3rd Congress of the European Academy of Neurology - Amsterdam 2017 Adult-onset Hypomyelinating Leukodystrophies: a clinical and genetic study of 15 individuals Ettore Salsano, MD Thank you Co-authors: D. Di Bella, S. Magri, L. Farina, D. Pareyson, F. Taroni

Hypomyelination (on brain MRI = in vivo) Adult-onset HLD Hypomyelination (on brain MRI = in vivo) Adult-onset GJC2/Cx47-related hypomyelinating leukodystrophy (HLD2) Mild T2-hyperintensity (diffuse) * U fiber involvement T1 (almost) normal signal Unchanged pattern on two MRIs at least 6 months apart Orthmann-Murphy JL, Salsano E, Abrams CK et al., Brain 2009 Schiffmann and Van der Knaap, Neurology 2009 Please, raise the hands the colleagues who know the features of hypomyelination on brain MRI

Methods Study design Observational study Setting Unit of Rare Neurological Diseases of Adulthood, Istituto Neurologico C. Besta; Jan 2006 - Dec 2015 Participants Subjects with adult-onset (≥16 years) hypomyelinating leukodystrophy (HLD) negative for PLP1 and GJC2/Cx47 mutations Gene analysis Probe-based customized panel covering 142 genes associated with genetic leukoencephalopathies

Results 15 subjects, 13 sporadic, M:F = 8:7 Identification of the causative gene in 6 (all sporadic) out of 15 subjects Patient 1 2 3 4 5 6 Age/Sex 46/F 43/M 53/M 42/M 57/M Age at onset (years) 20 35 45 30 First symptoms Gait disturbances Mood changes; unsteadiness (very mild) Key clinical features Spasticity (wheelchair-bound) Mild ataxia; mild cognitive impairment (without support) (without support); urinary urgency (unilateral support) Course (years) Slowly progressive (26) Very slowly progressive (7) Slowly progressive (8) Slowly progressive (12) Slowly progressive (12) Slowly progressive (12) Gene mutations GJA1 p.Ile132_Lys133 delinsMet* POLR3A p.Thr1274Pro*; c.3511_3594+277del* (p.Ala1171_Lys1198del) RARS p.Asp2Gly; p.Asp2Gly TUBB4A p.Gly96Arg* CYP7B1/SPG5 p.His285Leu; p.His285Leu SPG11 c.1891+1G>T; p.Leu166Pro* Other findings Corrected strabismus; no cognitive impairment (36y) Poor school performance I.Q. = 70 Poor school performance; minimal cognitive impairment No cognitive impairment NOT recognized intellectual impairment *new mutation

T1 (almost) normal signal Patients 2, 3 and 4 Pt 2 – POLR3A (HLD7) Pt 3 – RARS (HLD9) Pt 4 – TUBB4A (HLD6) Diffuse mild T2-hyperintensity T1 (almost) normal signal Unchanged pattern on two MRIs at least 6 months apart

SPG5 – Patient 5 (age 40) Mild T2 hyperintensity (U-fibers spared)   Controls (n=12) SPG5 (n=1) SPG4 (n=1) CST all FA 0.533  0.018 0.427  0.550 MD 0.748  0.020 0.810  0.734 AD 1.232  0.026 1.211 1.237 RD 0.506  0.024 0.610  0.483 Mild T2 hyperintensity (U-fibers spared) T1 normal signal Biancheri et al., White matter lesions in spastic paraplegia with mutations in SPG5/CYP7B1, Neuromuscular Disorders, 2009 Unchanged pattern on two MRIs at 1 year apart Can we speak of ‘hypomyelination’ in this case?

SPG11 – Patient 6 (age 51) Corpus callosum Mild T2 hyperintensity (periventricular) Unchanged pattern on two MRIs at 6 years apart Mild T1 hypointensity SPG11 (pt 6) TUBB4A (pt 4) Can we speak of ‘hypomyelination’ in this other case?

Take home messages  MRI suggestive of hypomyelination («HLD») can be prominent feature of adult-onset genetic disorders Inclusive screening approach allows diagnosis in 40% of adult-onset HLDs Adult-onset HLD can be caused by mutations in genes associated with the more severe early-onset HLD (POLR3A, RARS, TUBB4A) There is an overlap between HLD and SPG (at least in the adulthood) HLD SPG

An Etymological Digression aeme = river / current stelle = place Old Dutch The Dam in 1544, as an actual dam in the river Amstel  AMSTEL dam AMSTERDAM αίμα = blood Ancient Greek haematology

Oculodentodigital Dysplasia (ODDD) – Patient 1 HANDS Short middle phalanx of the 5th finger On retrospect TEETH Enamel hypoplasia  Selective tooth agenesis  Microdontia  SKIN, NAILS, & HAIR Yellow-orange hyperkeratosis on palms Brittle nails Fine, dry hair Sparse, slow-growing hair Dental Implant enamel [iˈnaməl] 50% of cases represent new mutations Hypomyelination on brain MRI Earlier diagnosis if the disease were called HLD?

Thank you for your attention Take home messages  Nomenclature’s Importance (clinical perspective) Look at/highlight key features, NOT unusual/atypical ones (at least in rare or ultra-rare diseases) Facing our mistakes “The practice of medicine is difficult enough without having to bear the yoke of perfection” D. Hilfiker, NEJM 1984 Thank you for your attention