Spastic Cerebral Palsy

In spastic CP, spasticity usually impairs mobility more than paresis. It causes slow, clumsy, and stiff movements that force affected children to walk with extended, unbending legs. The spasticity also precludes them from making normal isolated movements, such as tapping one foot while keeping the other one immobile. The usual signs of upper motor neuron injury – hyperactive deep tendon reflexes, clonus, and Babinski signs – accompany the spasticity.

As a result of the cerebral injury occurring prior to physical maturation, affected limbs experience growth arrest. Arms or legs, already weak and stiff, fail to grow to their proper length and muscle structure. The thumb and great-toe nail beds are also smaller on the abnormal side. A short Achilles tendon forces children to walk on the toes of that foot.

Diplegic CP (spastic diplegia) consists of bilateral symmetric paresis characteristically involving the legs more than the arms (Fig. 13-3). This CP variety usually forces children to hold their legs straight, drawn together (adducted), and crossed over each other (“scissored”). It also forces them to keep their feet and toes pointed downward (extended). When children begin to walk, this posture obligates them to stand on their toes with their legs brought closely together.

FIGURE 13-3 A, Spastic diplegia in this 10-year-old girl with low-normal intelligence causes straightening, inturning, and adduction of her legs; a tiptoe stance; and scissor-like gait. Her uncoordinated, awkward arm movements (posturing) also reflect her cerebral palsy. B, Another patient with spastic diplegia, an 18-year-old college engineering student, has typical increased muscle tone, adduction of his legs, and “toe-walking.” He also has a subtle, sustained right-sided Babinski sign.

Neurologists usually find this variety of CP in children who have been born prematurely and have sustained periventricular leukomalacia. Because the cerebral cortex has escaped major damage, both epilepsy and mental retardation occur in a relatively small proportion (about 25%) of these children. Moreover, many of them have no cognitive impairment.

Hemiplegic CP consists of spastic hemiparesis that typically affects the face and arm more than the leg (Fig. 13-4). The motor impairment of children and adults with hemiplegic CP resembles adults with strokes from middle cerebral artery occlusions, but they differ in three respects. While normal infants younger than 2 year old do not show hand preference, infants with hemiplegic CP show premature handedness. For example, unequivocal right-handedness in infants younger than 1 year old may mean that the left hand, if not the entire left arm, is paretic. Because left hemisphere injury during the perinatal period forces the right hemisphere to assume dominance, children and adults with congenital right hemiparesis maintain dominance in the right hemisphere and have no language impairment (aphasia). Their lack of aphasia accompanying right hemiparesis contrasts starkly with the results of a left middle cerebral artery stroke, where aphasia is often the most devastating result of damage to the mature left-sided perisylvian language arc. Finally, older children and adults with hemiplegic CP show growth arrest of the affected limbs. Compared to their normal limbs, affected ones are shorter, less muscular, and weaker.

FIGURE 13-4 Hemiparetic since birth, this 28-year-old woman with normal intelligence holds her spastic and weak arm, wrist, and fingers in a flexed posture. Growth arrest of her right hand has led to shortened fingers and a less broad thumb nail bed. Similarly, her right leg, especially the heel (Achilles) tendon, is short. The growth arrest causes her to walk on her right toes and circumduct that leg. Her posture and gait are similar to that of adults after a left middle cerebral artery infarction (see Figs. 2-3 to 2-5).

Quadriplegic CP is paresis of all four limbs, usually accompanied by pseudobulbar palsy. Extensive cerebral damage, often from anoxia during delivery, usually underlies this CP variety. In contrast, cervical spinal cord birth injury causes quadriplegia without cerebral damage; however, neurologists do not include this condition within a strict definition of CP.

