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Cognitive impairment, Epilepsy and Brain Atrophy in two families with different severities and outcomes. 1. 2. 1. 2. 2. 1 Department of Translational Medical Sciences, Section of Pediatrics University of Naples Federico II 2 CEINGE-Biotecnologie Avanzate, Department of Biochemical and

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G cappuccio g frisso c cozzolino f salvatore e del giudice

Cognitive impairment, Epilepsy and Brain Atrophy in two families with different severities and outcomes

1

2

1

2

2

1Department of Translational Medical Sciences, Section of Pediatrics

University of Naples Federico II

2CEINGE-Biotecnologie Avanzate, Department of Biochemical and

Medical Biotecnologies

G. Cappuccio, G. Frisso, C. Cozzolino, F. Salvatore, E. Del Giudice


G cappuccio g frisso c cozzolino f salvatore e del giudice

Family pedigree

I

II

III

4

3

5

6

7

ANTONIO

PIO

TERESA

ROSA


Case report

Case Report

Rosa

When 16 month-old seizures with loss of consciousness, lateral deviation of the head and eyes and clonic jerks lasting ten minutes, one episode per day

Valproic acid,

seizure improvement

Hypsarrhythmia

ACTH

Two months later extensor type infantile spasms

Lamotrigine

poor response

Delay in psychomotor milestones from the beginning. Loss of achieved skills such as independent ambulation. Presently she can walk with support

Topiramate

Good control

Diffused brain atrophy


G cappuccio g frisso c cozzolino f salvatore e del giudice

Case Report

Antonio Pio

Sleep EEG test

At 8 months infantile spasms of the flexor type

ACTH followed by Valproic Acid

Severe hypotonia and delay in psychomotor milestones

Uncomplete control of the spasms

Recurrent episodes of apnea and comatose state

Brain Atrophy

Exitus


G cappuccio g frisso c cozzolino f salvatore e del giudice

Case Report

Teresa

At eight months Flexor spasms

Valproic acid

Vigabatrin

Good seizure control

At 16 months recurrence

of flexor spasms on awakening

Sleep EEG test

Topiramate

seizure free

Severe hypotonia and psychomotor retardation (complete head lag, unable to sit).

Global brain atrophy, dismyelinization


G cappuccio g frisso c cozzolino f salvatore e del giudice

Neuroimaging

Rosa

Teresa

Different severity of fronto-temporal atrophy and white matter abnormalities


G cappuccio g frisso c cozzolino f salvatore e del giudice

Neuroimaging

Rosa

Teresa

Different degrees of brainstem and cerebellar atrophy with corpus callosum hypoplasia


Neuroimaging

Neuroimaging

Teresa

Rosa

Vascular damages: ischemic lesions and dural ectasia with bleeding


G cappuccio g frisso c cozzolino f salvatore e del giudice

At this point

what did the biochemical

and genetic

exams reveal??


