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380
Chapter 12 Metabolic Disorders
biosynthesis. The DHCR7 gene maps to 11q12-q13
locus. Plasma cholesterol levels are typically low, whereas
the levels of the precursor 7-dehydrocholesterol are
elevated.
22
Recurrence Risk
The disorder is autosomal recessive in its inheritance.
Each sibling of an affected individual has a 25% chance of
being affected, a 50% chance of being an asymptomatic
carrier, and a 25% chance of being unaffected and not a
carrier.
Diagnosis
Maternal serum and urinary dihydroxysteroid ratios
in combination with fetal anomalies detectable on US
greatly enhance the likelihood of establishing a prenatal diagnosis.
23 , 24
Identification of mutations in the gene
encoding the enzyme sterol delta-7-reductase are diagnostic; common mutations can currently be identified through
a polymerase chain reaction (PCR) assay.
25 , 26
Differential Diagnosis
The findings of SLO syndrome can be mimicked by other
conditions, both genetic and metabolic; however, rarely is
the combination of more than two of the above described
anomalies and the biochemical defect replicated in other
conditions. Other genetic considerations are trisomies 13
and 18, Meckel syndrome, and Simpson-Golabi syndrome.
Metabolic conditions that can be considered with similar
sterol synthesis defects include β-sitosterolemia (abnormal
sterol biosynthesis, normal to elevated cholesterol levels,
episodic hemolysis, tuberous xanthomatosis, and early atherosclerosis), CHILD syndrome (congenital hemidysplasia,
ichthyosiform nevus, and limb defects), desmosterolosis
(macrocephaly, hypoplastic nasal bridge, thick alveolar
ridges, gingival nodules, cleft palate, total anomalous
pulmonary venous drainage, ambiguous genitalia, short
limbs, and generalized osteosclerosis), mevalonic aciduria
(normal to slightly reduced cholesterol levels, developmental delay, dysmorphic facial features, central cataracts,
anemia, and hepatosplenomegaly), and X-linked dominant
chondrodysplasia punctata (alopecia, cataracts, ichthyosis, punctate calcification of bones, and rhizomelic limb
shortening).
Implications for Targeted Examination
A confirmed diagnosis of SLO syndrome in one child
would suggest that the biological parents are likely carriers; consequently, future pregnancies carry a definite
risk of recurrence. In such situations, the subsequent
pregnancies should be followed from the first trimester so
that abnormalities in the cleavage of the forebrain are not
missed.
Implications for Sonographic Screening
There is marked phenotypic variability in the presentation of SLO syndrome. A few reports have emphasized
the clinical significance of the association of intrauterine growth retardation and nuchal edema detected on
US examinations prenatally to be highly suggestive of
SLO syndrome; however, milder cases may be missed
despite the use of biochemical screening and prenatal
ultrasonography.
21 , 24
In a single large series examining the
antenatal expression of the disorder, intrauterine growth
retardation was the only consistent feature, often in
combination with other anomalies such as nuchal edema
and cerebral, renal, or limb malformations. A considerable proportion (∼15%) of the prenatal US studies were
reported as normal; an early diagnosis of multiple malformations was possible in only 10%
23
( Figure 12–6 ). A com-
bination of biochemical sterol analysis in the amniotic
fluid and ultrasonographic examinations may be more
helpful in milder cases.
*
B
A
Figure 12–6. Prenatal US images of the same patient as in Figure 12–5 at 25 weeks of pregnancy. ( A) Dysgenesis of the corpus callosum; the corpus
callosum is thick and short ( arrows ), the splenium is missing and replaced by a cyst of the cavum interpositum ( asterisk ). (B) Cerebellar hypoplasia; the
transverse cerebellar diameter is unusually small (2.06 mm = 19 weeks, 5 days). (C) Color Doppler of the heart showing atrioventricular canal. Other
findings, not shown, included intrauterine growth retardation, microcephaly, pulmonic stenosis, and cleft palate.
C
Chapter 12 Metabolic Disorders
381
Obstetric Management
When severe, SLO syndrome is identified in utero; where
legally possible, medical termination of pregnancy can be
considered as an option.
Prognosis
The prognosis is variable, with severe malformations
resulting in a shortened life span, whereas milder cases
may be compatible with a normal life span. Dietary cholesterol supplementation, as well as the use of simvastatin, a 3-hydroxy-3-methylglutaryl (HMG) CoA inhibitor,
improves the biochemical profile,
27
but the effects on
behavior remain unclear.
