Pediatric Neurology

Questions

1. An infant boy is born via normal spontaneous vaginal delivery after an uncomplicated 39-week pregnancy. On day 1 of life he is noted to experience repetitive clonic movements of the right arm that are not suppressible, up to 1 minute in duration. He is loaded with phenobarbital for suspected seizures, and the clonic movements stop. The exam shows an awake infant moving his arms and legs symmetrically, with a normal cranial nerve exam. Motor tone and bulk is normal, and deep tendon reflexes are normal and symmetric. Plantar reflexes are downgoing. An EEG reveals epileptiform discharges, occasionally occurring in rhythmic runs up to 3 seconds in duration, in the right temporal leads. What is the most likely etiology of the seizures?

A. Benign neonatal familial convulsions

B. Cortical malformation in the left temporal region

C. Grade IV intraventricular hemorrhage with extension into the right temporal region

D. Hypoglycemia

E. Perinatal arterial ischemic stroke affecting the left MCA

View Answer

1. Answer E. (MN-137) Ischemic strokes in newborns commonly present with focal seizures. There may or may not be evidence of movement asymmetry, which may not present for many months. Deep tendon reflexes and plantar responses are typically normal. Grade IV intraventricular hemorrhages are more commonly seen in premature infants. Hypoglycemia responds to dextrose infusion rather than phenobarbital. Benign neonatal familial convulsions typically do not have interictal EEG epileptiform discharges. Cortical malformations do not typically present with seizures on the first day of life.

2. A girl is born at 27 weeks’ gestation because of preterm premature rupture of membranes. On day 7 of life she receives a routine head ultrasound and is noted to have a grade I germinal matrix hemorrhage on the left. Vital signs are stable, tone is appropriate for gestational age, and respiratory function is stable on nasal CPAP.

What is the proper course of action?

A. Four-vessel cerebral angiogram to check for a source for the hemorrhage

B. Head CT because head ultrasound does not provide enough detail

C. Hematology consult to check for a bleeding diathesis

D. Reassurance and clinical follow-up because grade I hemorrhages typically have a good prognosis

E. Repeat head ultrasounds to assess for progression

View Answer

2. Answer E. (MN-137) While grade I germinal matrix hemorrhages typically do carry a good prognosis, they can progress to more extensive hemorrhages. Germinal matrix hemorrhages are usually related to the underlying capillary structure and not due to a vascular malformation or aneurysm, and there is usually not a bleeding diathesis. Ultrasonography is the standard imaging modality for diagnosis of germinal matrix-intraventricular hemorrhages; head CT is not preferred because of ionizing radiation.

3. A 40-week boy is born via emergency C-section after a nonreassuring fetal heart monitoring strip is observed (with minimal variability). The newborn is noted to be limp and cyanotic, with meconium below the cords. After suctioning and positive pressure ventilation, the baby is still limp but no longer cyanotic, but there is decreased respiratory effort and the baby is intubated. Which findings would best support a diagnosis of hypoxic-ischemic encephalopathy?

A. Abnormal liver function tests (elevated liver transaminases)

B. Apgar scores of 1, 5, and 8 (at 1, 5, and 10 minutes, respectively)

C. Bilateral grade II intraventricular hemorrhages

D. Immediate return to normal following infusion of dextrose

E. Choices B and C

View Answer

3. Answer A. (MN-137) Hypoxic-ischemic encephalopathy frequently correlates with multiorgan failure, caused by global hypoxemia/hypoxia, and normally does not show improvement in Apgar scores to 8 (Table 19.3.1). Clinical features consistent with hypoxic-ischemic encephalopathy include Apgar <5 at 5 and 10 minutes, cord pH < 7.0, and evidence of multiorgan injury, in addition to MRI brain consistent with this diagnosis. Intraventricular hemorrhages are more typically seen in premature infants and are not diagnostic of hypoxic-ischemic encephalopathy. Dextrose is a treatment of neonatal hypoglycemia.

TABLE 19.3.1 Apgar Scores^a

	Score of 0	Score of 1	Score of 2
Color	Blue or pale, entire body	Blue at extremities, body pink	No cyanosis
Heart rate	Absent	<100	>100
Reflex irritability	No response to stimulation	Feeble cry or grimace when stimulated	Cry or pull away when stimulated
Muscle tone	None	Some flexion	Flexed arms and legs
Respiratory effort	Absent	Weak, gasping, irregular	Strong, lusty cry
^aAdapted from Apgar V. A proposal for a new method of evaluation of the newborn infant. Curr Res Anesth Analg. 1953;32(4):260-267.

4. A full-term infant is noted on day 2 of life to be lethargic, with a poor suck and a paucity of limb movements despite noxious stimulus. The baby is noted to have decreased urine output. A head CT is done emergently and shows bilateral hemorrhages in the parasagittal parietal lobes. What might be an appropriate treatment course?

A. Anticoagulation therapy

B. EEG

C. Lumbar puncture to reduce intracranial pressure

D. Surgical evacuation of the bilateral hemorrhages

E. Therapeutic hypothermia protocol

View Answer

4. Answer A. (MN-137) The infant has experienced a superior sagittal sinus thrombosis, with bilateral hemorrhages from decreased venous outflow. Dehydration, as evidenced by the decreased urine output, is a risk factor for cerebral sinus venous thrombosis (SVT). Along with correction of the dehydration, anticoagulation is a treatment modality for SVT. Therapeutic hypothermia is used to treat HIE. Lumbar puncture and surgical evacuation may be considered in extreme cases of raised intracranial pressure but are usually not required. Given the risk of seizures in neonates with brain injury an EEG is a good idea; however, it can be performed at the discretion of the clinical team, and the procedure should not take precedence over empiric anticoagulation.

5. A 30-week premature infant has routine head ultrasound on day 30 of life and is noted to have bilateral cysts in the white matter, anteriorly and just adjacent laterally to the lateral ventricles. You are called to explain the findings to the patient’s parents and discuss prognosis. What would be a likely clinical outcome to discuss with them?

A. Increased intracranial pressure requiring the need for a ventriculoperitoneal shunt

B. Spastic diplegia

C. Spastic quadriplegia with mental retardation and intractable epilepsy

D. There would be no expectation of seizures because only white matter is affected

E. Visual impairment

View Answer

5. Answer B. (MN-137) Bilateral white matter cysts in the periventricular region are likely to be manifestations of periventricular leukomalacia in a premature infant. The lesions typically present clinically with spastic diplegia/cerebral palsy, very likely after the newborn period. Seizures are a possibility, but it would be unlikely for this patient to experience intractable epilepsy and also unlikely to have broad enough injury to cause spastic quadriplegia. Visual impairment more commonly is caused by lesions in the posterior white matter because of injury to the visual radiations.

6. A 7-day-old with a history of truncus arteriosus repair is experiencing nonsuppressible rhythmic clonic movements of the right arm and facial grimacing. Phenobarbital is loaded 20 mg/kg intravenously followed by another bolus of 10 mg/kg, but the movements persist. An EEG shows left frontal electroclinical seizures. What would be an appropriate course of action?

A. Intravenous lidocaine load 2 mg/kg and then maintenance infusion

B. Intravenous levetiracetam load 40 mg/kg followed by maintenance dosing

C. Intravenous phenytoin load 20 mg/kg/d followed by maintenance dosing

D. Intravenous topiramate 5 mg/kg followed by maintenance dosing

E. Load an additional 5 mg/kg of phenobarbital

View Answer

6. Answer B. (MN-137) Levetiracetam would be an appropriate medication to add to phenobarbital in this setting. Lidocaine should not be used in a patient with congenital heart disease because of risks of arrhythmia. Phenytoin similarly has cardiovascular side effects and would not be a good option (fosphenytoin has fewer cardiovascular side effects but still would carry risk). Topiramate is not available in the intravenous form. Given the failure to break seizures after 30 mg/kg of phenobarbital the patient should be loaded with a second agent and have a phenobarbital level checked as opposed to receiving additional phenobarbital. See Table 19.6.1 for dosing of antiseizure medications in neonates.

TABLE 19.6.1 Treatment of Acute Symptomatic Neonatal Seizures^a

Medication	Dosage	Notes
Phenobarbital	Load: 20-30 mg/kg IV, repeated once as needed; maintenance: 4-6 mg/kg/d divided twice a day (target serum level 40-60 µg/mL)	Side effects: respiratory depression, depressed level of consciousness, hypotension, hypotonia, hepatotoxicity, blood dyscrasia, skin rash
Fosphenytoin (and phenytoin)	Load: 20 mg/kg IV; maintenance: 5-8 mg/kg/d divided twice or three times a day (may need four times a day) (target level 20 µg/mL); may need to check free concentration (target level 1-2 µg/mL)	Cardiovascular, CNS, cutaneous side effects, which are less often seen with fosphenytoin compared with phenytoin. Variability in pharmacokinetics may result in inconsistent serum levels.
Levetiracetam	Load: 40-60 mg/kg IV; maintenance: 40-60 mg/kg/d divided twice or three times a day	Pharmacokinetics incompletely understood for neonates
Lorazepam	Load: 0.05-0.1 mg/kg IV	Side effects: respiratory depression, depressed consciousness, hypotension; myoclonus in neonates with low birth weight
Midazolam	Load: 0.15 mg/kg IV and then continuous infusion (1 µg/kg/min, titrating to effect, maximum 2-5 µg/kg/min)	Side effects: respiratory depression, depressed consciousness, hypotension
Topiramate	Load: 10 mg/kg/d divided twice a day, increase in 2 d by 5 mg/kg/d divided twice a day; goal dose 5-6 mg/kg/d	May be helpful for refractory seizures; no intravenous form is available; may result in metabolic acidosis and/or weight loss/appetite suppression
Lidocaine	Load: 2 mg/kg over 10 min, then continuous infusion 7 mg/kg/h for 4 h, then 3.5 mg/kg/h for 12 h, then 1.75 mg/kg/h for 12 h; initial infusion 3.5 h rather than 4 h if being treated with therapeutic hypothermia	Side effect: arrhythmia; should only be given in ICU setting with continuous cardiac monitoring. Avoid concurrent treatment with proarrhythmic drugs such as phenytoin. Avoid in patient with congenital heart disease and if patient has received phenytoin or fosphenytoin (because of arrhythmia risks).
CNS, central nervous system; ICU, intensive care unit; IV, intravenous.
^aAdapted with permission from Glass HC. Neonatal seizures: advances in mechanisms and management. Clin Perinatol. 2014;41(1):177-190; Ahrens S, Ream M, Slaughter L. Status epilepticus in the neonate: updates in treatment strategies. Curr Treat Options Neurol. 2019;21:8.