G cappuccio g frisso c cozzolino f salvatore e del giudice

Investigations


Shared phenotypical and biochemical features

Shared phenotypical and biochemical features

Teresa

Rosa

Hyperhomocysteinemia

  • Epileptic encephalopaty

  • Microcephaly

  • Cognitive impairment

  • Brain atrophy

More severe presentations

Antonio Pio


Hyperhomocysteinemia

Abnormal processing sample,

Respiratory distress, MTHFR polimorphisms,

Leukemia,

Hyothyroidism,

Epilepsy

Hyperhomocysteinemia

Methymalonic aciduria present

Methymalonic aciduria

absent

Megaloblastic anemia

absent

Megaloblastic anemia

present

Megaloblastic anemia

present

Cbl

Normal Cbl

Low Cbl

Normal/Low

Met

High

Met

Low

Normal

Normal TC

Low TC

IF deficiency

IF

deficiency

MTHFR deficiency

CBS deficiency

TC

TC deficiency

cblC

cblD

cblF

Normal

Low

cblG

cblE

TC deficiency


G cappuccio g frisso c cozzolino f salvatore e del giudice

Differential Diagnosis

  • Remethylation defects

Bishop et al., 2008; Schiff et al. 2011


G cappuccio g frisso c cozzolino f salvatore e del giudice

Remethylation Defects

MTHFR:Methylenetetrahydrofolate reductase

CblE: Methionine synthase reductase

CblG: Methionine synthase

CBS: Cystathionine-β-synthase


G cappuccio g frisso c cozzolino f salvatore e del giudice

Remethylation Defects


G cappuccio g frisso c cozzolino f salvatore e del giudice

Molecular analysis of MTHFR gene

MTHFR gene

  • At 1p36.3

  • Lenght 20 kb

  • 12 exons

  • mRNA 7150 bp

Exons/intron and of 5’- and 3’- UTR of MTHFR gene

DNA extraction from blood samples (Salting out)


G cappuccio g frisso c cozzolino f salvatore e del giudice

Molecular analysis of MTHFR gene

Direct Sequencing of PCR Products

Resultsfor Teresa & parents

Emilia

Luigi

c.547C>T

(p.R183X)/ WT

WT/ c.1013T>C

(p.M338T)

Teresa

c.547C>T (p.R183X) / c.1013T>C (p.M338T)


G cappuccio g frisso c cozzolino f salvatore e del giudice

Molecular analysis of MTHFR gene

Resultsfor Rosa & parents

Luisa

Massimiliano

Luigi

p.R183X/

WT

Emilia

WT/

p.M338T

WT/

c.1013T>C (p.M338T)

c.547C>T (p.R183X)/

WT

Teresa

p.R183X/

p.M338T

Rosa

c.1013T>C (p.M338T) / c.547C>T (p.R183X)


G cappuccio g frisso c cozzolino f salvatore e del giudice

Molecular analysis of MTHFR gene

Luigi

Emilia

Luisa

Massimiliano

WT/ p.M338T

p.A222V/WT

p.F435F/p.F435F

p.R183X/ WT

p.A222V/WT

p.F435F/p.F435F

WT/ p.M338T

p.A222V/WT

p.F435F/p.F435F

p.R183X/ WT

p.F435F/p.F435F

Teresa

Rosa

p.R183X/ .M338T

p.A222V/WT

p.F435F/p.F435F

p.M338T / p.R183X

p.A222V/WT

p.F435F/p.F435F


G cappuccio g frisso c cozzolino f salvatore e del giudice

Severe MTHFR Deficiency

  • MTHFR is the most prevalent inborn error of folate metabolism. More than 100 cases of MTHFR deficiency have been reported.

  • MTHFR deficiency results from the disruption of enzyme function less than 20% of controls.

  • Wide range of clinical manifestations from asymptomatic to severe psychomotor retardation, epilepsy, microcephaly. Sometimes central respiratory failure can be responsible for death. In the late childhood or adulthood arterial thrombosis or psychiatric disturbances can be the initial signs.

  • Diagnosis based on evaluation of serum Hcy and low normal level of Methionine in the absence of hemetological signs and Methylmalonicaciduria


Therapy

Therapy

Betaine (Cystadane)= 100-250 mg/Kg-6-9 gr/die

Folinic acid (Citofolin)= 1.55 mg/kg/die

B12 Vitamin (Dobetin)= 50-150 µg/die

B6??

Rosa

Therapy

Teresa

Therapy

Al Tawari et al., 2002, Schiff et al., 2011, Saudubray et al. 2006


Identical genotype vs variable phenotypic expression

Identical genotype vs variable phenotypic expression

  • Previous reports described intrafamilial phenotypic variation Tonetti et al., 2001; Tallur et al., 2005;

  • Outcomeenviromentalmodifiers

  • Treatment timing

  • Antiepilepticdrugs (Phenytoine, Carbamazepine) Arai and Osaka, 2011, Al Essa et al., 1999,

    Forges e t al., 2010

- Nitrous oxide

Selzer at al., 2003;

  • Combined defects in more

  • than one enzyme involved

  • in remethylation pathway

  • Different ability in Detoxification of Hcy-metabolites such as Hcy-thyolactone

  • Bleomycin hydrolase and Paraxonase 1 significantly contribute to Hcy-thyolactone metabolism protecting against neurodegenerationBorowczyk et al., 2012;

  • Age related onset of epileptic encephalopathy

NEUROTOXICITY IS A MULTIFACTORIAL EVENT!


