Neuropediatri Flashcards
Milestone, disorder anak
1
Q
Lapisan embrional utama sistem saraf
A
Ektoderm
2
Q
Notocord
A
notochord, a layer
of mesodermal cells in contact with the ectoderm, induces
formation of the neural plate from the ectoderm and later signals
differentiation of various cell types mediated by inductive signals.
The notochord later gives rise to the vertebral column
3
Q
Neurulation
A
Neurulation occurs at 3 to 6 weeks’ gestation.
Neurulation involves
proliferation and migration of ectodermal cells and invagination,
folding, and fusion of the neural plate in a specific pattern. An
important step in neurulation includes the formation of a midline
groove along which the lateral margins of the neural plate fold.
These lateral margins start to fuse in the center, so that for a
period of time, there are openings at each end, the anterior and
posterior neuropore. Fusion then reaches the neuropores, the
anterior one first, then the posterior one, and the neural tube is
thus formed.
4
Q
Abnormal neural plate fusion
A
Abnormal rostral fusion at the anterior
neuropore leads to abnormalities such as encephalocele or
anencephaly, whereas abnormal caudal fusion (at the posterior
neuropore) leads to disorders such as spina bifida
5
Q
Neural tube segmentation
A
Following neurulation, the neural tube undergoes segmentation
into three vesicles, in a process called specification, whereby
different segments begin to acquire cell types and characteristics
specific to the central nervous system (CNS) structure that will
eventually arise from them. The three segments include the prosencephalon,
mesencephalon, and rhombencephalon. Abnormalities
during specification, which occurs at 5 to 6 weeks of gestation,
lead to disorders such as septo-optic dysplasia
6
Q
The peripheral nervous system (including the autonomic ganglia)
forms from
A
Berasal Dari neural crest cells that are derived from the neural tube
after it fuses. In addition to peripheral nervous system structures,
neural crest cells give rise to the chromaffin tissue of the adrenal
medulla and melanocytes
7
Q
Prosencephalon membentuk
A
prosencephalon
subsequently forms the telencephalon, which gives rise to the
cerebral hemispheres, as well as the diencephalon, which forms the
hypothalamus and the thalamus.
8
Q
Mesencephalon membentuk
A
mesencephalon gives rise to
the midbrain, and the rhombencephalon gives rise to the rest of the
brainstem (pons and medulla) and the cerebellum
9
Q
Galactocemia
A
Patients present in the first days of life
with feeding difficulties, vomiting, diarrhea, and jaundice. They
also have hepatomegaly, failure to thrive, lethargy, and hypotonia.
Cataracts also occur and are caused by an accumulation of
galactitol. Late neurologic sequelae include developmental delay,
cognitive impairment, ataxia, and tremor, with brain MRI
demonstrating white matter changes and cortical and cerebellar
atrophy.
10
Q
Pyruvate dehydrogenase (PDH)
A
Pyruvate dehydrogenase (PDH) deficiency is caused by defects of
the PDH complex, which is responsible for the oxidative
decarboxylation of pyruvate to carbon dioxide and acetyl
coenzyme A.
linical presentation is variable, ranging from severe neonatal
lactic acidosis with death in the neonatal period to less severe
forms that are manifested in infancy, in which patients have lactic
and pyruvic acidosis, and episodic or progressive ataxia,
nystagmus, dysarthria, lethargy, weakness with areflexia,
hypotonia, and psychomotor retardation, which can be profound.
These patients have episodic exacerbations, which can be
spontaneous or triggered by infections, stress, or high-carbohydrate
meals. Some patients may have a Leigh’s disease–like presentation.
elevations of lactate and
pyruvate levels, with a low lactate:pyruvate ratio. Enzyme analysis
can be performed in leukocytes, cultured fibroblasts, muscle, or
liver biopsy specimens. Pathologically, there may be cystic lesions
in the white matter and basal ganglia, and certain cases of the
neonatal form may have agenesis of the corpus callosum.
Management of PDH deficiency includes ketogenic diet (high fat
with low carbohydrates) and thiamine supplementation. Carnitine,
coenzyme Q10, and biotin supplementation may be given, but their
efficacy is not well established. Acetazolamide may be used for the
treatment of episodes of ataxia.
11
Q
Neurofibromatosis type 1
A
neurofibromatosis type 1 (NF1) have
normal cognition or mild developmental delay. Other
neuropsychiatric manifestations in NF1 include behavioral
problems and learning disabilities.
Renal artery stenosis due to renal artery dysplasia occurs in some
patients with NF1 and can lead to hypertension.
Pheochromocytoma has also been associated with NF1 and the
latter two causes of hypertension should be considered in an NF1
patient with hypertension. Moyamoya syndrome and other
intracranial arterial abnormalities including intracranial aneurysms
may occur in patients with NF1.
Macrocephaly is common in patients with NF1 and occurs
independent of hydrocephalus, although aqueductal stenosis may
occur in NF1. Thinning of the cortex of long bones and other long
bone dysplasias may lead to pathologic fractures and
pseudarthrosis. Other skeletal abnormalities in NF1 include
scoliosis and sphenoid wing dysplasia
12
Q
glucose transporter type 1 (GLUT-1) deficiency
A
Glucose crosses the
blood–brain barrier facilitated by GLUT-1.
manifest with
an epileptic encephalopathy with infantile-onset seizures,
developmental delay, microcephaly, and complex involuntary movement. Cerebrospinal fluid (CSF) glucose level is low with a normal serum
glucose level, and other CSF studies are normal, excluding other
causes of hypoglycorrhachia (such as CNS infection).
Electroencephalogram (EEG) may show 2.5 to 4 Hz spikes and
waves and the interictal EEG findings may improve with glucose.
However, EEG findings are not specific, and some patients may
have normal interictal EEG. Neuroimaging does not show specific
abnormalities.
Ketogenic diet should be started as soon as the diagnosis is
suspected, since this treatment option improves seizure control and
the abnormal movements; however, it is less effective for the
psychomotor impairment.
13
Q
Anencephaly
A
Anencephaly is the complete absence of both cerebral
hemispheres. Because the underlying mesoderm also fails to
properly differentiate, a large cranial vault defect (in skull,
meninges, and skin) also occurs. This is not compatible with life,
and most such infants are stillborn; in rare cases in which the infant
is born alive, death occurs soon after birth.
14
Q
Encephalocele
A
Encephalocele is defined by herniation of neural tissues hamartomatous brain tissue, without recognizable architecture)
into a midline defect in the skull. Encephaloceles are most often
located in the occipital area and less often in frontal areas.
Clinically, they appear as round, protuberant, fluctuant masses
covered by an opaque membrane or normal skin. They are
compatible with life although they cause multiple complications.
Associated clinical features include microcephaly, developmental
delay (which is more severe in occipital as compared with frontal
encephaloceles), and invariably hydrocephalus. Chromosomal
aberrations commonly seen in patients with encephaloceles include
trisomy 13 and trisomy 18. Occipital encephaloceles should be
distinguished from cranial meningocele in which only
leptomeninges and CSF are herniated through a skull defect.
15
Q
phenylketonuria (PKU)
A
phenylketonuria (PKU) is a disorder of
phenylalanine metabolism, caused by a deficiency of phenylalanine
hydroxylase. This enzyme converts phenylalanine to tyrosine, and
its deficiency leads to accumulation of phenylalanine, which is then
metabolized by phenylalanine transaminase to phenylpyruvic acid,
which is subsequently oxidized to phenylacetic acid, responsible for
the musty odor of the sweat and urine.
Patients with PKU are
normal at birth, with a rise in the phenylalanine levels after
initiation of feeding. These patients will have developmental delay,
cognitive impairment, microcephaly, seizures, hypotonia, and
severe behavioral disturbances. A musty odor, as described, is
characteristic. These children are fair, with blond hair, blue eyes,
and pale skin given the lack of tyrosine and melanin pigment
treatment of PKU is dietary restriction of phenylalanine, and
these patients should be placed on a low-protein diet and
phenylalanine-free feeding formula as soon as possible after birth,
which will prevent neurologic deterioration. Tetrahydrobiopterin is
used as a treatment adjunct in select patients.
