Proposal for a simplified classification of IMD based on a … · 2020. 8. 18. · Almost all these...
Transcript of Proposal for a simplified classification of IMD based on a … · 2020. 8. 18. · Almost all these...
OR I G I N A L A R T I C L E
Proposal for a simplified classification of IMD based on apathophysiological approach: A practical guide for clinicians
Jean-Marie Saudubray1 | Fanny Mochel1,2,3,4 | Foudil Lamari1,2,5 | Angeles Garcia-Cazorla6
1Groupe de Recherche CliniqueNeurométabolique, Université Pierre etMarie Curie, Paris, France2Centre de Référence NeurométaboliqueAdulte, Groupe Hospitalier Pitié-Salpêtrière,Paris, France3Sorbonne Universités, UPMC-Paris6, UMR S 1127 and Inserm U 1127, andCNRS UMR 7225, and ICM, F-75013,Paris, France4Département de Génétique, AssistancePublique-Hôpitaux de Paris, GroupeHospitalier Pitié-Salpêtrière, Paris, France5Département de Biochimie, AssistancePublique-Hôpitaux de Paris, GroupeHospitalier Pitié-Salpêtrière, Paris, France6Neurology Department, NeurometabolicUnit and Synaptic Metabolism Lab, InstitutPediàtric de Recerca, Hospital Sant Joan deDéu, metabERN and CIBERER-ISCIII,Barcelona, Spain
CorrespondenceJean-Marie Saudubray, Groupe deRecherche Clinique Neurométabolique,Université Pierre et Marie Curie, 22 rueJuliette Lamber Paris 75017, France.Email: [email protected]
Communicating Editor: JohannesZschocke
Funding informationFondo Europeo de desarrollo regional(FEDER), Grant/Award Number: FIS:PI15/01082; ISCIII
AbstractIn view of the rapidly expanding number of IMD discovered by next generation
sequencing, we propose a simplified classification of IMD that mixes elements
from a clinical diagnostic perspective and a pathophysiological approach based on
three large categories. We highlight the increasing importance of complex mole-
cule metabolism and its connection with cell biology processes. Small molecule
disorders have biomarkers and are divided in two subcategories: accumulation and
deficiency. Accumulation of small molecules leads to acute or progressive postnatal
“intoxication”, present after a symptom-free interval, aggravated by catabolism and
food intake. These treatable disorders must not be missed! Deficiency of small mol-
ecules is due to impaired synthesis of compounds distal to a block or altered trans-
port of essential molecules. This subgroup shares many clinical characteristics with
complex molecule disorders. Complex molecules (like glycogen, sphingolipids,
phospholipids, glycosaminoglycans, glycolipids) are poorly diffusible. Accumula-
tion of complex molecules leads to postnatal progressive storage like in glycogen
and lysosomal storage disorders. Many are treatable. Deficiency of complex mole-
cules is related to the synthesis and recycling of these molecules, which take place
in organelles. They may interfere with fœtal development. Most present as neu-
rodevelopmental or neurodegenerative disorders unrelated to food intake. Peroxi-
somal disorders, CDG defects of intracellular trafficking and processing, recycling
of synaptic vesicles, and tRNA synthetases also belong to this category. Only few
have biomarkers and are treatable. Disorders involving primarily energy metabo-
lism encompass defects of membrane carriers of energetic molecules as well as
cytoplasmic and mitochondrial metabolic defects. This oversimplified classification
is connected to the most recent available nosology of IMD.
KEYWORD S
complex lipids disorders, complex molecules, inborn errors of metabolism classification,
neurodegenerative disorders, neurodevelopmental disorders, trafficking disorders
1 | INTRODUCTION
Metabolism involves thousands of proteins, mostly enzymes,cofactors, receptors and transporters, the deficit of which
Abbreviations: CD, congenital disorders of glycosylation; GSD, glycogenstorage disorders; IMD, inborn metabolic disorder; LSD, lysosomal storagedisorders; NGS, next generation sequencing.
Received: 6 January 2019 Accepted: 13 March 2019
DOI: 10.1002/jimd.12086
J Inherit Metab Dis. 2019;1–22. wileyonlinelibrary.com/journal/jimd © 2019 SSIEM 1
causes an IMD. According to Morava, the “classification ofa disorder as an IMD requires only that impairment of spe-cific enzymes or biochemical pathways is intrinsic to thepathomechanism”.1 Until recently, there was a tendency tomostly consider disorders affecting the catabolism of mole-cules while synthesis and transport defects were clearlyunderrepresented; in fact, they were almost ignored. In viewof the rapid recognition of these new categories of IMD bynext generation sequencing (NGS),2 it is now of utmostimportance to integrate them in the classification of IMDbased on these biochemical categories (synthesis, remo-deling, transport, catabolic and trafficking defects) ratherthan on an organelle-centric approach that splits arbitrarilymetabolic pathways.
2 | TOWARD A NEW ANDSIMPLIFIEDPATHOPHYSIOLOGICALCLASSIFICATION OF IMD
Using this extended definition of IMD, the most recent ten-tative of IMD nosology encompasses more than 1100 disor-ders, provisionally classified into 130 groups.3 This is auseful and exhaustive list primarily based on biochemicalconsiderations. It fulfills the critical requirements for data-base programming, and the possibility of linking to nomen-clatures via MIM gene numbers. In fact, this nosologyrepresents a framework in terms of nomenclature and“speaking a common language” within the metabolic com-munity. Additionally, it is linked to an updated websitewww.iembase.org/nosology/index.asp. However, and inaddition to this detailed and helpful nosology, there are sev-eral reasons why a simplified classification, based on a path-ophysiological approach, is needed:
1. Guidelines to help clinicians to suspect, detect, under-stand and treat IMD are critical. The day-to-day clinicalreasoning is far from being a list of disorders grouped inbiochemical and organelle-based categories. In particu-lar, such type of list has little in common with neurolo-gists' clinical approach. By contrast, the number of newIMD affecting the brain is growing very quickly. There-fore a classification including both clinical phenotypesand mechanisms of disease, easy to understand andgrouped into few categories, is more likely to be learntand integrated in the clinical practice not only of meta-bolic physicians, but also general pediatricians, neurolo-gists, internists, endocrinologists, etc.
2. The proposal of a simplified classification focuses alsoon pathophysiology-based treatments. Therefore it stim-ulates the clinical exercise of linking symptoms,
pathophysiology and therapeutic management, particu-larly in emergency situations.
3. Exhaustive and accurate descriptions of each disease areessential to deepen the knowledge of metabolic diseases.However, a holistic, integrative approach is crucial inorder to decipher the complexity of mechanisms andphenotypes in IMD. Our simplified classification is inline with a system biology practice, and combines bio-chemistry with cellular biology processes.
Accordingly, the following simplified classification isbased on a number of basic principles:
- Whatever their size, metabolites involved in IMD maybehave as signaling molecules, structural components andfuels, and many metabolites can play different roles duringdevelopment.4
- The proposal for a simplified classification of IMDmixes clinical diagnostic and pathophysiological approachesinto three large categories based on the size of molecules(“small” or “complex”) and their implication in energymetabolism (Figure 1).
- This approach has been used for a long time in our clin-ical practice and has been partly exposed in classic pediatric5
and metabolic textbooks6–8 as well as recent reviewpapers.9,10
- This proposal is organized into categories in order tofacilitate the diagnosis and treatment of patients with IMD.However, patients have disorders in complex, overlapping,non-categorical biologic systems. Accordingly, the authors,and the readers, are faced with the classic dilemma ofbalancing the practicality of categorical thinking with thereality of biology complexity and individual clinical diver-sity. Compromises were made in seeking that balance andreflecting the core mechanism of each disease that correlatesthe most with clinical signs and biomarkers. This is the keyto this simplified classification that, most of all, aims attransforming the enormous complexity of IMD into a usefultool for clinicians.
3 | CLASSIFICATION
3.1 | Group 1: small molecules
Almost all these IMD have plasma and/or urine metabolicmarker(s) (ie, small diffusible water-soluble molecules) thatcan be easily and rapidly measured in emergency, usually inone run (like amino acids, organic acids, acylcarnitines, por-phyrins, fatty acid, purines, pyrimidines, etc.), or by usingspecific methods (like metals or galactose metabolites).These markers are also useful for therapy monitoring sincemost of these IMD are amenable to treatment. This groupcan be divided in 2 subcategories (Table 1).
2 SAUDUBRAY ET AL.
3.1.1 | Accumulation of small molecules
The accumulation of small molecules causes acute or pro-gressive “intoxication” disorders. Signs and symptoms resultprimarily from the abnormal accumulation of thecompound(s) proximal to the block and can potentiallyreverse as soon as the compound(s) is (are) removed. Theydo not interfere with embryo and fetal neurodevelopmentand they present after a symptom-free interval (days toyears) with clinical signs of “intoxication” (acute, intermit-tent, chronic, and even progressive leading to neu-rodegeneration) provoked by fasting, catabolism, fever,intercurrent illness, and food intake. Most of these disordersare treatable and require the removal of the “toxin” by spe-cial diets, scavengers and cofactors (mostly vitamins).
This group encompasses IMD of amino acid catabo-lism—like phenylketonuria, maple syrup urine disease, orhomocystinuria—, urea cycle defects, organic acidurias—like methylmalonic or glutaric aciduria type 1—, galacto-semia, and metal accumulation—like Wilson disease, neuro-ferritinopathies and brain iron accumulation syndromes, orhypermanganesemia linked to SLC30A10 and SLC39A14mutations.15–17 Some small molecules accumulation may
lead to visible crystals in diverse tissues like cystine incystinosis (a lysosomal defect), oxalate in oxalosis(a peroxysomal defect) or homogentisic acid (ochronosis) inalkaptonuria.
Many purine and a few pyrimidine disorders may beclassified in this group. Indeed, most disorders involvingeither nucleotide synthesis, catabolism or salvage pathwaysmay be screened by plasma/urine purines and pyrimidinesprofiles. Clinical symptoms are very diverse and the patho-physiology is sometimes complex (linked to accumulation,deficiency or both) and still badly understood. Many enzy-matic defects involve brain development by intricated mech-anisms.18 Metabolite repair defects are a new growingcategory in which symptoms are linked to the accumulationof a toxic compound like in L-2-hydroxyglutaric aciduria,19
or NAXE mutations—NAXE catalyzes the epimerization ofNAD(P)HX, thereby avoiding the accumulation of toxicmetabolites.20
Vitamins (transport, and intracellular processing) interferewith many different metabolic pathways where they act asenzymatic cofactors, chaperones or signaling molecules. Inmost vitamin-responsive disorders, vitamin plasma levels arenormal and treatment relies on pharmacological doses of
FIGURE 1 Simplified classification « at a glance ». AA, amino acids; CDG, congenital disorders of glycosylation; FA, fatty acids; GAG,glycosaminoglycans; GSL, glycosphingolipids; ID, intellectual disability; IEM, inborn errors of metabolism; KB, ketone bodies; KC, Kreb's cycledefects; LSD, lysosomal storage diseases; Mit, mitochondrial; MPS, mucopolysaccharidosis; NRL, neurological; OLG, oligosaccharides, PC,pyruvate carboxylase deficiency; PDH, pyruvate dehydrogenase deficiency; PL, phospholipids; PPP, Pentose phosphate pathway; PT, pyruvatetransporter deficiency; Psych, psychiatric signs
SAUDUBRAY ET AL. 3
TABLE
1Simplifiedclassificatio
nof
inborn
errorsof
metabolism
CATEGORIE
SSimplified
classific
ation
GROUPSOF
DISORDERS
MAIN
DISORDERS
DIA
GNOST
ICTEST
STREATMENT
CATEGORIE
S/G
ROUPS
Upd
ated
Nosology3
I:Sm
allm
olecules
(water
soluble
diffusible)
Alm
osta
lltheseIM
Dha
veplasmaan
durines
metab
olicmarker(s)that
canbe
easily
andrapidlymeasured,
mak
ingametab
olicsign
atureeasily
accessible
Accum
ulation1.
Cause
acuteor
progressive
“intoxication”
2.Signsresultprim
arily
from
accumulationof
thecompoundandcan
reverseas
soon
asitis
removed.
