Transcript 7th Scientific Symposium on Niemann-Pick

EAN Teaching Course :
Neurometabolic Disorders presenting with psychosis
Olivier Bonnot, MD, PhD
Department of Child and Adolescent Psychiatry
University of Nantes, France
[email protected] website: www.u2peanantes.org
Report of potential conflict of interest
•
•
•
•
•
Actelion (AdBoard and Honoraria)
Orphan (Honoraria)
Lundbeck (Honoraria)
Sunovion (Honoraria)
Shire (Honoraria)
Outline
• Overview of organic disorders in psychiatry
• Focus on treatable IEM
• Could we suggest an efficient algorithm for
differential diagnosis?
• Conclusions
General Consideration
• Organic disorders are poorly recognised in psychiatric
patients
• Prevalence is unknown except in few
sub-samples
• Cross-discipline diseases are obviously more difficult to
diagnose
• Clinical features are crucial in psychiatry
Main Organic Disorders in Schizophrenia
Nutritional deficiency
Pellagra
(Vitamin B3 deficiency)
Biermer
(Vitamin B12 deficiency) Bushman 1999
Other vitamin deficiency?
Endocrine diseases
Addison’s Disease
Cushing's Disease Hirsh 2000
Dysregulation of thyroid and
hyper-parathyroid
Inborn errors of metabolism
Homocysteine metabolism disorders (MTHFR and CBs) Reif
2005
Wilson’s Disease Wichovicz 2006
Urea cycle disorders
Porphyria Ellencweig 2006
Niemann-Pick disease Type C
Xanthomatosis
Infectious diseases
Cerebral abscess
Encephalitis (HSV ++)
Neuro-syphilis
Auto-immune diseases
Chorea / Multiple Sclerosis
Lupus / Sarcoidosis
NMDA
Chromosomal abnormalities
Mac Carthy, Nat Genet 2009; Ingason, Mol Psy, 2011; Abdolmaleky, Am J Med Genet 2005, Stefansson, Nature 2009; Levinson, Am J Psy 2011
1q21, 2p53, 2q29, 15q11.2, 15q11.3, 17q12, 22q11.2
NRXN1 (Neurexin 1)
7q36.3, 25q11-13, 16p11.2, 16p13.1
Other CNS diseases
Toxic
Medication
Epilepsy
Not only in schizophrenia
Main Genetic Disorders in ASD
Pathology
% in ASD
% with ASD
Genes
Fragile X
2–5%
20–40%
FMR1
Tuberous Sclerosis
3–4%
43–86%
TSC1-TSC2
Duplication 15q
Angelman / Prader Willi
1–2%
sup 40%
UBE3A
GABAr
22q11 deletion
16p11 deletion
1%
High but
unknown
SHANK3
PCKB1
2q37 deletion
?
50
K1F1A, GBX2
Joubert Syndrome
?
40%
AH1
Timothy Syndrome
?
60–70%
CACNA1C
Focal Cortical Epilepsy with dysplasia
?
70%
CNTNAP2
ASD, autistic spectrum disorder
Main IEM in ASD
Diseases
ASD + associated signs
Diagnosis
Treatment
Phenylketonuria
Neonatal onset, seizure, microcephaly, musty
and mousy odour
Phenylpyruvic acid in urine
Plasma amino acids analysis
Restricted diet
Amino acids
Adenylosuccinase deficiency
Profound retardation
first year
epilepsy, hypotonia
Succinyl aminoimidazole, carboxamine riboside and
succinyl adenosine in urine and CNS
D-Ribose
Creatine deficiency
Mental retardation, hypotonia, epilepsy,
dyskinetic movements, regression +++
Blood and urinary creatinine, MRI, Spectroscopy
Oral creatine
Arginine restriction
Ornithine substitution
Smith-Lemli-Opitz
Onset in infancy, mental retardation, sensory
hyperactivity, sleep disturbance, hypotonia, …
Abnormal sterol pattern (low plasma and tissue
cholesterol and increased plasma and tissue
7-dehydrocholesterol reductase)
Cholesterol replacement therapy
Serotonin deficiency
Various
CNS serotonin level
Serotonin + L-Dopa?