GLUTARIC ACIDURIA TYPE I
Synonyms
Glutaric acidemia type I, glutaryl CoA dehydrogenase deficiency, OMIM 231670
Definition
Glutaric aciduria type I is an autosomal recessive disorder resulting from an inherited defect in the glutarylCoA dehydrogenase enzyme (GCDH; enzyme commission
number, EC 1.3.99.7; OMIM*231670). The disorder causes
an acute devastating neurologic syndrome in infants that
is characterized by sudden-onset hypotonia, dystonia, and
encephalopathy often in conjunction with a febrile illness.
Survivors often have dystonic movements, seizures, and
developmental delay.
Pathology
Neuropathologic features are fairly characteristic for this
disorder: macrocrania and increased brain size and weight,
subdural effusions and hematomas, a pattern of frontotemporal hypoplasia associated with incomplete opercularization, and atrophy of the caudate and putamina
bilaterally.
Associated Anomaly
Pathologic changes are confined to the nervous system;
macrocephaly at birth is usually a marker.
Pathogenesis
In a majority of patients, the principal pathologic changes
follow the occurrence of encephalopathic crises often in
postnatal life. A combination of the neurotoxic effects
of intracerebral accumulation of intermediaries such as
glutaric acid and 3-hydroxyglutaric acid and intrinsic vulnerability of striatal medium-sized γ-amino butyric acid
neurons to neurotoxins and metabolic stress underlie the
pathogenic effects.
28
Etiology
GCDH is involved in the degradative pathway of the
amino acids L-tryptophan, L-lysine, and L-hydroxylysine.
The metabolic block results in accumulation of toxic
intermediaries (glutaric acid [GA], 3-hydroxyglutaric acid
[3-OH-GA], and glutaconic acid) in blood and to a lesser
extent CSF. In the brain, de novo synthesis of these intermediaries and subsequent trapping due to poor efflux from
the neuron account for abnormally high levels of accumulation. Urine organic acid analysis shows excretion of
variable amounts of GA and 3-OH-GA and can be categorized into two groups, high and low excreters. Mutations
in the gene at the GCDH locus (19p13.2) are diagnostic.
There is considerable locus heterogeneity as well as a lack
of genotype–phenotype correlation in this disorder.
Recurrence Risk
Because the disorder is inherited in an autosomal recessive
manner, a 25% recurrence risk is to be expected. There
is strong evidence for intra- and interfamilial phenotypic
variability.
Diagnosis
Biochemical confirmation through assays of glutarylcarnitine in dried blood spots from the newborn using tandem
mass spectrometry is an alternative.
29
Molecular genetic
studies are available to identify GCDH mutations using
DNA from chorionic villous biopsy or cultured amniocytes, enabling prenatal diagnosis if the mutation in the
index case is already known.
30
Differential Diagnosis
GA1 must be distinguished from other organic acidurias
presenting in early life, such as propionic acidemia, methylmalonic acidemia, and isovaleric acidemia. This distinction can be performed on the basis of biochemical analysis
of body fluids using tandem mass spectrometry.
Implications for Targeted Examination
In families at risk of carrying a fetus with GA1 following
the diagnosis of the disease in a sibling, a targeted exam
should be obtained in the third trimester.
Implications for Sonographic Screening
Although the typical neuropathologic findings are easily
detected in the postnatal period on MRI, during the prenatal period, ultrasonographic studies seem to suggest that
the combination of macrocrania, abnormal opercularization of the sylvian fissure, ventriculomegaly, and subdural
effusions may be highly suggestive.
32 – 34
GA1 should also be
considered in the differential diagnosis of periventricular
pseudocysts ( Figure 12–7 ), particularly when associated
with macrocephaly or other CNS anomalies. After delivery, imaging findings can be confirmed through postnatal
scans, biochemical confirmation through newborn screening of blood spots, and molecular DNA diagnostic tests.
31
382
Figure 12–7. Prenatal appearance of glutaric aciduria in a 37-week fetus. (A) Axial plane showing huge bilateral periventricular pseudocyst (PVPC);
note the abnormal echogenicity of the brain tissue, probably due to edema ( arrowhead ). (B) Axial plane at the level of the caudate nuclei shows bilateral,
large PVPC. Note also in this section the almost complete lack of sulcation ( arrowhead ). The lateral ventricles are marked with an asterisk (*). (Courtesy
of Dr. Waldo Sepulveda, Santiago, Chile.)
Chapter 12 Metabolic Disorders
*
*
AB
Prognosis
Early diagnosis carries a significant impact on both survival
and timely interventions to prevent and mitigate complications of the acute encephalopathic crisis.
35
Prognosis is
variable, with improved outcome through supportive and
prompt interventions during acute symptomatic crises
reported for some groups, whereas the outcome remains
poor in other populations.