7. Failure of the posterior portion of the neural tube to close in utero will lead to what neurological defect?

A. Anencephaly

B. Encephalocele

C. Meckel syndrome

D. Microcephaly

E. Myelomeningocele (spina bifida)

View Answer

7. Answer E. (MN-138) Neurulation begins around day 14 in embryonic development. From around day 21 to day 26 the neuroectoderm cells begin to close in on themselves forming the neural tube. Errors in closure of the anterior or caudal neural tube can lead to encephaloceles (partial defect), or in extreme cases anencephaly, while failure of the posterior or rostral portion of the neural tube leads to defects in the formation of the spinal cord, ie, myelomeningocele-spina bifida. Meckel syndrome is a genetic disorder causing defects in anterior neural tube closure leading to an occipital encephalocele, cerebellar malformations, microcephaly, and renal dysplasia. There are multiple genetic and environmental causes of microcephaly; however, errors in the rostral neural tube closure would not lead to cranial malformation.

8. A baby is born with cyclopia, hypotelorism (flat nose), and midline cleft lip. He has myoclonic seizures and autonomic dysfunction and passes away after several months. The mother’s pregnancy was complicated by uncontrolled diabetes and retinoic acid exposure. MRI of the infant’s brain would most likely show which of the following?

A. Hemimegalencephaly

B. Holoprosencephaly

C. Microcephaly

D. Open lip schizencephaly

E. Septo-optic dysplasia (SOD)

View Answer

8. Answer B. (MN-138) The infant in the above vignette suffered from holoprosencephaly, which is defined as failure of the forebrain (prosencephalon) to sufficiently divide into double lobes and two cerebral hemispheres (Figure 19.8.1). Mutation in the Sonic Hedgehog gene is the most common cause of this disorder and may be seen with maternal diabetes or retinoic acid exposure in utero. Patients who suffer from sonic hedgehog mutations/holoprosencephaly often have midline defects, ie, cyclopia, cleft palate, myoclonic seizures, and autonomic dysfunction, and usually die in infancy. SOD is a neurodevelopmental disorder characterized by absence of septum pellucidum, optic nerve hypoplasia, and hypothalamic dysfunction. Hemimegalencephaly occurs when one hemisphere is larger than the other with corresponding large head size and is due to a disorder of neural migration versus neuroepithelial proliferation. These children suffer from intellectual disability, seizures, and hemiparesis and often require callostomy or hemispherectomy. Schizencephaly is a rare developmental birth defect characterized by abnormal slits or clefts in the cerebral hemispheres and is associated with SOD.

FIGURE 19.8.1 Failure of telencephalic cleavage. Holoprosencephaly in a fetus at 32 weeks’ gestation. Note the single ventricle with no division of the cerebrum into hemispheres on a coronal view (left panel). On a sagittal view (right panel), a dorsal cyst is noted that is typical for alobar holoprosencephaly. (Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.)

9. A child is diagnosed with intrauterine growth retardation during the second trimester and born at 39 weeks. The child is noted to have micrognathia, long philtrum, and sacral pits. MRI shows agyria with smooth cortical surface with large ventricles and colpocephaly. A mutation on which of the following chromosomes is most likely responsible for the child’s condition?

A. Chromosome 9

B. Chromosome 13

C. Chromosome 15

D. Chromosome 17

E. Chromosome 21

View Answer

9. Answer D. (MN-138) The patient in the above vignette suffers from type I lissencephaly known as Miller-Dieker syndrome. Lissencephaly is a disorder of neuronal migration leading to an improper quantity and distribution of neurons at the cortical surface. Patients with type I lissencephaly classically have a thickened cortex, smooth cortical surface, large ventricles, and agyria. Moreover, these patients commonly suffer from facial dysmorphisms and cardiac, sacral, and genital abnormalities. Deletions in the LIS1 gene chromosome 17 are found in the majority of patients with Miller-Dieker syndrome. Of note, the brain in type II lissencephaly or cobblestone lissencephaly is characterized by a smooth cortical surface (like type 1 lissencephaly) or polymicrogyria, and pachymicrogyria, while X-linked lissencephaly-band heterotopia syndrome is characterized by double cortex where an additional thick band of gray matter is located in what should be the white matter of the hemispheres (Figure 19.9.1).

FIGURE 19.9.1 Lissencephaly spectrum. Top panels are from a patient harboring a LIS1 deletion. To the left is an axial T1 magnetic resonance image demonstrating agyria posteriorly and pachygyria anteriorly. To the right is a lateral sagittal T1 magnetic resonance image from the same patient demonstrating the same gradient of posterior worse than anterior malformation. Bottom panels are from a female with a DOUBLECORTIN (DCX) mutation demonstrating the so-called double cortex (subcortical band heterotopia). (Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.)

10. An infant boy is born via normal spontaneous vaginal delivery after an uncomplicated 39-week pregnancy. After 48 hours, the child is brought in for lethargy, vomiting, and poor feeding. Laboratory analysis shows respiratory alkalosis and elevated ammonia, with normal glucose, normal renal and liver function, and absent ketones. Plasma amino acid levels are notable for absent citrulline, absent argininosuccinic acid, and reduced arginine, in addition to elevated urinary orotic acid. Based on the available clinical data what is the most likely diagnosis?

A. Arginase deficiency

B. Ornithine transcarbamylase (OTC) deficiency

C. Propionic acidemia

D. Pyruvate dehydrogenase (PDH) deficiency

E. Transient hyperammonemia of newborn

View Answer

10. Answer B. (MN-139) Hyperammonemia in the newborn in the absence of sepsis or liver disease should raise concern for a urea cycle disorder. Infants with hyperammonemia secondary to urea cycle enzyme disorders are typically well in the first 24 hours of birth, then become symptomatic at 48 to 72 hours after several feeds, while children with PDH deficiency are classically symptomatic within the first 24 hours of life. Transient hyperammonemia of the newborn is usually seen in premature, not full-term infants, and most infants remain asymptomatic. Organic acidurias, such as propionic academia, can lead to elevated ammonia, lethargy, and vomiting; however, these conditions (except maple syrup urine disease) also cause ketoacidosis. OTC is the most common urea cycle disorder characterized by absent plasma citrulline and argininosuccinic acid and reduced arginine, in addition to elevated urinary orotic acid (Table 19.10.1).

TABLE 19.10.1 Plasma Amino Acid and Urinary Acid Findings in Urea Cycle Defects

Enzymatic Deficiency	Citrulline	Argininosuccinic Acid	Orotic Acid	Arginine
Carbamoyl phosphate synthetase (CPS)	0 to trace	0	↓	↓
Ornithine transcarbamylase (OTC)	0 to trace	0	↑↑	↓
Argininosuccinate synthetase (citrullinuria)	↑↑	0	↑	↓
Argininosuccinase (argininosuccinic aciduria)	↑	↑↓	nl	↓
Arginase	nl	0	↑	↑↑
Transient hyperammonemia of newborn	nl or slightly ↑	0	nl	nl
↑, increased; ↓, decreased; nl, normal.
Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.

11. An infant child is found to have elevated levels of phenylalanine on newborn screening. Further testing shows reduced functioning of phenylalanine hydroxylase. What would be the next best step in management?

A. Reduced dietary glucose, consider keto diet

B. Reduced dietary phenylalanine intake

C. Sapropterin administration or tetrahydrobiopterin (BH₄) administration

D. Vitamin B₁₂ supplementation

E. Choices B and C

View Answer

11. Answer E. (MN-139) There are 21 amino acids required for normal human metabolism. Of these 21 amino acids, nine are designated “essential” as each must be obtained from exogenous sources as opposed to being synthesized from glucose. Phenylketonuria is a disorder of amino acid metabolism in which the child has reduced (or absent) functioning of phenylalanine hydroxylase enzyme, preventing hydroxylation of phenylalanine into tyrosine and leading to elevated levels of phenylalanine. If untreated, children can suffer from intellectual disability, seizures, eczema, and poor hair pigmentation. Treatment consists of specialty diets with low phenylalanine content (with weekly monitoring of phenylalanine levels) and administration of sapropterin, a synthetic form of BH₄, if their phenylalanine levels drop in response to a BH₄ challenge.