3.Donotinterfere
with
foetaldevelopm
ent
4.Presentafter
asymptom
-freeinterval
5.Crisisinducedby
food
andcatabolism
6.MostIMDareeasily
treatablebutm
etabolite
repair,m
anynucleic
acidsandfatty
acid
disorders
«Intoxicatio
n»disorders(potentia
llyreversible)
Aminoacidscatabolism
PKU,M
SUD,T
yr1and
Tyr
2,OAT
Hom
ocystin
urias.
Glutathione
AAC,O
AC
Toxin
removalSp
eciald
iets
Vitamins
Scavengers
Drugs
Supplemento
fdistal
product
Organ
transplantation
A-D
isorders
ofnitrogen-con
taining
compo
unds:
6-6-Disordersof
glutathionemetabolism
11-D
isordersof
phenylalanine
12-D
isordersof
tyrosine
metabolism
13-D
isordersof
sulfur
aminoacid
andsulfide
metab.
14-D
isordersof
branched-chain
aminoacid
metab.
15-D
isordersof
lysine
metabolism
16-D
isordersof
prolineandornithine
metabolism
18-D
isordersof
histidinemetabolism
24-D
isordersof
glycinemetabolism
B-D
isorders
ofvitamins,cofactors,metals
andminerals:
39-D
isordersof
molybdenum
metabolism
Organicacids
MMA,P
A,IVA
CerebralO
AOAC,acylcarnitin
esA-D
isorders
ofnitrogen-con
taining
compo
unds:
9-Aminoacylase
deficiencies
14-D
isordersof
branched-chain
aminoacid
metab.
15-D
isordersof
lysine
metabolism
B-D
isorders
ofvitamins,cofactors,metals
andminerals:
26-D
isordersof
cobalaminemetabolism
BVitamins
B6,B12,Folate
Biotin
(causing
homocystin
uriaor
organicacidurias)
AAC,O
AC,acylcarnitin
esA-D
isorders
ofnitrogen-con
taining
compo
unds:
15-D
isordersof
lysine
metabolism
(pyridoxine-dependent-epilepsy)
B-D
isorders
ofvitamins,cofactors,metals
andminerals:
4 SAUDUBRAY ET AL.
TABLE
1(Contin
ued)
CATEGORIE
SSimplified
classific
ation
GROUPS
OF
DISORDERS
MAIN
DISORDERS
DIA
GNOST
ICTEST
STREATMENT
CATEGORIE
S/G
ROUPS
Upd
ated
Nosology3
FAaccumulation
observed
inperoxysomedefects
sharemanyclinical
similaritieswith
complex
lipid
synthesis
disorderssuggestin
gthatmanyother
mechanism
sthan
intoxicatio
nare
involved
26-D
isordersof
cobalamin.2
7-folate.2
8-biotin
29-thiam
ine.30-riboflavin.
32-pantothenate.
33-pyridoxine
Ureacycledefectsand
related
hyperammonaemias
AAC,O
AC
Orotic
acid
A-D
isorders
ofnitrogen-con
taining
compo
unds:
7-Disordersof
ammoniadetoxificatio
n
Metals
Copper(W
ilson)
Iron
(NBIA
)Manganese
(SLC
39A14
SLC30A10)
Specificmetaltests
T1-weightedbrainMRI
B-D
isorders
ofvitamins,cofactors,metals
andminerals:
32-D
isordesof
pantothenatemetabolism
40-D
isordersof
copper
metabolism
41-D
isordersof
iron
metabolism
42-D
isordersof
manganese
metabolism
Carbohydrate
Galactosemias
HFI
Gal-1P,
GALT
Molecular
test
C-D
isorders
ofcarboh
ydrates
47-D
isordersof
galactosemetabolism
48-D
isordersof
fructose
metabolism
Glycerol
Glycerol
E.D
isorders
oflip
ids
87-D
isordersof
glycerol
metabolism
Porphyrins
Porphyrias
Blood/urines
porphyrins
F-Disorders
oftetrap
yrroles
98-D
isordersof
hememetabolism
Metabolite
repair
L-2-O
Hglutaric
D-2-O
Hglutaric
NAXEdeficit
AAC,O
AC
Not
orpoorly
treatable
D.M
itochon
driald
isorders
ofenergy
metab
olism
56-D
isordersof
metabolite
repair
Nucleicacids
Catabolicdisordersof
purinesandpyrimidines
andsalvagepathway
defects
purines/pyrimidines
profile,
uricandoroticacid
Low
purine
diet
Allo
purinol
ERT,B
MTandgene
therapyin
ADA,P
NP
andthym
idine
phosphorylase
A.D
isorders
ofnitrogen-con
taining
compo
unds:
1-Disordersof
pyrimidinemetabolism
2-Disordersof
purine
metabolism
I.2Deficiency
1.Sy
mptom
sresult
prim
arily
from
the
defectivesynthesisor
transportatio
nof
anessentialm
olecule
Mim
iccomplex
synthesisdefects.Mostb
utno
tallareirreversible
AAsynthesis
Serine,G
lutamine,
Asparagine,synthesis
defects
Glutathion
Plasma/CSF
aminoacids
Not
orpoorly
treatable
(Serine?)
A.D
isorders
ofnitrogen-con
taining
compo
unds:
6-Disordersof
glutathion
metabolism
21-D
isordersof
glutam
inemetabolism
22-D
isordersof
asparagine
metabolism
23-D
isordersof
serine
metabolism
24-D
isordersof
glycinemetabolism
SAUDUBRAY ET AL. 5
TABLE
1(Contin
ued)
CATEGORIE
SSimplified
classific
ation
GROUPS
OF
DISORDERS
MAIN
DISORDERS
DIA
GNOST
ICTEST
STREATMENT
CATEGORIE
S/G
ROUPS
Upd
ated
Nosology3
2.Defectsmay
cause
neurodevelopment
disruptio
n,with
congenitalp
resentation
3.Sh
aremany
characteristicswith
disordersin
the
complex
molecules
group
4.Metabolicmarkers
aredecreased
5.Afewareor
should
betreatableby
supplementin
gthe
missing
productd
istal
totheblocklik
eNiacin
intryptophan
malabsorbtio
n(H
artnup
disease)
andcatabo
lism
defects
AAbrainor
epith
elialtransport
SLC7A
5SL
C7A
7(LPI)
SLC6A
19(H
artnup
disease)
Plasma/CSF
AA
Plasma/urines
AA
BCAA?
Citrullin
e.Lysine;
Niacin
A.D
isorders
ofnitrogen-con
taining
compo
unds:
8-Disordersof
aminoacid
transport
14-D
isordersof
branched-chain
aminoacid
metab.
19-D
isordersof
tryptophan
metabolism
(Hartnup)
B.D
isorders
ofvitaminscofactors,metals
andminerals
31.D
isordersof
niacin
andNADmetabolism
BCKDH
BCAA
Plasma/CSF
AA
BCAAandhigh
protein
diet
A.D
isorders
ofnitrogen-con
taining
compo
unds:
14-D
isordersof
branched-chain
aminoacid
metab.
FAtransport
MFS
D2A
deficiency
FAtransportp
rotein
4deficiency
plasmaLPC
VLCFA
activ
ationin
fibroblasts
DHA?LPC
?E.D
isorders
oflip
ids:
83-D
isordersof
fatty
acid
oxidationand
transport
FAsynthesisandrecycling
ELOV1,4,5,
other
Leukotriene
defect
FAprofile
infibroblasts
Molecular
tests
Not
treatable
E.D
isorders
oflip
ids:
85-D
isordersof
fatty
acid
synthesisand
elongatio
n
Metals
SLC39A8(M
n)ATP
7A(Cu)
(Menkesdisease)
AP1S1(Cu)
SLC33A1(Cu)
(acetylCoA
transporter:
AT1)
PlasmaManganese
PlasmaCopper
Ceruloplasm
in
Chelatio
ntherapy
Zincacetate
Metalsupplementatio
n
B.D
isorders
ofvitamins,cofactors,metals
andminerals:
40-D
isordersof
copper
metabolism
42-D
isordersof
manganese
metabolism
43-D
isordersof
zinc
metabolism
44-D
isordersof
selenium
metabolism
45-D
isordersof
magnesium
metabolism
«Classical»
Neurotransm
itters
Synthesis
Catabolism
Transport
Receptors
GABA
Monoamines
Glycine
Serine
Glutamate
Plasma,urine,
CSF
Monoamines
AA,N
eopterins
UrinesOA
L-D
OPA
+carbidopa
Biopterins
Others
A.D
isorders
ofnitrogen-con
taining
compo
unds:
10-D
isordersof
monoaminemetabolism
11-D
isordersof
phenylalanineand
tetrahydrobiopterin
17-D
isordersof
betaandgammaam
inoacids
20-D
isordersof
glutam
atemetabolism
23-D
isordersof
serine
metabolism
Nucleicacids
disorders
Purine
andPy
rimidine
Synthesisdefects
purine/pyrim
idineprofile,
uricandoroticacid
Adenine
Thiopurines
A.D
isorders
ofnitrogen-con
taining
compo
unds:
6 SAUDUBRAY ET AL.
TABLE
1(Contin
ued)
CATEGORIE
SSimplified
classific
ation
GROUPS
OF
DISORDERS
MAIN
DISORDERS
DIA
GNOST
ICTEST
STREATMENT
CATEGORIE
S/G
ROUPS
Upd
ated
Nosology3
Allo
purinol
Uridine
(CAD,U
MPS
)1-Disordersof
pyrimidinemetabolism
2-Disordersof
purine
metabolism
II.C
omplex
molecules
(water
insoluble
poorly
diffusible)
Alth
ough
considered
assm
allm
olecules,fatty
acidsan
dcholesterolw
eread
dedto
thisgrou
pbecauseof
simila
ritie
sin
clinical
finding
swith
complex
lipidsan
dmolecules.
IMDthat
disturbthemetab
olism
ofcomplex
molecules;P
athw
aysinvolvecellu
lartraffic
king
andorganelles,requ
ireproteintran
sporters
orvesicles.
Symptom
sareperm
anent,progressivean
dindepend
ento
fund
ercurrente
vents,un
relatedto
food
intake.M
ostd
iseasesdo
notp
resent
with
metab
oliccrises.
May
presentlikeneurod
evelop
menta
ndneurod
egenerativedisorders
II.1
Accum
ulation
Catabolism
ortransport
defectslead
typically
tostorageof
avisible
compoundlik
ein
classicalL
SD.o
rGSD
.In
generalthere
isno
antenatal
manifestatio
ns.
Neurological
presentatio
nsdisplay
progressivedisorders
with
neurodegeneration
with
orwith
outo
bvious
visceral«storage»
signs.
