1. 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

2. 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

3. Methods
Study design Observational study Setting Unit of Rare Neurological Diseases of Adulthood, Istituto Neurologico C. Besta; Jan 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

4. 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_ del* (p.Ala1171_Lys1198del)
RARS
p.Asp2Gly;
p.Asp2Gly
TUBB4A
p.Gly96Arg*
CYP7B1/SPG5
p.His285Leu;
p.His285Leu
SPG11
c G>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

5. 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

6. 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?

7. 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?

8. 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

9. 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

10. 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?

11. 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