12. A 2-month-old girl is brought to clinic for developmental regression and poor suck and swallowing. The parents are both of Ashkenazi descent. On physical examination, the patient is noticed to have an enlarged liver and spleen, significant tenderness to palpation over long bones, bilateral esotropia, and unremarkable funduscopic examination. Metabolic testing in this patient would most commonly reveal deficiency in which enzyme?

A. Α-L-neuraminidase

B. B-glucosidase

C. Hexosamindase A

D. Iduronate-2-sulfatase deficiency (Hunter syndrome)

E. Sphingomyelinase

View Answer

12. Answer B. (MN-139) The patient in this vignette likely suffers from Gaucher disease. Gaucher disease is an autosomal recessive lysosomal storage disease characterized by intralysosomal accumulation of sphingolipids secondary to deficiency in B-glucosidase (or glucocerebrosidase). Gaucher disease is more common in Ashkenazi Jewish populations and can present in infancy, young adulthood, or adulthood. Common manifestations of Gaucher disease include hepatosplenomegaly, brainstem/bulbar dysfunction, bone fractures, and bone pain. These patients do not have macular cherry red spots. Hexosamindase A deficiency is found in Tachy-Sachs disease and results in accumulation of intralysosomal Gm2 ganglioside. Tay-Sachs is also most frequently seen in the Ashkenazi Jewish community and is characterized by progressive neurological and cherry red spots in the macula. Sphingomyelinase deficiency is seen in Niemann-Pick disease and should be suspected in patients with infants with progressive hepatosplenomegaly and cherry red macula. Iduronate-2-sulfatase deficiency is seen in Hunter syndrome, an X-linked recessive mucopolysaccharidoses (MPS). Patients with MPS have classic facial dysmorphic features, including thickened eyelids, frontal bossing, enlarged tongue in addition to hydrocephalus, and hepatosplenomegaly. This patient does not fit the phenotype of an MPS; moreover, it would be less likely for a female to suffer from an X-linked recessive disorder. Patients with sialidosis, another MPS, have a deficiency in Α-L-neuraminidase, and the condition resembles Hunter syndrome, in addition to having a characteristic macular cherry red spot.

13. A 16-year-old adolescent boy is brought to your office for cognitive and motor decline. The parents note that the child has had worsening performance in school over, in addition to trouble remembering to complete simple tasks such as household chores over the past 4 months. They also note increased fatigue and worsening gait. On exam, the patient has deficits in attention, executive functioning, and short-term memory, in addition to brisk reflexes and positive Romberg. MRI brain shows confluent posterior white matter lesions that spare the cortical U fibers. The patient most likely suffers from which of the following diseases?

A. Alexander disease

B. Krabbe disease

C. Metachromatic leukodystrophy (MLD)

D. Pelizaeus-Merzbacher disease (PMD)

E. X-linked adrenoleukodystrophy (ALD)

View Answer

13. Answer E. (MN-139) X-linked ALD is a peroxisomal storage disease, which presents as a progressive leukodystrophy of variable onset from 2.5 years to adulthood, and is characterized by progressive motor with spastic paraparesis, visual loss from optic atrophy, and cognitive impairment. Some patients may display signs of adrenal insufficiency, such as fatigue, vomiting, salt craving, and hyperpigmentation of the skin folds. MRI classically shows posterior white matter lesions sparing the U-fibers. Diagnosis is suggested by the presence of characteristic MRI abnormalities and with serum very-long-chain fatty acid levels and confirmed with genetic testing. Treatment consists of hematopoietic stem cell transplantation in early stages and exogenous glucocorticoids in times of stress.

Alexander disease is an autosomal dominant progressive leukodystrophy associated with gain-of function mutation in glial fibrillary acidic protein (GFAP) and classically presents in infancy with macrocephaly, developmental regression, and progressive spasticity. MRI shows predominately frontal white matter (Alexander is anterior) hyperintensities in addition to increased signal intensity in the medulla and long white matter tracts. MLD compromises a group of autosomal recessive disorders leading to a deficiency in the enzyme arylsulfatase A, which causes degeneration of the central and peripheral myelin. MLD can present in infancy or adolescence as progressive cognitive decline and spastic paraparesis, while MRI shows white matter changes focused along the bilateral centrum semiovale referred to as the “tigroid appearance” (Figure 19.13.1). Krabbe disease classically presents in infancy (3-6 months) with irritability, seizure, rigidity, and microcephaly and is due to a deficiency in galactocerebrosidase. PMD is an X-linked leukodystrophy caused by mutations in the gene encoding for central proteolipid protein, which presents in infancy with progressive intellectual disability, spasticity, ataxia, and choreoathetosis. MRI classically shows global hypomyelination, and most children do not survive past the first years of life.

FIGURE 19.13.1 (Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.)

14. A 7-year-old girl has global developmental delay, microbrachycephaly, ataxia, and periodic jerky limb movements. Which of the following genetic abnormalities could explain this presentation?

A. Imprinting defects

B. Maternal deletion of 15q11-13

C. Paternal uniparental disomy

D. Point mutations or small UBE3A intragenic deletions

E. All of the above

View Answer

14. Answer E. (MN-140) Angelman syndrome is primarily related to dysfunction of the ubiquitin ligase 3A gene. This can occur as a result of a number of genetic mechanisms, as listed in each of the answer options that result in loss of maternally imprinted allele on chromosomal region 15q11-13 (Table 19.14.1).

TABLE 19.14.1 Common Chromosomal Disorders

Genetic Abnormality/Eponym	Key Clinical Features	Diagnosis
Trisomy 21; chromosome 14/21 translocation; Down syndrome	Intellectual disability, hypotonia, atlantoaxial instability, short stature. Characteristic round facies with epicanthal folds. Early-onset dementia, congenital heart disease, increased risk of leukemia	Chromosome analysis
Prader-Willi syndrome; 15q11-13 deletion	Neonatal hypotonia and failure to thrive, followed by uncontrolled appetite with obesity (hypothalamic dysfunction); characteristic facial features, intellectual disability, and behavior (obsessiveness, mood swings, skin picking)	DNA methylation analysis (loss of paternal allele at SNRPN locus: includes 15q11-13 deletion, uniparental disomy, and imprinting defects—detects 99% of cases)
Angelman syndrome; 15q11-13 deletion	Characteristic facies, microbrachycephaly, protruding tongue, jerky limb movements (features may not be apparent until after 1 y); developmental delays and intellectual disability	DNA methylation analysis (loss of maternal allele: includes 15q11-13 deletion, uniparental disomy, and imprinting defects—78% of cases); UBE3A mutation analysis (11% of cases); chromosome analysis (translocations, inversions—1% of cases); no diagnostic test findings—10% of cases
22q11 deletion syndrome (CATCH-22; DiGeorge; velocardiofacial syndrome)	Cardiac malformations, facial clefts, other cranial and brachial arch anomalies, dysmorphism, intellectual disability, and psychiatric disorders (schizophrenia, OCD, ASD, and ADHD)	FISH, MLPA, chromosomal microarray (detects 95+% of cases)
ADHD, attention-deficit hyperactivity disorder; ASD, autism spectrum disorder; FISH, fluorescent in situ hybridization; MLPA, multiplex ligation-dependent probe amplification; OCD, obsessive-compulsive disorder.
Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.

15. A 10-year-old boy has a history of slowly progressive ataxia, punctuated by episodes of decompensation, precipitated by febrile illness or minor head trauma. MRI of the brain shows signal hypointensity of the white matter on T1-weighted sequences. Which of the following is the most likely diagnosis?

A. Angelman syndrome

B. Ataxia-telangiectasia

C. Cockayne syndrome

D. Seckel syndrome

E. Vanishing white matter disease

View Answer

15. Answer E. (MN-140) Vanishing white matter disease also known as Childhood Ataxia with Central Nervous System Hypomyelination (CACH). This autosomal recessive disorder results from mutations in any one of five genes encoding subunits of translation initiation factor 2B (Table 19.15.1). The disorder is characterized by slowly progressive ataxia, with episodes of decompensation associated with intercurrent illness or minor head trauma. The white matter gradually disappears over a period of years, to be replaced by cerebrospinal fluid.