Ofn
otecystineand
oxalate,although
they
aresm
allm
olecules
are
presentedin
thissection
becausethey
clinically
presentw
ithprogressivestorage
disordersleadingto
renalfailure
andmulti
system
icsigns
Progressive
storagediseaselead
ingto
loss
offunctio
n.Po
tentially
partially
reversibleon
treatm
ent
Glycogen(G
SD)
(cytoplasm
ic)
(lysosom
al)
Glycogenosis
(liver,m
uscle,heart,brain)
Heart,M
uscle
(Pom
pe)
Functio
ntests
Enzym
eassays
Molecular
tests
Speciald
iet
Organ
transplant
ERT,B
MT
Genetherapyin
clinical
trials
C.D
isorders
ofcarboh
ydrates:
51-G
lycogenstoragediseases
53-D
isordersof
glycolysis
GAG
MPS
Urinary
GAGS
Enzym
eassays
ERT,S
RT
BMT
G.S
torage
diseases:
105-Mucopolysaccharidoses
Fatty
acids
Prostaglandins
PZObiogenesisandFA
Odefects:
X-A
LD,X
-AMN
otherP
ZOFA
O,R
efsum
disease
Sjogren-Larsson
Plasma/fibro
VLCFA
profile
Enzym
etestingMolecular
tests
BMT,G
enetherapyin
X-
ALD
DietinRefsum
Zyleutonin
SLS
E-D
isorders
oflip
ids:
86-D
isordersof
thefatty
alcoholcycle
H.D
isorders
ofperoxisomes
andoxalate:
110-Disordersof
peroxisomebeta-oxidatio
n111-Disordersof
peroxisomealpha-oxidation
112-Disordersof
peroxisomalbiogenesis
Cholesterol
Niemann-Pick
Wolman
disease
Enzym
atic,m
olecular
tests
SRT:M
iglustat,
ERT
G.S
torage
diseases:
106-Disordersof
lysosomalcholesterol
metabolism
Sphingolipids
Sphingolipidosis(nervous
system
)Urinary
Sulfatides
Enzym
eassays
ERT,SRT
BMT
G.S
torage
diseases:
102-Sp
hingolipidoses
Lipopigments
Ceroidlip
ofucinosis
Enzym
eassays
Molecular
tests
Not
treatable
E.D
isorders
oflip
ids:
92-D
isordersof
palm
itoylation(CLN1)
Olig
osaccharides
Glycoproteins
Sialicacid
Glucosamines
Olig
osaccharidosis
Glycoproteinosis
Sialidosis
Mucolipidoses
Urinary
Olig
osaccharides
Not
orpoorly
treatable
G.S
torage
diseases:
102-Olig
osaccharidoses
104-Mucolipidoses
Neutrallip
ids
(steatosis)
NLSD
Manyothers
Jordan'sanom
aly
PlasmaTriglycerides
Molecular
test
Symptom
atic
E.D
isorders
oflip
ids:
88-D
isordersof
cytoplasmictriglyceride
metabolism
SAUDUBRAY ET AL. 7
TABLE
1(Contin
ued)
CATEGORIE
SSimplified
classific
ation
GROUPS
OF
DISORDERS
MAIN
DISORDERS
DIA
GNOST
ICTEST
STREATMENT
CATEGORIE
S/G
ROUPS
Upd
ated
Nosology3
Cystin
eCystin
osis
Leukocyte
cystine
Cysteam
ine
KidneyTransplant
G.S
torage
diseases:
107-Disordersof
lysosomaltransporto
rsorting
Oxalate
Oxalosis
PH1-PH
3Urinary
Oxalate
Molecular
tests
KidneyTransplant
B6in
PH1
H.D
isorders
ofperoxisomes
andoxalate:
113.
Peroxisomaldisordersnotinvolving
lipid
metabolism
114-Disordersof
oxalatemetabolism
II.2
Deficiency
Defectsof
synthesis,recycling.
Nostoragematerial.May
interferewith
fetald
evelop
ment.Mosta
reirreversibledisorders
Mosto
fthem
arenot
treatable
Onlyfewhave
metabolic
markersbut
peroxisomeand
cholesterold
isorders.
Fora
llothers
thediagnosisismostly
basedon
NGS.
UntargetedMetabolom
ics
andlip
idom
ics
areprom
isingmethods
LiposolublevitaminsA,
andEdefects
may
mim
icksome
clinicalfindings
ofcomplex
lipid
and
peroxisomedisorders.
Vitamin
DandKdefects
displayvery
specific
presentatio
ns:
Ricketsandhemorrhagic
syndromes
respectiv
ely
Glycogen
GSD
00A(liver)
0B(m
uscle)
Glycogenin
Molecular
tests
C-D
isorders
ofCarbo
hydrate
51.G
lycogenstoragediseases
Muscleglycogenin
1,Muscleglycogen
synthase
deficiency,H
epaticglycogen
synthase
deficiency
GAG
ManydefectsSL
C10A7is
themostrecent
Molecular
tests
None
I.Con
genitald
isorders
ofglycosylation
117-Disordersof
O-xylosylationand
glycosam
inoglycansynthesis
FAtransport
MFS
D2A
deficiency
FAtransportp
rotein
4deficiency
plasmaLPC
VLCFA
activ
ationin
fibroblasts
DHA?LPC
?E.D
isorders
oflip
ids:
83-D
isordersof
fatty
acid
oxidationand
transport
FAsynthesisandrecycling.
Arachidonicacid
derivativ
es
ELOV1,4,5,
other
Leukotriene
defect
CYP2
U1
FAprofile
infibroblasts
Molecular
tests
Not
treatable
E.D
isorders
oflip
ids:
85-D
isordersof
fatty
acid
synthesisand
elongatio
nE-D
isorders
oflip
ids:
91-D
isordersof
eicosanoid
metabolism
Non
mito
chondrialF
Ametabolism
(recyclin
g,synthesis,
catabolism
,transport)
Peroxysomebiogenesisand
FAOdefects
Refsum
disease
Sjogren-Larsson
FAelongatio
n
Plasma/fibro
VLCFA
profile
Enzym
etestingMolecular
tests
BMT(X
-ALD)
Diet(Refsum)
Zyleutonin
SLS
Manyarenottreatable
E-D
isorders
oflip
ids:
86-D
isordersof
thefatty
alcoholcycle
37.D
isorderof
vitamin
Emetabolism
H.D
isorders
ofperoxisomes
andoxalate:
110-Disordersof
peroxisomebeta-oxidatio
n111-Disordersof
peroxisomealpha-oxidation
112-Disordersof
peroxisomalbiogenesis
Ether
phospholipids
(Plasm
alogens)
PZOBiogenesis
plasmalogen
synthesis
defects(RCDPII-V
)FA
R
PlasmaRBC,P
lasm
alogens
FibroblastsEnzym
esMolecular
tests
None
H.D
isorders
ofperoxisomes
andoxalate:
109-Disordersof
plasmalogen
synthesis
8 SAUDUBRAY ET AL.
TABLE
1(Contin
ued)
CATEGORIE
SSimplified
classific
ation
GROUPS
OF
DISORDERS
MAIN
DISORDERS
DIA
GNOST
ICTEST
STREATMENT
CATEGORIE
S/G
ROUPS
Upd
ated
Nosology3
Sphingolipids
already>15
Disorders
Molecular
tests
Deoxy-sphingolip
ids
(MSM
S)
None
E-D
isorders
oflip
ids:
90.D
isordersof
non-lysosomalsphingolipid
metabolism
Phospholipids(PL):
Phosphatidylcholine,
Phosphatidylserine
Phosphatidyle-
thanolam
ine
Cholin
e,Ethanolam
ine
Retinol
disorders
PLsynthesisandrecycling
defects(>15)
Retinol
metabolism
Molecular
tests
None
E-D
isorders
oflip
ids:
35-D
isordersof
vitamin
Ametabolism:
89.D
isordersof
non-mito
chondrial
phospholipid
metabolism
A-D
isorders
ofnitrogen-con
taining
compo
unds:
5-Disordersof
cholinemetabolism
Phospholipids:
Phosphatidyl-inositid
esManytypes(O
CRL,F
IG4,
INPP
5K…)including
mTor
signalingpathway
Molecular
tests
None
E-D
isorders
oflip
ids:
93-D
isordersof
phosphoinositid
esmetabolism
Cholesterol
andbileacids
Bilirubinmetabolism
Biliarytransport
Cholesterol
Bile
acids
PlasmaOxysterols
PlasmaandurinaryBile
acidsprofile
Molecular
tests
Bile
acid
replacem
ent
E-D
isorders
oflip
ids:
95-D
isordersof
cholesterolb
iosynthesis
97-D
isordersof
bileacid
synthesis
99.D
isordersof
bilirubin
metabolism
and
biliary
transport
Steroiddisorders
andvitamin
Ddisorders
Glucocorticoids
Mineralocorticois
Androgens
Oestrogens
Hormone
measurementsin
plasma
Hormonalsubstitution
96.D
isordersof
steroidmetabolism
36.D
isordersof
vitamin
Dmetabolism
Coagulatio
nfactors
Vitamin
KInvestigations
ofcoagulation
Factorssupplementatio
nVitamin
KB.D
isorders
ofvitamins,m
etalsan
dminerals
38.D
isordersof
vitamin
Kmetabolism
II.3
Cellularprocessing
andtraffic
king
Nearlyallthe
molecules
reachtheircorrectintracellu
larlocatio
nsby
virtue
ofsoph
istic
ated
tran
sport-an
d-deliv
erysystem
sam
ongwhich
theintracellular
mem
bran
e-tran
sporta
pparatus
iscrucial.1
1Apa
rticular
mod
elof
compa
rtmentalized
sign
alingan
dmetab
olism
occurs
atthesyna
psethat
uses
anindepend
ento
rgan
elle,the
syna
pticvesicle1
2
Mostthese
disorders
sharefindings
with
disordersof
II.2
1.Onlyfewhave
metabolicmarkers
2.Manyhave
multisystemic
presentatio
n
CDGsyndromes
(>100)
Protein
Nglycosylation
O-G
lycosylatio
nLipid
glycosylation
GPI
anchor
Multip
lepathway
Dolichol
Deglycosylatio
n
Serum
tranferrin
and
Apolip
oproteinC-III
analysis
Glycomics
Molecular
tests
Not
treatable
butM
PI,D
PAGT1,
GFP
T1,
andPG
M1-CDG
I.Con
genitald
isorders
ofglycosylation
From
115to
1303
SAUDUBRAY ET AL. 9
TABLE
1(Contin
ued)
CATEGORIE
SSimplified
classific
ation
GROUPS
OF
DISORDERS
MAIN
DISORDERS
DIA
GNOST
ICTEST
STREATMENT
CATEGORIE
S/G
ROUPS
Upd
ated
Nosology3
3.Mostinvolve
nervous
system
4.Alm
ostallpresentas
chronicor
progressive
diseases
independento
ffood
andintercurrent
event
5.Theyarenottreatable
6.Diagnosisismostly
basedon
exom
e/genomesequencing
Trafficking
Vesiculation
Processing
QualityControl
Autophagy.
Manydisorders
SNAP29
AP5Z
1CHMP2B
Rabenosyn-5
Senda,Vicisyndrom
es…
Exome/genom
esequencing
Not
treatable
D-M
itochon
driald
isorders
ofenergy
metab
olism:
79-D
isordersof
mito
chondrialp
rotein
quality
control
80-O
ther
disordersof
mito
chondrial
homeostasis(ie,traffickingkinesin-
bindingprotein1[TRAK1]
deficiency)
G.S
torage
diseases:
100-Disordersof
autophagy
I.Con
genitald
isorders
ofglycosylation
128-Glycosylatio
ndisordersof
vesicular
trafficking
129-Disordersof
Golgi
homeostasis
Synapticvesicle(SV)
Manydefects:Structureand
compositio
nof
theSV
,Exocytic
andendocytic
processes,Proteins/lipid
interactions…
..
Exome/genomesequencing
Not
treatable
A-D
isorders
ofnitrogen-con
taining
compo
unds:
10-D
isordersof
monoaminemetabolism
(VMAT2,
DNAJC
12)
D-M
itochon
driald
isorders
ofenergy
metab
olism:
79-D
isordersof
mito
chondrialp
rotein
quality
control
(PIN
K1)
E-D
isorders
oflip
ids:
93-D
isordersof
phosphoinositid
emetabolism
(ie,synaptojanin
1deficiency)
G.S
torage
diseases:
100-Disordersof
autophagy(ie,SN
X14,
SPG11)
101-Neuronalceroidlipofuscinosis:CLN4
(DNAJC
5),A
TP1
3A2
t-RNA
synthetases
Mito
t-RNA
Cytot-RNA
Mit/cytt-RNA
(KARSandGARS)
Exome/genom
esequencing
Not
treatable
D-M
itochon
driald
isorders
ofenergy
metab
olism:
73.D
isordersof
mito
chondrialtRNA
Disordersof
nucleotid
emetabolism
Ribosom
opathies
DNArepairand
methylatio
n
Exome/genom
esequencing
Interferon
(AGS)
Not
treatable
A-D
isorders
ofnitrogen-con
taining
compo
unds:
3-Disordersof
nucleotid
emetabolism
10 SAUDUBRAY ET AL.
TABLE
1(Contin
ued)
CATEGORIE
SSimplified
classific
ation
GROUPSOF
DISORDERS
MAIN
DISORDERS
DIA
GNOST
ICTEST
STREATMENT
CATEGORIE
S/G
ROUPS
Upd
ated
Nosology3
D-M
itochon
driald
isorders
ofenergy
metab
olism:
71.M
itochondrialribosom
opathies
IIIDisorders
involving
prim
arily
energy
metab
olism
Diagn
osiscanbe
orientated
byfunctio
ntestsmeasuring
glucose,lactate,ketonesan
dotherenergetic
molecules
(AA,O
A,A
cylcarnitin
es)inblood,
CSF
and
urines
andconfirmed
byenzymeassays
andmolecular
testing
III.1
Cellm
embran
ecarriers
ofenergetic
molecules
Clin
ical
picturean
dtreatm
entd
ependon
tissue-specificexpression
(enterocytes,h
epatocytes,p
ancreatic
beta
cell,
rena
ltub
ular
cells,b
lood
brainba
rrier,glia
cells,thy
roid…
)and
substratespecificity
(glucose,lactate,k
eton
es,creatine,carnitine…
.)of
theaffected
tran
sporter.