16
Q
maple syrup urine disease
A
This is an autosomal
recessive condition caused by branched-chain α-ketoacid
dehydrogenase complex deficiency, leading to the accumulation of
branched amino acids and their ketoacids. The classic type is the most
severe and presents in the neonatal period with lethargy, poor
feeding, and hypotonia after ingestion of protein. At 2 to 3 days of life, a progressive encephalopathy develops with opisthotonus and
abnormal movements. At around 1 week, these patients may have
coma and respiratory failure, with subsequent cerebral edema and
seizures, and eventually death if untreated. Treatment is a low-protein diet, more specifically a branchedchain amino acid–restricted diet, which should be started early in
life (as soon as the diagnosis is suspected) to prevent cognitive
decline. Thiamine should be provided, since some patients may be
responsive to this vitamin. Orthotopic liver transplantation may be
a therapy for these patients.
17
Q
NTD
A
NTDs include meningocele, myelomeningocele,
diastematomyelia, diplomyelia, and sacral agenesis.
18
Q
Sacral agenesis
A
Sacral agenesis is absence of the sacrum rather than absence of the
sacral spinal cord and is frequently associated with other
malformations.
Sacral agenesis, or absence of the whole (or in some cases parts
of the) sacrum, classically occurs in association with a variety of
other urogenital, gastrointestinal, and spinal cord abnormalities. It
has been associated with maternal insulin-dependent diabetes.
Autosomal dominant forms associated with homeobox gene
mutations have been identified. Clinical manifestations range from
mild motor deficits to severe sensory and motor deficits and bowel
and bladder dysfunction
19
Q
Myelomeningocele
A
Myelomeningocele (also known as spinal dysraphism or
rachischisis) is protrusion of potentially all layers of intraspinal
contents through a bony defect: spinal cord, nerve roots, and
meninges. The spinal cord may either be exposed, or a thin
membrane may cover the protrusion. They most often occur in the
lumbosacral region but can occur at any level. This is a clinically
severe NTD associated with hydrocephalus, motor and sensory
abnormalities of the legs, and bowel/bladder dysfunction.
Myelomeningocele occurs in association with Chiari II
malformations
20
Q
Diastematomyelia
A
Diastematomyelia is splitting of the spinal cord into two portions
by a midline septum. Diplomyelia is duplication of the spinal cord
and is distinguished from diastematomyelia by the presence of two
central canals each surrounded by gray and white matter as in a
normal spinal cord.
21
Q
cardiac rhabdomyomas
A
cardiac rhabdomyomas, manifestations may include
heart failure due to obstruction or cardiomyopathy, arrhythmias,
and stroke from cerebral embolization. Surveillance with periodic
echocardiograms should occur in TSC (tuberous sclerosis complex) patients with rhabdomyomas
to ensure lack of enlargement and regression. Medical management
of arrhythmias, heart failure, or surgical removal is necessary in
some patients.
22
Q
tuberous sclerosis complex
A
- cardiac rhabdomyomas occur in more than half
of patients with tuberous sclerosis complex - Renal angiomyolipomas, benign tumors consisting of vessels,
smooth muscle, and fat, occur in more than half of patients with
TSC. - Lymphangiomyomatosis is a rare, often fatal pulmonary disease
occurring most often in female patients with TSC. - ophthalmologic manifestations may
occur. Retinal hamartomas may be seen, ranging from subtle to
classic mulberry-like lesions near the optic disc, and also including
plaques or depigmented lesions.
23
Q
Propionic acidemia
A
Propionic acidemia is an autosomal recessive disorder caused by
a deficiency of propionyl-CoA carboxylase. This enzyme normally
participates in the carboxylation of propionyl-CoA to Dmethylmalonyl-CoA, a step that requires the coenzyme biotin.
Children with propionic acidemia appear normal at birth but will
develop symptoms in the early neonatal period, in infancy, or later
in childhood. Patients present with feeding difficulty, lethargy,
hypotonia, dehydration, and attacks of metabolic acidosis with
ketosis and hyperammonemia. They may progress to have seizures
and coma. Other findings include hepatomegaly, pancytopenia, and
bleeding disorders including intracranial hemorrhage. Patients who
survive have developmental delay and involuntary movements
(resulting from basal ganglia involvement).
24
Q
spina
bifida occulta
A
spina
bifida occulta. This is a defect in the bony components along the
posterior aspect of the vertebral column. It can often be
asymptomatic, but an abnormal conus medullaris and filum
terminale are possible. The presence of a tuft of hair, associated
with underlying spina bifida occulta, does not necessarily imply
impending cognitive or motor delay. In fact, when early neurologic
development is normal, it will typically continue to be so.
However, associated neurologic dysfunction may portend future
neurologic impairment
25
occult spinal dysraphism
child with a
tuft of hair over the lumbar region but with no other evidence of
NTD.
variety of developmental abnormalities may
be seen involving the spinal cord or roots and posterior fossa, and
associated findings may include dermoid or epidermoid cysts,
intraspinal or cutaneous lipomas, and tethered cord.
Diastematomyelia, or splitting of the spinal cord, may also be seen.
Rarely, a sinus tract connects the dura with the surface of the skin.
In occult spinal dysraphism, neurologic manifestations vary widely
and may range from minimal motor deficits and ankle hyporeflexia
to bowel and bladder dysfunction, sensory loss, and paraparesis or
paraplegia. Although patients may be initially asymptomatic, these
neurologic deficits can develop subsequently and be irreversible
26
Lesch–Nyhan disease
Lesch–Nyhan disease, which is inherited in an Xlinked fashion and is caused by deficiency of the enzyme
hypoxanthine guanine phosphoribosyltransferase, which
participates in the salvage pathway of purine metabolism
The classic form may manifest in the newborn
period with severe hypotonia. These children will have delayed
motor development, progressive limb and neck rigidity with
dystonia, choreoathetotic movements, facial grimacing, seizures,
spasticity, and intellectual impairment. Aggressive behavior, selfmutilation, and progressive dementia are hallmarks of the
neurologic form of the disease.
27
Faktor resiko NTD (Neural Tube Defect)
Several risk factors for NTDs have been identified. Neural tube
defects are more common in females. Folate is involved in various
pathways of nucleic acid synthesis and DNA methylation reactions,
and maternal folate deficiency is a well-established risk factor for
NTD. Therefore, prenatal and perinatal maternal supplementation
with 0.4-mg folic acid is recommended. Teratogens associated with
NTDs include retinoic acid (vitamin A or the acidic form, tretinoin,
found in acne medications). Other teratogens associated with NTDs
include antiepileptics, particularly valproic acid and
carbamazepine, which may lead to NTDs by affecting folate
metabolism. Other risk factors for NTDs include maternal diabetes
and history of pregnancy resulting in an infant with an NTD
28
Niemann-Pick Disease
Niemann–Pick types A and
B are caused by acid sphingomyelinase deficiency, leading to
accumulation of sphingomyelin. This disorder is autosomal
recessive.
Type A involves the CNS as well as other viscera and manifests
in infancy with feeding difficulty, failure to thrive, hypotonia, head
lag, inability to sit, and eventual psychomotor retardation with
regression. Cherry-red spot is commonly seen, and these patients
have massive hepatosplenomegaly. Most affected children do not
survive beyond 3 years of age.
Type B is purely visceral and does not affect the CNS, presenting
with hepatosplenomegaly and interstitial lung disease. These
patients may present in mid-childhood and may survive into
adulthood.