As a general rule, the underlying cerebral damage in quadriplegic CP is worse than in spastic hemiparesis and much worse than in spastic diplegia. Thus, epilepsy and mental retardation occur more frequently in quadriplegic than in hemiplegic CP, and occur much more frequently than in diplegic CP. Physical and occupational therapy, bracing, and orthotics may all help these children. Neurologists often reduce spasticity by recommending surgery that transposes or lengthens tendons; prescribing oral antispasticity medications, such as baclofen and tizanidine; and administering intramuscular injections of botulinum toxin (see Chapter 18). However, epilepsy in these children resists treatment. Seizure control often requires two or more antiepileptic drugs (AEDs), which in turn may produce undesirable side effects, particularly sedation, cognitive impairments, paradoxical hyperactivity, and other behavioral disturbances.

Extrapyramidal Cerebral Palsy

Involuntary writhing movements (athetosis) of the face, tongue, hands, and feet punctuated by jerking movements (chorea) of the trunk, arms, and legs – embraced by the term choreoathetosis – define extrapyramidal CP (Fig. 13-5). Although choreoathetosis may remain subtle throughout a patient’s lifetime, it often interferes with fine hand movements, walking, and even sitting. Another manifestation – involuntary larynx, pharynx, and diaphragm movements – may lead to incomprehensible dysarthria.

FIGURE 13-5 The slow sinuous movements (athetosis) of her wrists, hands, and fingers, present since age 3 years, signify that this 13-year-old girl has congenital cerebral palsy-induced choreoathetosis. The athetosis intermittently forces her hands into flexion at the wrist and her fingers into extension with overlapping positions.

Physicians should distinguish choreoathetotic CP from dopamine-responsive dystonia, which produces similar involuntary movements in young children (see Chapter 18). In short, unlike CP, dopamine-responsive dystonia is progressive (albeit slowly), fluctuating in a characteristic diurnal pattern at its onset, and, most important, responsive to small doses of levodopa (L-dopa). Despite the differences, the clinical similarity can be so great that many neurologists insist on a therapeutic trial of L-dopa before accepting a diagnosis of choreoathetotic CP.

Neurologists usually attribute choreoathetotic CP to combinations of low birth weight, anoxia, and neonatal hyperbilirubinemia damaging the basal ganglia (kernicterus). In addition, because these insults also damage the auditory pathways, hearing impairment frequently complicates the clinical picture.

Unlike spastic CP, choreoathetosis may not become clinically apparent until children are 2–4 years old. By that time, the children should have acquired steady walking and fine motor skills, but the involuntary movements have probably delayed or prevented them from acquiring these and other milestones. Similarly, hearing impairment may remain unnoticed until 1 year of age, when the rudiments of language should commence.

In contrast to the burden of these impairments, probably because kernicterus tends to spare the cerebral cortex, choreoathetotic CP is associated with a relatively low – 10% – incidence of epilepsy and mental retardation. A superficial academic or medical evaluation may underrate children with choreoathetotic CP. Despite pronounced physical impediments, many CP patients are able to complete college. Thus, both choreoathetotic and diplegic CP qualify, along with polio, ALS, and several other neurologic disorders, as physically devastating conditions that allow normal cognition.

Most systemic medications provide little relief from the choreoathetosis. Although deep-brain stimulation reduces athetosis, the procedure remains risky and is not yet perfected for this situation.

Finally, mixed-form CP – combinations of spastic paraparesis and choreoathetosis – account for about 15% of cases. They reflect the most extensive central nervous system (CNS) injury, which is naturally associated with the highest incidence of epilepsy and mental retardation – 95%.

Upper Neural Tube Closure Defects

In an extreme example of a neural tube defect, the entire upper end of the neural tube fails to form. In this case, anencephaly, the fetus lacks a brain or has one consumed by a major malformation.

In an encephalocele, a skin-covered malformed brain, covered only by its meninges and cerebrospinal fluid (CSF), protrudes through an occipital skull defect. In a similar malformation, the Dandy–Walker syndrome, the posterior portion of the upper neural tube fails to mature. Posterior brain structures, particularly the cerebellar vermis, remain at an early embryonic stage. Expanding into the empty space, the fourth ventricle forms a large cystic structure.