Glucose,lactate,p
yruvate
andketone
bodies
are
themostimportant
molecules
involved
inenergetic
carrierdefects
The
solutecarrier(SLC)
SLC2andSL
C5gene
family
encodesfor
glucosecarrierswhile
SLC16
gene
family
encodesfor
monocarboxylate
transporters(M
CTs)
Glucose
monosaccharidetransporter
proteins
SGLT1(SL
C5A
1)SG
LT2(SLC
5A2)
(sodium
dependentg
lucose
transporter
Glucosuria,Melitu
ria,
monosaccharide,
tolerancetests
Speciald
iet
C-D
isorders
ofCarbo
hydrates
34-D
isordero
fvitamin
Cmetabolism:
46Disordersof
carbohydratetransportand
absorptio
n
GLUT1(SLC
2A1)
(Cerebral)
Low
CSF
Glucose
Speciald
iet
GLUT2(SLC
2A2)
(Hepatocyte,pancreatic
βcells
enterocyte)
Disturbed
glucose
homeostasis.
Tubulopathy
Speciald
iet
Monocarboxylic
transporter
MCT1(SLC
16A1)
Lactate,P
yruvate,
Ketones
transport
EIhyperinsulinism
(Overactivity
)Ketoacidosis
Muscleinjury
(deficiency)
Diazoxide
E-D
isorders
oflip
ids:
84.D
isorders
ofketone
body
metab
olism
Monocarboxylatetransporter1deficiency
and
superactivity
MCT12
(SLC
16A12)
Creatinetransport
Low
plasmacreatin
elowUcreatin
ine
Low
braincreatin
epeak
(NMR)
Creatine
A-D
isorders
ofnitrogen-con
taining
compo
unds:
4-Disordersof
creatin
emetabolism:
Creatinetransporterdeficiency
MCT8/SL
C16A2
Triiodothyronine
transporter
HighT3,lowT4andTSH
(AllanHerndon-D
udley
syndrome
T3analogues
Not
included
inFerreira'snosology
III.2
Cytop
lasm
icenergy
defects
Diagn
osisisgenerally
easy
tosuspecto
naclinical
basisan
dfunctio
ntestsin
Glycolysis,an
dGlycogendefectsan
don
brainH-N
MRspectroscopy
forcreatin
edefects
GlycolysisandPentose
PhosphatePathway
defects
Allenzymes
Hem
olyticanem
iaC-D
isorders
ofCarbo
hydrates
49-D
isordersof
thepentosephosphatepathway
andpolyol
metabolism
SAUDUBRAY ET AL. 11
TABLE
1(Contin
ued)
CATEGORIE
SSimplified
classific
ation
GROUPS
OF
DISORDERS
MAIN
DISORDERS
DIA
GNOST
ICTEST
STREATMENT
CATEGORIE
S/G
ROUPS
Upd
ated
Nosology3
53-D
isordersof
glycolysis
Glycogendefects
Synthesisandcatabolism
(See
complex
molecules
storage)
Glucose,lactate,K
etone
Bodies,CreatineKinase,
uricacid
Speciald
iet
Cornstarch
C-D
isorders
ofCarbo
hydrates
51-G
lycogenstoragediseases
52-D
isordersof
gluconeogenesis
Glucose-6-phosphatase
deficiency
Creatinedefects
Creatinesynthesis
Creatinetransport
Low
plasmacreatin
elowurinarycreatin
ine
lowbraincreatin
epeak
(NMRspectro.)
Creatine
A-D
isorders
ofnitrogen-con
taining
compo
unds:
4-Disordersof
creatin
emetabolism:
Insulin
disorders
Insulin
secretion
Insulin
signaling
Glucose,lactate,KB
NH3,AA,OA
Insulin
,peptid
eC
Glucagon
Diazoxide
Octreotide
Surgery
C-D
isorders
ofcarboh
ydrates
50-D
isordersof
insulin
secretionandsignaling
III.3
Mito
chon
driald
efects
Mito
chon
driald
iseasesareclinically
diversean
dcanpresenta
tany
age.Theycanman
ifestin
atissue-specificor
multisystemicman
ner,bu
tmosto
ften
affect
organs
with
thehigh
este
nergydeman
dssuch
asbrain,
skeletal
muscle,eyes
andheart.
Generaloxidative
metabolism:
ability
togenerateenergy
componentsof
the
TCAcycleandPD
Cthatfeed
into
OXPH
OS
Thiam
ine(for
oxdativ
edecarboxylation),
Biotin
(for
carboxylation)
Riboflavin(for
mito
chondrialF
Aoxidation)
arecrucial
cofactorsin
these
processes
Fatty
acid
oxidation
Carnitin
ecycle
β-oxidationdefects
Tango
IIMADdeficiency
Riboflavindefects
Functio
ntestsCarnitin
e,AAC,O
AC,
Acylcarnitin
esEnzym
e/molecular
Diet
Carnitin
eRiboflavin
E-D
isorders
oflip
ids:
82.D
isordersof
carnitine
metabolism
83.D
isordersof
fatty
acid
oxidationand
transport
B-D
isorders
ofvitamins,cofactors,metals
andminerals:
30-D
isordersof
Riboflavinmetabolism
Ketones
metabolism
Ketogenesis
Ketolysis
Anion
Gap,K
etonebodies
SpecialD
iet
E-D
isorders
oflip
ids
84-D
isordersof
ketone
bodies
metabolism
Pyruvate/lactateoxidation
PC,P
DC,M
PCThiam
inedefects
Biotin
defects
Lactate,p
yruvate,am
ino
acids,ketone
bodies,
organicacids,
acylcarnitines
SpecialD
iet
D-M
itochon
driald
isorders
ofenergy
metab
olism
54.D
isordersof
pyruvatemetabolism
C-D
isorders
ofcarboh
ydrates
52-D
isordersof
gluconeogenesis:
pyruvatecarboxylasedeficiency
B-D
isorders
ofvitamins,cofactors,metals
andminerals:
29-D
isordersof
thiamin
metabolism
28-D
isordersof
biotin
metabolism
Krebs
cycle
Lactate,o
rganicacids
None
D-M
itochon
driald
isorders
ofenergy
metab
olism
12 SAUDUBRAY ET AL.
TABLE
1(Contin
ued)
CATEGORIE
SSimplified
classific
ation
GROUPS
OF
DISORDERS
MAIN
DISORDERS
DIA
GNOST
ICTEST
STREATMENT
CATEGORIE
S/G
ROUPS
Upd
ated
Nosology3
55.D
isordersof
theKrebs
cycle
Respiratory
chain
(About
290genes
registered
sofar
classified
in5general
categories
accordingto
Frazier13
Recom
mendatio
nsfor
optim
aldiagnosisand
treatm
ento
fthislarge
evolving
groupare
constantly
reevaluated1
3,14
OXPH
OSsubunits,
assemblyfactorsand
electron
carriers
About
190of
the
mito
chondriald
isease
genesfallinto
oneof
these
categories,w
ithaprim
ary
rolein
OXPH
OS
biogenesis
Pathogenicmutations
have
been
reported
inall3
7mtDNAgenes
andalltRNAsynthetases
(19genes)
Blood
,urinesandCSF
biochemicaltesting
DNAtesting
(severalstrategies)
Pathologyandbiochemical
testingin
tissues
includingfunctio
nal
assays
(muscleandor
liver
biopsy,leukocytes,
fibroblasts
Neuroim
aging
Onlyfewaretreatableso
far:
Vitamins
CoQ …
D-M
itochon
driald
isorders
ofenergy
metab
olism
58-68Disordersof
complex
subunitsand
assembly
69-D
isordersof
mito
chondrialD
NAdepletion,
multip
ledeletio
n,or
intergenom
iccommunication
70-D
isordersof
mito
chondrialtranscriptio
nandRNAtranscript
processing
71-M
itochondrialribosom
opathies
72.-D
isordersof
mito
chondrialtranslatio
nfactors
73-74Disordersof
mito
chondrialtRNA
75-76Disordersof
mito
chondrialfission
and
fusion
77-D
isordersof
mito
chondrialp
hospholip
idmetabolism
78-80.Disordersof
mito
chondrialp
rotein
importquality
controland
homeostasis
81.P
rimaryCoQ
10deficiencies
B-D
isorders
ofvitamins,cofactors,metals
andminerals
25-D
isordersof
lipoicacid
andiron
–sulfur
metabolism
29-D
isordersof
thiaminemetabolism
D-M
itochon
driald
isorders
ofenergy
metab
olism
57.D
isordersof
mito
chondrialcarriers
mtDNAmaintenance
mtDNAexpression
mtaminoacyltR
NA
synthetases
enzymecofactors
mito
chondrialh
omeostasis
andquality
control
Abbreviations:A
A,A
minoacid;A
AC,A
minoacidchromatography;
ADA,A
denosine
deam
inase;PN
P,Pu
rine
nucleoside
phosphorylase;BCAA,B
ranchedchainam
inoacid;B
CKDH,B
ranchedchainketo
acid
dehydrogenase
kinase;BMT,Bonemarrow
transplantation;
CDG,Congenitaldisorder
ofglycosylation;
CSF
,Cerebrospinal
fluid;
DHA,Docosahexanoicacid;L-D
OPA
,3,4dihydroxyphenylalanine;EI,Exerciseinduced;
ERT,Enzym
ereplacem
enttherapy
ER,E
ndoplasm
icreticulum
;FA,F
atty
acid;F
ALDH,F
atty
aldehyde
dehydrogenase(deficient
inSjogrenLarsson
syndrome)
FAR,F
atty
acid
oxidoreductase;G
ABA,g
ammabutyricam
inoacid;G
AG,G
ly-
cosaminoglycans;Gal1P
,Galactose-1-phosphate;GALT,Galactasose-1-phosphate
uridily
ltransferase;
GPI,Glycophosphatidyl
inosito
l;GSD
,Glycogen
storagedisease;
HFI,Hereditary
fructose
intolerance;
IET,Iso-
electrofocusing
oftransferrin;
IVA,Isovalericacidem
ia;L-2-O
H,2
hydroxyglutaric
aciduria;LPC
,lysophosphatidyl
choline;
LPI,Lysinuric
protein
intolerance;
MAD,multip
leacylCoA
dehydrogenase;
MMA,
Methylm
alonicaciduria;M
PS,m
ucopolysaccharidosis;M
RI,Magnetic
resonanceim
aging;
MSU
D,M
aplesyrupurinedisease;mtDNA,m
itochondrialD
NA;m
TOR,m
echanistictargetof
rapamycin;N
AXE,N
ADH
Epimerase;
NBIA
,Neurodegeneratio
nwith
brainiron
accumulation;
NLSD
,Neutral
lipid
storagedisease;
NMR,N
uclear
magnetic
resonance;
OAC,o
rganic
acid
chromatography;
OA,O
rganic
acidurias;OAC,O
rganic
acid
chromatogra-
phy;
OAT,Ornith
ineam
inotranferase;OXPH
OS,
Oxydativ
ephophorylatio
n;PA
,Propionicacidem
ia;PD
C,Py
ruvate
decarboxylasecomplex;PH
,prim
aryhyperoxaluria;
P-ins,
phosphatidyl-inositid
es;PL
,phospholipids;
PKU,Ph
enylketonuria;
PZO,Peroxysomedefect;RBC,redbloodcell;
SLS,
SjogrenLarsson
syndromeSR
T,Su
bstratereductiontherapy;
T3,
Triiodothyronine;
TCA,Tricarboxylicacic
cycle;
tRNA,transfer
RNA
Tyr,
Tyrosinem
ia;U
LCFA
,Ultralongchainfatty
acid;V
LCFA
,verylong
chainfatty
acids.