Niemann–Pick type C, which is an autosomal
recessive disorder caused by defects in intracellular cholesterol
circulation, resulting in lysosomal storage of phospholipids and
glycolipids, with alteration in glycolipid metabolism.
29
Metachromatic leukodystrophy
Metachromatic leukodystrophy is an autosomal recessive disorder
caused by deficiency of the lysosomal enzyme arylsulfatase A with
accumulation of sulfatide, resulting in demyelination of the central
and peripheral nervous system.
30
Syringomyelia
Syringomyelia is a fluid-filled cavity within the spinal cord that is
separate from the central canal and lined by gliotic tissue
31
hydromyelia
hydromyelia is the term used to describe an enlargement in the
central canal itself, and the cavity wall is, therefore, lined by
ependyma.
32
Chiari I malformation
displacement of the
cerebellum and cerebellar tonsils downward through the foramen
magnum. In minor
downward displacement of less than 1 cm, the patient may be
asymptomatic, and care should be taken in attributing nonspecific
neurologic symptoms to the Chiari malformation. In more severe
downward displacem; headache, ataxia,
nystagmus, cranial nerve abnormalities, and other brainstem
symptoms may occur. Associated findings include syringomyelia.
The pathophysiology of Chiari I malformation may relate to
posterior fossa overcrowding due to posterior fossa hypoplasia
33
Chiari II malformation/ Arnold–Chiari
malformation
displacement of the cerebellar vermis and
tonsils in association with a myelomeningocele. Brainstem
dysfunction is often prominent, including cranial nerve
abnormalities, stridor, apnea, and feeding difficulties. Fourth
ventricle compression leads to hydrocephalus. The exact cause of
Chiari II is not known; however, a theory suggests that Chiari II
malformation may be secondary to the presence of the caudal
myelomeningocele, producing downward traction and hence
herniation of the brainstem and cerebellum through the foramen
magnum. Management of Chiari II malformation includes shunting
for hydrocephalus and surgical intervention for the
myelomeningocele. Treatment may include posterior fossa
decompression through suboccipital craniectomy. Management of
complications including seizures, feeding difficulties, and bowel
and bladder dysfunction is also necessary
34
Chiari III malformation
Chiari III malformation is cerebellar herniation into a cervical or
occipital encephalocele
35
Glycoproteinoses
Glycoproteinoses are a group of lysosomal storage disorders of
autosomal recessive inheritance, in which the enzymatic defect
leads to accumulation of oligosaccharides, glycopeptides, and
glycolipids. Accumulation in the brain and viscera leads to
vacuolization of multiple cell types. There are multiple phenotypes
depending on the enzyme affected. In general, these patients have
coarse facial features, skeletal abnormalities, and psychomotor
retardation.
Macam :
sialidosis Sialidosis is caused by deficiency of lysosomal α-N-acetyl
neuraminidase (sialidase), α-mannosidosis caused by α-
mannosidase deficiency, β-mannosidosis caused by β-mannosidase
deficiency, fucosidosis caused by α-fucosidase deficiency,
aspartylglucosaminuria caused by aspartylglucosaminidase
deficiency, and Schindler’s disease caused by α-Nacetylgalactosaminidase deficiency.
36
Joubert’s syndrome
Joubert’s syndrome is an autosomal
recessive disorder characterized clinically by developmental delay,
ataxia, oculomotor abnormalities, and respiratory difficulties.
MRi : molar tooth sign, which results from
cerebellar vermis hypoplasia with fourth ventricular enlargement,
a large interpeduncular fossa, and abnormal superior cerebellar
peduncles
37
COACH syndrome
COACH syndrome (cerebellar
vermis hypoplasia, oligophrenia, congenital ataxia, coloboma, and
hepatic fibrosis
38
Fabry’s disease
Fabry’s disease is an X-linked
disorder caused by deficiency of the enzyme α-galactosidase,
resulting in accumulation of ceramide trihexoside in epithelial,
mesenchymal, and neural cells.
The initial manifestations begin in childhood or adolescence,
presenting with dysesthesias, lancinating pain, and episodes of
burning sensation from small fiber neuropathy, which also may be
associated with autonomic dysfunction. Dermatologic
manifestations include the characteristic angiokeratomas (punctate,
nonblanching blue-black lesions), more prominent in the lower
abdomen and legs, especially in the groins, hips, and periumbilical
regions. Cardiac involvement manifests with valvular disease,
arrhythmias, cardiomyopathy, and ischemic heart disease. There is
also renal involvement from endothelial and glomerular damage,
causing acute renal failure and eventually chronic renal disease
leading to hypertension and uremia. Vascular compromise arises from endothelial and vascular smooth muscle involvement and can
lead to ischemic stroke. Another frequent clinical finding is corneal
opacity.
Pathologically, there is lysosomal storage of birefringent lipids,
with membrane-bound lamellar deposits on electron microscopy.
Treatment includes enzyme replacement therapy
39
holoprosencephaly.
Failure of the prosencephalon to form the telencephalon and
diencephalon, and failure of formation of two distinct cerebral
hemispheres
Macam :
- alobar : cerebral hemispheres are almost completely fused, with absence of
the interhemispheric fissure and corpus callosum. There is a single
midline ventricle. Variable dysgenesis and fusion of the thalamus,
hypothalamus, and basal ganglia is present.
- semilobar
holoprosencephaly, parts of the posterior hemispheres may be
separated by a fissure.
-lobar holoprosencephaly, only the most
anterior portions of the hemispheres are not separated, and there is
partial agenesis of the corpus callosum, but the splenium and genu
are present.
alobar holoprosencephaly, associated midline
facial defects such as cyclopia (single midline eye) and proboscis
(single-nostril nose) often occur, and these more severely affected
individuals are usually stillborn or do not survive long after birth.
If death does not occur in utero, the clinical picture includes severe
cognitive and motor delay, feeding difficulties, and seizures.
Endocrinologic problems including diabetes insipidus and
panhypopituitarism are frequent. Hydrocephalus is a frequent
complication.
40
arrhinencephaly
The olfactory bulb and tracts develop from the prosencephalon a
few days after the hemispheres divide. In severe forms of
holoprosencephaly, arrhinencephaly (agenesis of the olfactory bulb
and tract) invariably occurs. However, in less severe forms of
holoprosencephaly, arrhinencephaly may occur in isolation.
Kallmann’s syndrome, an X-linked dominant disorder, is
characterized by anosmia (due to arrhinencephaly) and
hypogonadism
41
Neuronal ceroid lipofuscinosis
is a group of autosomal recessive
disorders characterized by progressive psychomotor retardation,
seizures, and blindness, which can present in infantile, late
infantile, juvenile, and adult forms
The diagnosis is based on the clinical presentation and supported
with electron microscopic examination of lymphocytes or cells
from other tissues. Enzyme activity studies for PPT1 and TPP1 are
also available, as is genetic testing for the CLN genes. The
treatment is symptomatic.
42
Congenital aqueductal stenosis
Congenital aqueductal stenosis, or narrowing
of the cerebral aqueduct that connects the third and fourth
ventricle, may be a disorder of neurulation, related to
downregulation of genes in the vertical axis of the neural tube, and
associated with abnormal development of the dorsomedial septum
of the midbrain.
There are various causes of congenital aqueductal stenosis,
genetic or acquired. There is an X-linked form associated with
pachygyria. It may occur in association with holoprosencephaly or
Chiari II malformation. Acquired causes include congenital
infections such as cytomegalovirus or mumps virus, or a variety of
tumors such as ependymomas or hamartomas.
43
Zellweger’s syndrome,
The history and diagnostic studies including elevation of very long
chain fatty acids (VLCFAs) suggest Zellweger’s syndrome, a
peroxisomal disorder in which the white matter is involved.
Zellweger’s syndrome has been called “cerebrohepatorenal
syndrome” and is characterized by dysmorphic features such as a
high forehead, large fontanelles, flat supraorbital ridges,
hypertelorism, epicanthal folds, broad nasal bridge, micrognathia,
and flat occiput.