TABLE 19.15.1 Selected Disorders of DNA Synthesis, Maintenance, Transcription, and Translation

Disorder	Inheritance	Gene and Protein	Mechanism (Known or Putative)	Specific Features
DNA Maintenance and Transcription
Cockayne syndrome type 1 (CSA) MIM 216400	AR	CSA ERCC8	CSA/ERCC8 interacts with p44, CSB, and TFIIH. Mutations thus lead to RNA polymerase II dysfunction and impaired nucleotide excision repair.	Intellectual disability, accelerated aging, pigmentary retinal degeneration, optic atrophy, deafness, marble epiphyses, photosensitivity, and basal ganglia/cerebellar calcification
COFS MIM 214150	AR	CSB ERCC6	Abnormal nucleotide excision repair resulting from disturbed RNA polymerase I–TFIIH interaction within the CSBIP/150 complex, of which CSB/ERCC6 is a component	Microcephaly, microphthalmia, cataracts, dysmorphism, failure to thrive, recurrent pneumonias, axial hypotonia, appendicular hypertonia, hyperreflexia, and progressive contractures; calcifications in the periventricular frontal white matter and basal ganglia
Progeria MIM 176670	AR	LMNA Lamin A	Lamins are structural components of the nuclear membrane. Mutations in LMNA are associated with both defective nuclear mechanics and impaired transcriptional activation.	Postnatal onset of short stature, failure to thrive and accelerated aging, loss of scalp hair, subcutaneous fat, joint stiffness, and early atherosclerosis leading to strokes and myocardial infarcts, and premature death. Elevated prothrombin time, platelets, phosphorous; conductive hearing loss is also reported. Cognition is spared.
XP (de Sanctis-Cacchione syndrome—most commonly complementation group D—XPD) MIM 278730	AR	ERCC2 ERCC2	Abnormal nucleotide excision repair: XPD (ERCC2) interacts with the p44 subunit of TFIH stimulating 5′-3′ helicase activity. Mutations in XPD prevent the interaction with p44, leading to decreased XPD helicase activity.	Intellectual disability, short stature, facial freckling, spasticity, hypogonadism, and olivopontocerebellar atrophy
Trichothiodystrophy (TTD 1) MIM 601675	AR	ERCC2 ERCC2	As for XP; TFIIH also stabilizes thyroid hormone receptors in TTD mouse brain.	Intellectual disability, hair shaft abnormalities, ichthyosis, immature sexual development, short stature, and facial dysmorphism
Rett syndrome MIM 312750	X linked	MECP2 MeCP2	Regulation of gene expression, chromatin composition, and chromosomal architecture through binding to methylated DNA. MeCP2 is expressed ubiquitously by neurons; levels of MeCP2 expression increase during neuronal differentiation and remain at high levels in the adult brain.	Classic phenotype restricted to females; normal development for first 6 mo, followed by acquired microcephaly, loss of hand skills and replacement by stereotypies, regression of skills, seizures, spasticity, and scoliosis
Spinal muscular atrophy 1, 2, and 3 MIM 253300, 253550, 253400	AR	SMN1 SMN	SMN1 is a key component of the spliceosome complex; selective vulnerability of anterior horn cells is not yet understood.	Loss of anterior horn cells (and neurons of brainstem and thalami in severe cases)
DNA Translation and Translational Modification
CACH, Cree leukoencephalopathy, ovarioleukodystrophy MIM 603896	AR	EIF2B1 EIF2B2 EIF2B3 EIF2B4 EIF2B5 eIF2B	Translation initiation factor 2B catalyzes exchange of GDP for GTP, an essential stage in recycling of eIF2; GEF activity. Mutations in any of the five genes coding for subunits of eIF2B cause loss of normal downregulation of protein translation under stress, resulting in protein denaturation and accumulation of aggregates producing cellular toxicity.	Slowly progressive ataxia with diffuse loss of white matter; episodes of coma with fever and motor impairment with minor trauma
CDG-1a MIM 212065	AR	PMM2 PMM2	PMM2 is one of a family of enzymes catalyzing the assembly of the LLO precursor that is attached to the nascent polypeptide chain during cotranslational modification by N-linked glycosylation.	Intellectual disability, short stature, progressive ataxia, peripheral neuropathy, stroke-like episodes, seizures, immune dysfunction, intermittent hepatic failure, coagulopathies
Cell Cycle Regulation
Angelman syndrome MIM 105830	Multiple mechanisms, including maternal deletion of 15q11-13, paternal uniparental disomy, imprinting defects, and point mutations or small UBE3A intragenic deletions. Some patients have MECP2 mutations.	UBE3A Ubiquitin-protein ligase E3A	The UBE3A gene encodes sense and antisense RNA transcripts in the brain with neuron-specific imprinting of UBE3A in primary brain cell cultures. The maternal UBE3A allele is preferentially expressed in the neuronal nucleus and at synapses; absence of this allele is associated with abnormal dendritic spine morphology.	Psychomotor retardation, ataxia, hypotonia, epilepsy, absence of speech, large mandible, and tongue thrusting; optic atrophy and albinism in some
Ataxia-telangiectasia MIM 208900	AR	ATM ATM	The ATM protein is a PI3K that phosphorylates key substrates involved in DNA repair and/or cell cycle control.	Progressive ataxia, choreoathetosis, anterior horn cell loss, immune deficiency, scleral telangiectasia
Seckel syndrome 1 MIM 210600	AR	ATR ATR CEP152 Centrosomal protein 152	ATR is a PI3K involved in cell cycle progression, DNA recombination, and the detection of DNA damage; CEP152 regulates genomic integrity and cellular response to DNA damage.	Short stature, dysmorphism (“bird-headed dwarf”), congenital microcephaly, intellectual disability; no immune deficiency or cancers
AR, autosomal recessive; ATM, ataxia-telangiectasia mutated; ATR, ataxia-telangiectasia and Rad3-related; CACH, childhood ataxia with central nervous system hypomyelination; CDG-1a, congenital disorder of glycosylation 1a; COFS, cerebro-oculo-facio-skeletal syndrome; CSA, Cockayne syndrome group A; CSB, Cockayne syndrome group B; CSBIP, CSB IP/150, CSB immunoprecipitated fraction; eIF2, eukaryotic initiation factor 2; eIF2B, eukaryotic translation initiation factor 2B; ERCC2, excision repair cross-complementing rodent repair deficiency 2; ERCC6, excision repair cross-complementing rodent repair deficiency 6; ERCC8, excision repair cross-complementing rodent repair deficiency 8; GEF, guanine nucleotide exchange factor; LLO, lipid-linked oligosaccharide; MeCP2, methyl CpG-binding protein 2; PI3K, phosphatidylinositol 3-kinase; PMM2, phosphomannomutase 2; TFIIH, transcription factor II H; TTD, trichothiodystrophy; XP, xeroderma pigmentosum.
Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.

16. A 6-year-old girl has a history of recurrent pneumonia and otitis media. She has gait ataxia, ocular motor apraxia, and prominent blood vessels on the ocular sclera. Which of the following is the most likely diagnosis?

A. Angelman syndrome

B. Ataxia-telangiectasia

C. Cockayne syndrome

D. De Sanctis-Cacchione syndrome

E. Seckel syndrome

View Answer

16. Answer B. (MN-140) Ataxia telangiectasia. This is a disorder of cell cycle regulation characterized by immune deficiency with frequent sinopulmonary infections, progressive ataxia, ocular motor apraxia, and ocular telangiectasias (Table 19.15.1). Patients with ataxia-telangiectasia syndrome have a high risk of developing cancer, most commonly leukemia or lymphoma, as they have reduced ability to repair DNA injury from ionizing radiation. Seckel syndrome is an autosomal recessive disorder characterized by short stature, congenital microcephaly, and intellectual disability, without immune deficiency or cancers. Cockayne syndrome is caused by mutations leading to RNA polymerase II dysfunction leading to intellectual disability retinal degeneration, optic atrophy, and basal ganglia calcifications. De Sanctis-Cacchione syndrome is a rare and severe form of xeroderma pigmentosum and is also caused by mutations leading to impaired DNA repair resulting in facial freckling, intellectual disability, short stature, and olivopontocerebellar atrophy (see Table 19.15.1).

17. A 2-month-old term infant presents for evaluation of hypotonia. On examination, you observe an alert infant with bell-shaped thorax, paradoxical breathing, tongue fasciculations, weak cry, intact sensation, and areflexia. The patient has received all his scheduled vaccines, and the family deny any recent viral infections or alterations in awareness concerning for seizure activity. What is the best diagnostic test for the most likely diagnosis?

A. EMG/NCS

B. Molecular genetic testing for SMN1

C. MRI brain

D. Muscle biopsy

E. Muscle ultrasound

View Answer

17. Answer B. (MN-141) Given the diffuse symmetric lower motor neuron signs and intact sensation, one can localize the lesion to the anterior horn cell, the most common cause being 5q spinal muscular atrophy. Genetic testing for survival of motor neuron 1 (SMN1) disease-causing mutation is indicated to confirm the diagnosis. EMG and muscle biopsy were once a standard part of the diagnostic evaluation for SMA but are seldom needed now that molecular testing is widely available.

18. A term newborn infant presents for evaluation of hypotonia. On examination you observe microphthalmia, microcephaly, and brisk tendon reflexes with proximal weakness. Laboratory studies show elevated creatine kinase, 50-fold above the upper limit of normal. What is the most likely diagnosis?

A. Congenital cytomegalovirus (CMV) infection

B. Congenital disorder of glycosylation

C. Cerebral palsy

D. Duchenne muscular dystrophy

E. Spinal muscular atrophy type 1 (SMA 1)

View Answer

18. Answer B. (MN-141) The presence of microcephaly, upper motor neuron signs, and elevated creatinine kinase raises concern for a myopathy with central involvement. Congenital muscular dystrophies involving the central nervous system include those associated with congenital disorders of glycosylation as well as merosin-deficient congenital muscular dystrophy. The differential for newborn hypotonia is provided in Table 19.18.1. Patients with congenital CMV infection can display microcephaly, upper motor neuron signs, and seizures and classically have periventricular calcifications; however, they would not have an elevated creatinine kinase. SMA is a disorder of anterior horn cells; thus, it would not cause upper motor neuron signs suggested by brisk reflexes.

