cdg neurology: what you need to kno€¦ · summary 1. we know much, we need to know more 2. a wide...
TRANSCRIPT
![Page 1: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/1.jpg)
CDG Neurology: What you need to know
Mercedes Serrano MD PhD
Genetic Medicine and Child Neurology
Paediatric Institute of Rare Diseases
CIBERERLeuven, July 2017
![Page 2: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/2.jpg)
Summary1. We know much, we need to know more
2. A wide spectrum: different structures, different symptoms
2.2. How to study neurological disturbances
3. Central nervous system
2.1. Neurological manifestation of disease
4. Perypheral neuropathy
5. Skeletal muscle
6. The eyes
![Page 3: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/3.jpg)
_1We know much, we need to know more
![Page 4: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/4.jpg)
Pérez-Cerdá et al. 2017
![Page 5: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/5.jpg)
Clinical suspicion of CDG Sialotransferrin profile
Intellectual disability
Abnormal cranial growth
Peripheral neuropathy
COG1, COG2, COG4, COG5, COG8
COG8, GCS1,
ALG13
GMPPB
Ataxia/cerebellar atrophy
DK1, ALG3, ALG9, ALG11, ALG12, ALG13,DPAGT1, RFT1, DPM1, DPM2
YES
NO
ALG2, ALG3, ALG11, ALG13, RFT1, DPM2, MPDU1, PMM2
ST3GAL3 , SLC35C1
ALG14, MPI, DPM3
Microcephaly
Macrocephaly MAN1B1-CDG
Abnormal muscle tone
Hypotonia
Pyramidalism
Extrapyramidalism
ALG6, ALG8, DPAGT1, ALG1, ALG9, RFT1, ALG11, PMM2, DDOST, DPM2, DK1
COG1, GCS1
COG8
COG5, COG8ALG13
Skeletal muscle
Myopathy
Myasthenic syndrome
Limb girdle dystrophy
DPM1, DPM2 , DPM3 (inclusion body myopathy)
B4GALT1, PGM1
ALG2, ALG14 (congenital)
Epilepsy
Yes, severe
Yes, variable
ALG1, ALG2, ALG3, RFT1, ALG11, ALG13, DPM2, MPDU1, DPAGT1, DK1
COG2, COG6, SLC35A2
PMM2, ALG6, ALG19 ALG12
COG2, COG4 SLC35A1, GMPPB, RPN2PMM2, ALG8, ALG6, MPDU1, STT3A, STT3B
SLC35A1, GMPPB
DPM1, PMM2
GNE, GFPT1, SEC23B, SLC35D1,DHDDS PGM1, ATP6V0A2,
MGAT2, GCS1
COG7
Ne
uro
log
ica
l d
istu
rba
nce
s
MR
I, E
EG,
EMG
, N
MR
I, E
EG,
EMG
, V
CN
Pérez-Cerdá et al. 2017
Type I Type II Normal or not well defined
Isolated Retinitis Pigmentosa DHDDS
Multiorganic & Retinitis Pigmentosa
PMM2
Eye malformations (coloboma, optic nerve hypoplasia)
GMPPB, ALG2, SRD5A3Cataracts
ALG2, SRD5A3
Ophtalmological disease
Fundoscopy, ocular US, ERG, VEP
Type I
Normal or not well defined
![Page 6: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/6.jpg)
_2A wide spectrum:
different structures, different signs and symptoms
![Page 7: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/7.jpg)
Peripheral nerves
Muscle Eye disorders
Neuronal migration
Communication
Signaling
Central nervous system
Brain
Cerebellum
Spinal cord
![Page 8: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/8.jpg)
_3Central nervous system
![Page 9: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/9.jpg)
Hypotonia and other muscular manifestations
Hypotonia
Low muscle tone
Reduction of tendon reflexes
Hypotonia difficults the psychomotor development of children with CDG
Hypotonia or poor muscle tone have been described in ALG6-CDGIc, ALG8-CDGIh, DPAGT1-CDGIj, ALG1-CDGIk, ALG9-CDGIl, RFT1-CDGIn, ALG11-CDGIp, , PMM2-CDGIa, DDOST-CDGIr, DPM2-CDGlu,
DK1-CDGIm, COG1-CDGIIg, and GCS1-CDG IIb.
![Page 10: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/10.jpg)
Perinatal signs of hypotonia:
Polyhydramnios
Excess of amniotic fluid.
Difficulties in swallowing.
May associate high arched palate
Cryptorchidism
Failure of the testicles to descend to the scrotum.
Must be evaluated before the age of 2.
![Page 11: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/11.jpg)
Dysphagia and feeding disturbances
Behaviour!!!
Restrictive behaviour
Psychological-behavioural therapy
Hypotonia
Gastroesophageal reflux
DysphagiaSwallowing is very complexSuspect:
1. Takes long time2. Cough during feeding3. Frequent respiratory infections
Consequences:1. Nutrition2. Seccurity
Constipation
![Page 12: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/12.jpg)
Other muscular manifestations
Spasticity
Excessive muscle tone when stretching. Can be associated with hypotonia.