44
infantile syndromes of peroxisomal dysfunction
infantile syndromes of peroxisomal dysfunction include Zellweger’s
syndrome, neonatal adrenoleukodystrophy, and infantile Refsum’s
disease. Zellweger’s syndrome is the most severe form and is
caused by mutations in the PEX genes, the majority with PEX1
resulting in abnormal peroxisomal biogenesis.
45
Hereditary hemorrhagic telangiectasia / Osler-Weber-Rendu
Hereditary hemorrhagic telangiectasia, or Osler-Weber-Rendu
syndrome, is an autosomal dominant disorder in which
telangiectasia occurs in the skin, mucous membranes, and several
organs including the retina and the gastrointestinal tract. Recurrent
epistaxis is a common manifestation. Central nervous system
involvement results from single or multiple arteriovenous
malformations (AVMs) or cerebral embolism associated with
pulmonary AVMs. It results from a mutation in the HHT1 gene on
chromosome 9 that encodes for endoglin, a protein that binds
transforming growth factor-β (TGF-β), or from a mutation in the
HHT2 gene on chromosome 12. Wyburn–Mason syndrome is
another neurocutaneous disorder in which multiple AVMs occur on
the face, in the retina, and intracranially
46
pseudoxanthoma elasticum (Gronblad–Strandberg syndrome)
In pseudoxanthoma elasticum (Gronblad–Strandberg syndrome),
a connective tissue disorder that may be autosomal dominant or
recessive, yellowish xanthomas occur in various skin regions and
mucous membranes. Pigmentary changes in the retina result in a
peu d’orange (orange skin) appearance and angioid streaks
develop, which do not affect the vision directly, but due to
weakening of retinal vessels, hemorrhages may occur. Neurologic
manifestations relate to vascular occlusions and intracranial carotid
artery aneurysms.
47
Ehlers–Danlos syndrome
Ehlers–Danlos syndrome exists in at least 10 subtypes, with types
I, II, and III being the most common. These subtypes share the
occurrence of hyperelastic skin, hyperextensible joints, and
vascular lesions. This syndrome results from mutations in various
genes encoding for different types of collagen. The main
neurologic significance of this disorder is the increased risk of
intracranial aneurysms, carotid-cavernous fistulas (that may be
spontaneous or due to mild trauma), and arterial dissection.
48
Xeroderma pigmentosum
Xeroderma pigmentosum is a neurocutaneous disorder marked
by sensitivity to ultraviolet light that predisposes affected
individuals to skin freckling and multiple cutaneous malignancies
including melanoma, basal cell carcinoma, and squamous cell
carcinoma as well as other cutaneous and systemic tumors.
Neurologic abnormalities include progressive cognitive
dysfunction, hearing loss, tremor, chorea, and ataxia as well as
peripheral neuropathy. Xeroderma pigmentosum is autosomal
recessive associated with mutations on chromosome 9 that result in
abnormal DNA repair
49
septo-optic dysplasia
a group of malformations that include
hypoplasia or absence of the septum pellucidum, optic nerve and
optic chiasm hypoplasia, dysgenesis of the corpus callosum and
anterior commissure, and fornix detachment from the corpus
callosum. Arrhinencephaly (agenesis of only the olfactory bulb and
tract) and/or hypothalamic hamartomas may be associated
features. Other less commonly associated abnormalities include
cerebellar vermis defects and hydrocephalus. Septo-optic dysplasia
can also be associated with lobar holoprosencephaly and other
malformations of cortical development.
Clinical manifestations include vision loss, ataxia when the
cerebellum is involved, symptoms of hydrocephalus when it is
present, and endocrinologic disturbances that can range from
panhypopituitarism to isolated hormone deficiencies. Mutations in
the transcription factors HESX1, homeobox, and SOX genes may be
implicated in this disorder.
50
Cavum septum pellucidum
Cavum septum pellucidum, in which the septum pellucidum is
not fused, is considered nonpathologic, with little clinical
implications.
51
Adrenoleukodystrophy
impaired transport of very long chain fatty acids into
peroxisomes, preventing beta-oxidation with subsequent
accumulation in tissue and plasma. There are 3 phenotypes:
childhood onset cerebral type, adrenomyeloneuropathy, and pure
adrenal insufficiency
Patients with adrenoleukodystrophy have increased plasma
levels of very long-chain fatty acids, and adrenocorticotrophic
hormone (ACTH) is increased secondary to adrenal insufficiency.
Treatment involves supportive care with steroid replacement
therapy for adrenal insufficiency. “Lorenzo’s oil,” which consists of
4:1 glyceryl trioleate-glyceryl trierucate, has been shown to reduce
levels of very long-chain fatty acids in plasma. Dietary use of
Lorenzo’s oil may be beneficial in young asymptomatic patients but
not in patients with neurologic deficits. Bone marrow
transplantation may have a role in early stages of the disease.
52
Leigh’s syndrome or subacute encephalomyelopathy
mitochondrial
dysfunction. It may be sporadic or familial, with only some cases
with the typical maternal inheritance pattern, and may result from
mutations in mitochondrial or nuclear DNA encoding for different
subunits of the respiratory chain. This condition affects neurons of
the brainstem, thalamus, basal ganglia, and cerebellum. Most
affected patients have onset of neurologic manifestations in the
first year of life, but there are forms with late onset. Clinical
features manifest with decompensation associated with intercurrent
illnesses.
In infancy, patients present with hypotonia, loss of head control,
poor sucking, vomiting, irritability, seizures, and myoclonic jerks.
If the onset is beyond the first year, patients present with gait
disturbance, cerebellar ataxia, dysarthria, psychomotor retardation,
spasticity, external ophthalmoplegia, nystagmus, abnormal
movements with chorea or dystonias, peripheral neuropathy, and,
in some cases, with autonomic failure. Respiratory involvement is
often present, with manifestations such as apnea, sighing, periodic
hyperventilation, and irregular breathing. Respiratory failure may
lead to death. The disorder is progressive with episodic
deterioration.
Lactate level is increased in blood and CSF. Lactate and pyruvate
levels in blood are elevated during exacerbations. Magnetic
resonance imaging of the brain demonstrates bilateral symmetric
hyperintense T2 signal abnormalities in the basal ganglia as well as
other regions including the substantia nigra, inferior olivary nuclei,
periaqueductal gray matter, corpus callosum, and, in some cases,
the spinal cord
53
Kearns–Sayre syndrome
Kearns–Sayre syndrome, which is a disorder
caused either by a single large-scale mitochondrial DNA deletion or
less commonly by a duplication. The diagnosis is made with the
triad of progressive external ophthalmoplegia, onset before the age
of 20 years, and at least one of the following: short stature,
pigmentary retinopathy, cerebellar ataxia, heart block, and
increased CSF protein (>100 mg/dL). Chronic progressive external
ophthalmoplegia may be an isolated finding seen in some patients.
Patients with Kearns–Sayre syndrome have a gradual progression
of symptoms and most will have cognitive regression by third or
fourth decade of life. Although the disorder is usually sporadic,
affected women with large deletions may in a small percentage of
cases transmit the mutation.
An electrocardiogram is required to diagnose heart block, in
which case, a pacemaker is needed. Pathologically, patients may
have muscles with ragged red fibers and white matter showing
spongy myelinopathy without gliosis or macrophage reactions.
54
Congenital disorders of glycosylation (CDG) / carbohydrate-deficient glycoprotein syndrome
abnormal synthesis, modification, transport, and/or processing
of the carbohydrate moieties or glycans of glycoproteins,
therefore, affecting protein components in many tissues.