SAUDUBRAY ET AL. 13
vitamin supplements (vitamin dependency). By contrast,some other vitamin-responsive defects linked to theabsorbtion, or transport of the vitamin or its precursor—suchas secondary niacin deficiency due to tryptophan mal-absorbtion in Hartnup disease, folate deficiency in FOLRdefects, or thiamine, riboflavine transport defects—are char-acterized by low vitamin plasma (or CSF) levels and respondto physiological doses of vitamin (vitamin deficiency). How-ever, most of these IMD affecting vitamin metabolism mayturn out as intoxication disorders. For example, both B12malabsorbption and intracellular cobalamin defects lead tohomocysteine and methylmalonic acid (MMA) accumulation.
Furthermore, the elevation of one specific neutral AAlike phenylalanine in PKU or leucine in maple syrup urinedisease can result in secondary transport defect of otheressential AA. This observation has been used to treatPKU.21
Hyperglycinemias and dopamine transporter defect(accumulation of homovanillic acid in the synaptic cleft)behave more as neurotransmitter disorders and signalingmolecules than as intoxication (see later). In fact, in thebrain, molecules that accumulate can behave as signalingmolecules that activate biological pathways related to neuro-nal plasticity, excitability and survival.
3.1.2 | Deficiency of small molecules
Symptoms result primarily from the defective synthesis ofcompounds that are distal to the block or from the defectivetransport of an essential molecule through cellular or organ-elle membranes. Clinical signs are, at least in theory, treat-able by providing the missing compound. Most of thesedefects affect neurodevelopment, have a congenital presenta-tion (antenatal), and may present with birth defects. Theyshare many characteristics with disorders from the complexmolecules group (see later).
This group encompasses all carrier defects of essentialmolecules that must be transported through cellular mem-branes, inborn errors of non essential AA and FA synthesisand several pyrimidine disorders that affects the synthesis ofcytidine, uridine and thymidine nucleosides and are treat-able, like CAD deficiency,22 or the congenital oroticaciduria. The most paradigmatic IMD linked to brain carrierdefects are SLC7A5 mutations, resulting in the defectivetransport of branched chain AA (BCAA),23 and MFSD2Adeficiency resulting in the defective transport of essential FAsuch as docosahexanoic acid (DHA).24 Interestingly,branched chain dehydrogenase kinase deficiency, whichoveractivates BCAA oxidation and leads to very low levelsof BCAA as in SLC7A5 mutations, presents with a similarlysevere neurodevelopmental disease.25 Other transepithelialessential AA transport defects are linked to mutations in
SLC7A726 and SLC6A19,27,28 which are responsible forlysinuric protein intolerance (lysine and dibasic amino acids)and Hartnup disease (neutral aminoacids with secondary nia-cin deficiency), respectively. Both diseases display lowplasma amino acid levels and may present with postnatalmultisystemic manifestations.29 By contrast, transepithelialnon-essential AA transporter defects (SLC3A1, SLC7A9,SLC1A1) involving cystine, glycine, proline, hydroxypro-line, dicarboxylic acids present only with hyp-eraminoaciduria and remain mostly asymptomatic or withonly « local » symptoms (urolithiasis).
Non-essential AA synthesis defects may present also ante-natally with neurodevelopmental defects. All severe formsof serine synthesis defects cause Neu Laxova syndrome.30
Glutamine synthetase31 and asparagine synthetase32 defi-ciencies display an almost complete agyria and clinicallymanifest as severe congenital epileptic encephalopathies.
FA, either derived from dietary sources or synthesized denovo, can be converted into longer chain FA either satu-rated, mono- or poly-unsaturated to be further incorporatedinto complex lipids.33 Elongases ELOVL5 and ELOVL4deficiencies cause adult dominant spinocerebellar ataxia,SCA38 and SCA34, respectively.34,35 Autosomal recessiveELOVL4,36 and ELOVL1 deficiencies37 may present earlyin infancy with neurodevelopmental arrest and ichthyosissimilar to Sjogren-Larsson syndrome. FA synthesis/elonga-tion defects share many similarities with peroxysomal verylong chain FA catabolic disorders and complex lipid synthe-sis and remodeling deficiencies (see later). Leukotrienedefects are due to deficiencies of an eicosanoid, and themuch more common prostaglandin defects are associatedwith prostaglandin accumulation.
In addition to AA and FA defects, the group of smallmolecule defects also encompasses IMD affecting neuro-transmitters and metal deficiency. The manganese trans-porter deficiency syndrome, caused by SLC39A8 mutations,displays severe late-onset neurodegeneration with lowplasma manganese.38,39 Copper deficiency syndromes withlow plasma copper and ceruloplasmin include Menkes dis-ease related to ATP7A mutations affecting a copper trans-porter, MEDNIK syndrome due to the deficiency of thecopper regulator AP1S140 and the acetyl-CoA transporter(AT-1) deficiency related to SLC33A1 mutations.41 Classicinborn errors of neurotransmitters encompass monoaminetransport and synthesis, gamma amino butyric acid (GABA)synthesis and GABA receptor deficiency, glycine cleavageand transport defects and glutamate defects. The diagnosisof monoamine disorders is based on CSF monoamine andneopterin analysis. Glycine and GABA defects are in generaldetected by means of AA quantification in plasma and urine,and CSF for glycine related disorders.42
14 SAUDUBRAY ET AL.
In summary, most disorders related to small moleculedeficiencies produce major neurodevelopmental alterations,thereby leading to severe global encephalopathies wherealmost all neurological functions are chronically altered. Inearly-onset presentations, patients display severe psychomo-tor delays affecting both motor and cognitive milestones.These defects mimic early “non-metabolic” genetic encepha-lopathies that affect crucial neurodevelopmental functions.For instance, mutations in genes coding for tubulin subunits(TUBA1A, TUBB2B, TUBG1) and molecular motor proteins(KIF2A, KIF5C, DYNC1H1) can produce cortical migrationdefects and lead to severe complex encephalopathies43 in asimilar way than AA synthesis defects. This is because thesesmall molecules contribute to antenatal brain “construction”in terms of signaling, cytoskeleton guidance, synapse forma-tion and later on in experience-dependent synapse remo-deling.12 Interestingly, late-onset forms present asneurodegenerative disorders, reflecting the different roles ofmetabolism as the brain ages.
3.2 | Group 2: complex molecules
This expanding group encompasses diseases that disturb themetabolism of complex molecules that are neither water sol-uble nor diffusible. Such ubiquitous complex molecules areglycogen, triglycerides, sphingolipids (SPL), phospholipids(PL), bile acids, glycosaminoglycans, oligosaccharides, gly-coproteins, glycolipids and nucleic acids. To this group, weadded very long chain FA and cholesterol, although they aresimple molecules, because they can be a source of complexmolecules, such as triglycerides, glycolipids, PL, SPL andcholesterylesters—the deficiency of which share many clini-cal similarities with complex lipids.
Other specific circulating complex molecules like coagu-lation factors, liposoluble vitamins, or hormones synthesizedin very specialized endocrine glands can be also classified inthis group. However, they display very uniform clinicalexpression such as hemorragic syndromes, rickets, or adre-nal failure and diagnosis is easy to reach. The complex meta-bolic processes of synthesis and recycling of complexmolecules take place in organelles (mitochondria, lyso-somes, peroxisomes, endoplasmic reticulum, Golgi appara-tus and synaptic vesicles) and most pathways involveseveral organelles and require protein transporters or vesi-cles. Congenital disorders of glycosylation and trafficking,processing and quality control disorders belong to this cate-gory. In fact, complex molecule defects exemplify the newparadigm of connections between metabolic pathways andsubcellular organelles. Moreover, multiple pathophysiologi-cal mechanisms may be present within a single disease. Asan example, SLC10A7 mutation is a disorder of N-glycosylation giving rise to a biosynthesis defect of
glycosaminoglycans and a skeletal dysplasia withamelogenesis imperfecta.44
In this group, clinical symptoms are permanent, veryoften progressive, and independent of intercurrent events,unrelated to food intake. Most diseases do not present withmetabolic crises. Similarly to the group of small molecules,there are also two subcategories of complex moleculedisorders.
3.2.1 | Accumulation of complex molecules
Catabolism defects lead typically to storage of a visible com-pound that accumulates in the cytoplasm (eg, glycogenosis,steatosis), or in lysosomes (eg, LSD). They are the most typ-ical and historical group (such as sphingolipidoses,mucopolysaccharidoses or glycoproteinopathies) in whichsigns and symptoms primarily result from the abnormalaccumulation of compound(s) proximal to the block andpotentially reverse as soon as the accumulation is removed.In general, there is no antenatal manifestation although, insome severe forms, this is possible such as hydrops or mal-formations.45 Neurological presentations display progressivedisorders with late-onset neurodegeneration with or withoutobvious « storage » signs. Diagnosis is mostly based onurine screening (mucopolysaccharides, oligosaccharides,sulfatides, sialic acid) and leukocytes enzyme analysis. Agrowing number of disorders that involve trafficking andautophagy may mimick classical LSD (see below).Intracellular cytoplasmic phosphoglyceride disorders displaynon-cerebral presentations including hepatic steatosis withhypertriglyceridemia, neutral lipid storage disorders (such asChanarin Dorfman syndrome), and congenital lipodystrophywith insulin resistance and diabetes and several other tissuespecific disorders.33 Glycogen catabolism defects presentwith hepatic, muscular/cardiac or cerebral glycogenosis.
3.2.2 | Deficiency of complex molecules
Glycogen depletion syndromes with no visible glycogen arearbitrarily classified like glycogenosis type 0a and 0b (glyco-gen synthase liver and muscle type, respectively), or linkedto GYG1/2 mutations encoding for glycogenin.46 This groupis also related to energy depletion.
Phospholipids (PL), glycosphingolipids (GSL) and FA(long, very long, ultra long chain FA) synthesis and remo-deling defects represent a rapidly expanding new group.33,47
PL and GSL synthesis and remodeling defects lead to a vari-ety of progressive neurodegenerative symptoms, myopathyand cardiomyopathy (like in Barth or Sengers syndrome),orthopedic signs (bone and chondrodysplasia, malforma-tion), syndromic ichthyosis, and retinal dystrophy. Pho-sphatidylinositides (P-ins) are PL synthesized from cytidyl
SAUDUBRAY ET AL. 15
diphosphate diacylglycerol and inositol, and are highly regu-lated by a set of kinases and phosphatases. The P-ins3Kinases are a family of signaling enzymes that regulate awide range of processes including cell growth, proliferation,migration, metabolism and brain development.48 Manymutations affecting this system are responsible for neuro-development and neurodegenerative disorders such as sev-eral congenital ataxias related to mutations in the inositol1,4,5-triphosphate (IP3) receptor (IP3R),
49 or Joubert orMORM syndromes.50 Overall, given the very short half-lifeof phosphatidylinositides, there are no easy metabolicmarker for these diseases and diagnosis relies on NGS tools.
Peroxisomal disorders encompass a number of moleculardefects affecting either the peroxisome biogenesis or a spe-cific matrix enzyme involving the catabolism of very longchain, and branched chain fatty acids (phytanic acid), orcomplex molecule synthesis like bile acids or plasmalogens.All these defects imply complex lipids and metabolic path-ways that are not limited to peroxisomes but rather crossover several other cellular compartments. They should bereclassified as non-mitochondrial FA metabolism in a vastcomplex lipid category. Many present at birth with apolymalformative syndrome, like Zellwegger syndrome.Others present later between the 1st and 2nd decade of life,or in adulthood, with neurodegenerative disorders (Refsumdisease, X-ALD/AMN or a peroxisomal biogenesis defect)very similar to complex lipid synthesis and remodelingdefects.33,47 Plasmalogens synthesis (a subcategory of PL)involve several compartments: not only peroxisomes butalso the endoplasmic reticulum (ER). As an example,ACBD5 deficiency disrupts lipid transfer between the ERand the peroximes and produces decreased synthesis ofplasmalogens associated with a progressive leukodystrophywith ataxia and retinal distrophy.51
Diagnosis is first performed using blood tests measuringVLCFA, phytanic, pristanic and pipecolic acids in plasma,and plasmalogens from erythrocytes. Non-mitochondrial FAhomeostasis defects share many similarities with Sjogren-Larsson syndrome or deficiencies in Elongase ELOV1,4 and 5.