36
Obstetric Management
Routine. Usually there are no perinatal sequelae directly
attributable to delivery. However, postnatal follow-up,
early diagnosis, and supportive interventions are critical
to outcome.
CONGENITAL DISORDERS
OF GLYCOSYLATION
Synonyms
Carbohydrate-deficient glycoprotein syndrome, CDG,
OMIM 212065
Definition
This is a group of recessively inherited disorders resulting from enzyme defects in the glycosylation pathways
(pre-Golgi, endoplasmic reticulum, and Golgi complex).
These disorders present with multisystem involvement,
particularly the central and peripheral nervous system and
coagulation and endocrine systems.
There are two types of glycosylation reactions:
N-glycosylation and O-glycosylation. The first disorder
37 , 38
in the glycosylation pathway was first described in 1980
and was named the carbohydrate-deficient glycoprotein
syndrome. The past decade has seen an explosion of
interest resulting in the identification of several subtypes,
and the original syndromic term has been replaced by
disorders of glycosylation. Of the more than 10 subtypes
known currently, CDG type Ia is the most frequently
encountered and is the one with severe enough manifestations involving fetal brain malformations that can be
detected by prenatal US.
39
We will restrict our discussion
to this subtype.
Pathology
Cerebellar hypoplasia is a consistently noted feature
in this disorder. There is considerable heterogeneity in
the presentation of this condition; therefore, it is likely
that prenatal US may only be useful if the abnormalities are severe and above the threshold sensitivity for
detection.
Associated Anomalies
The initial descriptions of this condition included facial
dysmorphic features, inverted nipples, and abnormal
distribution of fat pads.
37
Pathogenesis
Deficient glycosylation of proteins results in improper
trafficking and functioning of secretory and membranous glycoproteins, as well as lysosomal enzymes. This
leads to widespread and multisystem effects of varying
severity.
Chapter 12 Metabolic Disorders
383
Etiology
CDGIa results from mutations in the PMM2 gene coding
for the enzyme phosphomannomutase (OMIM 601785,
EC 5.4.2.8). The resulting deficiency leads to reduced
availability of guanosine diphosphate (GDP)–mannose
required for the assembly of the dolicholpyrophosphatelinked oligosaccharide in the endoplasmic reticulum.
39
Recurrence Risk
A 25% recurrence risk is to be expected in this recessively
inherited condition.
Diagnosis
The diagnosis relies on demonstration of hypoglycosylation of serum proteins, particularly transferrins, using
isoelectric focusing, which will show a cathodal shift in the
presence of partial sialyl groups in transferrin.
40
Although
the enzyme assay can be performed on cultured fibroblasts
and amniocytes, the results are not considered uniformly
reliable, as low values have been reported in the presence
of a normal genotype. A molecular diagnostic study leading to prenatal diagnosis is possible in the presence of an
affected proband.
39
Differential Diagnosis
In the postnatal period, the differential diagnosis is very
wide, considering that infants present with central hypotonia. However, the combination of clinical features of
inverted nipples, abnormal fat pads, and cerebellar hypoplasia is often considered highly suggestive of the diagnosis. There is considerable phenotypic variability, with
milder cases diagnosed during adult life.
Implications for Targeted Examination
In families at risk of having a fetus with CDG1a following the diagnosis of the disease in a sibling, targeted exam
should be obtained from the second trimester to look for
abnormal cerebellar development and hydrops fetalis.
all that can be offered, as there is no treatment currently
available for this disorder.
Obstetric Management
Routine management when termination of pregnancy is
not an option
NONKETOTIC HYPERGLYCINEMIA
Synonyms
NKH, OMIM 605899, glycine encephalopathy
Etiology
Nonketotic hyperglycinemia (NKH) is an inborn error of
glycine metabolism in which large quantities of glycine
accumulate in all body tissues, including the brain. It is
caused by a defect in the glycine cleavage system (EC
2.1.2.10), which is confined to the mitochondria and composed of four protein components: P protein (a pyridoxal
phosphate–dependent glycine decarboxylase), H protein
(a lipoic acid–containing protein), T protein (a tetrahydrofolate-requiring enzyme), and L protein (a lipoamide
dehydrogenase). NKH may be due to a defect in any one
of these enzymes.
Associated Anomaly
Only affects the CNS
Pathogenesis
The placental circulation cannot lower the plasma glycine
level sufficiently to lower the CSF/brain glycine level to the
normal range. The intracellular accumulation of metabolites such as glycine can produce direct neurotoxic effects.
Elevated glycine affects the developing fetal brain from
early pregnancy. The first sign is agenesis of the corpus
callosum.