55
“steer
horn sign,” / “racing car sign” coronal MRI
Agenesis corpus callosum
56
Hypomelanosis of Ito
Hypopigmented streaks or patches that follow skin lines
57
phakomatoses
The phakomatoses are a group of disorders that share in common
the occurrence of dysplastic lesions and the tendency for tumor
formation. They include neurofibromatosis, tuberous sclerosis, Sturge–Weber syndrome (SWS), epidermal nevus syndrome (ENS),
and HI
58
incontinentia pigmenti
incontinentia pigmenti, skin involvement occurs in stages
including vesiculobullous lesions present at birth, verrucous lesions
that appear at approximately 6 weeks of age, and then
hyperpigmented lesions that follow the Blaschko lines (lines of skin
development). Hyperpigmentation decreases over time, with
tendency to disappear or become hypopigmented and atretic later
in life. Some patients have normal cognition and no evidence of
neurologic dysfunction; neurologic manifestations include
intellectual impairment, pyramidal tract findings, and ocular
abnormalities. It is X-linked dominant in inheritance and affects
only females; it is thought to be lethal in males. It results from a
mutation in the NEMO gene, which encodes a protein involved in
the nuclear factor κ B pathway.
59
Neurocutaneous melanosis
Neurocutaneous melanosis is characterized by the presence of
various types of congenital cutaneous lesions that are abnormally
pigmented (such as giant hair pigmented nevi and congenital
melanocytic nevi) in association with leptomeningeal melanosis.
The leptomeningeal areas most often affected include those around
the base of the brain, brainstem, and cerebellum. Hydrocephalus is
a common complication. The pathophysiology of this disorder is
not well defined; the cells of origin of the leptomeningeal
melanosis are thought to be melanoblasts, pigmented cells
normally found in the pia mater. There is high risk of developing a
melanoma.
60
Parry–Romberg syndrome
Parry–Romberg syndrome is characterized by progressive loss of
facial tissue, cartilage, and bone, leading to hemifacial atrophy,
often with ipsilateral loss of eyelashes, eyebrows, and scalp hair.
This begins typically in early childhood and the atrophy
progression ceases by the third decade of life. Neurologic
manifestations include headaches, Horner’s syndrome, seizures, and
hemiparesis. Patients with Parry–Romberg syndrome are at
increased risk of a variety of benign tumors. The disorder must be
distinguished from scleroderma and lipodystrophy.
61
Maffucci’s syndrome, multiple enchondromas
In Maffucci’s syndrome, multiple enchondromas (tumors of
cartilage) occur in association with secondary hemangioma formation and various skin findings, including vitiligo,
hyperpigmented patches and nevi, and café-au-lait spots. These
enchondromas grow over time, leading to disfigurement and
skeletal abnormalities. Twenty to thirty percent of enchondromas
may develop sarcomatous changes. Neurologic manifestations
result from the association of this syndrome with various CNS
tumors, including pituitary and brainstem tumors and other
gliomas. Compression of nervous system structures by the
enchondromas, such as cerebral compression by calvarial
enchondromas, may also occur.
62
Periventricular nodular heterotopia
Periventricular nodular heterotopia is a disorder of neuronal
migration. This disorder is characterized by nodules of gray matter
lining the ventricles and extending to the lumen. The most
common presentation is seizures, and patients often have learning
disabilities. Developmental delay and other malformations can be
seen.
63
Malformations of cortical development
Malformations of cortical development are divided into four
categories on the basis of the underlying cause: disorders of cell
proliferation, migration, cortical organization, and malformations
of cortical development not otherwise classified. Disorders of
neuronal proliferation include some forms of megalencephaly and focal cortical dysplasia. Disorders of neuronal migration include lissencephaly (agyria, pachygyria, and
subcortical band heterotopia), cobblestone complex malformations,
and all types of heterotopia, including periventricular nodular
heterotopia. Disorders of cortical organization include
polymicrogyria, focal cortical dysplasia with normal cell types,
microdysgenesis, and schizencephaly
64
Focal cortical dysplasia
Focal cortical dysplasia includes a wide variety of cortical
malformations in which there are abnormal cells (dysmorphic,
enlarged neurons, balloon cells) and abnormal lamination. Focal
cortical dysplasia may be seen in isolation or in the setting of
tuberous sclerosis. One type of focal cortical dysplasia is
characterized pathologically by the presence of balloon cells, which
result from proliferation of abnormal cells within the germinal
matrix. This is a common pathology in focal epilepsy, with seizures
often being intractable to medical therapy.
65
Miller–Dieker syndrome
Miller–Dieker syndrome (four-layer variant, formerly a
lissencephaly type 1) is characterized by lissencephaly associated
with microcephaly, typical facies including micrognathia (small
jaw), low-set ears, thin upper lip, short nose with upturned nares,
prominent forehead, bitemporal hollowing, and other features.
Clinical manifestations include global developmental delay,
hypotonia and later spasticity, and intractable seizures. Life
expectancy is often short. Miller–Dieker syndrome has been
associated with microdeletions on chromosome 17 in the LIS1 gene,
which encodes for a protein involved in regulation of microtubules
and dynein function, and mutations interfere with microtubuledirected migration of neurons from the ventricular zone. Mutations
in LIS1 gene can also lead to isolated lissencephaly (so-called
isolated lissencephaly sequence, without other features of MDS).
66
Lissencephaly
Lissencephaly is a malformation of cortical development from
abnormal neuronal migration resulting in impaired formation of
gyri. It is characterized by the presence of reduced cortical
gyration and, in the most severe form, no gyri, or agyria, resulting
in a smooth brain.
Formerly, lissencephaly was classified in two groups, type 1 and
type 2. Type 1 included MDS and but applied also for other
variants. Type 2 consisted of the cobblestone lissencephalies. A newer classification groups
lissencephalies into lissencephaly variants 4,3,2 layers (according
to the number of layers, in which MDS or classic lissencephaly is
included as a four-layer variant), cobblestone cortical malformation
, microlissencephaly spectrum, and other
lissencephalies.
67
Cobblestone lissencephaly
Cobblestone lissencephaly (rather than subcortical band
heterotopia), formerly known as lissencephaly type 2, is seen in
several disorders, including Walker–Warburg syndrome, Fukuyama
muscular dystrophy, and muscle–eye–brain disease of Santavuor.
Cobblestone malformations are neuronal migration disorders
(not malformations of cortical organization) in which the cortical
gray matter has reduced number of gyri and sulci that appear like
cobblestones. There is reduced and abnormal white matter, and the
cerebellum and brainstem may be abnormal or hypoplastic.
Microscopically, the cortex has no recognizable layers and is
dysplastic and thick. Hydrocephalus frequently occurs. Congenital
muscular dystrophy and eye abnormalities are seen in these
patients.
68
neurofibromatosis type 1 (NF1) / von Recklinghausen
disease.
In order for a diagnosis of NF1 to be made, two or more of the
following must be present: six or more café au lait macules (>5
mm in diameter in prepuberty or >15 mm in diameter in
postpuberty), inguinal or axillary freckling,
two or more cutaneous neurofibromas or one plexiform
neurofibroma ,two or more Lisch’s nodules (iris
hamartomas), optic pathway glioma, bony lesion (such as sphenoid
wing dysplasia, or thinning of long bone cortex with or withou
69
Cafe au lait, ashleaf spots, shagreen patches, Lisch’s nodules, terdapat pada
Café au lait macules may be seen in the localized, segmental
forms of NF1 in the setting of postsomatic mutations in the NF1
gene. Lisch’s nodules, or iris melanocytic hamartomas,
that are pathognomonic for neurofibromatosis type 1 (NF1).
ashleaf spots are hypopigmented
and are seen in tuberous sclerosis complex , Shagreen patches are connective tissue
hamartomas also seen in tuberous sclerosis.
