Section XIV. Pediatric Neurology

XIV.1. Answer a.

Genetic advances in embryogenesis have unfolded a com-

plex orchestration of gene expressions in place of the tra-

ditional developmental epochs (induction, neurulation,

proliferation, migration, organization, synaptogenesis, and

myelination). Causes of malformation of the central ner-

vous system are multifactorial. Genetic causes, vitamin

excess or deficiency, infections, or teratogens any time

during pregnancy may disturb the preprogrammed

mechanisms.

XIV.2. Answer c.

Myelomeningocele (spina bifida cystica) consists of her-

niation of the spinal cord and meninges through a verte-

bral defect. Lumbosacral involvement is most common,

and the neurologic deficit depends on the level of the

lesion. Brain imaging shows complex malformation of the

craniovertebral junction, brain, and brainstem (Chiari type

II malformation) and associated hydrocephalus in more

than 80% of patients with myelomeningocele.

XIV.3. Answer d.

Periventricular heterotopia may be X-linked due to a

filamin-1 gene (FLN1) mutation. Mutations in the double-

cortin gene (DCX) on chromosome X result in anterior-

dominant subcortical band heterotopia in heterozygous

females and lissencephaly in hemizygous males. Affected

females can be asymptomatic from band heterotopia.

Posterior-dominant subcortical band heterotopias are

associated with lissencephaly type 1 gene (LIS1) muta-

tions on chromosome 17. Sonic Hedgehog gene (SHH)

mutation and trisomy 18 can be genetic causes of holo-

prosencephaly.

XIV.4. Answer c.

At age 15 months, a typically developing child would be

expected to be able to walk backward, scribble with an

immature grasp, use a spoon and cup, and speak 4 to 6

words. By comparison, a 2-year-old child would be

expected to be able to walk up and down stairs, jump,

draw a line, undress, and speak 2-word phrases.

XIV.5. Answer b.

The development of this 5-year-old child is normal in the

gross motor, fine motor/adaptive, language, social, and

emotional domains. However, she has demonstrated per-

sistent difficulties learning and using number facts and

calculations, which is consistent with a specific learning

disorder with mathematics impairment.

XIV.6. Answer d.

According to the Diagnostic and Statistical Manual of

Mental Disorders (Fifth Edition), adults with moderate

intellectual disability have elementary-level academic

skills and need considerable support in the workplace.

The adult can be independent for eating, personal hygiene,

and household tasks but will require continued support.

XIV.7. Answer a.

If all 4 limbs are involved in a child with cerebral palsy,

but the lower extremities are involved more than the upper

extremities, the classification is diplegia.

XIV.8. Answer b.

The clinical findings are those expected with tuberous

sclerosis complex (TSC). MRI findings in TSC may include

cortical tubers, subependymal nodules, and subependy-

mal giant cell astrocytomas. Bilateral acoustic neuromas

occur in neurofibromatosis type 2. Cerebellar hemangio-

blastomas are a manifestation of von Hippel-Lindau dis-

ease. Optic gliomas may be seen in neurofibromatosis type 1. Leptomeningeal angiomatosis is a characteristic of

Sturge-Weber syndrome.

XIV.9. Answer e.

Multiple meningiomas may occur in patients with neuro-

fibromatosis type 2, but they are not among the diagnostic

criteria for NF1. The other 4 choices are diagnostic criteria

for NF1.

XIV.10. Answer c.

Bilateral acoustic neuromas are characteristic of neurofi-

bromatosis type 2. Inheritance is autosomal dominant.

XIV.11. Answer a.

Neurofibromatosis type 1 is the most common neurocuta-

neous disorder. With a prevalence of approximately 1 in

3,000 persons, it is more than 10 times more common than

neurofibromatosis type 2.

XIV.12. Answer b.

SEGAs are seen in patients with tuberous sclerosis com-

plex. These patients may also have cortical tubers.

XIV.13. Answer d.

Infants with glucose transporter 1 deficiency may present

with intractable seizures associated with low CSF glucose

and low or low-normal CSF lactate levels. Patients respond

to therapy with a ketogenic diet, which provides an alter-

native fuel source in the form of ketone bodies. Barbiturates,

methylxanthines, and valproic acid can exacerbate the

condition and should be avoided.

XIV.14. Answer d.

Homocystinuria is inherited as an autosomal recessive

disorder and is due to deficiency of various enzymes,

including cystathionine β-synthase. Patients have a mar-

fanoid appearance with long limbs, arachnodactyly, and

ectopia lentis with downward dislocation of the lens.

Approximately 50% of patients have intellectual disabil-

ity. Most acute neurologic features result from cerebral

thromboembolic disease. Approximately 40% of patients

with cystathionine β-synthase deficiency respond to pyri-

doxine therapy.

XIV.15. Answer b.

Urea cycle disorders present in the neonatal period with

clinical findings as described for this patient. The diagno-

sis is suggested by marked hyperammonemia in the pres-

ence of respiratory alkalosis. OTC deficiency is an X-linked

disorder that has a poor neurologic outcome if the hyper-

ammonemia is not treated promptly and aggressively.

Treatment must include discontinuation of protein intake,

hemodialysis, sodium benzoate, sodium phenylacetate,

and arginine hydrochloride. Organic aciduria can present

with hyperammonemia but in the presence of metabolic

acidosis. The other conditions generally do not present

with hyperammonemia.

XIV.16. Answer b.