Implications for Sonographic Screening
Current neurosonographic techniques are sophisticated
enough to permit detection of posterior fossa abnormalities in the right hands on serial imaging. However, there
are diagnostic pitfalls that need to be considered that have
been described in detail.
41
If the combination of cerebellar hypoplasia and fetal akinesia is detected, in our opinion, CDG1a should be a consideration. Other features,
such as presentation with nonimmune hydrops fetalis,
hyperechoic kidneys, and cardiomyopathy, have also been
detected in prenatal studies leading to a diagnosis of
CDG1a.
42 – 44
Prognosis
The outcome is variable; most infants demonstrate developmental delay, mental retardation, and failure to thrive.
Symptomatic treatment measures and supportive care are
Risk of Recurrence
Autosomal recessive disorder with a recurrence rate of 25%
Sonographic Diagnosis
Agenesis of the corpus callosum is a pathognomonic
feature.
MRI Diagnosis
MRI demonstrates agenesis or thinning of the corpus
callosum, dysmyelination, and gyral abnormalities.
Implications for Targeted Examination
In families at risk of having a fetus with NKH following the
diagnosis of the disease in a sibling, targeted exam should
be obtained from the second trimester to look for abnormal callosal development.
45 – 48
384
Chapter 12 Metabolic Disorders
The differential diagnosis upon prenatal diagnosis of
agenesis of the corpus callosum with or without associated
cortical malformations should include NKH.
Implications for Sonographic Screening,
Including Earliest Recognition
Paupe et al
49
reported the prenatal diagnosis at 22 postmenstrual weeks of hypoplasia of the corpus callosum in a
fetus that was diagnosed with NKH.
Prenatal diagnosis for pregnancies at increased risk
is possible by analysis of DNA extracted from fetal cells
obtained by amniocentesis. Prenatal testing using measurement of amniotic fluid glycine concentration and the
glycine/serine ratio are unreliable because normal and
affected values overlap.
Prognosis
Death may occur in the neonatal period. Long-term survival may occur, usually with minimal mental development, but surprisingly little gross brain destruction.
Obstetric Management
When legally possible, termination of pregnancy should
be offered.
MITOCHONDRIAL DISORDERS
Synonyms
Disorders of energy metabolism, respiratory chain disorders, oxidative phosphorylation disorders
of 2 cytochromes (cytochromes a and a3), 2 copper
atoms, and 13 different protein subunits. During the
oxidation process, electrons are transferred to oxygen via
the energy-transducing complexes of the RC. The free
energy generated from the redox reactions is converted
into a transmembrane proton gradient. Complex V (ATP
synthase) allows protons to flow back into the mitochondrial matrix and uses the released energy to synthesize
ATP. Three ATP molecules are produced for each NADH
molecule oxidized.
50
The mitochondrial RC is composed of approximately
100 different proteins. Only 13 of the proteins are encoded
by mitochondrial genes; the others are encoded by nuclear
genes. All complexes of the RC except complex II have a
double genetic origin.
Associated Anomalies
Von Kleist-Retzow et al
respiratory chain enzyme deficiency for fetal development.
Twenty patients had an antenatal presentation, the most
common being intrauterine growth retardation and multiple anomalies of organs sharing no common function or
embryologic origin.
51
reviewed 300 cases of proven
Pathogenesis
Mitochondrial disorders can present at any age and affect
all organs; however, they rarely present in utero. Aerobic
metabolism in the brain tends to increase during periods of
rapid neuronal proliferation, differentiation, and neuronal
migration. Therefore, disorders of the respiratory chain
are associated with multiple developmental defects in the
nervous system.
Pathology
Mitochondrial disorders are disorders of the respiratory chain that cause defective oxidative phosphorylation
resulting in energy deficiency of any organ or tissue. The
decrease in energy supply may manifest any time, from
prenatal to postnatal life. The most affected organs are
those that require the largest amount of energy (brain,
muscle, and heart).
The mitochondrial respiratory chain (RC) catalyzes
the oxidation of fuel molecules and the concomitant
energy transduction into adenosine triphosphate (ATP)
via five complexes, which are embedded in the inner
mitochondrial membrane. Complex I (nicotinamide adenine dinucleotide [NADH] coenzyme Q [CoQ] reductase)
carries reducing equivalents from NADH to CoQ
(ubiquinone) and consists of 40 different polypeptides.