Kayser–Fleisher rings are seen in Wilson’s disease. Brushfield’s
spots are white spots in the iris seen in Down’s syndrome. Iris
colobomas (defects in the iris) are seen in a variety of disorders,
including epidermal nevus syndrome and CHARGE syndrome
(coloboma, heart defects, atresia of the choanae, retardation of
development, genitourinary abnormalities, ear abnormalities)
70
Legius’s syndrome
Legius’s syndrome is an autosomal dominant cutaneous
syndrome caused by mutation in the SPRED1 gene located at
15q14. It is characterized by café au lait macules and axillary and
inguinal freckling just like NF1. Unlike NF1, Legius’s syndrome is
NOT associated with optic gliomas, neurofibromas, Lisch’s nodules,
nor risk of malignancy. There are mild dysmorphisms including
hypertelorism and macrocephaly, and there may be associated
learning or attention deficits
71
Subependymal giant cell astrocytoma (SEGA)
Subependymal giant cell astrocytoma (SEGA) is an uncommon
tumor, but it is seen almost exclusively in patients with tuberous
sclerosis complex (TSC) and is a major diagnostic criterion for TSC. This is a benign, low-grade astrocytoma but
leads to symptoms due to mass effect and ventricular obstruction.
Surgery is usually curative. Rapamycin may be of benefit in the
treatment of SEGA and other TSC-related tumors.
72
Neurofibromatosis type 2
NF2 is less common than NF1 and
has distinct diagnostic criteria, clinical manifestations, and
pathophysiology.
Diagnostic criteria for NF2 include one of the following:
• Bilateral schwannomas of cranial nerve (CN) VIII.
• Unilateral vestibular schwannoma and a family history of a
first-degree relative with NF2.
• A family history of a first-degree relative with NF2 combined
with any two of the following lesions: neurofibroma,
schwannoma, meningioma, glioma, posterior subcapsular
lenticular opacities.
• Unilateral vestibular schwannoma and two of the following:
meningioma, glioma, neurofibroma, schwannoma, and
posterior subcapsular lenticular opacities.
• Multiple meningiomas and unilateral vestibular schwannoma or
two of the following: glioma, neurofibroma, schwannoma,
cataract.
73
Sturge-Weber syndrome
Sturge-Weber syndrome (SWS), also referred to as
encephalotrigeminal angiomatosis, in which gyral calcifications
result from angiomatosis of the leptomeninges and brain. SWS is a
neurocutaneous disorder characterized by the presence of
cutaneous angioma of the face, also known as the port-wine nevus,
which often occurs in a trigeminal distribution
74
Cobb’s syndrome / cutaneomeningospinal angiomatosis
Cobb’s syndrome, or cutaneomeningospinal angiomatosis, is a
variant of SWS in which cutaneous angiomas occur in a dermatome
corresponding to a spinal dural angioma.
75
Nonketotic hyperglycinemia / glycine encephalopathy
Nonketotic hyperglycinemia or glycine encephalopathy is caused
by a defect in one of three proteins that together make up the
mitochondrial glycine cleavage system, resulting in complete
absence of function and the accumulation of glycine in all body
tissues. The
onset is in newborns, who, within a few hours to days after birth
become irritable with poor feeding and hiccups. Subsequently, they
develop a progressive encephalopathy with hypotonia, myoclonic
seizures, and respiratory failure requiring mechanical ventilation.
Patients who survive the acute phase will have profound
intellectual disability, spasticity, and intractable epilepsy. Brain
MRI may reveal a hypoplastic or absent corpus callosum, gyral
malformations, and cerebellar hypoplasia. In the acute phase, the
EEG shows burst suppression and hypsarrhythmia.
76
Krabbe’s disease / globoid cell leukodystrophy
Krabbe’s disease or globoid cell leukodystrophy is a disorder
with autosomal recessive inheritance, caused by mutations in the
galactocerebrosidase gene (GALC, 14q31.3), leading to loss of
enzymatic activity. leading to the formation of globoid cells and to
progressive demyelination, but with sparing of the U fibers. It can
involve the peripheral nervous system, leading to a demyelinating
neuropathy, but affects predominantly the CNS.
77
Pelizaeus–Merzbacher disease,
Pelizaeus–Merzbacher disease, which is a
hypomyelinating leukodystrophy inherited in an X-linked recessive
fashion. The onset of clinical manifestations is in the first few months of
life, with intermittent nodding movements of the head, pendular
nystagmus, and other abnormal eye movements. Ataxia, chorea,
athetosis, dystonia, spasticity, and laryngeal stridor also occur, and
psychomotor development arrests with subsequent regression. Late
manifestations include seizures and optic atrophy. Patients with
later onset may have slower progression, and some patients
survive into adulthood.
The MRI demonstrates diffuse hypomyelination characterized by
T2 hyperintensity and loss of white matter with relative thinning
of the corpus callosum. Pathologically, there is a noninflammatory
demyelination sparing the U fibers and islands of white matter.
78
Epidermal nevus syndrome (ENS), Proteus syndrome
, Becker nevus syndrome
Epidermal nevus syndrome (ENS) includes several disorders that
are characterized by the presence of epidermal nevi and neurologic
manifestations. These disorders include Proteus syndrome
(characterized by asymmetric and often marked hypertrophy of
soft tissues and bones and epidermal nevi), Becker nevus syndrome
(hairy hyperpigmented plaque, smooth muscle hyperplasia, breast
hypoplasia, and rib defects), Sebaceous nevus syndrome,
Phakomatosis pigmentokeratotica, Nevus comedonicus syndrome,
and CHILD (Congenital hemidysplasia with ichthyosiform nevus
and limb defects) syndrome. Epidermal nevi are slightly raised
patches of hyperpigmentation that are present at birth or appear in
childhood. They may enlarge over time. Not all patients have
neurologic manifestations; occurrence of nevi over the face and
scalp predict neurologic involvement. Neurologic manifestations
may include intellectual disability, seizures, and cranial
neuropathies. In patients with hemimegalencephaly (which often
occurs ipsilateral to a facial nevus), contralateral hemiparesis may
be seen. Other brain malformations seen in patients with ENS
include focal pachygyria, lissencephaly, heterotopic gray matter,
and other abnormalities of cortical development. Cerebral vascular
abnormalities may also occur.
79
Tangier disease
Tangier disease : very low serum cholesterol and high triglyceride concentrations.
Given the severely reduced HDL level, cholesteryl esters
accumulate in various tissues, including tonsils, peripheral nerves,
cornea, bone marrow, and other organs of the reticuloendothelial
system. A typical clinical finding is the enlarged orange tonsils.
Peripheral neuropathy is common and manifests with sensory loss
to pain and temperature that may have a pattern in the upper
extremities similar to that seen in syringomyelia, or may affect the
entire body. Motor involvement may manifest with weakness that
affects the upper and lower extremities and particularly the hand
muscles. A symmetric polyneuropathy is common; however, a
mononeuropathy presentation can also be seen. Deep tendon
reflexes are depressed. Cranial nerves may also be involved.
Premature atherosclerosis also occurs
80
Menkes disease, also known as kinky hair syndrome
Menkes disease / kinky hair syndrome, is a disorder
of intracellular copper transport characterized by the presence of
brittle coarse and lightly pigmented hair (pili torti), hyperelastic
skin, and thin or absent eyebrows. Neurologic manifestations
include seizures, severe developmental delay, cerebral
vasculopathy with tortuous and kinked intra and extracranial
vessels, progressive cerebral atrophy, and subdural hematomas
and/or hygromas. Other organ systems are involved, including the
skeletal, gastrointestinal, and genitourinary tract. Abnormal
fullness of the cheeks, osteoporosis, and metaphyseal dysplasia are
often seen. Cephalohematomas and spontaneous bone fractures are
seen in newborns, which may raise the suspicion for nonaccidental
trauma.
In the classic presentation, patients present in the first months of
life with hypotonia, hypothermia, failure to thrive, neurologic
regression with severe developmental delay, and psychomotor
retardation and seizures, with rapid progression and death by the
third or fourth year of life.