Increase of tendon reflexes
Spasticity has been described in some CDG, such as ALG13-CDG and COG5-CDG
Extrapyramidal involuntary movements
Dystonia, chorea…
Have been described in ALG13-CDG.
![Page 13: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/13.jpg)
EpilepsyEpileptic seizureSimultaneous abnormal discharge of a group of neuronsInterferes with normal activity!
PrevalenceCommon finding in CDG, sometimes refractory, sometimes mild
Refractory and predominant symptom: GMPPB-CDG, ALG3-CDG, ALG2-CDG, RFT1-CDG, ALG11-CDG, ALG13-CDG, DPM2-CDG, MPDU1-CDG, COG2-CDG, COG6-CDG, DPAGT1-CDG and sometimes West syndrome in ST3GAL3-CDG, SLC39A8-CDG and NGLY1-CDG.
Less serious and treatable: PMM2-CDG, ALG6-CDG, ALG12-CDG, ALG1-CDG, ALG9-CDG,MGAT2-CDG, and GCS1-CDG.
Focal
Generalized
Epileptic seizure ≠ Epilepsy
![Page 14: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/14.jpg)
Epilepsy Diagnosis
Clinical interview + ElectroencephalogramSleep
Hyperventilation
Intermittent light stimulation
Type of seizuresType of paroxysmal
activity
Personalized therapy: AED +/- other
![Page 15: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/15.jpg)
Microcephaly/macrocephaly
Measuring the occipitofrontal circumference is an easy way to monitor the appropriate growth of the brain.
The measure need to be compare with normal range for age and sex.
We need to consider the value but, more importantly, the evolution: the child’s curve
Microcephaly: less cranial growth than normalMacrocephaly: excessive cranial growth
In CDG, microcephaly is more frequent than macrocephalyMicrocephaly: GMPPB-CDG , ALG3-CDG, ALG12-CDG , DPAGT1-CDG, ALG9-CDG, RFT1-CDG, ALG11-CDG, ALG13-CDG, DPM1-CDG, DPM2-CDG, DK1-CDG, SLC35C1-CDG, COG1-CDG, COG2-CDG ,COG4-CDG, COG5-CDG and COG8-CDGMacrocephaly: Man1B1-CDG, EXT2-CDG
![Page 16: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/16.jpg)
Cerebellum
Part of the Central Nervous System: posterior fossa.
The cerebellum integrates information on our movements and
sensations in order to control movements to be coordinated and
fluid.
The cerebellum collects information from the eyes and the ears to
maintain posture and balance. This integration is continuous.
The cerebellum maintains the muscle tone
Injured cerebellum
Difficulties in gait and sitting
Difficulties in speech
Limb movement dyscoordinate, tremor
Difficulties in controlling the direction of our gaze
Cognitive (attention, language, learning,…) and behaviouralfunctions (ASD!)
Difficulties in learning, processing, social
abilities…
![Page 17: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/17.jpg)
Cerebellum: structure
2H
2F
2C
Age (years)
Cere
bellar
vo
lum
e(c
m3)
Age
0-10 years 11-17 years
Pe
rce
ntu
allo
ss
of
MV
RD
pe
r ye
ar
De Diego et al. JIMD 2017
![Page 18: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/18.jpg)
Cerebellar motor functions
ICARSInternational Cerebellar Ataxia Rating Score (19 items
Serrano M et al, OJRD 2015, Serrano NL et al, 2017 Submitted
![Page 19: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/19.jpg)
Unexpected Stressful Underdiagnosed
Stroke-like
![Page 20: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/20.jpg)
Stroke likeAcute event consisting of sudden onset of a focal neurological deficit, irritability or decreased consciousness that may associate with seizures, headache or other transient symptoms, in the absence of another diagnosis explaining these symptoms
Irritability or decreasedconciousness
Lethargy
Residual focal deficit
![Page 21: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/21.jpg)
Findings and Treatment
Check coagulation
Antiepileptic drugs
Treat hyperthermia
Vasogenic edema
≠ Cytotoxic edema ( ischemia/infarction)
![Page 22: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/22.jpg)
_4Peripheral neuropathy
![Page 23: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/23.jpg)
Perypheral neuropathy
Injury to peripheral nerves.
Patients with peripheral neuropathy usually show muscular weakness, reduction of or disappearance of bone-tendon reflexes, and atrophy of the muscles.
The condition is detected by physician’s exploration and neurophysiological study (electromyography and neurography).
