Alexandra Nelson, MD, PhD February 14, 2020 Patient Presentation 37 - - PDF document

Alexandra Nelson, MD, PhD February 14, 2020 Patient Presentation 37 yo man presenting with longstanding problems with balance. The patient and his family report noticing that his coordination was poor as early as age 5 or 6, when he had difficulty learning to ride a bicycle, and later using a skateboard. However, he was an active child and played baseball. He also had difficulty with fine motor tasks, such as writing, and eventually teachers appointed other children to take notes for him. He was “never good in school”, and things needed to be explained to him slowly. Despite these symptoms, he was never referred for motor or cognitive evaluation as a child. He graduated from high school without any special education support. He had a single convulsive seizure at age 18 and does not take anti- epileptic drugs. As an adult, he cannot tell if his symptoms are progressive or static. Currently he feels his walking is unsteady. If he walks quickly, then he has a tendency to trip. His job entails working on a tour boat and he does not fall. He rides a bicycle to and from work without difficulty. He continues to note difficulty with fine motor tasks like writing or buttoning. He has trouble grabbing hold of things. He still has to have things explained to him slowly or repeatedly. He is forgetful and inattentive, which has been an issue in both his work and relationships. His personality is stable: he has always been fairly quick to anger. He can be irritable but has not had incidents of aggression or

• violence. His mood is positive.

He was the product of a normal gestation and delivery, and met early developmental milestones. He has no other medical problems and takes no medications. He has two siblings without similar

• problems. Neither of his parents, nor any of his grandparents, had any trouble with coordination.

The general examination was normal and there were no dysmorphic features. Mental status examination revealed normal conversational speech, appropriate behavior and affect, although processing speed appeared to be mildly slowed. His speech was noted to be mildly slow and irregular, with rare slurring. Cranial nerve examination was normal. Motor examination revealed mildly increased tone in both legs. Fast finger movements and toe taps were normal. Reflexes were 3+ and there was clonus at the ankles. The plantar response was flexor. The coordination exam showed irregularity with RAMs, slight overshoot with finger following, as and difficulty maintaining contact with the shin on HKS. His gait was moderately wide-based, but showed good stride length and arm swing, He was unable to tandem. The sensory examination was normal. Cognitive testing showed mild impairments in several domains, especially frontal/executive (slowed processing speed, verbal fluency, difficulties in sequencing and set-switching, as well as abstraction). A diagnostic procedure was performed.

References

• 1. Fogel BL, et al. JAMA Neurol. 71(10):1237-46, 2014.
• 2. Horvath R, et al, JNNP 83(2): 174-178, 2012
• 3. Sun M, et al, Genetic Med. 21(1):195-206, 2019.
• 4. Teive H and Ashizawa T. Curr Opinion Neurol. 28(4): 413-422, 2015.

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Case Presentation: Chronic Imbalance

Alexandra Nelson MD, PhD UCSF Department of Neurology RAIN 2020

Outline

• History and examination
• Initial testing
• Differential diagnosis
• Additional testing
• Working diagnosis and management
• Take home points

History

37 year old man with longstanding problems with gait and balance. In childhood:

• Coordination poor compared to peers, starting age 5-6, but

eventually learned to ride bike, played baseball

• Writing effortful and poor (was assigned a note-taker)
• Comprehension and learning slower than peers, but completed

high school

• None of problems severe enough to merit school evaluation or

medical referral

• Single GTC seizure age 18 (none since)

History

In adulthood, symptoms have been almost imperceptibly progressive:

• Gait irregular, tendency to trip
• Balance poor, but works on boat and no falls
• Clumsy, drops things, difficulty with buttoning, writing
• Slow speech, sometimes can slur if tired
• Needs others to speak slowly and sometimes repeat

instructions

• Forgetful, inattentive

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Additional History

• No numbness or other sensory symptoms
• No involuntary movements or tremor
• No syncope/presyncope
• No bladder/bowel symptoms
• No diplopia
• Occasional coughing or choking
• Mood and sleep are good; no change in behavior
• Developmental: Normal gestation and delivery, met early

developmental milestones on time

• Functional: Independent on ADLs and iADLs, but does not drive

a car due to his own concern about coordination (rides bike)

Additional History

• PMH: Migraines
• Medications: none
• FH: Parents healthy, 2 healthy brothers, no known family

members with a movement disorder or developmental delay

• SH: Graduated HS, works on tour boat, lives with girlfriend of

two years, no children

Examination

Mental Status: Alert, appropriate, but processing and speech appear slowed. Cranial Nerves: EOMs entirely normal. Facial strength and sensation normal. Speech is slowed and occasionally slurred. Motor: Normal bulk, mild spasticity in both legs. No involuntary

• movements. Strength full.