Clinical features of mucopolysaccharidoses include a

chronic and progressive course, multisystemic involve-

ment, organomegaly, dysostosis multiplex, and coarse

facies. Inheritance of Hunter disease is X-linked recessive.

XIV.17. Answer a.

Fabry disease is an X-linked recessive disorder of glyco-

sphingolipid catabolism resulting from deficiency of the

enzyme α-galactosidase. The other conditions are inher-

ited in an autosomal recessive manner. Hurler syndrome

and Sanfilippo syndrome are autosomal recessive muco-

polysaccharidoses. Pompe disease is an autosomal reces-

sive glycogen storage disease due to deficiency of

lysosomal acid maltase (acid α-glucosidase). Tay-Sachs

disease is an autosomal recessive disease caused by a deficiency of the α subunit of β-hexosaminidase A, which

results in GM2 gangliosidosis.

XIV.18. Answer a.

GM2 gangliosidoses are a group of inherited disorders

caused by excessive accumulation of GM2 ganglioside in

the central nervous system. Hydrolysis of GM2 ganglioside

requires 3 gene products: the α and β subunits of β-hexosa-

minidase isoenzymes and the GM2 activator protein.

Deficiencies in these gene products give rise to different

forms of GM2 gangliosidoses. Tay-Sachs disease is caused

by a deficiency of the α subunit of β-hexosaminidase A.

Mucopolysaccharidoses are a group of disorders due to

defects in the breakdown of glycosaminoglycans, includ-

ing heparan sulfate, dermatan sulfate, keratan sulfate,

chondroitin sulfate, and hyaluronan. Cerebroside sulfate

may be found in patients with metachromatic leukodystro-

phy and globoid cell leukodystrophy. Globoid cell leuko-

dystrophy is caused by deficiency of the lysosomal enzyme

galactosylceramidase, which leads to accumulation of psy-

chosine in the nervous system.

XIV.19. Answer d.

Alexander disease is a primary disorder of astrocytes due

to a toxic gain-of-function mutation in the gene that

encodes glial fibrillary acidic protein, GFAP. MRI findings

suggestive of Alexander disease include extensive cerebral

white matter changes with frontal predominance.

XIV.20. Answer e.

Leukoencephalopathy with vanishing white matter dis-

ease is an autosomal recessive condition due to muta-

tions in the genes encoding each of the 5 subunits of

eukaryotic translation initiation factor eIF2B. The course

is chronic and progressive with episodes of deterioration

initiated by minor infections, minor head trauma, or

acute fright.

Diffuse symmetrical cerebral white matter changes are

present early and spare the subcortical U fibers, outer cor-

pus callosum, internal capsules, and anterior commissure.

Progressive cystic degeneration results in replacement of

the white matter by cerebrospinal fluid.

XIV.21. Answer b.

Diagnosis of the most common form of metachromatic leu-

kodystrophy is confirmed with the presence of sulfatides

in the urine associated with low arylsulfatase A activity.

Sulfatides are not excreted in the urine when the decreased

arylsulfatase A activity is due to the presence of the benign

pseudodeficiency alleles; affected patients are asymptom-

atic. The finding of sulfatides in the urine with normal

arylsulfatase A activity suggests the presence of saposin B

(activator protein) deficiency.

XIV.22. Answer d.

PMD is an X-linked disorder due to deficient formation of

proteolipid protein (PLP) in the central nervous system

associated with mutations or duplication of the PLP gene.

Patients with classic PMD present with rotatory eye move-

ments and hypotonia, followed by slowly progressive

involuntary movements and spasticity. MRI reveals a

severe reduction or absence of central myelin. Nerve conduction studies may show evidence of demyelinating

peripheral neuropathy.

XIV.23. Answer d.

Mitochondrial DNA point mutations are usually mater-

nally inherited. More than half the reported disease-

related point mutations are located within mitochondrial

transfer RNA genes. Common disorders are MELAS,

MERRF, LHON, and NARP.

XIV.24. Answer e.

Leigh syndrome (subacute necrotizing encephalomyelopa-

thy) is the most frequent presentation of mitochondrial

disease in children. The signs of classic Leigh syndrome, a

rapidly progressive neurologic disorder, usually begin

between the ages of 3 months and 2 years. In most chil-

dren, the first noticeable sign is the loss of previously

acquired motor skills. About 50% of affected children die

by age 2 to 3 years. Leigh syndrome is characterized by

bilaterally symmetrical lesions in the basal ganglia, thala-

mus, and brainstem. Rare adult-onset forms have been

reported.

XIV.25. Answer c.

MELAS is a maternally inherited mitochondrial disorder

characterized by strokes that are often in a nonvascular ter-

ritory pattern as shown in the MRI sequences. Patients

may have other features, including short stature, hearing

loss, migraine headaches, seizures, type 2 diabetes melli-

tus, and gastrointestinal dysmotility with recurrent vomit-

ing or intestinal pseudo-obstruction. Elevated levels of

lactate in serum or cerebrospinal fluid (or both) in addition

to muscle biopsy and genetic testing can be diagnostically

helpful. These strokes are more likely than watershed

infarcts to cross the middle cerebral and posterior cerebral

territories and are not characteristic of strokes due to atrial

fibrillation or endocarditis. Susac syndrome is a vasculitic

condition characterized by involvement of the brain (often

the corpus callosum), cochlea (hearing loss), and eye

(branch retinal artery occlusions).