TABLE 19.18.1 Differential Diagnosis Hypotonic Infant

Central causes:
1. Vascular
	A. Hypoxic-ischemic encephalopathy B. Intraventricular hemorrhage C. Ischemic or hemorrhagic stroke
2. Structural
	A. Brain malformations B. Cerebral palsy C. Intracranial neoplasms
3. Metabolic
	A. Toxic metabolites B. Energy metabolism C. Intracellular small molecules
4. Systemic
	A. Congenital infections B. Sepsis/CNS infection C. Endocrine disorders D. Electrolyte disturbance
5. Chromosomal disorders
	A. Prader-Willi syndrome B. Trisomy 21 C. DiGeorge syndrome
6. Spinal cord
	A. Dysraphism/spina bifida B. Ischemic injury
Peripheral causes:
1. Anterior horn cell
	A. Spinal muscular atrophy 5q B. SMARD1 C. Poliomyelitis D. Acute flaccid myelitis
2. Brachial plexus injury
	A. Erb palsy b. Klumpke palsy
3. Peripheral nerve
	A. Demyelinating neuropathies
		i. Early-onset demyelinating neuropathies with CNS involvement
			a. Waardenburg syndrome and Hirschsprung disease: SOX10 b. Severe forms of Cockayne syndrome: ERCC6 and ERCC8 c. Krabbe disease: GALC d. Merosin-deficient congenital muscular dystrophy: LAMA2 e. Navajo neurohepatopathy: MPV17 f. Congenital disorders of glycosylation: multiple genes g. Congenital cataracts, facial dysmorphism, and neuropathy: CTP1 h. POLG-related hepatocerebral mtDNA depletion syndromes: POLG1 i. Leigh syndrome: multiple genes j. PRUNE1 k. PTRH2
	B. Axonal neuropathies
		i. Early-onset axonal neuropathy with CNS involvement
			a. Infantile neuroaxonal dystrophy (INAD): PLA2G6 b. Twinkle mutations with severe encephalopathy, abnormal movements, and deafness
	C. Mixed neuropathies
4. Neuromuscular junction
	A. Transient neonatal myasthenia gravis B. Fetal acetylcholine receptor inactivation syndrome (FARIS) C. Congenital myasthenic syndromes D. Infantile botulism
4. Muscle
	A. Congenital muscular dystrophies
		i. Merosin deficient ii. Congenital disorders of glycosylation iii. Congenital myotonic dystrophy
	B. Congenital myopathies
		i. Nemaline myopathy ii. Central core myopathy iii. Myotubular myopathy
	C. Metabolic myopathies
		i. Acid maltase deficiency (Pompe disease) ii. Mitochondrial myopathy
CNS, central nervous system; mtDNA, mitochondrial DNA; POLG, DNA polymerase subunit gamma; SMARD1, spinal muscular atrophy with respiratory distress type 1.
Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.

19. A 4-month-old term infant presents for evaluation of hypotonia. He was well until 24 hours before presentation when he developed feeding difficulties and bilateral ptosis. He has also been constipated for the past 3 days. On examination you observe hypotonia, weakness, and ophthalmoplegia, with mid-size fixed pupils. What would you suspect?

A. Guillain-Barré syndrome

B. Infantile botulism

C. Myasthenia gravis

D. Spinal muscular atrophy type 2 (SMA 2)

E. Urea cycle disorder

View Answer

19. Answer B. (MN-141) The rapid onset of hypotonia, starting with cranial nerve dysfunction (poor suck), and progressing caudally, associated with constipation, in a previously normal infant, strongly suggests infantile botulism. Botulin toxin inhibits release of acetylcholine at peripheral cholinergic synapses of the somatic, parasympathetic, and sympathetic nervous systems and contributes to clinical features described including autonomic nervous system involvement. Any infant with clinical signs, symptoms, or history suspicious for botulism should be hospitalized and monitored for signs of respiratory failure; stool samples should be collected and examined for botulinum spores. Intravenous botulism immune globulin antitoxin should be administered as early as possible. Spinal muscular atrophy and myasthenia gravis only involve the somatic nervous system. Postnatal Guillain-Barré syndrome in infants has only been reported in a handful of cases, typically in the context of severe weakness leading to respiratory failure. Depending on the defect, urea cycle disorders typically present closer to birth, although mild cases may follow acute illness or surgery.

20. An 18-week-old term infant was admitted for respiratory distress. Her mother describes generalized weakness and feeding difficulties since the first few weeks of life. While reviewing her chart, you notice poor weight gain and a cardiothoracic ratio of 70% on the chest radiograph. On examination you notice hepatomegaly. Her creatine kinase level is elevated twenty-fold. EMG shows small early recruitment and myotonic discharges. Laboratory testing in this individual would most likely reveal which of the following?

A. DMPK gene mutation

B. Mutation of SMN1 gene on chromosome 5

C. PMP22 gene duplication

D. Reduced acid alpha-glucosidase (GAA) enzyme activity in white blood cells

E. Reduced plasma acylcarnitine

View Answer

20. Answer D. (MN-141) Severe hypotonia presenting in early infancy and associated with cardiomyopathy and failure to thrive suggests an inborn metabolic disorder, specifically Pompe disease, due to lysosomal acid alpha-glucosidase deficiency (GAA deficiency, or glycogen storage disease type II, or acid maltase deficiency). Diagnosis can be made by measuring GAA enzyme activity in white blood cells or dried blood spots. EMG/NCS in Pompe disease classically shows myopathy changes and myotonic discharges. Mutations in the SMN gene would be characteristic of spinal muscular atrophy, an isolated anterior horn cell pathology. Reduced plasma acylcarnitine is a nonspecific finding for a variety of inborn errors of metabolism associated with myopathy. PMP22 gene duplication is seen in Charcot-Marie-Tooth, specifically CMT1A, an inherited peripheral neuropathy. DMPK gene mutations are seen in myotonic dystrophy type 1, a multisystem disorder that can present as hypotonia in infancy (congenital myotonic dystrophy type 1), although it would not be associated with cardiomegaly or hepatomegaly.

21. A 9-month-old girl presents to the office because of concern of using her left hand less than the right. The parents observe more spontaneous use of the right hand, without any clear change depending on time of day. The child was born full-term and has no family history of neurological disease or stroke. The neurological examination reveals less spontaneous use of the left arm and hand than the right. Face and leg movements are symmetrical. Reflexes are slightly brisker on the left. What would be the next best step in the management of this patient?

A. EEG to rule out seizures with resulting Todd (postictal) paralysis

B. EMG of arms to rule out a brachial plexus or peripheral nerve problem

C. Genetic screening for a developmental disorder

D. MRI brain

E. Reassurance: hand preference emerges in the first year of life

View Answer

21. Answer D. (MN-142) Hand preference usually emerges at 2 to 3 years of age, and hand preference in the first year is pathological. Children should be able to transfer objects between hands by 5 to 8 months (Table 19.21.1). The localization of the process is most likely in the right cerebral hemisphere; brisker reflexes on the left suggests an upper motor neuron sign as opposed to a peripheral nerve or brachial plexus problem. Brain imaging with MRI is indicated to determine the etiology of the hand preference. There is no indication that the decreased hand use is associated with seizures, and a postictal (Todd) paralysis should only occur intermittently and after seizures. The most likely finding will be a developmental brain injury (eg, stroke) leading to hemiparetic cerebral palsy.

TABLE 19.21.1 Motor Development Milestones in the First 5 Years^a

Gross Motor	Age Range
Hold head steady	2-4 mo
Roll over	2-5 mo
Sit without support	5½-7 mo
Pull to stand	8-10 mo
Walk	11-15 mo
Run	14-20 mo
Jump	21-28 mo
Hop	3-4 y
Balance on one foot for 4 s	3½-5 y
Fine Motor	Age Range
Grasp rattle	3-4 mo
Reach	4-6 mo
Transfer objects	5-8 mo
Pincer grasp	7-10 mo
Scribble	12-17 mo
Feed self with spoon	13-18 mo
Stack two blocks	13-21 mo
Hold crayon using fingers (not fist)	2-3 y
Copy a circle	3-4 y
Refined tripod pencil grip, print own name, copy a square	4-5 y
^aAge range indicates approximately the 25th to 90th percentile for each milestone according to the Denver II Developmental Screening Tool.
Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.

22. A 7-year-old boy presents with a spastic gait and difficulty walking down stairs. He was born at 28 weeks and spent 10 weeks in the neonatal ICU. He has no other history of trauma or hospitalization. There is no family history of difficulty with gait. The motor exam shows scissoring of the legs and toe walking with good arm and hand movements. The most likely finding on neuroimaging is:

A. Bilateral motor cortex malformations

B. Hemorrhage in cerebellar vermis

C. Hydrocephalus

D. Periventricular leukomalacia (PVL)

E. Thoracic spinal cord injury due to myelomeningocele

View Answer

22. Answer D. (MN-142) Prematurity predisposes to several brain injuries, the two most common being PVL and intraventricular hemorrhage. PVL is caused by injury to the oligodendrocyte precursors, resulting in hypomyelination of the periventricular white matter, particularly around the atria. The most common associated phenotype is spastic diplegia, the pattern of impairment observed in this case, which comprises about a third of cases of cerebral palsy. Bilateral cortical malformations likely cause quadriparesis, with both arm and leg dysfunction. Myelomeningocele causes a lower motor neuron syndrome with muscle weakness, sensation loss, bowel and bladder dysfunction, and depressed tone and reflexes. Hydrocephalus typically presents with headache, gait disturbance, vomiting, and visual changes. Although cerebellar injury can present with ataxia, the isolated lower extremity motor symptoms and pronounced spasticity make this diagnosis less likely.