Complex II (succinate-CoQ reductase) carries reducing equivalents from 5,10-methylenetetrahydrofolate
reductase (FADH2) to CoQ and contains four polypeptides, including the FAD-dependent succinate dehydrogenase and iron-sulfur proteins. Complex III (reduced
CoQ–cytochrome c reductase) carries electrons from
CoQ to cytochrome c; it contains 11 subunits. Complex
IV (cytochrome c oxidase [COX]), the terminal oxidase
of the RC, catalyzes the transfer of reducing equivalents
from cytochrome c to molecular oxygen. It is composed
Risk of Recurrence
Disorders of the respiratory chain may be inherited in
all modes of inheritance: maternal, autosomal recessive,
autosomal dominant, and X-linked. Large-scale deletions
in the mitochondrial DNA (mtDNA) may occur de novo.
The risk of recurrence depends on the specific genetic
defect.
Sonographic Diagnosis
Fetal brain involvement that can be depicted by US
includes ventriculomegaly, porencephalic cysts, DandyWalker malformation, cerebellar hypoplasia, pontocerebellar hypoplasia, and agenesis of corpus callosum.
In one reported case, ventriculomegaly and porencephalic
germinal matrix cysts were found at 22 weeks’ gestation
and later resolved.
51
We have also found periventricular
pseudocysts in a fetus that later developed a Leigh disease
presentation ( Figure 12–8 ).
Samson et al
54
described ventriculomegaly and
intracerebral calcifications in two fetuses with a familial
mitochondrial encephalopathy. An autopsy showed extensive encephalopathy with cavitation and calcification in the
cerebral hemispheres, polymicrogyria, multiple neuronal
heterotopia, partial callosal dysgenesis, and severe
Leigh syndrome. We have also observed white matter
51 , 52 , 53
Figure 12–8. Periventricular pseudocysts in a fetus at 38 weeks’
gestation diagnosed postnatally as suffering from Leigh syndrome.
calcifications in two consecutive pregnancies of fetuses
with multiple mtDNA deletions ( Figure 12–9 ).
MRI Diagnosis
Gire at al
neonates with mitochondrial disorders. Five had antenatal
55
described the neuroradiological features of six
Chapter 12 Metabolic Disorders
385
involvement. A prenatal MRI in one demonstrated ventricular and parenchymal hemorrhages.
Implications for Targeted Examination
When a previous child with a diagnosed mitochondrial
disorder shows fetal brain involvement, US should be
obtained from the second trimester to look for ventriculomegaly, periventricular cysts, calcifications, and cerebellar
abnormalities.
Implications for Sonographic Screening
Abnormalities of the respiratory chain may cause both
brain dysplasia and disruption. There is a continuum of
early and late brain involvement that can be identified by
US at different stages of gestation. The US may identify
agenesis of the corpus callosum as early as midpregnancy, and later in the third trimester identify cerebellar
hypoplasia and malformations of cortical development.
56
Ventriculomegaly and periventricular pseudocysts may
prove to be a relatively common presentation of in utero
energy deficiency.
When a fetus presents with an association of multiorgan malformations without a common embryologic origin, intrauterine growth retardation, and brain dysplasia/
AB C D
EF G H
Figure 12–9. Siblings with autosomal recessive multiple mitochondrial DNA (mtDNA) deletions. (A) T2-weighted brain MRI of the propositus at
3 years of age shows diffuse white matter involvement and caudate nuclei cystic formations. (B) Coronal transvaginal sonography (TVS) of the first fetus
at 24 weeks is normal. (C). (D) Abnormal US findings diagnosed at 33 weeks’ gestation in the same fetus as in B showing hyperechogenic caudate nuclei
( arrows ) and small calcification foci (arrowhead). Coronal (E) and sagittal (F–H) images of the second fetus at 34 weeks’ gestation show caudothalamic
calcifications ( arrows ) and abnormal occipital white matter with abnormal sulcation ( arrowhead ).
386
Chapter 12 Metabolic Disorders
disruption, a mitochondrial disorder should be suspected.
However, when there is no family history, prenatal diagnosis cannot be offered.
Prognosis
When mitochondrial disorders present in utero, the postnatal presentation is usually early (neonatal period to
infancy), and the course is frequently fatal.
51
The presentation may be fulminant, with lactic acidosis and multiorgan
failure culminating in early demise.
Obstetric Management
When the disease-causing mutation in the nuclear DNA
is known, prenatal diagnosis is available. However, when
the mutation is in the mtDNA, very little information is
available, because the ratio of mutant versus wild-type
mtDNA (heteroplasmy) in fetal DNA is considered to be
a poor indicator of postnatal outcome. Nevertheless, prenatal diagnosis has been attempted in MELAS (myopathy,
encephalopathy, lactic acidosis, and strokelike syndrome)
due to the 3243 mtDNA
nally related Leigh syndrome due to the 8993 mtDNA
mutation.