Sensory: intact to light touch, vibration, proprioception, pinprick Coordination: Modest (3 cm) overshoots on finger following, clumsiness on RAMs and HKS. Gait: Wide based, but good stride length and arm swing. Cannot

• tandem. No retropulsion.

Brief Cognitive Testing

MoCA: 24/30 (+1 for education) Episodic Memory: Very mild impairments for age/education on both verbal and visuospatial memory Visuospatial: Very mild impairment on figure copy Frontal/Executive: Mild-moderate slowing of processing speed, errors on sequencing and set-switching tasks

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Test Results: MRI Brain Test Results: MRI Brain (13 years ago) Differential Diagnosis

Key features to narrow diagnosis: slow progression, presence of cerebellar ataxia by history and examination (Also: childhood-

• nset, cognitive impairment, seizure, lack of family history)
• Toxic/Metabolic, Nutritional, Endocrine: Too slow for most, or

imaging makes unlikely (rule out with labs)

• Immune-mediated: Too slow for most, consider gluten, anti-

GAD (rule out with labs)

• Neurodegenerative: Spinocerebellar ataxias, genetic and

idiopathic (evaluate with genetic testing)

Test Results: Laboratory tests (Normal)

Initial screen for:

• Toxic/Metabolic (Chemistry, LFTs, lactate, pyruvate)
• Nutritional (B12, folate, methylmalonic acid, homocysteine,

copper)

• Endocrine (TSH)
• Immunological (ANA, anti-endomysial, anti-GAD, thyroid)
• Infectious (RPR, HIV)

Unlikely in this case, based on clinical features:

• Immunological (paraneoplastic panel, CSF sample)
• Toxic/Metabolic (heavy metals, lysosomal enzymes, urine
• rganic acids, long chain fatty acids)

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Differential Diagnosis

Key features to narrow diagnosis: slow progression, presence of cerebellar ataxia by history and examination (Also: childhood-

• nset, cognitive impairment, seizure, lack of family history)
• Toxic/Metabolic, Nutritional, Endocrine: Too slow for most, or

imaging makes unlikely (rule out with labs)

• Immune-mediated: Too slow for most, consider gluten, anti-

GAD (rule out with labs)

• Neurodegenerative: Spinocerebellar ataxias, genetic and

idiopathic (evaluate with genetic testing)

What is the diagnostic yield of typical ataxia genetic panel testing in this setting?

• A. About 1%
• B. About 5%
• C. About 10%
• D. About 50%

A b

• u

t 1 % A b

• u

t 5 % A b

• u

t 1 % A b

• u

t 5 %

9% 20% 50% 21%

What is the diagnostic yield of whole-exome

• r whole-genome sequencing in this setting?
• A. About 1%
• B. About 5%
• C. About 10%
• D. About 50%

A b

• u

t 1 % A b

• u

t 5 % A b

• u

t 1 % A b

• u

t 5 %

9% 32% 48% 12%

Test Results: Ataxia Genetic Panel

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How is the clinical relevance of a gene variant determined?

• A. Its frequency in the population
• B. Impact on protein structure and function
• C. Segregation studies
• D. All of the above

I t s f r e q u e n c y i n t h e p

• p

u l a t i

• n

I m p a c t

• n

p r

• t

e i n s t r u c t u r . . . S e g r e g a t i

• n

s t u d i e s A l l

• f

t h e a b

• v

e

23% 68% 0% 9%

Test Results: Interpretation of VUS

Variant of Unknown Significance (VUS):

• variant in gene sequence found that is not currently accepted

as pathogenic

• informed by geneticists at testing companies & the literature
• shouldn’t (generally) be interpreted as diagnostic, or used to

make clinical decisions

Test Results: Interpretation of VUS

VUS Pathogenicity estimates are based on:

• Five-tiered system (pathogenic/likely pathogenic/uncertain/likely

benign/benign)

