Lost in the Sauce

A 41-year-old male was referred to Neuro-ophthalmology for 'pseudotumor cerebri and hypertensive retinopathy' and decreased vision. Three months prior the examination, the patient reported a fairly rapid painless decline in the vision in both eyes over a week. He also reported heavy polysubstance abuse (1L cognac, 1 pack cigarettes, marijuana use daily), and had prior diagnoses of alcoholic cirrhosis and hypertension. Review of systems was positive for weight loss, abdominal pain, recurrent hematemesis, myalgias, paresthesias, frequent falls, peripheral neuropathy, and depressed mood.

NANOS 2023 WALSH LECTURE “LOST IN THE SAUCE” Jessica A. Kraker, MD, MS Lisa A. Schimmenti, MD John J. Chen, MD, PhD ©2021 Mayo Foundation for Medical Education and Research | slide-1 Jessica Kraker NO DISCLOSURE OF RELEVANT FINANCIAL RELATIONSHIP(S) WITH INELIGIBLE COMPANIES ©2021 Mayo Foundation for Medical Education and Research | slide-2 CASE PRESENTATION • 41 Y M presented to his local optometrist for blurry vision • HPI: rapidly progressive central blur and photophobia OU x 2 months • Optometry Exam: dry eye, conjunctival injection, mildly tortuous retinal vessels OU, disc edema OU, disc heme OS • Referred to neuro-ophthalmology for disc edema and heme that did not resolve after resuming antihypertensive medications ©2021 Mayo Foundation for Medical Education and Research | slide-3 NEURO-OPHTHALMOLOGY VISIT Medical Hx Social Hx Family Hx ROS Fatty liver disease, HTN, GERD Poor diet, heavy polysubstance abuse HTN, T2DM, alcoholism, blindness in a brother Systemic/MSK: weight loss, myalgias GI: abdominal pain, hematemesis, hematochezia, bloating Neuro/Psych: paresthesias, frequent falls, visual hallucinations (noted by partner), depressed and anxious mood ©2021 Mayo Foundation for Medical Education and Research | slide-4 NEURO-OPHTHALMOLOGY EXAM Vision Color Plates IOP Pupils EOMs VF Anterior Segment Blood Pressure 20/200 OU 2/13 OD, 1/13 OS 13 OD, 15 OS Equal, round, brisk, no rAPD Full, ortho, no nystagmus Full to confrontation PEEs, conjunctival icterus and injection Normotensive ©2021 Mayo Foundation for Medical Education and Research | slide-5 ©2021 Mayo Foundation for Medical Education and Research | slide-6 ©2021 Mayo Foundation for Medical Education and Research | slide-7 ©2021 Mayo Foundation for Medical Education and Research | slide-8 DIFFERENTIAL & WORKUP Nutritional BMP, Ca, Mg 1.5 (normal 1.7-2.2), vitamin B12, folate, thiamine Toxic Heavy metal urine screen – Cadmium 14.5 (normal < 5) Infiltrative, Infectious, WBC 14.5 (normal 4.5-11.5k), ESR, Lyme, Syphilis, Inflammatory ANA, ANCA, ACE Compressive Hereditary Lumbar puncture (including cell count, protein, glucose, oligoclonal bands, paraneoplastic ab panel, lyme, bartonella, VDRL, HSV, VZV, mycobacterium) MRI orbits with and without contrast Genetic panel & Fluorescein Angiography ©2021 Mayo Foundation for Medical Education and Research | slide-9 Axial T1 with fat saturation Axial T2 FLAIR ©2021 Mayo Foundation for Medical Education and Research | slide-10 9:59 4:23 ©2021 Mayo Foundation for Medical Education and Research | slide-11 Live Content Slide When playing as a slideshow, this slide will display live content Poll: What is your leading diagnosis? ©2021 Mayo Foundation for Medical Education and Research | slide-12 DIFFERENTIAL DIAGNOSIS A) Nutritional (tobacco, alcohol) optic neuropathy