Cerebal folate deficiency
Ataxia, abnormal movement
Controversial
CNS folate
Folic acid
ASD, autistic spectrum disorder; CNS, central nervous system; IEM, inborn error in metabolism; MRI, magnetic resonance imaging
Tableau I – Principales causes de retard mental : classification, étiopathogénie, et fréquence estimée (d’après Szymanski et Bryan, 1999)
Classification
Exemples
Etiopathogénie
Causes prénatales d’origine
génétiquea
– 32 %
Aberrations chromosomiques
Syndrome de Down ou Mongolisme
95 % : trisomie 21 (non transmise) ; 5 % : translocation (peut être transmise)
Mutations monogéniques
X Fragile
Phénylcétonurie
Sclérose tubéreuse
Lié à l’X ; répétition CGG > 230
Autosomique récessif ; déficit enzymatique
Autosomique dominant
Multifactoriel
Retard mental « familial »
Mixte: génétique, environnementale…
Microdélétion
Syndrome Vélo-Cardio-Facial
Syndrome de Prader-Willi
Syndrome d’Angelman
Syndrome de Williams-Beuren
Délétion sur le chromosome 22 (q11)
Délétion sur le chromosome 15 (q11-q13) d’origine paternelle
Délétion sur le chromosome 15 (q11-q13) d’origine maternelle
Microdelétion du chromosome 7 (q11.23)
Metaboliques
82 treatable causes
of IEM
in Intellectual Deficiency
82 causes de pathologies neurométaboliques
enzymatiques
Causes prénatales d’origine externe – 12 %
Infections maternelles
Causes toxiques
Causes obstétricales
Infection VIH
Encéphalopathie virale
Syndrome d’alcoolisme fœtal
Exposition in utero à l’alcool
Prématurité
Variable, multifactorielle
Malformations d’origine inconnue – 8 %
Malformations du SNC
Non fermeture du tube neural
Parfois associé à une hydrocéphalie
Syndrome poly-malformatifs
Syndrome de Cornelia de Lange
Inconnue
Infections
Encéphalite
Causes périnatales – 11 %
Infection au virus Herpes Simplex 2
Problèmes pendant la délivrance
Anoxie néonatale
Variable, infarctus cérébral
Autres
Hyperbilirubinémie
Incompatibilité rhésus mère enfant
Infections
Encéphalite
Causes post natales – 8 %
Infection virale ou bactérienne
Causes toxiques
Saturnisme
Intoxication au plomb
Psychosocial
Pathologie de déprivation
Malnutrition, abus, négligence, dépression anaclitique
Autres
Traumatismes ou tumeurs cérébrales
Variable, atteinte du SNC
Causes inconnues – 25 %
CLINICAL CASE
•Age 6:
–
tendency to fall frequently as well as clumsiness in writing and fine
movements.
–
Impairments in drawing, writing, spelling and mathematics
•He became hyperactive, impulsive and sometimes violent.
•Early development was unremarkable
•He was, however, able to attend regular school despite his learning
difficulties and behavioral disturbances
Bonnot et al, CNS Spectrum 2010
Age 13


hospitalized after an episode of aggressiveness towards his
mother
subsequently admitted to a day-hospital for four years.
Diagnose was : borderline intelligence associated with
dysgraphia, ADHD predominant hyperactive-impulsive
subtype and oppositional defiant disorder (ODD)
Organic symptoms found in history (scares)

pes cavus at the age of 13, necessitating a
bilateral anterior tarsectomy

Chronic diarrhea
 Age 18 a physical examination revealed





A bilateral extensor plantar response,
A distal muscular atrophy of the anteroexternal aspect of
the legs,
A distal hypoesthesia at the lower extremities up to the
ankles.
An electroneuromyograph showed a sensorimotor axonal
polyneuropathy affecting all extremities.
The MRI was considered normal
•Age 21 ! Diagnose is finnaly made !
