoid agents that inhibit glucose transport

  • AEDs:
    • Phenobarbitone, diazepam, chloral
  • Methylxanthines
    • caffeine + Theophylline
  • Tricyclic antidepressants
  • Some general anaesthetics
82
Q

What does MELAS stand for

A

mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS)

83
Q

How is MELAS inherited?

A

maternally inherited multisystemic disorder caused by mutations of mitochondrial DNA

84
Q

What are hallmark features of MELAS

A

occurrence of stroke-like episodes that result in hemiparesis, hemianopia, or cortical blindness. Other common features include focal or generalized seizures, recurrent migraine-like headaches, vomiting, short stature, hearing loss, and muscle weakness

85
Q

What mutations are involved in MELAS?

A

A multitude of tRNA mutations can be responsible for MELAS but 80 percent of cases are related to the m.3243A>G mutation and 10 percent to the m.3271T>C transfer RNA mutation.

86
Q

Describe the stroke-like episodes in MELAS. How are they different from thrombotic or embolic strokes?

A

The stroke-like episodes that occur in patients with MELAS are characterized by the acute onset of neurologic symptoms and high signal on diffusion-weighted MRI brain imaging. These episodes are different from typical embolic or thrombotic ischemic strokes and thus are called “stroke-like” for several reasons:

●The brain lesions do not respect vascular territories

●The apparent diffusion coefficient on MRI is not always decreased (as it would be with tissue infarction) but may be increased or demonstrate a mixed pattern

●The acute MRI signal changes are not static and may migrate, fluctuate, or resolve more quickly and more often than would occur in a typical ischemic stroke

87
Q

When does MELAS typically manifest and what is the long term prognosis?

A

MELAS usually manifests in childhood after a normal early development. A relapsing-remitting course is most common, with stroke-like episodes leading to progressive neurologic dysfunction and dementia.

88
Q

What is MERRF?

A

Myoclonic epilepsy with ragged red fibers (MERRF) is characterized by myoclonus, typically as the first symptom, and is associated with generalized epilepsy, ataxia, and myopathy. Additional features can include dementia, optic atrophy, bilateral deafness, peripheral neuropathy, spasticity, lipomatosis, and/or cardiomyopathy with Wolff-Parkinson-White syndrome.

89
Q

When does MERRF present?

A

Childhood onset after a normal early development is common.

90
Q

What mutations are involved in MERRF?

A

MERRF is caused by mutations in mitochondrial DNA. More than 80 percent of patients suffering from MERRF harbor an A to G mutation at nucleotide 8344 in the mitochondrial MT-TK gene encoding tRNA(Lys).

KK Paediatric Neurology study (2 decks)

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