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.
2/14/2020 Outline Case Presentation: • History and examination • Initial testing Chronic Imbalance • Differential diagnosis • Additional testing • Working diagnosis and management • Take home points Alexandra Nelson MD, PhD UCSF Department of Neurology RAIN 2020 1 2 History History 37 year old man with longstanding problems with gait and balance. In adulthood, symptoms have been almost imperceptibly In childhood: progressive: • Coordination poor compared to peers, starting age 5-6, but • Gait irregular, tendency to trip eventually learned to ride bike, played baseball • Balance poor, but works on boat and no falls • Writing effortful and poor (was assigned a note-taker) • Clumsy, drops things, difficulty with buttoning, writing • Comprehension and learning slower than peers, but completed • Slow speech, sometimes can slur if tired high school • Needs others to speak slowly and sometimes repeat • None of problems severe enough to merit school evaluation or instructions medical referral • Forgetful, inattentive • Single GTC seizure age 18 (none since) 3 4 1
2/14/2020 Additional History Additional History • No numbness or other sensory symptoms • PMH: Migraines • No involuntary movements or tremor • Medications: none • No syncope/presyncope • FH: Parents healthy, 2 healthy brothers, no known family • No bladder/bowel symptoms members with a movement disorder or developmental delay • No diplopia • SH: Graduated HS, works on tour boat, lives with girlfriend of • Occasional coughing or choking two years, no children • 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) 5 6 Examination Brief Cognitive Testing Mental Status: Alert, appropriate, but processing and speech MoCA: 24/30 (+1 for education) appear slowed. Cranial Nerves: EOMs entirely normal. Facial strength and Episodic Memory: Very mild impairments for age/education on sensation normal. Speech is slowed and occasionally slurred. both verbal and visuospatial memory Motor: Normal bulk, mild spasticity in both legs. No involuntary movements. Strength full. Visuospatial: Very mild impairment on figure copy Sensory: intact to light touch, vibration, proprioception, pinprick Coordination: Modest (3 cm) overshoots on finger following, Frontal/Executive: Mild-moderate slowing of processing speed, clumsiness on RAMs and HKS. errors on sequencing and set-switching tasks Gait: Wide based, but good stride length and arm swing. Cannot tandem. No retropulsion. 7 8 2
2/14/2020 Test Results: MRI Brain Test Results: MRI Brain (13 years ago) 9 10 Differential Diagnosis Test Results: Laboratory tests (Normal) Initial screen for: Key features to narrow diagnosis: slow progression, presence of cerebellar ataxia by history and examination (Also: childhood- • Toxic/Metabolic (Chemistry, LFTs, lactate, pyruvate) onset, cognitive impairment, seizure, lack of family history) • Nutritional (B12, folate, methylmalonic acid, homocysteine, copper) • Toxic/Metabolic, Nutritional, Endocrine: Too slow for most, or • Endocrine (TSH) imaging makes unlikely (rule out with labs) • Immunological (ANA, anti-endomysial, anti-GAD, thyroid) • Immune-mediated: Too slow for most, consider gluten, anti- • Infectious (RPR, HIV) GAD (rule out with labs) Unlikely in this case, based on clinical features: • Immunological (paraneoplastic panel, CSF sample) • Neurodegenerative: Spinocerebellar ataxias, genetic and idiopathic (evaluate with genetic testing) • Toxic/Metabolic (heavy metals, lysosomal enzymes, urine organic acids, long chain fatty acids) 11 12 3
2/14/2020 What is the diagnostic yield of typical ataxia Differential Diagnosis genetic panel testing in this setting? Key features to narrow diagnosis: slow progression, presence of 50% A. About 1% cerebellar ataxia by history and examination (Also: childhood- onset, cognitive impairment, seizure, lack of family history) B. About 5% C. About 10% • Toxic/Metabolic, Nutritional, Endocrine: Too slow for most, or D. About 50% imaging makes unlikely (rule out with labs) 21% 20% • Immune-mediated: Too slow for most, consider gluten, anti- GAD (rule out with labs) 9% • Neurodegenerative: Spinocerebellar ataxias, genetic and idiopathic (evaluate with genetic testing) % % % % 1 5 0 0 1 5 t t u u o o u t u t b b o o b b A A A A 13 14 What is the diagnostic yield of whole-exome Test Results: Ataxia Genetic Panel or whole-genome sequencing in this setting? 48% A. About 1% B. About 5% C. About 10% 32% D. About 50% 12% 9% % % % % 1 5 0 0 1 5 t t u u t t o o u u b b o o A A b b A A 15 16 4
2/14/2020 How is the clinical relevance of a gene Test Results: Interpretation of VUS variant determined? 68% A. Its frequency in the population B. Impact on protein structure and function C. Segregation studies D. All of the above 23% Variant of Unknown Significance (VUS): 9% • variant in gene sequence found that is not currently accepted 0% as pathogenic • informed by geneticists at testing companies & the literature s e n e o . v . . i o i r d t u u b a a • shouldn’t (generally) be interpreted as diagnostic, or used to l t t u c s e p u n h o r o t p t s t i f e n a o h i g l e e A l make clinical decisions t t r n o g i r e y p S c n n o e u c t q a e p r f m s I t I 17 18 Test Results: Interpretation of VUS 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) Karbassi et al, Human Mutation 2016 19 20 5
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