58
Assessment of the respiratory chain in amniotic cells
is not reliable because the abnormal enzyme activity may
be tissue specific and not involve amniotic cells, and the
expression of respiratory chain deficiency during fetal life
is time dependent due to differential expression or regulation of the mutant proteins.
57
mutation, and in mater-
59
of teratogenicity in the offspring, with microcephaly and
mental retardation in 75% to 90%. There is a dose-response
relationship with progressively lower frequencies of these
abnormalities at lower phenylalanine levels.
The pathogenesis may be related to inhibition by phenylalanine of large neutral amino acid transport across the
placenta or to direct toxicity of phenylalanine, a phenylalanine metabolite, or both in certain fetal organs. Although
phenylalanine hydroxylase is expressed in the fetus as
early as the sixth week of gestation, the large load of toxic
phenylalanine from the mother overwhelms the limited
hydroxylating capacity of the fetus.
61
The oligodendroglia
switch to a nonmyelinating phenotype that expresses an
astrocyte marker, glial fibrillary acidic protein. The impairment of intrauterine myelination can explain the hypoplastic corpus callosum.
Risk of Recurrence
The teratogenic effects of phenylalanine can recur in
every pregnancy if the mother does not keep a strict lowphenylalanine diet.
Sonographic Diagnosis
Dysgenesis of the corpus callosum associated with progressive microcephaly is pathognomonic of maternal PKU.
MRI Diagnosis
Brain MRI may demonstrate a dysgenetic corpus callosum
and delayed myelination.
61
MATERNAL PHENYLKETONURIA
Synonym
Maternal PKU
Definition
The maternal phenylketonuria (PKU) syndrome refers
to the teratogenic effects of phenylalanine during pregnancy. These effects include mental retardation, microcephaly, congenital heart disease, and intrauterine growth
retardation.
Pathology
Phenylketonuria (OMIM 261600) is an autosomal recessive IEM resulting from a deficiency of phenylalanine
hydroxylase (PAH; EC 1.14.16.1), an enzyme that catalyzes
the hydroxylation of phenylalanine to tyrosine, the ratelimiting step in phenylalanine catabolism.
Associated Anomaly
Congenital heart disease in 15%
Pathogenesis
When the mother has classic PKU with a blood phenylalanine level > 1200 μM (20 mg/dL), there is a high frequency
60
Implications for Targeted Examination
When the mother has PKU, she should be monitored
for phenylalanine levels even before conception, and
her diet should be strictly adjusted. A fetal US should be
obtained serially throughout pregnancy. It can demonstrate
progressive microcephaly and dysgenesis of the corpus callosum associated with a congenital heart defect.
Implications for Sonographic Screening,
Including Earliest Recognition
Dysgenesis of the corpus callosum can be recognized by
US as early as 22 weeks, whereas progressive microcephaly
can only be diagnosed in the third trimester.
Prognosis
Because the fetus does not have PKU, the effect of the
increased phenylalanine levels in utero is nonprogressive.
The child may be born microcephalic with a congenital
heart defect and then show a picture of static developmental delay.
Obstetric Management
The treatment of maternal PKU consists of biochemical control through a phenylalanine-restricted diet during pregnancy. The best results are obtained with diet
Chapter 12 Metabolic Disorders
387
initiation before conception or no later than the earliest
weeks of pregnancy.
PEROXISOMAL BIOGENESIS DISORDERS
Synonyms
PBD; OMIM 601539
Definition
The peroxisomal biogenesis disorders (PBDs) are autosomal recessive disorders of peroxisome assembly that lead
to deficiency of multiple peroxisomal enzymes. They have
overlapping phenotypic features and various genetic causes
(defects in over 25 PEX genes). Due to their heterogeneity,
PBDs had been divided into four groups: Zellweger syndrome (ZS; MIM 214100), neonatal adrenoleukodystrophy
(NALD; MIM 202370), infantile Refsum disease (IRD;
MIM 266510), and rhizomelic chondrodysplasia punctata
(RCDP; MIM 215100).
Pathology
Peroxisomes are organelles present in almost all eukaryotic cells. They are essential for the metabolism of
branched chain and very long chain fatty acids (VLCFAs),
ether lipids, polyamines, amino acids, and glyoxylate.
During some of these metabolic processes, peroxisomes
generate and subsequently inactivate reactive oxygen
62
species.
It has been estimated that at least 85 proteins
are associated with peroxisome structure and function in
humans. Peroxisome matrix proteins are synthesized in
the cytosol prior to import into the peroxisome. Peroxins,
encoded by a family of PEX genes, are involved in per-
oxisome biogenesis, with functions ranging from membrane synthesis and matrix protein import to organelle
division.