A group of malformations, collectively termed the Arnold–Chiari malformation, constitute a variety of upper neural tube closure defects. Usually not obvious by external appearances, the Arnold–Chiari malformation consists of downward displacement of the lower portion of the medulla and cerebellum through the foramen magnum (Figs 13-6 and 20-22). In older children and adults, who may previously have escaped detection, this malformation may produce headaches (especially when bending), bulbar palsy, and neck pain. Patients with compression of the medulla or cerebellum require “unroofing” of the upper cervical spine and occipital portion of the skull.

In many patients, these congenital abnormalities lead to mental retardation and, because of aqueductal stenosis, obstructive hydrocephalus. Those who develop hydrocephalus typically require neurosurgical insertion of ventriculoperitoneal shunt. In addition, these upper neural tube defects are associated with comparable lower neural tube defects, such as meningomyelocele (see later).

Lower Neural Tube Closure Defects

In the most benign variety, spina bifida occulta, lumbar vertebrae simply fail to fuse. With both the underlying spinal cord and cauda equina remaining intact, this disorder usually remains asymptomatic.

In meningocele, a more serious variety, the meninges and skin protrude through a lumbosacral spine defect to form a large, CSF-filled bulge. Although this condition may remain asymptomatic, it frequently causes symptoms originating in dysfunction of the lumbar and sacral nerves, such as leg weakness, gait impairment, and bladder-emptying problems. Thus progressive hydronephrosis often complicates the deficit. Meningomyelocele (myelomeningocele), which occurs far more frequently than meningocele, is the most serious variety. It consists of a tangle of a rudimentary lower spinal cord, lumbar and sacral nerve roots, and meninges protruding into a saclike structure overlying the lumbosacral spine (Fig. 13-7). The disrupted nerve tissue causes paraparesis, areflexia, and incontinence. In addition, hydrocephalus and other brain abnormalities are comorbid in about 25% of cases. Approximately 10% of infants born with meningomyelocele die from the defect.

FIGURE 13-7 The meningomyelocele of this newborn infant has a typical broad-based, loose, translucent sac of thin, friable skin arising from the lumbar area. It contains rudiments of a spinal cord and lumbosacral nerves. Its surface weeps a mixture of serum and cerebrospinal fluid. The infant’s legs, lacking innervation, remain weak, flaccid, and areflexic. Similarly, the bladder, also lacking innervation, distends.

Meningoceles and meningomyeloceles also deprive the lower CNS of the multiple tissue barriers – intact skin, vertebrae, and meninges – that normally shield it from the environment. To prevent bacteria from entering the CSF through the defective meninges and causing meningitis, infants with meningoceles and more serious varieties must undergo neurosurgery. Therefore, neurosurgeons usually repair these defects during the infant’s first week of life not to correct the paraplegia but to prevent meningitis. Most survivors of meningomyeloceles eventually require ventricular shunting. In addition, as affected children physically mature, they often require urinary and fecal diversion procedures, revision of their ventricular shunt, and further surgery on the spine. Some neurosurgeons’ recent publications have described in utero or “prenatal” meningomyelocele surgery that reduces the risk of death and need for shunting, and may improve mental and motor function.

Causes

Some studies have implicated genetic factors. For example, the risk of a neural tube defect occurring in a sibling of an affected child is 5%. With two affected children, the risk for a third increases to 10%. Similarly, a frequent occurrence of neural tube defects in individuals with three copies of chromosome 13 (trisomy 13) or chromosome 18 (trisomy 18) suggests a genetic basis.

Other studies have attributed neural tube defects to carbamazepine and valproate, folic acid deficiency, autoantibodies to folate receptors, radiation, and various toxins, including potato blight. Although there is no complete answer, the tendency of AEDs to reduce serum folate level and thus raise homocysteine levels may explain their relationship to neural tube defects.

