Neurodegenerative and movement disorders Flashcards

Question

What are the different forms/presentations of adrenoleukodystrophy?

Answer 1

Forms/presentations: * Childhood cerebral (48%) * Adolescent cerebral (5%) * Adult Cerebral (3%) * Adrenomyeloneuropathy (25%) * Addisons only (8%) * Symptomatic heterozygote female carriers (10-15%)

Answer 2

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

Answer 3

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

Answer 4

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

Answer 5

Autosomal recessive peroxisomal disorder * Mutations in any PEX genes (perixisomal biogenesis) * Thus no peroxisomal formation \> multi-system disorder * Wide spectrum

Answer 6

Severe mental retardation / GDD then regression Hypotonia Seizures Sensorineural deafness Brain malformations * Polymicrogyria * Abnormal white matter * Callosal dysgenesis

Answer 7

Progressive neurodegenerative diosorder Early megalencephaly, psychomotor retardation, spasticity, seizures Death by 6years

Answer 8

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

Answer 9

Developmental regression as infant Visual loss, progressive macrocephaly Seizures, spasticity, optic atrophy Death in childhood

Answer 10

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)

Answer 11

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)

Answer 12

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

Answer 13

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

Answer 14

Diagnosis: Clinical findings, vacuolated histiocytes and demonstration of sphingomyelinase deficiency Genetics testing available now

Answer 15

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

Answer 16

Dx: hexosaminadase A deficiency Mutations in hexosaminadase A, alpha polypeptide gene (HEXA)

Answer 17

Autosomal recessive disorder of copper metabolism Mutation in an ATPase – Cu++ transporting beta polypeptide gene (ATP7B) \*transports copper accross cell membrane

Answer 18

Prevalence = 30 / million Carrier frequency = 1 in 90

Answer 19

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

Answer 20

Basal ganglia * Caudate * Putamen * Ventrolateral thalami

Answer 21

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

Answer 22

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

Answer 23

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

Answer 24

Supportive although IM copper also used Variable response, better early and for missense (rather than nonsense) mutations

Answer 25

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

Answer 26

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

Answer 27

}NCL1: Infantile form (Santavuori type) }Onset from 2yrs \> visual impairment, myoclonus }Rapid regression, hypotonia, ataxia

Answer 28

}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

Answer 29

}NCL3: Juvenile form (Spielmeyer-Vogt-Sjogren) }Mean onset 6yrs }Inital: decreasing vision \> dementia \> seizures

Answer 30

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

Answer 31

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

Answer 32

Once needed liver and muscle biopsies for Dx Blood and CSF lactate may be normal ! Now investigations are genetic – exome/genone/mtDNA

Answer 33

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

Answer 34

Psychomotor delay / hypotonia in first year Subsequently: Abnormal extra-ocular movements Optic atrophy Cerebellar dysfunction Respiratory disturbances Peripheral neuropathy Cardiomyopathy Movement disorder

Answer 35

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

Answer 36

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

Answer 37

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

Answer 38

Cerebellar hypoplasia Corpus callosum hypotrophy (underdeveloped) Dandy Walker Malformation Brain demyelination Eye abnormalities * Retinopathy * Optic atrophy * Corneal dystrophy * Iris and retinal coloboma

Answer 39

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

Answer 40

Dystonia or tremor Hypotonia or rigidity Diurnal variation of movement disorder (fluctuation) Oculogyric crises Excessive sweating Temperature instability Hypoglycaemia

Answer 41

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)

Answer 42

X-linked adrenoleukodystrophy (ALD) X-linked adrenmyeloneuropathy (AMN) Peroxisomal biogenesis disorders (Zellweger spectrum) Isolated disorders of peroxisomal b-oxidation

Answer 43

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

Answer 44

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

Answer 45

Diversity of Phenotype: * No seizures with choreo-athetosis + dystonia * No seizures / paroxysmal events with: * Mental retardation, ataxia, dystonia +/- microcephaly

Answer 46

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)

Answer 47

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

Answer 48

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

Answer 49

maternally inherited multisystemic disorder caused by mutations of mitochondrial DNA

Answer 50

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

Answer 51

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.

Answer 52

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

Answer 53

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.

Answer 54

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.

Answer 55

Childhood onset after a normal early development is common.

Answer 56

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).