Download Inborn errors of metabolism

ESPEN Congress Nice 2010
From child to adult nutrition
Inborn errors of metabolism
Pascal Crenn
Inborn errors of metabolism:
from child to adult
Pascal Crenn
Hôpital Raymond Poincaré
92380 Garches. France
Inborn errors of metabolism
(IEM)
= Hereditary metabolic disorders
• Rare
• Genetic enzymatic deficiencies (synthesis
or breakdown pathway)
What are problems and specificities
for adult doctors?
• Continuation of paediatric treatment
• Primary IEM diagnosis in adults
IEM in France (incidence for 2 yrs)
Children
Adults
Total
Intoxication
62
5
67
Energetic deficiencies
34
9
43
Complexes mol.
83
40
123
Other
4
3
7
Total
183
57
240
Adapted from Saudubray
Specific nutrition in IEM?
• Intoxication: avoid catabolism
– Acute: UCD, leucinosis, homocystinuria
– Chronic : PKU…
• Energetic deficiencies
– beta oxydation and peroxysome: avoid lipolysis
ie fasting (CHO 70%)
– glucose transportation: ketogenic diet (fat 70%)
– others
IEM in adult: acute
clinical/biological presentation
1. Acute encephalopathy -coma
2. Acute psychiatric symptoms
3 Acute neurological sign: stroke, ataxia, PN..
4. Sudden death -life threatening event
5. Rhabdomyolisis
6. Abdominal pain
7. Acute cardiac failure
8. Bone crisis
9. Hepatic failure
10. Metabolic acidosis
11. Ketosis
12. Hypoglycemia
13. Hyperlactacidemia
14. Hyperammonemia
Progress in global care after
paediatric follow up
•
•
•
•
Specific diet
Drugs, enzymes
Care of social and psychological problems
Pregnancy (PKU+++)
Ø Improvement
(survival, quality of life
of child affected)
Limits with specific diet in IEM
• Restrictive (psychological problems): withdrawal
with acute decompensation for some
• Possibilities to various deficiencies (AA, EFA,
vitamins…): specific/mixture solutions (ex PKU)
• Specialized and trained dietetician mandatory
• Avoid fasting for some IEM (b oxydation)
• Avoid catabolism for others (UCD)
Hepatic glycogen storage
disease (GSD) in adults
Hepatic glycogen storage disease
type
0
I
III
IV
VI
II
V
enzyme
Glycogen Synthase
Glucose-6-Phosphatase
Debranching enzyme
Branching enzyme
Phosphorylase
a glycosidase lysosomal
(Pompe)
Muscle phosphorylase
(Mac Ardle)
frequencies
?
27 %
28 %
2%
7%
GSD1
- Glycogen
= hepatomegaly
G-6-Phosphatase
Liver, kidney
Glycogen
Glucose-1-P
- Uric acid
Glucose-6-P
- Triglycerids
Kr
Resp. ch
Pyruvate
I
Glucose ¯
Lactate LIVER BLOOD
GSD1 in child
• Clinic :
– Liver enlargement (+ adenomas), truncal and head
obesity
– Hypoglycaemia with fasting
– Kidney disease (tubulopathy)
– ….
• Biology :
– Post absorptive : hypoglycaemia + hyperlactacidemia
– HyperTG, hyperuricemia
– Others : Transa -, rachitism…
GSD1 in adults
• Same clinic, various severity, trend to
ameliorate metabolic equilibrium (fast
hypoglycaemia)
• Specific complications :
• Renal failure
• Osteopenia
• Hepatocellular carcinoma*
*Franco et al, JIMD 2005
Treatment GSD with hypoglycemia
• Frequent meals (2 to 4 h) with slowly
resorbed carbohydrates: maldodextrin,
starch, Maïzena® (uncooked corn-starch)
• In some case enteral nutrition during night
Phenylketonuria
in adults
Continuation of PKU paediatric
management (neonatal screening)
2 major concerns:
1) Phe-restricted diet continuation?
2) Pregnancy in PKU women
Phe-restricted diet continuation?
• Diet withdrawal in 50 to 90% PKU adults
• In most patients with a restricted diet continuation Phe
> recommendations (variable depending country) in
adults (> 16 yrs)
–
–
–
–
< 600 µmol/L (USA) (10 mg/dL)
< 700
(UK)
< 1200
(Germany)
< 1300
(France)
*Hanley WB, Am J Med 2004
Phe-restricted diet continuation?
• Arguments
– Neurological abnormalities
– Psychological disorders and social
misadaptation
– Pregnancy preparation
• But no clear demonstration of clinical
interest
• Difficulties to restricted diet
Mitchell & Scriver, 2000
Walter et al., Lancet 2002
Pregnancy in PKU women
• Fetopathy (20-30%) in pregnant PKU mothers
(if Phe>360 mmol/L): microcephalia, fetal
growth, cardiac malformations; abortion…
• Metabolic control (Phe 90 - 180 µmol/L) before
and during all pregnancy
• Specific nutritional need, compensate
deficiencies…
• Women information+++
Factors influencing outcomes in the offspring of
mothers with PKU during pregnancy: the
importance of variation in maternal blood Phe
• Methods: 67 mothers PKU/105 children at ages 1, 4,
8, and 14, and the times of starting a Phe-restricted
diet, either before or after conception..
• Results:
-women with PKU should start a Phe-restricted diet
before conception for development quotient and
congenital heart disease
-Phe levels should be consistent throughout the
pregnancy to avoid any later developmental
complications (IQ).
Maillot et al, Am J Clin Nutr 2009
Urea cycle disorders (UCD)
Orotic acid
MITOCHONDRIA
NH +
4
Acetyl-CoA
•
Carbamylphosphate
Ornithine
+
Œ
Glutamate
CYTOSOL
N-Acetyl-Glutamate
‘
Ž
OTC
Citrulline
• Biochemical diagnosis
– AA chromato P and U
– Orotic acid U
UREA
Arginine
•
•
Argininosuccinate
Mitochondrial disorders
• MNGIE (« polip syndrom »)
– Young adult
– Thymidine phosphorylase defect
– Intestinal pseudo-obstruction (CIPO) and
cachexia
– PN in severe cases
• Various defects* with malnutrition and/or
myointestinal involvement
*Amiot et al, Gastroenterology 2009
Abeta and hypobetalipoproteinemia
• Hypocholesterolemia and lipid
malabsorption
• Spinocerebellar degeneration and ataxia
• Genetic test
• Treatment by fat soluble vitamins (E++: 2
to 4 g/d)
Diet in various neuro-IEM in adults
Crenn, Maillot. Rev Neurol 2007
Conclusions
• Heterogeneity of nutrition management:
various diet; enteral nutrition or parenteral
nutrition for some
• Specific (vitamins…) complementation
• Network with paediatricians and
dieteticians
• For a lot of IEM no nutritional specific or
dietetic treatment (with exception of
deglutition abnormalities: PEG…)
Crenn, Maillot. Rev Neurol 2007