• How frequently that mutation is observed in healthy people
• Whether the mutation is expected to change protein structure
• Any existing segregation studies (genotype/phenotype match)
• Any existing functional studies (how does the protein work)

Test Results: Interpretation of VUS

Karbassi et al, Human Mutation 2016

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Test Results: Interpretation of VUS

Based on clinical suspicion and review of protein structure data, we contacted other ataxia specialists

• Same mutation had been found in several other patients with

ataxia syndrome, including some in which segregation studies had been done

• Several papers now have been published describing these

cases and families

Test Results: ADCK3-associated Ataxia

• Gene codes for CoQ8, an enzyme

in synthesis of Coenzyme Q10

• As of end of 2019, 53 patients, 38

different mutations confirmed

• Other mutations in ADCK3

associated with SCAR9 (CoQ10 Deficiency 4)

• Variable phenotype

Galosi et al, Parkinsonism and Related Disorders 2019 Liu et al, JNNP 2014

Test Results: ADCK3-associated Ataxia

• Early onset (80% in childhood, remainder in young adults)
• Gait, speech, limb ataxia
• Handwriting impairment, limb dystonia
• +/- epilepsy, migraine, tremor, bradykinesia, developmental

delay/cognitive symptoms (1/3)

Galosi et al, Parkinsonism and Related Disorders 2019

Test Results: Pathogenic Mutation in ADCK3

Other published cases of ADCK3 mutations Arg301Trp:

• Case: Compound heterozygous mutation, young onset (11), very slowly

progressive, with fine motor deficits, upper limb dystonia, speech and gait ataxia, confirmed by segregation (Chang et al, 2018)

• Case: Compound heterozygous mutation, young onset (3), slowly

progressive, gait and speech ataxia, mild cognitive impairment, dystonia, epilepsy (Galosi et al, 2019)

• Case: Compound heterozygous mutation, young-onset (8) with

developmental delay (Sun et al, 2019)

• Case: Compound heterozygous mutation, adult onset (33) with epilepsy

(Sun et al, 2019)

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Test Results: Pathogenic Mutation in ADCK3

• ADCK3 in the “protein-kinase like”

family

• Located in the mitochondrial matrix
• Stabilizes other enzymes involved

in CoQ synthesis

• Most disease-related mutations lead

to changes in nucleotide binding (and enzymatic efficiency)

Stefely et al, Molecular Cell, 2015

Test Results: Pathogenic Mutation in ADCK3

Liu et al, JNNP 2014 Kinase-Like Domain

Which of the following is true regarding the clinical management of inherited ataxias?

• A. Often, a disease-modifying therapy is available
• B. Large randomized-controlled trials have identified

several medications that provide symptomatic relief

• f cerebellar symptoms
• C. Antisense oligonucleotide (ASO) therapies are in

development for treatment of SCA1 and SCA3

• D. All of the above

O f t e n , a d i s e a s e

• m
• d

i f y i n g t . . . L a r g e r a n d

• m

i z e d

• c
• n

t r

• l

l e d . . . A n t i s e n s e

• l

i g

• n

u c l e

• t

i d e ( . . . A l l

• f

t h e a b

• v

e

0% 19% 78% 3%

Clinical Management

• Some patients with ADCK3-associated ataxia have benefited

from treatment (supplementation with ubiquinone/CoQ10, at 15 mg/kg/day), but others have not

• Likelihood of benefit in ADCK3 patients hard to predict based
• n specific mutations or syndrome
• No rigorously proven disease-modifying or symptomatic

therapies for SCAs or ataxia generally (studies ongoing)

• Supportive therapy as in other spinocerebellar ataxias

(exercise, rehabilitation strategies, and consider symptomatic therapies)

Chang et al, Movement Disorders Clinical Practice, 2018; Schirinzi et al, Cerebellum Ataxias, 2019

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Take Home Points

• In patients with slowly progressive cerebellar symptoms,

consider spinocerebellar ataxias

• Many spinocerebellar ataxias have non-cerebellar features
• Genetic testing has a maximum yield of about 50% in ataxia
• Genetic testing can yield treatable causes of ataxia
• Use caution when interpreting VUS results, but also look up the

variant yourself, and check the literature

Fogel et al, JAMA Neurology 2014; Sun et al, Genetic Med, 2019

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