Prenatal testing may provide early warning of a meningomyelocele or other neural tube defect. For example, excessive concentrations of α-fetoprotein in amniotic fluid and maternal serum indicate a neural tube defect. Fetal ultrasound examination, a complementary test, may show neural tube defects as well as other congenital malformations.

Women who eat adequate amounts of fruits and vegetables, which contain folic acids and other nutrients, reduce the risk of neural tube defects by 70%. Moreover, studies have found that a folic acid intake of 5 mg daily before conception and during the first month of pregnancy reduces the incidence of neural tube defects by 85%. Based on this evidence, the US Food and Drug Administration has ordered manufacturers to add folic acid to pasta, breakfast cereals, and corn meal. In addition, neurologists avoid prescribing carbamazepine or valproate to women who are pregnant or planning to conceive.

Tuberous Sclerosis

Tuberous sclerosis usually causes conspicuous smooth and firm nodules, facial angiofibromas (adenoma sebaceum), on the malar surface of the face (Fig. 13-8), but this illness-defining skin lesion usually fails to appear until adolescence. However, during infancy and childhood, the skin shows several other characteristics: subtle hypopigmented macules (ash-leaf spots); shagreen patches, which are leathery, scaly areas, on the lower trunk and buttocks; and periungual fibromas of the fingers.

FIGURE 13-8 Adenoma sebaceum (facial angiofibromas), the cutaneous component of tuberous sclerosis, consists of nodules several millimeters in diameter, firm, and uniformly pale. They spread over the malar surface of the face. Although adenoma sebaceum may resemble acne, acne pimples have a liquid (pus) center surrounded by inflammation. Also acne pimples accumulate on the trunk as well as the face.

The classic triad of tuberous sclerosis stigmata, which actually occurs in total in only one-third of affected children, consists of epilepsy, mental retardation, and the angiofibromas. Almost any variety of seizure may be a manifestation of the epilepsy. Refractory epilepsy, which commonly complicates the illness, portends serious mental retardation. In children with tuberous sclerosis the retardation may worsen, eventually reaching the severity of dementia. Although mental retardation and epilepsy force many children into institutions, some have a benign form that causes only minimal cognitive impairment and readily controlled epilepsy.

In another important aspect of the illness, some tuberous sclerosis children display autistic behavior. Thus, neurologists consider tuberous sclerosis as one of several neurologic causes of autism-like symptoms (Box 13-1).

The CNS counterpart of the skin lesions consists of cerebral tubers that are potato-like brain nodules, 1–3 cm in diameter. The tubers frequently grow to compress and irritate the surrounding cerebral cortex, thus producing the epilepsy and progressive cognitive impairment. Although usually benign, tubers sometimes undergo malignant transformation. In addition, retinal, renal, and cardiac tumors develop.

Especially because tubers tend to calcify, computed tomography (CT) and sometimes even plain skull X-rays identify them; however, magnetic resonance imaging (MRI) is the better test to detect and monitor tubers. Removing the tubers may reduce intracranial pressure, relieve obstructive hydrocephalus, excise a malignancy, and reduce seizure frequency, but neurosurgery is usually not feasible when tubers are numerous and deeply situated. Emerging forms of chemotherapy include everolimus, which inhibits a gene product and thus reduces the size of the tubers.

The majority of tuberous sclerosis cases (70%) occur spontaneously. Nevertheless, whether inherited in autosomal dominant pattern or arising sporadically, the disorder is attributable to mutations in either of two tumor suppressor genes: tuberous sclerosis complex (TSC 1) on chromosome 9, and TSC 2 on chromosome 16.

Neurofibromatosis

Commonly occurring neurofibromatosis, neurofibromatosis type 1 (NF1) – previously called von Recklinghausen disease or “peripheral-type” neurofibromatosis – also causes a clinical triad: multiple café-au-lait spots, neurofibromas, and Lisch nodules.