23. A 9-year-old girl in the fourth grade presents with a concern for poor school performance. She was born full-term and walked at 12 months and spoke more than 50 words at age 2 years. She had normal eye contact and has developed friendship among her peers. In school, she has difficulty with math, reading, and writing. According to her school evaluation, she is performing at the third-grade level in all subjects. Intelligence testing, however, shows that she has a full-scale intelligence quotient of 95 (IQ; mean is 100, standard deviation is 15). What is the most appropriate diagnosis?

A. Autism spectrum disorder (ASD)

B. Cerebral palsy

C. Developmental language disorder

D. Intellectual disability

E. Learning disability

View Answer

23. Answer E. (MN-142) Learning disability is an impairment in school performance with at least average intelligence. In this case, the early development was normal (speaking >50 words at 2 years), so developmental language disorder is ruled out. In addition, the IQ is normal, ruling out intellectual disability. ASD requires impairments in social behavior and communication, and these are intact. The child’s normal birth and motor development are not characteristic of cerebral palsy.

24. A 3-year-old boy presents with concern for poor communication and hand flapping. He was born full-term to unrelated parents. He sat at 7 months, walked at 12 months, and spoke his first words at 13 months. His parents say that he never liked hugs and makes infrequent eye contact. He uses only a few phrases and is reluctant to communicate. When left alone, he will spend hours flapping his hands without interacting with others. What is the most appropriate diagnosis?

A. Autism spectrum disorder (ASD)

B. Cerebral palsy

C. Developmental language disorder

D. Global developmental delay

E. Learning disability

View Answer

24. Answer A. (MN-142) ASD is a disorder of social function and language with restricted interests or repetitive movements, which describes this child. The motor milestones are normal, so global developmental delay and cerebral palsy are unlikely. The early language milestone was normal, ruling out developmental language disorder. Finally, while learning disability may coexist with ASD, the primary issue seems to be with social and communication skills.

25. A 20-month-old boy with full-term uncomplicated birth presents with concern for poor walking and talking. He started walking holding on to furniture (cruising) at 14 months and will only take one to two steps unassisted before falling. He points and makes vowel sounds but does not associate any person or object with a particular sound. He also has difficulty feeding himself with a spoon. What is the most appropriate diagnosis?

A. Autism spectrum disorder (ASD)

B. Cerebral palsy

C. Developmental language disorder

D. Global developmental delay

E. Intellectual disability

View Answer

25. Answer D. (MN-142) Delays in multiple domains constitutes global developmental delay (Tables 19.21.1 and 19.25.1). This child displays delay in gross motor (walking), fine motor (feeding), and communication (not speaking). Autism requires impairments in social function and communication, while developmental language disorder requires that the impairment be specific to language and cerebral palsy requires nonprogressive motor impairment at birth. Intellectual disability describes deficits in the cognitive domain with intact motor function.

TABLE 19.25.1 Language and Social/Emotional Milestones

Age	Receptive Skills	Expressive Skills	Social/Emotional
0-2 mo	Startle, eye widening to sound	Range of cries (from hunger to pain)	Smiles spontaneously
2-4 mo	Quiets to voice, eye blinking to sound	Coos in response to voice	Smiles responsively
4-9 mo	Head turns to sound, responds with raised arms when mom says “up” and reaches for child, responds appropriately to friendly or angry voices	Babbling, repeats self-initiated sounds	Laughs to social attentions
9-12 mo	Listens selectively to familiar words, begins to respond to “no” and to one-step commands (usually accompanied by gesture), understands 10 words	Repeats parent-initiated sounds, symbolic gestures, jargoning, says “mama/dada” nonspecifically	Responds and plays social games: pat-a-cake, peek-a-boo. Joint attention emerges.
12-18 mo	Points to three body parts, understands up to 50 words, recognizes common objects by name, follows one-step commands accompanied by gestures	Uses words to express needs, 10 words by 18 mo, word usage may be inconsistent and mixed with jargon	Responds to name, joint attention established, functional play
18 mo-2 y	Points to pictures when asked “show me,” begins to distinguish “you” from “me”	Telegraphic two-word phrases “go bye-bye,” “mama up,” “baby go”; 2 y: vocabulary of at least 50 words and 50% intelligible by strangers	Symbolic play (feed baby, mix food in bowls)
2½ y	Follows two-step commands, can identify actions in pictures and objects by use	Two- to three-word sentences develop, adjectives and adverbs appear, begins to ask questions	Imaginative play
3 y	Knows several colors; knows what to do when we are hungry, thirsty, or sleepy; aware of past and future, understands “today” and “not today”	Uses pronouns and plurals, sentence length increases to three to five words, can tell stories that begin to be understood; uses negatives “I can’t” and “I won’t”; verbalizes toileting needs; tells full name, age, and gender	Starts to join in play with other children, begins dramatic play
3½ y	Answers questions as “do you have a doll?” and “what toys do you have?”	Can relate experiences in sequential order, asks for permission	More independent in play with other children, shares toys and takes turns with assistance
4 y	Understands same vs different, can follow three-step commands, understands why we have houses, umbrellas, etc.	Can tell a story, uses past tense, names primary colors, asks many questions, nearly all speech understood by strangers	Fully plays and interacts with other children, improving in turn taking and cooperation, very imaginative with self and others
5 y	Understands what we do with eyes and ears; understands “if,” “because,” “when,” “why”; understands differences and comparisons; begins to understand left and right	Asks definition of specific words, makes serious inquiries (“how does this work?” “what does it mean?”), language is now complete in structure and form, all parts of speech are used as well as all types of sentences and clauses	Respects reasonable authority, wants to do what is expected, plays games with rules
Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.

26. Which one of the following statements concerning autism spectrum disorder (ASD) is most likely to be correct?

A. It cannot be diagnosed in an adult (over age 21 years)

B. Most patients will have delayed motor milestones

C. Reliable blood test for making a diagnosis has been developed in the last year

D. The ability of a person to graduate from college excludes the diagnosis

E. The diagnosis is highly subjective and varies greatly from clinician to clinician

View Answer

26. Answer B. (MN-143) ASD is a neurodevelopmental disorder usually diagnosed in infancy or childhood (sometimes in adulthood) characterized by impairments in social communication, social interactions, and restricted/repetitive patterns of behavior and activities. Persons later diagnosed with ASD may have a history of delayed motor milestones. ASD can be accurately diagnosed by clinicians using a battery of neuropsychiatric examinations, such as the Social Communication Questionnaire, the Autism Diagnostic Observation Schedule-2, or the Autism Diagnostic Interview-Revised. Many students in college carry diagnoses of ASD.

27. Which of the following neurological and psychiatric comorbidities are more often diagnosed in children with autism spectrum disorders (ASD)?

A. Attention-deficit hyperactivity disorder

B. Epilepsy

C. Intellectual disability

D. Language disorder

E. All of the above

View Answer

27. Answer E. (MN-143) Many of these diagnoses are often seen in individuals with autism as there are many neurological and psychiatric comorbidities that overlap with ASD. In particular, epilepsy occurs in up to one-third of individuals with ASD. Tuberous sclerosis, fragile X syndrome, Rett syndrome, and Angelman syndrome are associated with both ASD and epilepsy.

28. For a newly diagnosed patient with autism spectrum disorder (ASD), a brain MRI should be performed among children with which of the following findings?

A. History of a focal EEG

B. Neurocutaneous lesions

C. Seizures

D. Staring spells

E. All of the above

View Answer

28. Answer E. (MN-143) All individuals with ASD should have a thorough history and examinations in addition to formal audiology examination to exclude hearing impairment and a basic genetic workup starting with a family pedigree, microarray analysis, and Fragile X testing (Table 19.28.1). There is no strong evidence-based literature to indicate routine brain imaging in all individuals with ASD, although some indications for brain MRI include presence of microcephaly, neurocutaneous lesions, focal neurological deficits, or a history of seizures (Table 19.28.2).

TABLE 19.28.1 Genetic Testing for Autism Spectrum Disorder (ASD)

Chromosomal karyotype

Comparative genomic hybridization array for copy number variants

Fragile X DNA testing

Single nucleotide polymorphism arrays

Gene panel testing—sequencing high-risk genes for ASD (such as TSC1 and TSC2, SHANK3, MECP2, CACNA1C)

Whole exome sequencing

Whole genome sequencing

Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.

TABLE 19.28.2 Clinical Indicators That Might Prompt Neuroimaging With Brain Magnetic Resonance Imaging

Seizures or history of focal EEG
Microcephaly
Extreme (>3 SD above mean) or progressive macrocephaly
Neurocutaneous lesions
Suspicion of CNS structural abnormality
Focal motor findings or a change in motor examination
Active or recurrent regression

CNS, central nervous system; EEG, electroencephalogram; SD, standard deviation.

Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.

29. A 41-year-old man is referred to a neurologist for assessment for possible autism spectrum disorder (ASD). In order to establish that diagnosis in this patient, which one of the following must be determined?