62
Biochemical studies performed in blood and urine
are used to screen for PBD. They include elevated
plasma, VLCFAs, bile acids, and phytanic, pristanic, and
pipecolic acids contrasting with low plasma plasmalogens. Impaired enzymatic activity of dihydroacetonephosphate acyltransferase deficiency can be detected in
fibroblasts.
Associated Anomalies
Zellweger syndrome, also known as cerebrohepatorenal
syndrome, is the classic and most severe peroxisomal
biogenesis disorder. Associated anomalies are prominent
forehead, large anterior fontanelle, hypoplastic supraorbital
ridges, broad nasal bridge, hypertelorism and deformed
earlobes, limb anomalies, hepatomegaly, cataracts, stippled
epiphyses, and renal cysts.
62
Risk of Recurrence
Inheritance is autosomal recessive. The risk of recurrence
is 25%.
Sonographic Diagnosis
Migration anomalies can be diagnosed in utero by ultrasonography based on the presence of specific deviations
from the normal pattern of development as early as the
18th postmenstrual week.
56
The ultrasonographic findings
leading to the diagnosis of malformations of cortical development are abnormally overdeveloped gyri and sulci for
gestational age, delay in sulcation, abnormally thin cortex,
and abnormally wide and broad sulci.
MRI Diagnosis
Migration anomalies are well documented in peroxisomal
disorders. In the Zellweger syndrome spectrum, these
anomalies consist of lissencephaly, perirolandic and occipital pachygyria, frontal and perisylvian polymicrogyria
( Figure 12–10 ), periventricular heterotopias, band heterotopias, hypoplastic corpus callosum, abnormal layering of
the cerebellum, and dysplasia of the inferior olivary nuclei
and olfactory bulb.
MRI features in two fetuses with Zellweger syndrome.
One depicted asymmetric ventriculomegaly, abnormally
small cerebral convolutions, mostly in the frontal and in
the perisylvian cortex, periventricular leukodystrophy
predominating in the frontal area, and germinolytic cysts
in the subependymal areas; the other depicted bilateral
ventricular enlargement associated with a large cavum,
abnormal gyration pattern mostly in the frontal and perisylvian cortex, and periventricular leukodystrophy, mainly
in the frontal area and irregular ventricular walls revealing
bilateral subependymal pseudocysts. The combination of
cortical malformations of the perisylvian and perirolandic
regions, hypomyelination, and germinolytic cysts seems
specific for Zellweger syndrome.
Implications for Targeted Examination
When there is a history of a previously affected child,
specific deviations from the normal pattern of cortical
development should be evaluated by US every 2 to 3 weeks
starting at 22 weeks’ gestation.
Implications for Sonographic Screening
The first sign of fetal Zellweger syndrome is increased
nuchal translucency.
in a fetus with hypokinesia, cerebral ventricular enlargement, renal hyperechogenicity, and hepatosplenomegaly.
Prenatal US supplemented with MRI can identify abnormal cortical development in the third trimester.
63 – 72
Mochel et al
74
Later, suspicion would be raised
73
described the fetal
Pathogenesis
Accumulation of phytanic acid, VLCFAs, pipecolic acid,
and abnormal bile acids in multiple organs are thought to
be the underlying mechanism of this fatal condition.
Prognosis
There is a clinical overlap between Zellweger syndrome,
neonatal adrenoleukodystrophy, and infantile Refsum
disease. Affected individuals can be recognized at birth
388
Figure 12–10. Zellweger syndrome. Brain MRI T2-weighted images in fetus at 35 weeks’ gestation. Axial (A) and coronal (B) sections show bilateral
frontal polymicrogyria ( arrowheads ) and abnormally high signal intensity of the frontal and temporoparietal white matter ( arrows ) consistent with
abnormal white matter maturation. Note the presence of asymmetric ventriculomegaly (*) and a large cavum septi pellucidi (+). (Courtesy of Dr. Gregor
Kasparian and Daniela Prayer, Vienna, Austria.)
Chapter 12 Metabolic Disorders
+
*
*
AB
because of prominent hypotonia, hyporeflexia, seizures,
craniofacial dysmorphism, limb abnomalities, liver dysfunction, optic atrophy, glaucoma, cataract, failure to
thrive, renal cysts, stippled epiphyses, and prominent mental retardation. Death usually occurs within the first year of
life in Zellweger syndrome.