Plasma cholestanol was found to be elevated (ratio
cholestanol:cholesterol=1:100, N<1:1000).
Sequencing of the CYP27A1 gene in the patient and his
parents revealed that he had the Arg 395 / Cys point mutation
inherited from his mother and the Arg 479 / Cys point
mutation from his father.
XCT
Treatment with chenodeoxycholic acid (250 mg, three times a day).
IMPROVEMENT IN BEHAVIOUR WITH NO PSYCHOTROPIC
MEDICATION !!!
IMPROVEMENT IN
COGNITION
+ speed in
writing
Bonnot et al, CNS Spectrum 2010
10
8
5
0
3
Unspecified
Dementia
Catatonia
Psychosis
Depression
4
0
Childhood
1
0
4
1
0
1
0
2
5
2
4
0
1
2
1
Case 2
 25-year old girl with no specific history
 Come to ER with Auditory hallucinations ,
change of behavior
 Risperidone partially reduced the hallucinations
at first, she is admitted in psychiatric care
 Diagnosis is brief psychotic state, no toxic,
clinical exam is normal.
 Worsening after few days, increasing
risperidone (not efficient), try quetiapin, worse
again. Dysarthria ++
 MRI after 6 months = Brain MRI showed
bilateral T2 hyperintensity involving putamen,
thalami, and brainstem. Involvement of
brainstem revealed the characteristic “double
panda sign.”
Wilson Disease
Brother an Sister
• 22 years old boy
• Brief and acute Psychotic symptoms after cannabis
• 14 hospitalizations in 4 years (same symptoms, same
context)
• Diagnose is Schizophrenia
• AP are poorly efficient
Hanon et al, L’Encéphale 2013
Age 26
•
•
•
•
Speech and swallowing impairments
Abnormal movements
Blank stare
Cognitive decline
• No change with AP stop or down-titration
AP, antipsychotic medication
Maubert A, et al. Encephale 2014: In press
Age 26
Same signs, different perspective
•
•
•
•
•
Choreo-dystonic movements
Cerebellum syndrome
Dysmetria / dysarthria
Frontal syndrome
VSGP
Niemann-Pick disease Type C
Improvement of psychotic symptoms with no
treatment other than miglustat
Maubert A, et al. Encephale 2014: In press
Key point at this stage
• Psychiatric symptoms + ANYTHING is
suspicious
• Treatment resistance to AP is suspicious
• Long decline of cognitive functions is
suspicious
• Atypical feature are possible to highlight.
Focus on treatable IEM
There are lots of IEM in schizophrenia :
•
Lysosomal disorders, Metachromatic leucodystrophy, Fabry, (Gaucher), Tay-Sachs,
Neuronal Ceroid Lipofuscinosis, α-Mannosidosis Type II, Peroxisomal Disorders, Xlinked Adrenoleukodystrophy, Maple Syrup Urine Disease, Pelizaeus-Merzbacher
Disease, Myoclonic Epilepsy with Ragged Red Fibers (MERRF) , Wolfram Disease
(DIDMOAD) … and counting 
Find the complete list in Kaplan & Sadock’s Comprehensive TextBook of Psychiatry
Walterfang, Bonnot et al... 2016
Bonnot et al, Orphanet Journal of Rare disease 2014
Bonnot et al, Frontiers in Neurosciences, 2015
NP-C and Psychiatric Signs
• AR complex disorder of lipid storage.
• Large clinical presentation
• Main signs are ataxia, dysathria and Vertical
Supranuclear Galse Palsy
• Schizophrenia may occur
• Cognitive decline is common.