Cholesterol and bile acid synthesis defects present either withpolymalformative syndromes—such as in Smith-Lemli-Opitz(SLO) syndrome—, neonatal cholestasis, or with late-onsetneurodegenerative disorders—such as cerebrotendinousxanthomatosis treatable by chenodeoxycholic acid.52 The patho-genesis of sterol disorders is complex and may result from cho-lesterol deficiency during embryonic development, accumulationof toxic sterol intermediates proximal to each enzymatic block,abnormal feedback regulation, generation of abnormal bioactiveoxysterols, and/or abnormal signaling by hedgehog proteins thatnormally contain bound cholesterol.53 Diagnosis is first per-formed using blood tests measuring cholesterol and oxysterols
profile. Squalene synthase deficiency is a recently described cho-lesterol synthesis defect. Patients present with facial dysmorphy(SLO-like), and severe neurological involvement. Plasma choles-terol levels are low but there is also an accumulation ofmethylsuccinic acid, mevalonate lactone, mesaconic acid and3-methyladipic acid.54
Glycosaminoglycans (GAG) synthesis disorders havebeen recently reviewed (56) GAGs are constructed throughthe stepwise addition of respective monosaccharides by vari-ous glycosyltransferases and maturated by epimerases andsulfotransferases. GAGs play a wide range of biologicalactivities. Mutations in the human genes encodingglycosyltransferases, sulfotransferases, and related enzymesresponsible for the biosynthesis of GAGs do not presentwith preponderant neurological symptoms. GAG synthesisdefects should be suspected in patients with a combinationof characteristic clinical features in more than one connec-tive tissue: bone and cartilages (short long bones with orwithout scoliosis), ligaments (joint laxity/dislocations) andthe subepithelium (skin, sclerae). Some of these defects pro-duce distinct clinical syndromes, some share characteristicswith CDG. The commonest laboratory tests used for thisgroup of diseases, are molecular testing while analysis ofGAGs and enzyme assays are rather for specialized labs andresearch setting.55 Oligosaccharide synthesis disorders areclassified with congenital disorders of glycosylation (seebelow).
Finally, nucleic acid disorders are much more than theclassic purine and pyrimidine defects if we consider cyto-plasmic and mitochondrial tRNA synthetases defects,56,58
ribosomopathies,57 diseases affecting mechanisms ofDNA/RNA damage reparation such as subtypes of Aicardi-Goutières syndrome and disorders related to DNA methyla-tion (DNAm) such as CHARGE and Kabuki syndromes inwhich highly specific and sensitive DNAm signatures havebeen recently identified.58
3.2.3 | Cellular trafficking and processingdisorders
Congenital disorders of glycosylation (CDG) syndromeshave become one of the largest group of IEM CDG shouldbe considered in any unexplained clinical condition particu-larly in multiorgan disease with neurological involvementbut also in non-specific developmental disability.59 ManyCDG interfere with neurodevelopment in the fœtal life,mostly disorders of protein O-glycosylation, lipid O-glycosylation and glycosylphosphatidylinositol.60 Screeningmethods are limited to serum transferrin and serum apolipo-protein C-III analysis. Clinical glycomics may confirm to bea very efficient diagnostic system.61 NGS is increasinglyused in the diagnostic workup of patients with CDG-X.
16 SAUDUBRAY ET AL.
Detailed classification of this vast and complex growinggroup is beyond the scope of this simplified paper.
Many other defects affecting systems involved in intra-cellular vesiculation, trafficking, processing of complex mol-ecules, and quality control processes (like protein foldingand autophagy) can be anticipated. This is illustrated forexample by (i) the CEDNIK neurocutaneous syndrome dueto mutation in SNAP 29 coding for a SNARE protein impli-cated in intracellular vesiculation,62 (ii) mutations in AP5Z1that encodes a protein facilitating specialized cargo sortingin vesicular-mediated trafficking, causing hereditary spasticparaplegia, and the cellular phenotype of which bears strik-ing resemblance to features described in a number ofLSDs,63 (iii) mutations in CHMP2B and GRN, which encodethe charged multivesicular body protein and progranuline,respectively, are characterized by neuronal lysosomal stor-age pathology presenting with familial frontotemporaldementia,64,65 (iv) similarly, a single point mutation inZFYVE20 coding for Rabenosyn-5 (with evidence of defec-tive endocytotic trafficking) presents with a complex pheno-type including intractable seizures.66 Congenital disorders ofautophagy are another emerging class of IMD presenting ascomplex neurometabolic disorders like SENDA or Vici syn-drome.67,68 These new defects, all identified by NGS with-out obvious metabolic markers, raise the question of abroader definition of LSDs with the accumulation of indi-gestible material in the endosomal/lysosomal system.
Synaptic vesicle cycle disorders form a new group ofIMD that has been very recently individualized (72) Thesynapse is a highly specialized cell junction that connects apresynaptic transmitting neuron with a postsynaptic receiv-ing neuron. The concept of « synaptic metabolism » hasbeen recently introduced and could be defined as the specificchemical composition and metabolic functions occurring atthe synapse.12 The synaptic vesicle (SV) is an independentcomplex and specialized organelle. Vesicular glycolysis wasrecently discovered to be capable of providing a constantintrinsic source of energy, independent of mitochondria, forthe rapid axonal movement of vesicles over long distances.69
Mutations coding for many different proteins that regulatethe SV exocytic-endocytic pathway have been described asresponsible of a variety of disorders that share general char-acteristics of complex molecule disorders.70,71 In particular,trafficking, intracellular vesiculation, chaperon proteins(folding, unfolding and disaggregation), protein-protein,protein-lipid, and lipid-lipid interaction compose the mainmechanisms of this group of diseases.71
Aminoacyl tRNA synthetases deficiencies compose a groupof already more than 30 disordersWith the exception of GARSand KARS, mitochondrial and cytoplasmic aaRSs are encodedby distinct nuclear genes.72,73 Aminoacyl-tRNA synthetasesdeficiencies present with a broad clinical spectrum with manyneurological phenotypes. Mitochondrial aaRSs deficiencies may
mimick OXPHOS disorders with hyperlactatemia.74 Diagnosisshould be facilitated by aminoacylation assays as shownrecently for patients with LARS2 and KARS mutations.75 Muta-tions in KARS and GARS, which act in both the mitochondriaand the cytosol, as well as several cytosolic aminoacyl tRNAsynthetases open a new field of IMD since cytoplasmatic tRNAsynthetases are necessary for all proteins of the cell and there-fore all organelles. The same occurs for other factors related tocytoplasmatic protein synthesis (eg, regulatory factors likeEIF2AK3, etc.), nuclear factors related to gene expression andsplicing.
3.3 | Disorders involving primarily energymetabolism
These consist of IMD with symptoms due, at least in part, toa deficiency in energy production or utilization within theliver, myocardium, muscle, brain, and other tissues. Diagno-sis can be orientated by functional tests measuring glucose,lactate, ketones and other energetic molecules (AA, organicacids, acylcarnitines) in blood, CSF and urines and con-firmed by enzyme assays and molecular testings. Energy-generating processes are master regulators of cell life. In par-ticular, the mitochondrion is both origin and target of severalmetabolic signals which orchestrate cellular function andhomeostasis. Mitochondrial diseases are the most commongroup of IMD and are among the most common forms ofinherited neurological disorders. Mitochondrial medicine haslargely developed to the extent of becoming a subspecialtyof IMD. Because of its complexity, we will just briefly high-light the basic subgroups and core concepts related to energymetabolism (Table 1 part III).
3.3.1 | Membrane carriers of energeticmolecules
Glucose, lactate, pyruvate and ketone bodies are the mostimportant molecules involved in energetic carrier defects.The solute carrier (SLC) SLC2 and SLC5 gene familiesencode glucose carriers, GLUT and SGLT, respectively,while the SLC16 gene family encodes for monocarboxylatetransporters (MCT) for FA, ketone bodies, and monocarbox-ylic acids.85,86 GLUT and MCT display many tissue specificisozymes such as GLUT1 (the glucose cerebraltransporter),76 GLUT2 (the glucose hepato-intestinal trans-porter) or MCT177 (Table 1 III.1).
3.3.2 | Cytoplasmic energy defects
They are generally are generally less severe. They includeglycolysis, glycogen metabolism, gluconeogenesis, hyperin-sulinism, which are all treatable, creatine metabolism disor-ders, which are partially treatable, and inborn errors of the
SAUDUBRAY ET AL. 17
pentose phosphate pathways, untreatable, with a phenotypemostly linked to defective NADP/NADPH production.78
Diagnosis is generally easy to suspect on a clinical basis plusfunctional tests in glycolysis, and glycogen defects, and onurine creatine/creatinine ratio and brain 1H-NMR spectros-copy for creatine defects.
3.3.3 | Mitochondrial defects
They encompass aerobic glucose oxidation defects pre-senting with congenital lactic acidemia (pyruvate transporter,pyruvate carboxylase, pyruvate dehydrogenase system, andKrebs cycle defects), mitochondrial respiratory-chain disor-ders, mitochondrial transporters of energetic and other indis-pensable molecules, coenzyme Q biosynthesis, FAoxidation, and ketone body defects. Some of thiamine andriboflavin defects may also be included in this group giventhat these vitamins serve as cofactors for oxidative decarbox-ylation and fatty acid beta-oxidation, respectively. A largeand growing group of already >110 disorders involves themitochondrial machinery (mitochondrial fusion, fission, rep-lication, mitochondrial protein import and protein qualitycontrol, ribosomopathies, mitochondrial DNA depletion andintergenomic modification, mitochondrial tRNA synthetasesand tRNA modification, and phospholipid membrane metab-olism).13 Mitochondrial diseases are clinically diverse andcan present at any age. They can manifest in a tissue-specificor multisystemic manner, but most often affect organs with
the highest energy demands such as brain, skeletal muscle,eyes and heart. About 290 genes registered so far are classi-fied in five general categories according to Frazier et al.13
Recommendations for optimal diagnosis and treatment ofthis large evolving group are constantly reevaluated.13
4 | DISCUSSION AND CONCLUSION
The oversimplified classification proposed here does notpretend to take into account the diversity of cellular biologynor the totality of disorders listed in the updated nosology.Likewise, the pathophysiology based on distinction betweendisorders with an accumulation vs a deficiency of com-pounds is not always clear. Both accumulation and defi-ciency may coexist in a single disease like for example incholesterol synthesis or purines/pyrimidines defects.
The connection map between our three categories and thenine groups from the nosology classification allows to high-light several main « Highways » (Figure 2): (1) Group1(small molecules) is strongly linked to A (nitrogen com-pounds), B (vitamin, metals and cofactors), and also F (tet-rapyrrholes) and C (carbohydrate) but not to groups D(mitochondrial disorders) and I (CDG). (2) By contrastgroup 2 (complex molecules) is strongly linked to G (storagedisorders), E (lipids), I (CDG) and H (peroxisome) but alsowith A and D, while there is almost no connection withB. (3) Group 3 (energy) is strongly correlated to D (mito-chondrial) and with C and E.