A. He did not graduate from college

B. He has been unemployed for most of his adult life

C. He has frequent stereotyped blinking and episodes when he swears for no apparent reason

D. He has no close friends

E. His symptoms can be well documented to have begun before age 5 years

View Answer

29. Answer E. (MN-143) To establish a diagnosis of ASD in an older child or adult, the symptoms must be present in early childhood, before age 5 years. Episodes of stereotyped motor and vocal tics are indicative of Tourette syndrome; this and other neuropsychiatric conditions may be more common in ASD but do not comprise criteria for ASD. Unemployment is frequent in ASD but is not sufficient to establish a diagnosis of this disorder.

30. A 21-year-old woman presented with headaches, difficulty comprehending others, and impaired speech for 3 days. Since childhood, she had been shorter and thinner than her peers. On examination, she was alert but had a mixed aphasia and mild right hemiparesis. Sensory examination is unreliable. Tendon reflexes are slightly brisker in the right arm than left. Brain MRI showed hyperintense T2 and FLAIR lesions in the left frontal, parietal, and superior temporal cortex. Routine blood testing revealed elevated resting venous lactate 3.0 mM (normal −0.5-2.2). EEG monitoring showed no epileptiform activity. Family history is notable for an asymptomatic 17-year-old sister and a mother with diabetes and deafness. Which diagnostic test will most effectively confirm the diagnosis?

A. Follow-up venous lactate measurements

B. Muscle biopsy to screen for ragged-red fibers

C. Screening blood for mitochondrial DNA deletions

D. Whole exome sequencing

E. Whole mitochondrial DNA sequencing

View Answer

30. Answer E. (MN-144) The patient has features strongly suggesting mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) The stroke-like episodes in MELAS do not fit a classical arterial vascular distribution and commonly present with migraine-like headaches (Table 19.30.1). The most frequent cause of MELAS is the m.3243A > G mitochondrial DNA (mtDNA) pathogenic variant, which is present in about 80% of patients; however, more than 20 additional mtDNA point mutations have been reported to cause this disease. Screening the whole mtDNA using next-generation sequencing is the most cost-effective test to identify the causative mutation and determine its heteroplasmic level.

TABLE 19.30.1 Paradigms of Mitochondrial DNA Mutation Disorders^a

		mtDNA Single Deletions		tRNA		ATPase6
Tissue	Symptom/Sign	KSS	Pearson	MERRF	MELAS	NARP	MILS
CNS	Seizures	−	−	+	+	−	+
	Ataxia	+	−	+	+	+	±
	Myoclonus	−	−	+	±	−	−
	Psychomotor retardation	−	−	−	−	−	+
	Psychomotor regression	+	−	±	+	−	−
	Hemiparesis/hemianopia	−	−	−	+	−	−
	Cortical blindness	−	−	−	+	−	−
	Migraine-like headaches	−	−	−	+	−	−
	Dystonia	−	−	−	+	−	+
PNS	Peripheral neuropathy	±	−	±	±	+	−
Muscle	Weakness	+	−	+	+	+	+
	Ophthalmoplegia	+	±	−	−	−	−
	Ptosis	+	−	−	−	−	−
Eye	Pigmentary retinopathy	+	−	−	−	+	±
	Optic atrophy	−	−	−	−	±	±
	Cataracts	−	−	−	−	−	−
Blood	Sideroblastic anemia	±	+	−	−	−	−
Endocrine	Diabetes mellitus	±	−	−	±	−	−
	Short stature	+	−	+	+	−	−
	Hypoparathyroidism	±	−	−	−	−	−
Heart	Conduction block	+	−	−	±	−	−
Heart	Cardiomyopathy	±	−	−	±	−	±
GI	Exocrine pancreas dysfunction	±	+	−	−	−	−
GI	Intestinal pseudo-obstruction	−	−	−	−	−	−
−, absent; +, present; ±, variably present; CNS, central nervous system; GI, gastrointestinal; KSS, Kearns-Sayre syndrome; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; MERRF, myoclonus epilepsy with ragged red fibers; MILS, maternally inherited Leigh syndrome; mtDNA, mitochondrial DNA; NARP, neuropathy, ataxia, and retinitis pigmentosa; PNS, peripheral nervous system; tRNA, transfer RNA.
^aTypical features are highlighted in red for each disorder except MILS, which is diagnosed neuropathologically.
Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.

31. A patient with presumed mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) has an unaffected 17-year-old sister. Their mother has diabetes and deafness. Is the mother’s syndrome relevant to the patient’s diagnosis?

A. No, because diabetes and deafness are uncommonly seen in mitochondrial diseases

B. No, because the mother’s condition is different from the patient’s MELAS

C. The relationship between the mother’s condition to the patient’s disease is unclear

D. Yes, because carriers of nuclear gene mutations that cause autosomal recessive mitochondrial diseases often manifest diabetes and deafness

E. Yes, because diabetes and deafness are frequent manifestations of mitochondrial diseases

View Answer

31. Answer E. (MN-144) Because mitochondrial DNA (mtDNA) mutations typically vary in heteroplasmic level and tissue distribution, matrilineal relatives may manifest different clinical symptoms (the mother’s diabetes) or even be asymptomatic (like the sister) in contrast to the proband.

32. If the genetic testing of a proband with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and her mother reveals that both have a pathogenic mtDNA variant, is an asymptomatic sister likely to transmit the mitochondrial DNA (mtDNA) mutation?

A. More information about the patient’s family history is needed before a definitive answer can be made

B. No. Because she is asymptomatic, she is unlikely to carry the mtDNA mutation

C. No, because the disease is due to a nuclear DNA defect

D. No, because the disease is transmitted through paternal mtDNA

E. Yes. Because she is likely to carry the mutation, she is likely to transmit it to her children

View Answer

32. Answer E. (MN-144) Although the sister shows no clinical manifestations of the mtDNA pathogenic variant, she is likely to be an asymptomatic carrier and likely to transmit the mutation to her children, because her mother and brother carry the mutation. The sister should be referred for genetic counseling and potential genetic testing. MtDNA is transmitted through the maternal lineage.

33. An 8-month-old boy presented at birth with neonatal pneumonia and hypotonia. He improved with antibiotics, but at age 3 months, he developed refractory partial seizures. At age 7 months, he was admitted for severe vomiting requiring use of a feeding tube and noted to have nephrotic syndrome. On examination, he was very hypotonic and unable to sit. He has occasional jerking movements in the left arm. Reflexes were present. Babinski signs were absent. Admission blood tests revealed severely elevated venous lactate 7.5 mM (normal 0.5-2.2) with elevated anion gap in the basic metabolic panel. Complete blood count, hepatic function panel, and prothrombin time were normal. Brain MRI showed symmetric increased T2 and FLAIR signal lesions in the bilateral globi pallidi and putamen. Family history is unremarkable. What is the most likely clinical diagnosis?

A. Alpers-Huttenlocher syndrome

B. Barth syndrome

C. Leigh syndrome

D. Myoclonus epilepsy with ragged-red fibers (MERF)

E. Pearson syndrome

View Answer

33. Answer C. (MN-144) The clinical presentation with psychomotor retardation, seizures, and hypotonia with basal ganglia lesions in a brain MRI scan indicate that the child has Leigh syndrome. Although the infantile-onset refractory seizures suggest Alpers-Huttenlocher syndrome, absence of hepatopathy makes this diagnosis unlikely. There is no indication of anemia to suggest Pearson syndrome. Barth syndrome is characterized by neutropenia, myopathy, cardiomyopathy, and stunted growth, which are not evident in this child. Although the patient has seizures, he does not display the core clinical manifestations of MERF, including myoclonus and ataxia. Moreover, the MRI lesions would be atypical of MERF (see Table 19.30.1 and Figure 19.33.1).

FIGURE 19.33.1 Characteristic brain magnetic resonance imaging abnormalities in mitochondrial encephalomyopathies. These T2-weighted images show bilateral putaminal hyperintensities in a child with cytochrome c oxidase–associated Leigh syndrome (top left panel), bilateral globus pallidus hyperintensities in a child with a familial Leigh syndrome phenotype (top right), a left posterior cerebral hyperintense stroke-like lesion in a child with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) (bottom left), and bilateral white matter hyperintensities in a child with Kearns-Sayre syndrome (KSS) (bottom right). (Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.)

34. Genetic testing for Leigh syndrome reveals two suspicious variants in PDSS2, which encodes an enzyme required for synthesis of coenzyme Q₁₀ (CoQ₁₀). Each of the parents carries one variant. Which of the following tests can be used to confirm that the PDSS2 variants are likely to be pathogenic?

A. Brain proton magnetic resonance spectroscopy to assess CSF and brain lactate

B. Muscle biopsy to measure CoQ₁₀ level and OxPhos enzyme activities

C. Serum coenzyme Q₁₀ level

D. Sequencing of mitochondrial DNA

E. Urine organic acids

View Answer

34. Answer B. (MN-144) Functional testing is necessary to assess pathogenicity of the PDSS2 variants. If pathogenic, the muscle biopsy is likely to reveal CoQ₁₀ deficiency with decreased activities of CoQ₁₀-dependent OxPhos enzyme complexes I + III and II + III (CoQ₁₀ shuttles electrons from complexes I and II to complex III). In contrast, isolated activities of complex I, II, and III will be normal. Serum or plasma level of CoQ₁₀ reflects dietary intake rather than endogenous CoQ₁₀ biosynthesis. It is important to diagnose CoQ₁₀ deficiency because the condition can be treated with high doses of CoQ₁₀ supplement.