DPM1-CDG and PMM2-CDG
![Page 24: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/24.jpg)
_5Skeletal muscle
![Page 25: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/25.jpg)
Muscular and neuromuscular disease
Myopathy
Muscle disease
Myopathy has been described in some CDG, such as GNE-CDG (Inclusion bodies myopathy as unique symptom), DPM3-CDG (myopathy is the nuclear symptom), PGM1-CDG, B4GALT1-CDG, TRAPP11-CDG.
Myasthenic syndrome
Muscular disease characterized by fatigability: decrease of strength with maintained effort.
Have been described in GFPT1-CDG, ALG14-CDG, ALG2-CDG, DPAGT1-CDG…They can be symptomatically treated!
http://falconierivisuals.com/?portfolio=neuromuscular-junction
![Page 26: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/26.jpg)
Muscular and neuromuscular disease
Muscular dystrophy
Disruption in the muscular cell membrane.
High muscular proteins (enzymes, CKs) can be detected in
blood
Muscular dystrophy has been described in some CDG, such as
GMPPB-CDG and in O-mannose pathways: αDystroglycanopathies
![Page 27: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/27.jpg)
Skeletal muscular cell Skeletal muscular cell
![Page 28: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/28.jpg)
α Dystroglycanopathies
![Page 29: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/29.jpg)
![Page 30: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/30.jpg)
Electromyography and study of nerve conduction
Measures muscle activity
Measures velocity and amplitude of nerve conduction
![Page 31: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/31.jpg)
_6Eye
![Page 32: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/32.jpg)
Eye
Optical
Electrical
Muscular
http://www.apsubiology.org/anatomy
http://nn.cs.utexas.edu/web-pubs/bednar.thesis
http://www.telescope-optics.net/eye_aberrations.htm
![Page 33: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/33.jpg)
Eye
Neuronal (electric)
Optic nerve malformation (ALG2-CDG)
Pigmentary retinitis (DHDDS-CDG, PMM2)
Sixth-nerve paralysis.
Cortical blindness.
Motor (muscular)
Strabismus.
Saccadic pursuit.
Nistagmus
Paroxysmal tonic upgaze
![Page 34: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/34.jpg)
Pigmentary retinitis
Pigmentary retinitis is not a disease, but rather a symptom that may be caused by various genetic alterations.
It involves the loss of photoreceptors (especially the rods) with the depositing of pigment on the retina.
Tunnel vision from pigmentary retinitis.Source: Wikimedia Commons. http://goo.gl/ORjCfS
![Page 35: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/35.jpg)
Cognitive and behaviour
Behavioural phenotype: rigidity, tantrums….
Stereotypes
Sociability
…..
Behavioural phenotype
![Page 36: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/36.jpg)
_7The challenge
![Page 37: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/37.jpg)
• Identify symptoms and help to reach a diagnosis
• Treat and help as much as possible: hypotonia,epilepsy, spasticity, strabismus… school and academic adaptations
• Observe and quantify signs/symptoms
![Page 38: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/38.jpg)
How to monitor PMM2-CDG cerebellar syndrome evolution?
Difficulties in gait and sitting
Difficulties in speech
Limb movement dyscoordinate, tremor
Difficulties in controlling the direction of our gaze
Difficulties in learning, processing, social abilities…
Cerebellar volume
ICARSInternational Cerebellar Ataxia Rating Score
SCAFI
Speech Oculomotor
Videoculonistagmography
Psychometric test
Volumetry and MVRD
![Page 39: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/39.jpg)
VICTOR DE DIEGO ALMARZABELÉN PÉREZ-DUEÑASINMA GARCIA JIMENEZ PILAR POO ARGUELLES BERNABE ROBLES DEL OLMO PILAR QUIJADA FRAILE M TERESA GARCÍA SILVARAMÓN VELÁZQUEZ FRAGUALORENA MONGE GALINDO LUIS GONZALEZ GUTIÉRREZ SOLANA SERGIO AGUILERA ALBESA EDUARDO LOPEZ LASO FRANCISCO CARRATALÁANA FELIPEALFONS MACAYARAMÓN CANCHO CANDELACONCHI MIRANDALLANOS CARRASCOSUSANA ROLDÁNMARI LUZ COUCEEDUARDO AISA
PAULA TALBERTALBALIDIAMARTASERGIOGABRIELOSCARELENAJORGEMARTAPAULA SCRISTINA
RUILIDIALAURAHÉCTORJOSE MARIAJUANJOCARLOSAITORALMAPOLMIGUELJUANINES
JOSE CARLOSIVÁNSANTIAGOIAGOMARTINA MAMENANTONIOLUCHOLUCIAMARTIMNIKOLAYDANIELLARISA
BELÉN PÉREZCELIA PEREZ-CERDÁ
![Page 40: CDG Neurology: What you need to kno€¦ · Summary 1. We know much, we need to know more 2. A wide spectrum: different structures, different symptoms 2.2. How to study neurological](https://reader035.vdocument.in/reader035/viewer/2022071216/6047330baedb874b125b772e/html5/thumbnails/40.jpg)
Gracias.