81
Mitochondrial encephalopathy, lactic acidosis and strokes (MELAS)
Mitochondrial encephalopathy, lactic acidosis and strokes (MELAS)
is a mitochondrial disorder with typical maternal inheritance;
however, sporadic cases may occur.
Patients are normal at
birth, later manifesting with seizures, migraine headaches,
vomiting with anorexia, exercise intolerance, and weakness.
Failure to thrive, growth retardation, and progressive deafness are
common in these children. Stroke-like episodes occur, presenting
with transient hemiparesis, cortical blindness, and altered
consciousness, with cumulative residual effects leading to gradually
progressive neurologic impairment, cognitive deterioration and
encephalopathy. The MRI demonstrates
multifocal infarcts that do not correlate with definite vascular
territories. Initially, the infarcts occur in the posterior cerebral
regions, with eventual involvement of other cerebral and
cerebellar cortices, basal ganglia, and the thalamus. The infarcts
are extremely epileptogenic. Lactate level is elevated in the blood
and CSF. Muscle biopsy may demonstrate ragged red fibers
82
Abetalipoproteinemia/ Bassen–Kornzweig syndrome
Abetalipoproteinemia, or Bassen–Kornzweig syndrome, is an
autosomal recessive disorder caused by a molecular defect in the
gene for the microsomal triglyceride transfer protein (MTTP gene),
which is localized in chromosome 4q23. This condition manifests from birth with failure to thrive,
vomiting, and loose stools. During infancy, there is progressive
psychomotor retardation with cerebellar ataxia and gait
disturbance. Proprioceptive sensation is lost in the hands and feet,
with less compromise of pinprick and temperature sensation. Deep
tendon reflexes are depressed. This is likely from demyelination of
posterior columns and peripheral nerves. Visual disturbance is the
result of retinitis pigmentosa, and nystagmus is common.
Laboratory studies demonstrate acanthocytosis, absence of very
low-density lipoproteins, absence of apolipoprotein B, low levels of
vitamin E, and severe anemia.
83
acute intermittent porphyria
acute intermittent porphyria manifest with attacks of neurovisceral
symptoms, with markedly elevated levels of plasma and urinary
concentrations of the porphyrin precursors aminolevulinic acid
(ALA) and porphobilinogen (PBG). Levels are usually elevated
during attacks and may be normal in between. The attacks may be
triggered by drugs such as antiepileptics (especially barbiturates),
sulfonamides, and hormones among other medications. Attacks
may also be triggered by a low-carbohydrate diet, infections
Commonly, these patients experience limb pain and muscle
weakness resulting from a peripheral neuropathy that is
predominantly motor and axonal, affecting more proximal than
distal segments and more the upper than the lower extremities.
Deep tendon reflexes are depressed. The radial nerve has been
described as being classically involved, and in severe cases, there
may be bulbar and respiratory involvement. Seizures can occur
from neurologic involvement or may result from the hyponatremia
that is seen in these patients. Neuropsychiatric symptoms such as
anxiety, insomnia, depression, disorientation, hallucinations, and
paranoia may occur.
The diagnosis is based on clinical suspicion and elevated urinary
excretion of ALA and PBG during the attacks. Genetic testing and
enzyme analysis are also helpful.
84
Mucopolysaccharidoses
Mucopolysaccharidoses are caused by impaired lysosomal
degradation of glucosaminoglycans which
are long unbranched molecules of repeating disaccharides. Various
enzymatic defects lead to the accumulation of glucosaminoglycans
in lysosomes and the extracellular matrix.
MPS include types I, II, III, IV, VI, VII, and IX
85
Alexander’s disease
Alexander’s disease, which is a progressive
disorder of astrocytes caused by mutations in the gene for glial
fibrillary acidic protein (GFAP gene, 17q21.31).
Brain MRI demonstrates diffuse white matter T2 hyperintensity,
predominantly in the frontal lobes and anterior cerebral regions,
with involvement of the U fibers. In the adult-onset form, the
“tadpole sign” on sagittal MRI results from dramatic thinning of
the upper cervical spinal cord. The brains of these patients are
large, and histopathologically, there are Rosenthal fibers. The
histopathologic specimen shows multiple Rosenthal
fibers, which are elongated eosinophilic fibers seen with
hematoxylin and eosin stains, and they are diffusely distributed
throughout the brain with clusters in the subpial, subependymal,
and perivascular areas. Rosenthal fiber deposition is associated
with severe myelin loss and cavitation of the white matter. They
are not pathognomonic for Alexander’s disease and are seen in
other conditions associated with gliosis. There is no specific
treatment.
86
Canavan’s disease
Canavan’s disease, which is an autosomal recessive
disorder caused by deficiency of aspartoacylase, leading to
accumulation of N-acetylaspartic acid in the brain. This condition
occurs more commonly in Ashkenazi Jews and is caused by
homozygous (or compound heterozygous) mutations of the ASPA
gene on chromosome 17p13. These patients have an onset of
symptoms between 10 weeks and 4 months of life and present with
poor fixation and tracking, psychomotor arrest and regression,
irritability, feeding difficulties, hypotonia with poor head control
and inability to sit, and subsequent spasticity. Megalencephaly
(enlarged brain) is present.
Urinary N-acetylaspartic acid level is elevated, and MRI
demonstrates diffuse symmetric T2 hyperintensity in the white
matter, with characteristic involvement of the U fibers. Magnetic
resonance spectroscopy shows an increased peak of Nacetylaspartic acid. Cerebrospinal fluid is normal and there is no
inflammation. There is no specific treatment available and death
usually occurs in the second decade of life
87
Tay–Sachs disease /infantile GM2 gangliosidosis
In Tay–Sachs disease, the CNS is the only affected system,
differentiating it from Sandhoff’s disease which affects both the
CNS and the viscera, resulting in hepatosplenomegaly. Onset is
between 3 and 6 months of age, with increased startle response
and subsequent motor regression, spasticity, blindness with optic
atrophy, and seizures. There is a delay in reaching developmental
milestones, with subsequent developmental regression. A cherryred spot in the macula is commonly seen, and these patients have
macrocephaly. Progression to severe intellectual disability occurs,
and most children die by the age of 5 years. The diagnosis is
suspected in patients with psychomotor retardation and a cherryred spot and is confirmed with the detection of hexosaminidase A
deficiency with normal activity of hexosaminidase B. Targeted
mutation analysis or gene sequencing of the HEXA gene to detect
specific mutations may be helpful to identify asymptomatic carriers
in the family and to differentiate between disease-causing
mutations and so-called pseudodeficiency alleles that result in
decreased hexosaminidase A activity in the laboratory but do not
cause disease. Treatment of Tay–Sachs disease is supportive.
88
Gaucher’s disease
Gaucher’s disease, which is inherited in an
autosomal recessive fashion and is caused by deficiency of the
enzyme glucocerebrosidase (acid β-glucosylceramidase) leading to
lysosomal accumulation of glucocerebrosides (glucosylceramide). It
is caused by mutations in the gene GBA on chromosome 1q21 and
is more common in Ashkenazi Jews.
Gaucher’s cells are caused by the lysosomal storage of
glucocerebroside in macrophages. These cells are found in the
liver, spleen, lymph nodes, and bone marrow, and have large
cytoplasm with striated appearance, what has been likened to
“wrinkled tissue paper.” In the CNS, the brainstem and deep nuclei
are most severely affected, and neuronal degeneration is seen,
likely from neurotoxic action of glucosylsphingosine.
89
Dandy–Walker malformation
Dandy–Walker malformation is characterized by cerebellar vermis
hypoplasia, fourth ventricular cystic dilatation, and elevation of the
torcula and the tentorium cerebelli. Posterior fossa enlargement
and hydrocephalus are common. It is associated with various
chromosomal anomalies. Neural tube defects, including
encephalocele, and anomalies in other organ systems, including the
heart, may occur. Another association is with facial hemangiomas.