B) Toxin (Cadmium) associated optic neuropathy C) Leber’s Hereditary Optic Neuropathy D) Other Unspecified But Likely Mitochondrial Optic Neuropathy ©2021 Mayo Foundation for Medical Education and Research | slide-13 A DIAGNOSTIC TEST WAS PERFORMED ©2021 Mayo Foundation for Medical Education and Research | slide-14 Gene DNA change Amino acid change Genomic position Classification DLD c.918T>A p.C306* Chr7:10755 7281 Likely pathogenic DLD c.44G>A p.G15D Chr7:10753 3649 Variant of uncertain significance Biochemical testing revealed elevated serum branch chain amino acids: Leucine 223 (normal < 206) Isoleucine 164 (normal < 106) Valine 310 (normal < 346) Allo-Isoleucine 11 (normal < 5) ©2021 Mayo Foundation for Medical Education and Research | slide-15 MAPLE SYRUP URINE DISEASE (MSUD) Common mitochondrial enzymatic subunit • Branched chain alpha-ketoacid dehydrogenase • Alpha-ketoglutarate dehydrogenase • Pyruvate dehydrogenase • Glycine cleavage system Due to defective BCAA catabolism • Ketogenic tissues primarily affected • Excretion of metabolic intermediates in cerumen and urine creates a sweet “maple syrup” like odor Karwi Q et al. Cardiovasc Drugs Ther. 2022. ©2021 Mayo Foundation for Medical Education and Research | slide-16 MSUD Phenotypes Clinical Presentation Classical (< 2% activity) Intermediate (< 30% activity) Intermittent (< 50% activity) Neonatal rapidly progressive neurologic dysfunction • Dramatically elevated BCAAs Infantile neurologic impairment • Persistently elevated BCAAs Infants with normal development and intelligence but acute decompensation with metabolic stress • Elevated BCAAs only during crises ©2021 Mayo Foundation for Medical Education and Research | slide-17 OPHTHALMOLOGIC MANIFESTATIONS OF MSUD • Optic disc edema • Optic atrophy • Grey optic papilla • Nystagmus • Ophthalmoplegia • Strabismus • Cortical blindness Li Y et al. World J Clin Cases. 2021 ©2021 Mayo Foundation for Medical Education and Research | slide-18 FOLLOW UP: ONE YEAR LATER Vision: 20/200 OU ©2021 Mayo Foundation for Medical Education and Research | slide-19 THE FINAL DIAGNOSIS ©2021 Mayo Foundation for Medical Education and Research | slide-20 WHEN SHOULD I SUSPECT MSUD? Painless, bilateral, and symmetric optic neuropathy: 1) Nutritional/Toxic 2) Inflammatory 3) Compressive 4) Genetic (with FA) • LHON – pseudoedema • DOA - no optic disc edema • Other rare etiologies • MSUD - true disc edema ©2021 Mayo Foundation for Medical Education and Research | slide-21 GENETIC TESTING 1) Combined mitochondrial full genome plus mitochondrial focused nuclear gene panel 2) Whole genome sequencing 3) Genetics referral Stewart J et al. Nat Rev Genet. 2021 ©2021 Mayo Foundation for Medical Education and Research | slide-22 QUESTIONS? ©2021 Mayo Foundation for Medical Education and Research | slide-23 RADIOLOGY PEARLS • Symmetric diffusion restriction is unusual and limits the differential • Diffusion abnormalities implies ongoing or active dysmyelination in MSUD • Pediatric appearance (common) • Corticospinal tract involvement, top to bottom • Adult appearance (rare) • Periventricular zones, posterior brainstem, cerebral peduncles Pathology Pearls • Microscopic pathology best described in cattle with spontaneous mutations and in engineered transgenic murine models • Marked vacuolization of cerebellar white matter as well as reactive astrocytes (inset) is shown in the cow brain on the right