35. A 15 month-old boy was normal in the first year of life. At age 6 months, he was able to babble, transfer objects from one hand to the other, and sit without support. At age 12 months, he was cruising but his mother noted that he had difficulty holding his head upright. He rapidly became weak, and at age 15 months, he was no longer able to sit, cruise, or hold up his head. He was admitted to a local hospital where he was noted to be weak with frog legs, unable to lift his head or limbs against gravity with a weak cry. He responded to pain. Reflexes were intact without corticospinal tract signs. Admission labs showed elevated venous lactate 3.9 mM (normal 0.5-2.2) and creatine kinase 1,290 U/L (normal 24-295). Other routine blood tests were normal. Family history is notable for parental consanguinity with no other relative affected with neuromuscular or mitochondrial diseases. Which of the following diagnostic tests would be most appropriate?

A. Acyl-carnitine profile

B. Muscle biopsy under general anesthesia

C. Skin biopsy to culture fibroblasts

D. Whole exome sequencing

E. Whole mitochondrial DNA sequencing

View Answer

35. Answer D. (MN-144) Because of parental consanguinity and absence of affected relatives in the maternal lineage, the child is likely to have an autosomal recessive disease, so whole exome sequencing or mitochondrial nuclear gene panel would be most appropriate. In this case, whole exome sequencing revealed a known homozygous TK2 pathogenic variant, indicating that the child has thymidine kinase 2 (TK2) deficiency, a form of mitochondrial DNA depletion syndrome that manifests predominantly as a myopathy.

36. If the child has TK2 deficiency, which of the following recommendations would be most appropriate?

A. Inform the parents about the diagnosis with genetic counseling and that they may wish to consider deoxynucleoside therapy through an FDA-approved mechanism

B. Inform the parents that the child has a progressive disease and no therapy exists

C. Inform the parents that the disease will improve spontaneously

D. Recommend allogeneic hematopoietic stem cell transplantation

E. Withhold the diagnosis from the family

View Answer

36. Answer A. (MN-144) TK2 deficiency is a progressive disease, and in the early childhood–onset forms, the disease has early mortality. Genetic counseling is important to help the parents understand the disease and risk of recurrence in future pregnancies. Patients and parents should be informed of FDA-approved clinical treatment trials, in which they may opt to participate.

37. Which of the following disorders is associated with somatic mosaicism for GNAQ mutations?

A. Hypomelanosis of Ito

B. Incontinentia pigmenti

C. Neurofibromatosis, type 1

D. Sturge-Weber syndrome

E. Tuberous sclerosis complex

View Answer

37. Answer D. (MN-145) Sturge-Weber syndrome (Encephalotrigeminal angiomatosis) is characterized by a nevus flammeus in the distribution of one or more divisions of the trigeminal nerve; it is typically unilateral, but bilateral cases do occur. There is an extensive capillary malformation of the surface of the brain ipsilateral to the cutaneous lesion, which is associated with progressive atrophy, calcification, and frequently intractable focal seizures. Biopsy of the affected skin demonstrates the presence of mutations in GNAQ, which are not detectable in the blood. Almost all patients with encephalotrigeminal angiomatosis carry somatic mosaic activating mutations in GNAQ gene.

38. A 3-month-old girl presents with increasingly frequent episodes of flexion of the trunk accompanied by extension of the arms, occurring in clusters of five or six spells at a time. Her skin appears normal. An echocardiogram demonstrates a lesion consistent with a rhabdomyoma. Which of the following is the most likely diagnosis in this child?

A. Hypomelanosis of Ito

B. Incontinentia pigmenti

C. Neurofibromatosis, type 1

D. Neurofibromatosis, type 2

E. Tuberous sclerosis complex

View Answer

38. Answer E. (MN-145) The vignette describes infantile (epileptic) spasms which are a classic presentation of tuberous sclerosis complex (TSC). Cutaneous lesions are not always apparent at this age. The presence of a cardiac rhabdomyoma is highly suggestive of TSC. In children with TSC, MRI of the brain classically demonstrates the presence of multiple tubers and subependymal nodules, confirming the clinical diagnosis.

39. A 10-year-old boy presents for evaluation of learning difficulties. His examination shows macrocephaly, bowing of the right tibia, and eight smooth-bordered café-au-lait patches, all greater than 2 cm in the greatest dimension, distributed over the trunk and limbs. Which of the following is the most likely diagnosis?

A. Hypomelanosis of Ito

B. Incontinentia pigmenti

C. Neurofibromatosis, type 1

D. Neurofibromatosis, type 2

E. Tuberous sclerosis complex

View Answer

39. Answer C. (MN-145) Neurofibromatosis type 1 (NF-1) is one of the most common neurocutaneous disorders. It frequently presents in children with learning disabilities and is commonly accompanied by macrocephaly. Pseudoarthrosis of the tibia is a classic, although relatively infrequent, manifestation. Diagnostic criteria require the presence of at least six café-au-lait patches, greater than 5 mm in the greatest dimension, before puberty.

40. What tests should be performed as routine surveillance in the management of patients with neurofibromatosis type 1 (NF-1)?

A. Dilated fundoscopic examination

B. EKG and echocardiography

C. Liver function testing

D. MRI brain

E. Choices A and D

View Answer

40. Answer E. (MN-145) Persons with NF-1 are at risk for gliomas involving the brain and optic nerve. A dilated funduscopic examination and surveillance brain MRIs are recommended, although there are no set time frames for monitoring. NF-1 does not typically have cardiac or hepatic involvement.

41. A girl was noted to have hypotonia at age 4 months but normal early gross motor development. She sat at 8 months, crawled at 9 months, and pulled up to stand and cruise at 12 months. She did not take steps until age 19 months; by age 25 months, she was taking a few steps without assistance and initiating walking. At age 19 months, she was evaluated by pediatric neurology for delayed motor milestones, hypotonia, and weakness. The bilateral weakness involved the axial and proximal limb muscles more than the distal muscles; the weakness was asymmetric with greater involvement of the right arm and left leg. Muscle bulk was reduced. Electromyography showed ongoing denervation with evidence of reinnervation in multiple muscles of legs and arms. Sensory nerve conduction studies were normal, whereas motor responses were of low amplitude but with normal conduction velocities. She received intensive physical therapy and aqua therapy and walked with assistance until age 9 years. What is the most likely diagnosis?

A. SMA type II

B. SMA type IIIA

C. SMA type IIIB

D. SMA type IV

E. Spinal muscular atrophy (SMA) type I

View Answer

41. Answer B. (MN-146) Most likely, molecular testing will support the clinical diagnosis of SMA and may demonstrate homozygous deletion of SMN1 and three copies of the SMN2 gene. The diagnosis in this case is SMA type IIIA, given the child was able to stand and walk with onset of motor symptoms before age 3 years (Table 19.41.1). These children often regress functionally and lose the ability to stand and walk after years. Her motor accomplishments, achieved in the era prior to current treatments and despite the early signs of hypotonia and weakness, underscore possible mitigating factors that can alter the natural history of SMA. Children with SMA type I are not able to sit unsupported, while the highest motor milestone for SMA type II is to sit unsupported, and those with SMA type IV achieve all motor milestones and become symptomatic after age 21 years.

TABLE 19.41.1 Clinical Classification of Spinal Muscular Atrophy^a

SMA Type	Other Names	Age at Onset	Life Span	Highest Motor Milestone Achieved	Other Features	Proportion of Total SMA (%)
Type IA	Prenatal, congenital SMA, Werdnig-Hoffmann disease	Prenatal	<6 mo	Mostly unable to achieve motor milestones	Severe weakness at birth Profound hypotonia Facial diplegia Areflexia Early respiratory failure Joint contractures	60^b
Type 1B, type IC	Werdnig-Hoffmann disease, severe SMA (“nonsitters”)	Type 1B (0-3 mo) Type IC (3-6 mo)	<2 y without respiratory support	Never sits supported	Weakness “Frog leg” posture, hypotonia Tongue fasciculations Hyporeflexia, areflexia Suck and swallow difficulties Respiratory failure	60
Type II	Intermediate SMA (“sitters”), Dubowitz disease	6-18 mo	>2 y ~70% alive at 25 y of age	Sits independently, never stands or walks	Proximal weakness, hypotonia Postural hand tremor Hyporeflexia Average or above average intellectual skills by adolescence Scoliosis	27
Type III	Kugelberg-Welander disease, mild SMA (“walkers”)	>18 mo Type IIIA (prior to 3 y) Type IIIB (after 3 y)	Almost normal	Stands and walks	May have hand tremor Resembles muscular dystrophy	12
Type IV	Adult SMA	>21 y	Normal	Normal		1
SMA, spinal muscular atrophy.
^aModified from Markowitz JA, Singh P, Darras BT. Spinal muscular atrophy: a clinical and research update. Pediatr Neurol. 2012;46:1-12. Copyright © 2012 Elsevier. With permission.
^bSMA types IA, IB, and IC collectively have a 60% proportion of total incidence of SMA.

42. Two male infants were diagnosed with spinal muscular atrophy (SMA) via the newborn screening program. Physical examination was normal in each infant, with normal muscle tone, strength, and 1 to 2+ reflexes. The diagnoses were confirmed; infant BR was found to have zero copies of SMN1 and two copies of SMN2, while infant TS was found to have zero copies of SMN1 and four copies of SMN2. Which of the following statements is most accurate about each infant’s prognosis?

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