BONNOT ET AL 2016,
SUBMITTED
40
Behaviour
Number of cases
30
Memory loss
20
Schiz-like
Cognitive
decline
10
0
Psychiatric symptoms
NP-C/PSY
Bonnot et al 2016, submitted
Mean age (years)
Median age
(years)
Onset of psychiatric signs
22.2 ± 12.1
18
Onset of neurological NP-C signs
17.9 ± 13.3
18
Diagnosis of NP-C
28.3 ± 15.8
25
Compared to previous knowledge
©◊
Frontal-like
Syndrome ++
Cognitive decline
Schizophrenia-like
©◊
Garver WS, et al. Med Genet Part A 2007;143A:1204–1211
Cysthionine beta Synthetase (22q22.3)
•
•
•
•
•
•
•
•
Marphan Like
Episodic depression (10%), chronic disorders of
Myopia (17%), obsessive-compulsive disorder
behavior
Dg:
Homocysteinemia
(5%),
and
personality
disorder (19%) (n=63)
Thromobosis
Aggressive
tt: Vitbehavior
B6
Scoliosis
A 31 year old woman presented with a three
Severe
week
history of delirium and inappropriate and
labile affect
Abbott et al. Am J Med Genet 1987 Apr;26(4):959-969. Li SC & Stewart PM. Pathology
1999 Aug;31(3):221-224.
MethylTetraHydroFolate Reductase deficiency 1p36.3
(usually severe neonat apnea microcephalia)
• Insidious
• Acute (after surgery) with visual and/or auditory
Dg:
Homocysteinemia
hallucinations, thought disorder and delusions.
tt: Vit
B12 -schizophrenia
Folate and bipolar
• Unipolar
depression,
disorders (MTHFR C677T gene variant )
• Not uncommun
Mattson et al. Trends Neurosci 2003 Mar;26(3):137-146. Roze E et al. Arch Neurol 2003 Oct;60(10):1457-1462.
Gilbody S et al, American journal of epidemiology 2007 Jan 1;165(1):1-13.
Urea Circle Disorders
• Pathways to eliminate nitrogen (various enzyme defect levels)
• Psychosis as presentation is possible
• Atypical Depressions
•Dg:
LateAmoniemia
onset UCD may be presenting with a
psychiatric (essentially behavioral and with
tt:hallucination)
Proteineand
restricted
Diet
organic signs,
especially
vomiting
• Anorexia – like disorders with protein refusal
Aggravation : Protein // Youth// Valproate //
Corticoïdes
Arn et al. N Engl J Med 1990 Jun 7;322(23):1652-1655. Enns et al. Obstetrics and gynecology 2005 May;105(5 Pt 2):1244-1246. Bachmann et al. European journal of pediatrics
2003 Jun;162(6):410-416. Krivitzky et al. Pediatric research 2009 Jul;66(1):96-101. Legras et al. Critical care medicine 2002 Jan;30(1):241-244. Myers et al. The American journal
of emergency medicine 1996 Oct;14(6):553-557 Panlaqui et al. Intensive care medicine 2008 Oct;34(10):1922-1924. Thurlow et al Annals of clinical biochemistry 2010 May;47(Pt
WD
•copper accumulation in the liver, brain, kidney and skeletal system, caused by reduced
excretion in the bile
 Between 6y et 20 y++++
 Psychiatric Signs 50 % --- Preseting 20 % ++++
 Schizophrénie like in 10 % - Worsted with AP ++++
(even if chelator)
 But also MDD / BPD / change in Personnality and
behavoiur
Dg: Copper
tt: Chelation
 Visuo-Saptial Impairement and Memory Loss.