Epileptic encephalopathy

Epileptic Encephalopathy

And MTHFR deficiency!!!!

Epileptic Encephalopathies in Infancy and Early Childhood, 2007


Take home messages

Take-home messages

  • MTHFR deficiency is a rare entity. Infantile spasms are a possible initial manifestation.

  • Its important not to miss such disorders because specific and early treatment interventions are possible. The neurological outcome is more favorable earlier the treatment is administered.

  • Diagnostic work-up is simple and inexpensive.

  • Neurotoxicity in MTHFR deficiency is a multifaceted process in which the hyperhomocysteinemia may be considered a trigger and not a primary cause, increasing the susceptibility of CNS to other indipendent influences.


G cappuccio g frisso c cozzolino f salvatore e del giudice

Merci à tout le monde

The aim of medicine is to know the disease….

..to relieve the sufferings

itcauses


Main clinical problems

Rosa

12 years and 5 months

Main clinical problems

  • Epileptic encephalopathy

  • Microcephaly

  • Severe cognitive impairment

  • Brain atrophy


Geni modificatori

Geni modificatori???

Identificati SNPs in geni implicati nel metabolismo dell’acido folico e della vitamina B12. Di questi, il gene ALDH1L1 (membro della famiglia aldeide deidrogenasi), si è dimostrato interagire con MTHFR


G cappuccio g frisso c cozzolino f salvatore e del giudice

Mainclinicalproblems

  • Epileptic encephalopathy

  • Mycrocephaly

  • Severe cognitive impairment

  • Congenital hypothyroidism

  • Brain atrophy

Exitus at 16 months

3 years and 7 months

Teresa

Antonio Pio

  • Epileptic encephalopathy

  • Mycrocephaly

  • Hypotonia

  • Brain atrophy

  • Acute respiratory distress


Mthfr deficiency

MTHFR deficiency

  • Più frequente disordine del metabolismo dei folati, AR

  • I polimorfismi in cis rispetto alla presenza di mutazioni patogeniche possono portare ad una riduzione dell’attività enzimatica

  • Neurotossicità cerebrale associata ad un aumento di Hom e riduzione die livelli di SAM Severità del fenotipo correla con la riduzione dell’attività enzimatica

  • I segni iniziali sono per lo più neurologici


G cappuccio g frisso c cozzolino f salvatore e del giudice

Mutazione p.R183X in MTHFR

  • Mutazione nonsenso

  • Grave fenotipo clinico

  • Assenza di attività enzimatica della proteina MTHFR


G cappuccio g frisso c cozzolino f salvatore e del giudice

Mutazione p.M338T in MTHFR

  • Mutazione missenso che causa alterazione del folding della proteina

  • Ridotta attività enzimatica della proteina MTHFR


G cappuccio g frisso c cozzolino f salvatore e del giudice

I polimorfismi di MTHFR

MTHFR p.F435F

MTHFR p.A222V


G cappuccio g frisso c cozzolino f salvatore e del giudice

Famiglia MTHFR

C. Luisa

WT/ p.M338T

C. Massimiliano

p.R183X/ WT

C. Giuseppe

WT/ p.M338T

C. Stefania

WT/ p.M338T

I. Luigi

p.R183X/ WT

C. Emilia

WT/ p.M338T

C. Rosa

p.R183X/ p.M338T

I. Assunta

WT/p.M338T

I. Vincenzo

WT/p.M338T

I. Teresa

p.R183X/ p.M338T


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