FIGURE 2 Connection map betweenthe simplified classification and the IMDupdated nosology. A, NITROGENcontaining compounds; B, VITAMINS,cofactors, metals, minerals;C, CARBOHYDRATES;D, MITOCHONDRIAL disorders;E, LIPIDS; F, TETRAPYRROLES;G, STORAGE disorders;H, PEROXISOME and oxalate; I, CDG
18 SAUDUBRAY ET AL.
Rather than analytical approaches focusing only ongenotype-phenotype correlations, this classification claimsfor exploring pathophysiological mechanisms based on anintegrated approach that takes into account changes in meta-bolic pathways and substrates. In this respect, our simplifiedclassification highlights the increasing relevance of complexmolecules in the whole scenario of IMD. They contribute toexplain the interconnection between cellular organelles andopen new windows of differential diagnosis in complex neu-rological and multisystem presentations. In fact, in those clin-ical pictures we should now consider not only the « classicalgroups » of lysosomal, mitochondrial, peroxisomal andCDGs, but also disorders of autophagy, vesiculation, traffick-ing, complex lipid synthesis and remodeling defects, amongothers. Accordingly, this underscores the need formaintaining and further developing a strong capacity for met-abolic investigations in biochemical genetic labs (eg, met-abolomics, lipidomics) besides their increasing access toNGS. Indeed, metabolomics and lipidomics stand out amongomics as the study of the end products of cellular processes,therefore are more likely to be representative of clinical phe-notypes than genetic variants or changes in gene expression.89
Many clinical presentations remain difficult to foresee:
1. For example, the deficiency of adenylate kinase 2, anenzyme that is expressed in many tissues, presents withreticular dysgenesia syndrome, severe combinedimmune-deficiency and sensory neural deafness.79
2. Clinical consequences of compounds accumulated proxi-mal to an enzymatic block can be unexpected. For exam-ple, thymidine accumulation in thymidine phosphorylasedeficiency results in impaired mtDNA maintenance withaccumulation of multiple mtDNA deletions and mtDNAdepletion responsible for MNGIE syndrome. Abnormalaccumulation in the fetus of polyols, osmolyte sub-stances implicated in fetal water metabolism is responsi-ble for hydrops fetalis with the oligohydramniosobserved in transaldolase deficiency.80
3. Ubiquitous dominant activating mutations can leadto unexpected organ specific manifestations likehyperinsulinism associated with hyperammonemia, orinduced by exercise,87 in glutamate dehydrogenase andmonocarboxylate transporter 1, respectively, with apparentclinical consequences in pancreatic beta cells only.81
4. Some mitochondrial enzymes such as those implicated inthe urea synthesis (carbamyl phosphate-synthetase I,ornithine-transcarbamylase, glutamate dehydrogenase) areregulated by sirtuins (SIRT), proteins that are induced bynutritional state (protein intake, fast, catabolism) and ableto activate these enzymes through an acetylation/deacetylation process. SIRT3 and SIRT5 mutations couldbe responsible for hyperammonemia without defects of the
urea cycle enzymes, although it has never been observed inhuman so far.82 SIRT4, a lysine deacylase, has beenrecently found to control leucine metabolism at themethylcrotonyl carboxylase step and insulin secretion.83
5. Finally, an increasing number of adult-onset IEM hasnow been recognized, as new metabolomics and molecu-lar diagnostic techniques have become available. Mecha-nisms underlying pediatric vs adult phenotypicdifferences are numerous and still not well understood.Indeed, the phenotype is the net sum of hereditary andenvironmental factors. It depends on phenotypic plastic-ity (modulations in response to changes in the environ-ment) and is age-dependent (ontogenic changes andaging). A greater understanding of phenotypic variabilitywill be critical to personalize, or at least weigh in, theinitiation of long-term, sometimes burdensome, thera-pies in diseases detected by expanded newborn screen-ing but that can manifest only in adulthood.84
To conclude, this simplified classification aims to pro-vide basic and practical rules to orientate the clinical think-ing in an increasingly complex field. Nowadays, physiciansare faced with a rapidly growing number of new diseasesand pathophysiological categories that challenge our previ-ous knowledge. However, large amounts of information donot necessarily imply a better understanding. In fact, there isa risk of being lost in exhaustive lists of genes and diseasesunless they are associated to a structure that links both clini-cal signs and pathophysiology. Although every disease isunique in terms of clinical peculiarities, specific signs, andnatural history, similar pathophysiological mechanisms tendto have similar spectrum of symptoms. Therefore there is anecessity of combining both in-depth knowledge of individ-ual diseases with an integrative overview, in order to under-stand the global interconnected field of IMD.
ACKNOWLEGMENT
A.G.C. is funded by FIS: PI15/01082 (Instituto de SaludCarlos III: ISCIII and “Fondo Europeo de desarrolloregional” FEDER).
CONFLICT OF INTEREST
The authors have no conflict of interest to report.
Author contributions
J.M.S. has contributed the original idea and is the intellectualauthor of the article. A.G.C. has contributed to the neuro-paediatric and neurobiological aspects, and together withJ.M.S. have drafted, conducted and supervised the
SAUDUBRAY ET AL. 19
manuscript. F.M. and F.L. provided informations on adultneurometabolic presentations and complex lipids classifica-tion respectively and contributed to the criticism, discussionsand revision of the manuscript.
ORCID
Jean-Marie Saudubray https://orcid.org/0000-0003-2010-9831
REFERENCES
1. Morava E, Rahman S, Peters V, Baumgartner MR, Patterson M,Zschocke J. Quo vadis: the re-definition of “inborn metabolic dis-eases”. J Inherit Metab Dis. 2015;38:1003-1006.
2. Van Karnebeek CDM, Wortmann SB, Tarailo-Graovac M, et al.The role of the clinician in the multi-omics era: are you ready.J Inherit Metab Dis. 2018;41:571-582.
3. Ferreira CR, van Karnebeek CDM, Vockley J, Blau NA. Proposednosology of inborn errors of metabolism. Genet Med. 2019;21:102-106.
4. Garcia-Cazorla A, Saudubray JM. Cellular neurometabolism: atentative to connect cell biology and metabolism in neurology.J Inherit Metab Dis. 2018;41:1043-1054.
5. Saudubray JM, Clarke JTR. Principles of inborn errors of metabo-lism. In: Rudolph CD, Rudolph AM, Lister GE, First LR,Gershon AA, eds. Rudolph's Pediatrics. 22nd ed. New York: McGraw-Hill Companies; 2011:541-560.
6. Saudubray JM, Charpentier C. Clinical phenotypes: diagnosis/-algorithms in Scriver, Beaudet, Valle, Sly. The Metabolic &Molecular Basis of Inherited Disease. 8th ed. New York: McGraw-Hill Companies; 2001:1327-1403.
7. Saudubray JM, Sedel F. Enfermadades metabolicas hereditarias:generalidades, grupos clinicos y algoritmos diagnosticos. In:Sanjurjo P, Baldellou A Diagnostico y Tratamento de lasEnfermadades Metabolicas Hereditarias. 3rd ed. Ergon Arboleda;2009:66-113.
8. Saudubray JM, Baumgartner M, Walter J (2016). Inborn metabolicdiseases Diagnosis and treatment. 6th edition Heidelberg(Germany): Springer:1-658.
9. Saudubray JM, Garcia-Cazorla A. Inborn errors of metabolismoverview: pathophysiology, manifestations, evaluation, and man-agement. Pediatr Clin North Am. 2018a;65:179-208.
10. Saudubray JM, Garcia-Cazorla A. An overview of inborn errors ofmetabolism affecting the brain: from neurodevelopment to neuro-degenerative disorders. Dialog Clin Neurosci. 2018b;20:107-131.
11. De Matteis MA, Luini A. Mendelian disorders of membrane traf-ficking. N Engl J Med. 2011;365:927-938.
12. Garcia-Cazorla A, Artuch R, Bayes A. Synaptic metabolism andbrain circuitries in inborn errors of metabolism. J Inherit MetabDis. 2018;41:909-910.
13. Frazier AE, Thorburn DR, Compton AG. Mitochondrial energygeneration disorders: genes, mechanisms and clues to pathology.J Biol Chem. 2017;12.
14. Parishk S, Goldstein A, Konig MK, et al. Diagnosis and manage-ment of mitochondrial disease: a consensus statement from themitochondrial medicine society genetics in medicine. Genet Med.2015;17:689-701.
15. Quadri M, Federico A, Zhao T, et al. Mutations in SLC30A10cause parkinsonism and dystonia with hypermanganesemia, poly-cythemia, and chronic liver disease. Am J Hum Genet. 2012;90:467-477.
16. Tuschl A, Clayton PT, Gospe SM, et al. Syndrome of hepatic cir-rhosis, dystonia, polycythemia, and hypermanganesemia causedby mutations in SLC30A10, a manganese transporter in man.Am J Hum Genet. 2012;90:457-466.
17. Tuschl K, Gregory A, Meyer E, et al. SLC39A14 deficiency. In:Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®
[Internet]. Seattle, WA: University of Washington; 2017:1993-2019.
18. Fumagalli M, Lecca D, Abbracchio MP, Ceruti S. Pathophysiolog-ical role of purines and pyrimidines in neurodevelopment:unveiling new pharmacological approaches to congenital brain dis-eases. Front Pharmacol. 2017;8:941.
19. Rzem R, Achouri Y, Marbaix E, et al. A mouse model of L-2-hydroxyglutaric aciduria. A disorder of metabolite repair. PLoSONE. 2015;10(3):e0119540.
20. Kremer LS, Danhauser K, Herebian H, et al. NAXE mutations dis-rupt the cellular NAD(P)HX repair system and cause a lethal Neu-rometabolic disorder of early childhood. Am J Hum Genet. 2016;99:894-902.
21. Matalon R, Michals-Matalon K, Bhatia G, et al. Large neutralamino acids in the treatment of phenylketonuria (PKU). J InheritMetab Dis. 2006;29:732-738.
22. Koch J, Mayr JA, Alhaddad B, et al. CAD mutations and uridine-responsive epileptic encephalopathy. Brain. 2017;140:279-286.
23. T�arlungeanu DC, Deliu E, Dotter CP, et al. Impaired amino acidtransport at the blood brain barrier is a cause of autism spectrumdisorder. Cell. 2016;167:1481-1494.
24. Guemez-Gamboa A, Nguyen LN, Yang H, et al. Inactivatingmutations in MFSD2A, required for omega-3 fatty acid transportin brain, cause a lethal microcephaly syndrome. Nat Genet. 2015;47:809-813.
25. Novarino G, El-Fishawy P, Kayserili H, et al. Mutations inBCKD-kinase lead to a potentially treatable form of autism withepilepsy. Science. 2013;338:394-397.
26. Torrents D, Mykkänen J, Pineda M, et al. Identification ofSLC7A7, encoding y+LAT-, as the lysinuric protein intolerancegene. Nat Genet. 1999;21:293-296.
27. Kleta R, Romeo E, Ristic Z, et al. Mutations in SLC6A19, encodingB0AT1, cause Hartnup disorder. Nat Genet. 2004;36:999-1002.
28. Seow HF, Broer S, Broer A, et al. Hartnup disorder is caused bymutation in the gene encoding the neutral amino acid transporterSLC6A19. Nat Genet. 2004;36:1003-1007.
29. Broer S. Diseases associated with general amino acid transportersof the solute carrier 6 family (SLC6). Curr Mol Pharmacol. 2013;6:74-78.
30. Acuna-Hidalgo R, Schanze D, Kariminejad A, et al. Neu Laxovasyndrome is a heterogeneous metabolic disorder caused by defectsin enzymes of the L-serine biosynthesis pathway. Am J HumGenet. 2015;95:285-293.
31. Häberle J, Görg B, Rutsch F, et al. Congenital glutamine defi-ciency with glutamine synthetase mutations. N Engl J Med. 2005;353:1926-1933.
32. Ruzzo EK, Capo-Chichi J-M, Ben-Zeev B, et al. Deficiency ofasparagine synthetase causes congenital microcephaly and a pro-gressive form of encephalopathy. Neuron. 2013;80:429-441.
20 SAUDUBRAY ET AL.
33. Lamari F, Mochel F, Saudubray JM. An overview of inborn errorsof complex lipid biosynthesis and remodeling. J Inherit MetabDis. 2015;38:3-18.
34. Di Gregorio E, Borroni B, Giorgio E, et al. ELOVL5 mutations causespinocerebellar ataxia 38. Am J Hum Genet. 2015;95:209-217.