Executive function
Rathbun, 1986; Medalia, 1989
– Portala et al., 2002; Dening et al., 1989 & Akil et al., 1995
Porphyria (acute form)
•accumulation of porphyrins and/or their precursors – delta-aminolevulinic
acid (ALA) and porphobilinogen (PBG) – in the liver or bone marrow
 Psychiatric
Signs 24-70 % ---acid
Preseting
%
Dg:
delta-aminolevulinic
(ALA)40
and
++++
porphobilinogen (PBG) in urine
 Hallucinations +++++ and Delirium ACUTE
tt:
injection
 13year-old of
boyhuman
with sixhemin
episodesand/or
of
psychosis
with
various
presentations,
perfusion
carbohydrates
including of
delusions,
hallucinations,
hypomania and catatonia, but with no
obvious organic signs
Main IEM in Schizophrenia
Disorder
Clinical signs
Context
Wilson
Tremor
Dystonia
Dysarthria
Urea cycle
Confusion
Abdominal pain
Nausea vomiting
Protein diet
Post-surgery
Drugs
(valproate / corticoids)
Homocysteinemia (CbS)
Thromboembolism
Scoliosis
Marfan-like
Cerebellar signs
Protein diet
Post-surgery
Homocysteinemia (MTHFR)
Early-onset severe disease usually
with microcephaly/ apnea / convulsion
Niemann-Pick
disease Type C
Dystonia + ataxia Dysarthria
Splenomegaly
Cerebrotendinous
xanthomatosis
Chronic diarrhoea
Spastic paralysis
Porphyria
Urine black or red
Constipation
Confusion
Abdominal pain
Nausea / vomiting
Eye exam
Biological markers
Kayser-Fleischer ring
Coeruloplasmin
Ammoniaemia
Severe myopia
Ectopic lens
Homocysteiniemia
Methioninemia
Homocysteiniemia
Methioninemia
Neonatal icterus
Slow progression
Periodic
Supranuclear vertical
Gaze palsy
Skin-biopsy
Filipin test
NPC1 and NPC2 gene test
Juvenile cataract
Cholesteanoemia
Porphobilinogens (URINE)
Atypical Psychiatric Features
Atypical Psychiatric Signs of
Schizophrenia
No
0
Visual hallucinations more important than
auditory
0
Confusion
0
Catatonia
0
Progressive cognitive decline
0
Slightly
1
Evident
2
3
Treatment resistance
1
Fluctuating schizophrenia core symptoms
2
Acute onset
Early onset
Main clinical
feature
3
0
Intellectual disabilities
1
Unusual side effects
(level and type)
1
Atypical Psychiatric Features
• Suggest the need for a more extensive
search
• Are probably not accurate for acute
(infections, toxic)
Could be a starting point for a large
algorithm
Differential Diagnosis Algorithm
• A large list of diseases
– 61 disorders
Differential Diagnosis Algorithm
•
An even larger list of signs and symptoms (293)
•
Try to make it simple for clinical use…
•
Not an easy task…!
Symptom categories
Physical phenotype
Bone/connective tissue
Cardiovascular
Dermatological
Endocrine
Genitourinary
Haematological
Hearing
Miscellaneous
Neuroimaging
Neurological
Renal
Speech
Visceral
Visual
Differential Diagnosis Algorithm
Symptom categories
Physical phenotype
Bone/connective tissue
Cardiovascular
Dermatological
Haematological
Endocrine
Hearing
Genitourinary
Miscellaneous
Neuroimaging
Speech
Neurological
Visceral
Renal
Visual
Differential Diagnosis Algorithm
1
Diagnostic loop 1
Assess/Treat/Refer
No, but more
potential
diagnoses
(i.e. move
down the
ranked list)
No, but more
potential
diagnoses
(i.e. move
down the
ranked list)
Yes
Suspicion of psychosis
[entry criteria to be defined]
2
Obvious cause?
3
Abnormal MRI
4
Symptom checker
Diagnostic loop 2
Assess/additional
examinations
Diagnosis confirmed?
Yes
Treat/Refer
Diagnostic loop 3
Assess/additional
examinations
Diagnosis confirmed?
Yes
Treat/Refer
No
Tier 1
Yes
No more potential
diagnoses
No more potential
diagnoses
5
Possible to provide short list
of high likelihood diagnoses?
6
Symptom checker
Tier 2
7
Ranked list of
potential diagnoses
8
No diagnosis possible
No
Differential Diagnosis Algorithm
• Still a work in progress
• Simple and accurate
• IEM and other genetic diseases
• Atypical psychosis signs are a good entry point
• Few discriminative neurological (and / or other)
symptoms must be identified…
Conclusion and Take Home Messages
• Schizophrenia is present in 1% of the general population
• An underestimated proportion may be associated with
organic disorders
• Not only inborn errors of metabolism
• Atypical signs of psychosis are a clear indication
to perform an extensive search of organic causes