Familial dystonia with cerebral calcification case report and - - PowerPoint PPT Presentation

• M. Signaevski, A.K. Wszolek, A.J. Stoessel, R. Rademakers, and I.R. Mackenzie

Vancouver General Hospital, BC, Canada Mayo Clinic Jacksonville, Florida, USA Pacific Parkinson Research Centre, BC, Canada

Familial dystonia with cerebral calcification

case report and genetic update

nothing to disclose

Genealogy tree

Canadian family with dystonia-plus syndrome and brain calcinosis:

• followed since mid 80s
• 6 generations
• AD, highly penetrant

Wszolek et al, Neurology, 2006;67:620–625

Family phenotype

Symptoms

• dystonia (oromandibular) +/- “plus”
• dysarthria
• chorea
• ataxia
• Parkinsonism
• variable intellectual decline

Cerebral calcifications:

• basal ganglia
• thalamus
• subcortical white matter
• cerebellum

11 symptomatic 8 asymptomatic

Wszolek et al, Neurology, 2006;67:620–625

11 symptomatic 8 asymptomatic

Wszolek et al, Neurology, 2006;67:620–625

b a s a l g a n g l i a t h a l a m u s c e r e b e l l u m W M

11 symptomatic 8 - with dystonia all cases: range: 8-70 age at onset: mean ~19 dystonia+ cases range: 8-20

age of onset: mean ~ 13

Wszolek et al, Neurology, 2006;67:620–625

b a s a l g a n g l i a t h a l a m u s c e r e b e l l u m W M

8 asymptomatic

Wszolek et al, Neurology, 2006;67:620–625

11 symptomatic

b a s a l g a n g l i a t h a l a m u s c e r e b e l l u m W M

8 asymptomatic still asymptomatic in mid life age range 45-57 mean =50

Wszolek et al, Neurology, 2006;67:620–625

b a s a l g a n g l i a t h a l a m u s c e r e b e l l u m W M

Wszolek et al, Neurology, 2006;67:620–625

III-9

Genealogy tree

Wszolek et al, Neurology, 2006;67:620–625

age symptoms 10

• dysarthria and involuntary movements / oromabdibular

18

• right arm athetosis

28

• generalized involuntary movements

52

• CT scan: bilateral symmetric calcifications:
• basal ganglia, thalamus, and cerebellum
• subcortical white matter: occipital, temporal, parietal, frontal
• frontal and parietal cortex

67

• follow up CT scan - no change
• Ca, Cu, Phosphate, Fe - normal

~ 51-71

• generalized dystonia (predominantly upper body)
• dysarthria, dysphagia
• depression
• repeated falls

71 year old female with progressive movement disorder, dystonia, and intellectual decline

Clinical history

CT scan, age 67

frontal WM lentiform

Gross pathology

thalamus cerebellar dentate

Gross pathology

Various parenchymal calcification patterns, H&E

cerebellar dentate cerebellar WM & vessels thalamus basal ganglia

Cortical WM, H&E and von Kossa

von Kossa

Vessel calcification patterns, H&E

von Kossa

minor gliotic reaction to calcifications GFAP

Pathology: striatum

Cerebellar vermis

Purkinje cells preserved in calcified and in non-calcified areas

Cerebellar hemispheres

Purkinje cell loss and Bergmann’s gliosis

Pathology: IHC

Negative:

• tau
• alpha-synuclein
• FUS
• TDP-43

ubiquitin ubiquitin

Hippocampus: CA1 Hippocampus: alveus

Genetic considerations: background

Historically:

Familial Idiopathic Basal Ganglia Calcification (IBGC, Fahr’s disease):

• movement abnormalities: dystonia, Parkinsonism, ataxia, chorea
• may be asymptomatic

To date: links to

• Chr 14q (fIBGC1)
• Chr 2q37 (fIBGC2)
• Chr 8p21.1 (fIBGC3*: various mutations in SLC20A2)

Mayo Clinic study (co-authors):

• mutation analysis of SLC20A2 in 27 cases of IBGC**
• Mayo Clinic Jacksonville brain bank
• including a member of Canadian IBGC family with dystonia-plus syndrome
• brother of our case

* Wang et al, Nature genetics, 2012, 4(3): 254-256 ** Baker et al, Neurogenetics, 2014 ,15(1): 23-30

III-3 (brother)

Baker et al., Neurogenetics. 2014 March ; 15(1): 23–30.

85M with ~60-year history of progressive movement disorder and dystonia-plus Pathology:

• same pattern as III-9:
• parenchymal
• vascular

Genetic analysis

Copy number analysis:

• deleted ~563Kb region on 8p11.21 in this member of the family

Sequencing:

• complete deletion of 7 genes:
• VDAC3, SLC20A2, c8ORF40, CHRNB3, CHRNA6, THAP1, RNF170
• partially HOOK3

*Baker et al., Neurogenetics. 2014 March ; 15(1): 23–30.

Mayo genetic study*:

• cohort of 27 cases, histologically proven IBGC
• two with SLC20A2 mutations were identified:
• one - novel C338G nonsense mutation
• another - deletion on chromosome 8p

SLC20A2

Gene:

• SLC20A2
• chromosome 8p11.21

Protein: Sodium-dependent phosphate transporter 2 (PiT2)

• homodimer
• inorganic phosphate transport - pumps Phosphate into cell
• ubiquitously expressed
• highest in basal ganglia

Mutations: loss-of-function

• about 20 mutations in more than 40 families worldwide
• truncated protein or loss of protein
• explains 41% familial cases and 14% sporadic
• excess of phosphate in the presence of Calcium => calcifications

Disease:

• idiopathic basal ganglia calcification
• no dystonia phenotype is identified with isolated SLC20A2 loss.

THAP1

Gene:

• THAP1
• chromosome 8p11.21

Protein:

• THAP Domain Containing, Apoptosis Associated Protein 1

(THanatos Associated Protein 1)

• DNA-binding transcription factor
• endothelial cell proliferation
• G1/S cell-cycle progression.
• possible pro-apoptotic activity via TNF-induced apoptosis.

Mutations: loss-of-function:

• Over 90 point mutations
• autosomal dominant, penetrance of 40–60%

Disease:

• causes dystonia (DYT6)
• one of the two genetically determined dystonias

calcinosis dystonia ~563Kb

calcinosis dystonia

dysarthria chorea ataxia Parkinsonism intellectual decline

? +/- plus:

?

calcinosis dystonia

dysarthria chorea ataxia Parkinsonism intellectual decline

? +/- plus:

?

calcinosis dystonia

dysarthria chorea ataxia Parkinsonism intellectual decline

? +/- plus:

? ?

calcinosis dystonia

dysarthria chorea ataxia Parkinsonism intellectual decline

? +/- plus:

calcinosis

?

calcinosis dystonia

dysarthria chorea ataxia Parkinsonism intellectual decline

? +/- plus:

Questions

Canadian family:

• Cerebral Calcification +/- Dystonia-Plus syndrome
• Autosomal Dominant
• deletion on chromosome 8p11
• involving SLC20A2 and THAP1 genes

Thank you