Clinical presentation is variable and depends on the presence of
hydrocephalus and associated anomalies. In severe forms, there is
neonatal macrocephaly from hydrocephalus, brainstem
dysfunction, and feeding and respiratory problems. Severe
developmental delay and ataxia may be present. In some cases,
however, no symptoms are present and the malformation may be
detected only incidentally on imaging in adulthood. Treatment
involves surgical management of hydrocephalus (when indicated)
and supportive care.
90
Prader–Willi syndrome
genetic disorder characterized by profound infantile
hypotonia often requiring a gastric feeding tube in the neonatal
period, short stature, dysmorphic facies including a wide mouth,
small feet, developmental delay, hypogonadism (with
cryptorchidism in males), hyperphagia, and obesity. Infants feed
poorly but then become hyperphagic when older. Another disorder
associated with developmental delay and obesity is Laurence–Moon
syndrome.
91
Angelman’s syndrome
Angelman’s syndrome is a genetically related disorder
characterized by intellectual disability, microcephaly, intractable
epilepsy, ataxia, inappropriate laughter with a wide-based stance
and flailing of the arms at the sides during ambulation (hence the
name “happy puppet syndrome”), prominent jaw with thin upper
lip, and impaired speech development.
92
Cri-du-chat syndrome
Cri-du-chat syndrome is characterized by an abnormal, cat-like
cry, intellectual disability, presence of epicanthal folds,
hypertelorism (in which the eyes are farther apart than normal),
micrognathia, and other features. It is caused by a deletion on
chromosome 5p.
93
Methylmalonic acidemia
Methylmalonic acidemia is an autosomal recessive condition most
commonly caused by the deficiency of methylmalonyl-CoA mutase
(MUT, 6p12.3). Affected children appear normal at birth, becoming symptomatic
within the first week of life, manifesting with lethargy, failure to
thrive, vomiting, dehydration, hypotonia, and respiratory distress.
Hematologic abnormalities, including bleeding disorders leading to
intracranial hemorrhage, may also occur. Patients who survive are
left with intellectual disability, developmental delay, and recurrent
acidosis. The diagnosis should be suspected in newborn patients
with metabolic acidosis, ketosis, hyperglycinemia, and
hyperammonemia. Methylmalonic acid is elevated in plasma and
urine, and the enzyme activity can be analyzed in fibroblasts. B12-
responsive forms of methylmalonic acidemia are associated with
mutations in genes that affect the transport or synthesis of 5′-
Deoxyadenosylcobalamin (cblA, cblB, or cblD variant 2 type), or
deficiency of the enzyme methylmalonyl-CoA epimerase. Patients
with these forms may present later than patients with MUT
mutations and may improve with specific forms of vitamin B12
supplementation.
94
Rett’s
syndrome
Rett’s
syndrome, a syndrome of motor and cognitive regression with
eventual severe disability. The presentation is one of initially
normal development with subsequent regression at approximately 6 to 18 months of age. Hand wringing and other motor
stereotypies are a classic feature; patients with Rett’s syndrome
often place their hands in their mouth or may hold their hands
fisted, with their fingers flexed over their thumb. Arrest of head
growth with eventual (acquired) microcephaly, seizures, scoliosis,
dysautonomia including respiratory dysfunction with apneas, and
spasticity emerge as the disease progresses.
Rett’s syndrome results from a mutation in the MECP2 gene
located at Xq28 that encodes methyl CpG binding protein 2, which
is involved in binding to methylated DNA, modulating gene
expression.
95
Fragile X
syndrome
Fragile X
syndrome is the most common inherited form of intellectual
disability. It results from expansion of the CGG trinucleotide repeat
(>200 repeats) in the Familial Mental Retardation 1 (FMR1) gene
on chromosome Xq27.3. (A mnemonic for remembering the CGG
trinucleotide repeat is, Child with Giant Gonads). The FMR1
protein appears to be an important RNA-binding protein that binds
to mRNAs from many genes associated with autism spectrum
disorders, though its exact cellular function is yet to be fully
elucidated. Because this gene is on the X chromosome, and because
random X inactivation (lyonization) occurs in females, they are less
often and less severely affected. Clinical manifestations in males
include an elongated face, with a high forehead and elongated jaw,
protuberant ears, and enlarged testes (in postpubertal patients).
The degree of intellectual disability ranges from mild and subtle to
severe. A family history of intellectual disability in males may be
present. In adults with a premutation, other neurologic
manifestations may occur
96
Down’s syndrome / trisomy 21
Down’s syndrome, or trisomy 21, results from inheriting three
copies (i.e., trisomy) of the 21st chromosome. Diagnosis is made in the majority of cases
through karyotyping. Increased maternal age is a risk factor. The
frontal lobes are small and underdeveloped, and the superior
temporal gyri are small and thin. Clinical features include presence
of medial epicanthal folds, slanting palpebral fissures, micrognathia
(small mouth) leading to an apparently large tongue, the so-called
simian crease (in which there is a single palmar crease),
Brushfield’s spots (white spots of depigmentation in the iris),
clinodactyly (incurving of the fingers), short stature, and other
features. In addition to varying degrees of intellectual disability,
seizures (including infantile spasms), hematologic malignancies
(such as leukemia), and congenital heart defects occur. Early
dementia with Alzheimer-type pathology is seen, as the β-amyloid
gene is on chromosome 21. These patients are at risk of cervical
spinal cord compression due to atlantoaxial instability
97
Trisomy 13 or Patau’s syndrome
Trisomy 13 or Patau’s syndrome is characterized by
microcephaly, microphthalmia, iris coloboma, low-set ears, cleft lip
and palate, polydactyly (excess number of fingers), prominence of
the heels, and cardiac abnormalities. Life expectancy is typically
not beyond early childhood
98
Trisomy 18
Trisomy 18 is characterized by microcephaly, ptosis, overlapping
of the third finger over the second finger, rocker-bottom feet,
umbilical hernia, congenital heart disease, and other findings. Life
expectancy is typically not beyond early infancy.
99
Klinefelter’s syndrome
Klinefelter’s syndrome, two X chromosomes are present in a
male: XXY. Clinical features include intellectual disability, a wide
arm span, high-pitched voice, gynecomastia (enlarged breasts), and
small testes.
100
Developmental delay
Developmental delay is defined by performance on standardized
tests of function, that is, more than 2 standard deviations below
the mean. Intellectual disability is a diagnosis made on the basis of
testing IQ and is characterized as mild, moderate, or severe on the
basis of the IQ, the degree of impairment, and the level of
assistance in daily activities and other activities that are required.
Mild intellectual disability is defined by an IQ of 55 to 70, whereas
severe intellectual disability is defined by an IQ of 25 to 40. A
myriad of causes for developmental delay exist, including but not
limited to genetic disorders, toxin exposure, and metabolic
disorders.
101
Autism spectrum disorder
Autism spectrum disorder is characterized by the presence
of impaired social interaction and social communication skills and
restricted and/or repetitive repertoire of activities, interests, and
behavior patterns. The symptoms begin in early developmental
stages and limit daily function, causing impairment of social,
occupational, and/or other aspects of the child’s life.
Impaired communication skills entail both verbal and nonverbal
skills. Social skill abnormalities include lack of eye contact or
atypical eye contact, failure to develop peer relationships, and lack
of emotional reciprocity. Motor stereotypies, repetitive voluntary
behaviors, lack of flexibility,
persistent preoccupation with specific objects or part of an object,
and ritualistic patterns of behavior occur.
When making a diagnosis of ASD, additional information should
be specified, such as the presence of intellectual disability,
accompanying language impairment, presence of catatonia, and if a
medical, genetic, or environmental condition is associated (such as
ASD associated with mitochondrial cytopathy). The severity of
autism is graded as follows: level 1 (requires support), level 2
(requires substantial support), and level 3 (requires very
substantial support).
