1. Raili Raininko and Atle Melberg
Radiological aspects of genetic disorders with adult-onset CNS symptoms
Raili Raininko and Atle Melberg
Departments of Radiology and Neuroscience
Uppsala University
Uppsala, Sweden

2. Genetic disorders with neurological symptoms:
Often pediatric diseases
Adult types may occur in some of them
- Disorders giving symptoms only in adulthood

3. Mitochondrial disorders
Clinical onset most often in childhood
Course: Static - Progressive - Episodes of exacerbation
typical
Typical symptoms: epilepsy, progressive external ophthalmoplegia (PEO), myopathy, diabetes mellitus
Examples:
- Leigh syndrome
- MELAS (mitochondrial encephalopathy, lactic
acidosis and stroke-like episodes)
- POLG-1-associated encephalopathy syndromes

4. POLG-1 mutation (mitochondrial DNA-polymerase gamma)
1. Autosomal recessive
- Epilepsy (episodes of focal status epilepticus)
- Stroke-like episodes
- Ataxia
- Ophtalmoplegia
- Sensoric neuropathy
- (Liver insufficiency ← Valproate)

5. POLG-1 mutation 2. Dominant form – a different clinical picture
PEO, muscular weakness, parkinsonism, ataxia
Diagnosis:- Muscle biopsy
- mitochondrial DNA analysis for mtDNA deletions
- sequencing POLG-1 gene

6. POLG-1 mutation, autosomal recessive
18-year-old man
CT n:o CT 2 days later

7. POLG-1 mutation 4 days from the symptom onset
DWI:
trace images
b= 1000
T2-w FLAIR

8. POLG-1 mutation Follow-up: 2 mo 3 wk
DWI: trace, b=1000
ADC maps
T2-w FLAIR

9. POLG-1 mutation Patient 2 24-year-old man
Twin brother succumbed at age of 19 in status epilepticus
T2-w SE

10. Hepatolenticular degeneration = Wilson´s disease
Autosomal recessive
Hepatic or neurologic symptoms or dementia
Tremor, speech disorders, clumsiness, dystonia,
personality changes
Defect in copper metabolism
Diagnosis: - Blood test: caeruloplasmin, copper
- Urine test: copper
- Liver biopsy
- Genetic analysis, ATP7B gene

11. Wilson´s disease Man, 22 yr, dementia
T2-w SE

12. Wilson´s disease
Man, 34 yr, treated
T2-w SE

13. : Polycystic lipomembranous osteodysplasia
and sclerosing leukoencephalopathy
(PLOSL) = Nasu-Hakola disease :
Bone cysts
Pain in bones
Fractures

14. Nasu-Hakola disease Later, ~ at age of 30: Symptoms of dementia
Death: under age of 50
Autosomal recessive
Mutations in DAP12 or TREM2 genes
Diagnosis: Clinical + radiological findings

15. Nasu-Hakola disease
Man, 33 yr CT

16. Nasu-Hakola disease
Man
32 yr
T2-w SE

17. Leukodystrophies - Onset most often in childhood
Most often recessive inheritance
- Also sporadic forms
- Some are x-linked
Uncommon:
Adult-onset forms
Dominant inheritance

18. Metachromatic leukodystrophy (MLD) Types of MLD: - late infantile
- juvenile
- adult-onset
The adult-onset type most often begins with
psychiatric symptoms
Diagnosis: Arylsulfatase A activity low in leukocytes
Sulfatide excreation ↑ in urine
Autosomal recessive
different types of mutations in ARSA gene .

19. Adult-onset metacromatic leukodystrophy Woman, 25 yr
Psychiatric symptoms
for 6 years
T2-w
T2-w
T1-w
PD-w
T1-w

20. = globoid cell leukodystrophy (GLD)
Krabbe disease
= globoid cell leukodystrophy (GLD)
Many types: - congenital
- early infantile
- late infantile
- juvenile
- adult-onset
Adult-onset type: spastic paraparesis, hemiparesis,
ataxia, deteriorating vision
Diagnosis: Galactocerebrosidase activity deficiency
About 60 different mutations found in GALC gene