Obstetric Management
When there is a family history, and both disease-causing
alleles of the affected family member have been identified,
a molecular diagnosis can be made. However, when the
suspicion is raised because of the association of the typical
brain anomalies with kidney and liver abnormalities, the
prenatal diagnosis can be made by VLCFA content and
plasmalogen synthesis measured in cultured chorionic
villus sampling (CVS) or amniocytes.
75
MOLYBDENUM COFACTOR DEFICIENCY
Synonyms
MOCOD, OMIM 252150, combined deficiency of sulfite
oxidase, xanthine dehydrogenase, and aldehyde oxidase,
molybdenum cofactor deficiency, complementation group
A, molybdenum cofactor deficiency, complementation
group B, molybdenum cofactor deficiency, complementation group C
Definition
Molybdenum is a trace element that, in its complex
form molybdopterin, is essential for the function of
three enzymes: sulfite oxidase, xanthine dehydrogenase,
and aldehyde oxidase. Molybdenum cofactor deficiency
(MoCD) is a rare autosomal recessive disorder that may be
mistaken for ischemic encephalopathy.
Pathology
MoCD can be caused by mutations at either of two
separate steps in the formation of molybdenum cofactor.
MOCS1 (603707) encodes two enzymes for synthesis of
the precursor. The conversion of the precursor into the
organic moiety of molybdenum cofactor is catalyzed by
molybdopterin synthase (MOCS2; 603708), which encodes
the small and large subunits of this heteromeric enzyme.
MOCS1 is defective in patients with complementation
group A deficiency. MOCS2 is defective in patients with
complementation group B deficiency. The phenotype is
identical in both complementation groups. In addition, a
third type of MoCD, complementation group C, is caused
by mutation in the gephyrin gene (GEPH; 603930). The
diagnosis is established by the presence of low blood uric
acid levels, positive urine sulfite reaction, and MoCD gene
analysis.
76
Associated Anomalies
MoCD mainly affects the CNS, but renal stones and dislocated lens may be associated anomalies.
Pathogenesis
Disruption of mitochondrial energy production by sulfite
accumulation inhibits glutamate dehydrogenase. Sulfurcontaining compounds that are formed as a result of
Chapter 12 Metabolic Disorders
389
MoCD cause excitotoxic neuronal injury in the presence
of excess magnesium. Pockets of neuronal cell death or
focal ischemia may lead to encephaloclastic lesions, such
as porencephalic cysts.
77 – 80
These lesions may develop at
the end of pregnancy.
Risk of Recurrence
Autosomal recessive inheritance, 25% risk of recurrence
Sonographic Diagnosis
Encephaloclastic white matter cysts associated with cerebellar hypoplasia are pathognomonic of MoCD
sometimes be identified in utero ( Figure 12–11 ).
81
and may
MRI Diagnosis
The MRI demonstrates shortly after birth atrophy of
the cerebral hemispheres in association with multiple
cystic cavities resembling multicystic encephalomalacia located in the subcortical region. The cerebellum is
hypoplastic. There may be bilateral subacute subdural
hematoma.
82 – 86
Implications for Targeted Examination
Following the birth of an affected child, the pregnancy
should be monitored for abnormal cerebellar development
and ischemic lesions toward the end of pregnancy.
Implications for Sonographic Screening,
Including Earliest Recognition
It is not clear how often brain involvement is manifested
prenatally. In some cases, there is documentation that the
first US/MRI was normal
81 , 86
and that the lesions developed
in the neonatal period. It seems obvious that the ischemic
like brain cysts develop either at the very end of pregnancy
or shortly after delivery.
Prognosis
The prognosis is poor. Most of the infants die in the first
days or weeks of their lives, and effective therapy is not
available for this rare disease. Presentation is usually in the
newborn period or early infancy with intractable seizures,
metabolic acidosis, intracranial hemorrhage, feeding difficulties, exaggerated startle reactions, dysmorphic facial
features, profound mental retardation, alterations in muscle tone, microcephaly, lens dislocation, and renal stones.
87
3v
ABC
3v
DEF
Figure 12–11. Prenatal appearance of molybdenum cofactor deficiency in fetus at 35 weeks’ gestation. (A) Transabdominal axial plane shows only
mild ventriculomegaly (lateral ventricle width (LVW) 10.2 mm). (B) Transabdominal axial plane shows cerebellar hypoplasia with mega cisterna magna.
(C) Transvaginal coronal plane at the level of the third ventricle shows lateral and third ventricle dilation; the subcortical white matter has been replaced by
multiple encephaloclastic lesions. (D) Transvaginal paramedian plane shows the multiple, multilocular pattern of the cysts. (E , F) Paramedian planes show
severe dysgenesis of the corpus callosum with abnormal vasculature particularly from vessels originating from the aberrant anterior cerebral artery.
3v