35. Ozaki K, Doi H, Mitsui J, et al. A novel mutation in ELOVL4leading to spinocerebellar ataxia (SCA) with the hot cross bun signbut lacking erythrokeratodermia: a broadened spectrum of SCA34.JAMA Neurol. 2015;72:797-805.
36. Aldamesh MA, Mohamed JY, Alkuraya HS, et al. Recessive muta-tions in ELOV4 cause ichthyosis, intellectual disability and spasticquadriplegia. Am J Hum Genet. 2011;89:754-750.
37. Kutkowska-Kaźmierczak A, Rydzanicz M, Chlebowski A, et al.Dominant ELOVL1 mutation causes neurological disorder withichthyotic keratoderma, spasticity, hypomyelination and dysmor-phic features. J Med Genet. 2018;55:408-414.
38. Boycott KM, Beaulieu CL, Kernohan KD, et al. Autosomal reces-sive intellectual disability with cerebellar atrophy syndrome cau-sed by mutation of the manganese and zinc transporter geneSLC39A8. Am J Hum Genet. 2015;97:886-893.
39. Park JH, Hogrebe M, Gruneberg M, et al. SLC39A8 deficiency: adisorder of manganese transport and glycosylation. Am J HumGenet. 2015;97:894-903.
40. Martinelli D, Travaglini L, Drouin CA, et al. MEDNIK syndrome:a novel defect of copper metabolism treatable by zinc acetate ther-apy. Brain. 2013;136:872-881.
41. Huppke P, Brendel C, Kalscheuer V, et al. Mutations in SLC33A1cause a lethal autosomal-recessive disorder with congenital cata-racts, hearing loss, and low serum copper and ceruloplasmin.Am J Hum Genet. 2012;90:61-68.
42. Tristán-Noguero A, García-Cazorla AI. Synaptic metabolism:towards new categories of neurotransmission defects. J InheritMetab Dis. 2018;41:1065-1075.
43. Parrini E, Conti V, Dobyns WB, Guerrini R. Genetic basis of brainmalformations. Mol Syndromo. 2016;7:220-233.
44. Dubail J, Huber C, Chantepie S, et al. SLC10A7 mutations cause askeletal dysplasia with amelogenesis imperfecta mediated by GAGbiosynthesis defects. Nat Commun. 2018;6(9):3087.
45. Vianey-Saban C, Acquaviva C, Cheillan D, et al. Antenatalmanifestations of inborn errors of metabolism: biologicaldiagnosis. J Inherit Metab Dis. 2016;39:611-624.
46. Moslemi AR, Lindberg C, Nilsson J, Tajsharghi H, Andersson B,Oldfors A. Glycogenin-1 deficiency and inactivated priming ofglycogen synthesis. N Engl J Med. 2010;362:1203-1210.
47. Garcia-Cazorla A, Mochel F, Lamari F, Saudubray JM. The clini-cal spectrum of inherited diseases involved in the synthesis andremodeling of complex lipids. A tentative overview. J InheritMetab Dis. 2015;38:19-40.
48. Waugh MG. PIPs in neurological diseases. Biochim Biophys Acta.2015;1851:1066-1082.
49. Ando H, Hirose M, Mikoshiba K. Aberrant IP3 receptor activitiesrevealed by comprehensive analysis of pathological mutationscausing spinocerebellar ataxia 29. Proc Natl Acad Sci USA. 2018;115:12259-12264.
50. Ramos AR, Ghosh S, Erneux C. The impact of PI 5-phosphataseson phosphoinositides in cell function and human disease. J LipidRes. 2019;60:276-286.
51. Ferdinandusse S, Falkenberg KD, Koster J, et al. ACBD5deficiency causes a defect in peroxisomal very long-chain fattyacid metabolism. J Med Genet. 2017;54:330-337.
52. Degos B, Nadjar Y, Amador M del M, et al. Natural history ofcerebrotendinous xanthomatosis: a paediatric disease diagnosed inadulthood. Orphanet J Rare Dis. 2016;11:41-44.
53. Herman GE, Kratz L. Disorders of sterol synthesis: beyond Smith-Lemli-Opitz syndrome. Am J Med Genet C Semin Med Genet.2012;160c:301-321.
54. Coman D, Vissers LELM, Riley LG, et al. Squalene synthase defi-ciency: clinical, biochemical, and molecular characterization of adefect in cholesterol biosynthesis. Am J Hum Genet. 2018;103:125-130.
55. Sasarman F, Maftei C, Campeau PM, Brunel-Guitton C,Mitchell GA, Allard P. Biosynthesis of glycosaminoglycans: asso-ciated disorders and biochemical tests. J Inherit Metab Dis. 2016;39:173-188.
56. Wallen RC, Antonellis A. To charge or not to charge: mechanisticinsights into neuropathy-associated tRNA synthetase mutations.Curr Opin Genet Dev. 2013;23:302-309.
57. Mills E, Green R. Ribosomopathies: There is Strength in Numbers.Science. 2017;358:608-616.
58. Butcher DT, Cytrynbaum C, Turinsky AL, et al. CHARGE andkabuki syndromes: gene-specific DNA methylation signaturesidentify epigenetic mechanisms linking these clinically over-lapping conditions. Am J Hum Genet. 2017;100:773-788.
59. Jaeken J, Morava E. Congenital disorders of glycosylation,Dolichol and Glycophosphatidyl-inositol metabolism. In:Saudubray JM, Baumgartner M, Walter J, eds. Inborn MetabolicDiseases Diagnosis and Treatment. Heidelberg, Germany:Springer; 2016:609-622.
60. Barone R, Fiumara A, Jaeken J. Congenital disorders of glycosyla-tion with emphasis on cerebellar involvement. Semin Neurol.2014;34:357-366.
61. Bakar NA, Lefeber DJ, van Scherpenzeel M. Clinical Glycomicsfor the diagnosis of congenital disorders of glycosylation. J InheritMetab Dis. 2018;41:499-513.
62. Sprecher ED, Ischida-Yamamoto A, Mizrahi-Koren M, et al. Amutation in SNAP29,coding for a SNARE protein involved inintracellular trafficking, causes a novel neurocutaneoussyndrome characterized by cerebral dysgenesis, neuropathy, ich-thyosis, and palmoplantar keratoderma. Am J Hum Genet. 2005;77:242-251.
63. Hirst J, Edgar JR, Esteves T, et al. Loss of AP-5 results in accumu-lation of aberrant endolysosomes: defining a new type of lyso-somal storage disease. Hum Mol Genet. 2015;24:4984-4996.
64. Clayton EL, Mizielinska S, Edgar JR, et al. Frontotemporal demen-tia caused by CHMP2B mutation is characterised by neuronal lyso-somal storage pathology. Acta Neuropathol. 2015;130:511-523.
65. Mole SE, Coteman SL. Genetics of the neuronal ceroidLipofuscinoses (batten disease). Biochim Biophys Acta. 2015;1852:2237-2241.
66. Stockler S, Silvia Corvera S, Lambright D, et al. Single pointmutation in Rabenosyn-5 in a female with intractable seizures andevidence of defective endocytotic trafficking. Orphanet J RareDis. 2014;9:141-152.
67. Ebrahimi-Fakhari D, Saffari A, Wahlster L, et al. Congenital disor-ders of autophagy: an emerging novel class of inborn errors ofneuro-metabolism. Brain. 2016;139:317-337.
68. Saitsu H, Nishimura T, Muramatsu K, et al. De novo mutations inthe autophagy gene WDR45 cause static encephalopathy of child-hood with neurodegeneration in adulthood. Nat Genet. 2013;45:445-449.
SAUDUBRAY ET AL. 21
69. Zala D, Hinckelmann MV, Yu H, et al. Vesicular glycolysis provideson-board energy for fast axonal transport. Cell. 2013;152:479-491.
70. Cortès-Saladelafont E, Tristán-Noguero A, Artuch R, Altafaj X,Bayès A, García-Cazorla A. Diseases of the synaptic vesicle: apotential new group of neurometabolic disorders affecting neuro-transmission. Semin Pediatr Neurol. 2016;23:306-320.
71. Cortès-Saladelafont E, Lipstein N, García-Cazorla À. Presynapticdisorders: a clinical and pathophysiological approach focused onthe synaptic vesicle. J Inherit Metab. 2018;41:1131-1145.
72. Meyer-Schuman R, Antonellis A. Emerging mechanisms ofaminoacyl-tRNA synthetase mutations in recessive and dominanthuman disease. Hum Mol Genet. 2017;26(R2):R114-R127.
73. Sissler M, González-Serrano LN, Westhof E. Recent advances inmitochondrial aminoacyl-tRNA synthetases and disease. TrendsMol Med. 2017;23:693-670.
74. Diodato D, Ghezzi D, Tiranti V. The mitochondrial aminoacyl tRNAsynthetases: genes and syndromes. Int J Cell Biol. 2014;2014:787956.
75. van der Knaap MS, Bugiani M, Mendes MI, et al. Biallelic vari-ants in LARS2 and KARS cause deafness and (ovario)leukodys-trophy. Neurology. 2019;92:e1225-e1237. https://doi.org/10.1212/WNL.0000000000007098.
76. Pons R, Collins A, Rotstein M, Engelstad K, De Vivo DC. Thespectrum of movement disorders in GLUT-1 deficiency. Mov Dis-ord. 2010;25:275-281.
77. van Hasselt PM, Ferdinandusse S, Monroe GR, et al.Monocarboxylate transporter 1 deficiency and ketone utilization.N Engl J Med. 2014;371:1900-1907.
78. Qian Y, Banerjee S, Grossman CE, et al. Transaldolase deficiencyinfluences the pentose phosphate pathway, mitochondrial homeosta-sis, and apoptosis signal processing. Biochem J. 2008;415:123-134.
79. Lagresle-Peyrou1 C, Six EM, Picard C, et al. Human adenylatekinase 2 deficiency causes a profound hematopoietic defect associ-ated with sensorineural deafness. Nat Genet. 2009;41:106-111.
80. Valayannopoulos V, Verhoeven NM, Mention K, et al. Trans-aldolase deficiency: a new cause of hydrops fetalis and neonatalmulti-organ disease. J Pediatr. 2006;149:713-7.
81. Arnoux JB, Saint-Martin C, Montravers F, et al. An update oncongenital hyperinsulinism: advances in diagnosis and manage-ment. Expert Opin Orphan Drugs. 2014;2:779-795.
82. Nakagawa T, Lomb DJ, Haigis MC, Guarente L. SIRT5deacetylates carbamoyl phosphate synthetase 1 and regulates theurea cycle. Cell. 2009;137:560-570.
83. Zaganjor E, Vyas S, Haigis MC. SIRT4 is a regulator of insulinsecretion. Cell Chem Biol. 2017;24:656-658.
84. Saudubray JM, Mochel F. The phenotype of adult versus pediatricpatients with inborn errors of metabolism. J Inherit Metab Dis.2018;41:753-756.
85. Balasubramaniam S, Lewis B, Greed L, et al. Heterozygousmonocarboxylate transporter 1 (MCT1, SLC16A1) deficiency as acause of recurrent ketoacidosis. JIMD Rep. 2016;29:33-38.
86. Fisel P, Schaeffeler E, Schwab M. Clinical and functional rele-vance of the monocarboxylate transporter family in disease patho-physiology and drug therapy. Clin Transl Sci. 2018;11:352-364.
87. Otonkoski T, Jiao H, Kaminen-Ahola N, et al. Physicalexercise-induced hypoglycemia caused by failed silencing ofmonocarboxylate transporter 1 in pancreatic beta cells. Am J HumGenet. 2007;81:467-474.
88. Valayannopoulos V, Verhoeven NM, Mention K, et al. Trans-aldolase deficiency: a new cause of hydrops fetalis and neonatalmulti-organ disease. J Pediatr. 2006;149:713-717.
89. Wevers R, Blau N. Think big-think omics. J Inherit Metab Dis.2018;41:281-283.
How to cite this article: Saudubray J-M, Mochel F,Lamari F, Garcia-Cazorla A. Proposal for a simplifiedclassification of IMD based on a pathophysiologicalapproach: A practical guide for clinicians. J InheritMetab Dis. 2019;1–22. https://doi.org/10.1002/jimd.12086
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