21. Adult-onset Krabbe disease
Woman, 28 yr, 5-year history of spastic paraparesis
T2-w FSE
T2-w FLAIR

22. Adult-onset Krabbe disease
Atrophic spinal cord
T2-w FSE

23. Alexander disease Types: - infantile - juvenile - adult-onset
Adult-onset type: diverse symptoms,
episodic or progressive course
Bulbar and pseudobulbar symptoms, spasticity, ataxia, dementia, nystagmus, palatal myoclonus
GFAP mutation, Diagnosis = Genetic tests
- Almost all cases sporadic
- Autosomal dominant form exists

24. Adult-onset Alexander disease
Woman
34 yr
Ataxia,
motor clumsiness,
exaggerated
reflexes,
overactive bladder
T2-w
FLAIR

25. Adult-onset Alexander disease
T2-w FSE
Patchy contrast
enhancement may occur

26. Adult-onset Alexander disease
C II
Pathologic white matter
C IV
Normal SI
Atrophic
spinal cord
T2-w FSE

27. Adult onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms
Age of clinical onset between years of age
Autonomic symptoms (bladder and bowel dysfunction, orthostatic hypotension) usually precede cerebellar and pyramidal symptoms
Genetic basis: duplication of Lamin B1 with subsequent overexpression
Diagnosis: - Clinical symptom constellation + MRI - Genetic analysis

28. Adult-onset ADLD with autonomic symptoms
Asymptomatic
family member
Man, 37 yr

29. Adult-onset ADLD with autonomic symptoms
34-year-old asymptomatic family member

30. Adult-onset ADLD with autonomic symptoms
Patient, 55 years

31. Adult-onset ADLD with autonomic symptoms
Man, 57 years, with spasticity
and ataxia
Man, 51 years,
wheel chair bound

32. Control Patients Woman, 59 years Woman, 49 years Man, 51 years T2 C 2

33. CADASIL = Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
Age at onset < 50 yr
At least two of these symptoms:
Stroke-like episodes with permanent neurologic signs
Migraineous headache
Major mood disturbances
Subcortical dementia
Diagnosis: Skin, muscle or brain biopsy
Mutation in the NOTCH3 gene

34. CADASIL Woman 47 years T2-w FLAIR Douhan, Viola 19520105-1405
MRT
- Hereditet för CVS: Syster med multipla övergående CVS liknande episoder och mycket utbredd vitsubstansförändring vid CT och MRT.
- Migränepisoder av komplex natur. Sommaren 1998 högersidig hemipares som väsentligen gått tillbaka. Leukoarios vid CT.
- Nu vidareutredning.
Dg: CADASIL (Cerebral autosomal dominant arteriopahy with subcortical infarcts and leukoangiopathy)
T2-w FLAIR

35. Multiple cavernomas Familial form
A 21-year-old woman, numbness in the right leg
Her brother had had a bleeding in the spinal cord
T2-w FSE T2*-w GRE T1-w SE
contrast enhanced

36. Multiple cavernomas
Familial form
T2*-w GRE
SWI sequence

37. Multiple cavernomas Familial form T2*-w GRE T1-w SE
plain contrast enhanced
T2-w FSE T2*-w GRE

38. Hereditary spastic paraparesis and thin corpus callosum (HSP-TCC)
Autosomal recessive
Genetically heterogenic
In 35%, mutation in SPG 11 or SPG 15 gene
SPG11 mutation: central retinal degeneration (Kjellin syndrome)
Spastic paraparesis, cognitive decline, amyotrophy
Symptom onset in 1st to 3rd decade
Diagnosis: Clinical constellation + MRI
+ sequencing of candidate genes SPG 11 and SPG15

39. Hereditary spastic paraplegia and thin corpus callosum (HSP-TCC)
The first MRI at age of Female
46 yr.

40. Patient 2: 18 yr

41. atrophic and signal intensity changes
Thorough and systematic analysis of
atrophic and signal intensity changes
Ruling out diseases
with the same or
similar symptoms
Specific diagnosis
Some alternative
diagnoses

42. with clinicians and geneticists essential
Thorough and systematic analysis of
atrophic and signal intensity changes
Ruling out diseases
with the same or
similar symptoms
Specific diagnosis
Some alternative
diagnoses
Collaboration
with clinicians and geneticists essential