Café-au-lait spots, the signature of neurofibromatosis, are areas of uniformly light brown, oval, and flat skin (Fig. 13-9). Although individual café-au-lait spots are found in at least 10% of normal individuals, the presence of more than six of them, each larger than 5 mm in children and 1.5 cm in adults, strongly suggests a diagnosis of neurofibromatosis. Freckling in the axilla and groin – two skin surfaces sheltered from sun exposure – often accompanies NF1-related café-au-lait spots.

FIGURE 13-9 Café-au-lait spots are flat, light-brown skin lesions. The diagnosis of neurofibromatosis requires six or more lesions, each measuring at least 1.5 cm in adults and 0.5 cm in children.

Neurofibromas consist of soft, palpable, subcutaneous growths, each a few millimeters to several centimeters in size, that emerge along peripheral nerves (Figs 13-10 and 13-11). They can also grow from nerve roots within the spinal canal and compress the spinal cord or cauda equina. They occasionally reach grotesque proportions or induce extraordinary growth of an affected limb. However, the famous nineteenth-century “elephant man,” Joseph Merrick, commonly cited as an example of neurofibromatosis, probably suffered from a related condition, Proteus syndrome.

FIGURE 13-10 Neurofibromas often grow to several centimeters of disfiguring protuberances on the face.

FIGURE 13-11 Neurofibromas are often subtle, multiple, subcutaneous, soft, and typically less than 0.5 cm in size.

Lisch nodules, the least obvious but most common manifestation, are multiple, asymptomatic, macroscopic, yellow to brown nodules (melanocytic hamartomas) situated on the iris (Fig. 13-12). Although a slit-lamp examination may be required to detect Lisch nodules and then differentiate them from inconsequential pigment collections, they are almost pathognomonic of the disorder.

FIGURE 13-12 Lisch nodules, virtually pathognomonic of neurofibromatosis type 1, are pigmented aggregations on the iris that are often visible with the unaided eye.

Excision of neurofibromas, except for those compressing the spinal cord or other vital structures, is impractical because NF1 involves innumerable peripheral nerves. However, laser therapy can blanch café-au-lait spots.

Although its cutaneous manifestations probably represent the most conspicuous sign of any neurocutaneous disorder, NF1 is not entirely peripheral. As with other disorders in this group, NF1 induces intracerebral tumors, particularly optic nerve gliomas, as well as intraspinal neurofibromas.

NF1 has a close association with attention deficit hyperactivity disorder (ADHD) and learning disabilities. Some tests detect sustained attention difficulties and learning disabilities in the majority of NF1 children. The IQ of NF1 children is about 5–10 points lower than average.

Despite those comorbidities, NF1 children and adults do not greatly differ from the general population. Only 4–8% are mentally retarded and psychosis occurs at no greater frequency than in the general population. Moreover, unlike the increased prevalence of autistic behavior in tuberous sclerosis, such behavior is not associated with either variety of NF.

Approximately 50% of patients inherit NF1 in an autosomal dominant pattern, usually because of a gene situated on chromosome 17. In the remainder of patients, NF1 arises sporadically. (The mnemonic for recalling the abnormal chromosome is “von Recklinghausen contains 17 letters.”) The incidence of NF1, like Down syndrome, increases with advanced paternal age.

Neurofibromatosis type 2 (NF2), which occurs only 10% as frequently as NF1, is an almost completely different disorder. NF2, also called familial acoustic neuroma or “central-type” neurofibromatosis, is characterized by bilateral acoustic neuromas (vestibular schwannomas) that steadily impair hearing until deafness ensues. It may induce a few neurofibromas and large, pale café-au-lait spots, but its hallmark remains the acoustic neuromas (see Fig. 20-27). In fact, NF2 is usually unrecognized until acoustic neuromas are discovered.

This neurocutaneous disorder is associated with two neoplastic complications, acoustic neuroma and meningiomas. Gadolinium-enhanced MRIs can readily show these complications. Although neurosurgeons can remove acoustic neuroma, sometimes they must sacrifice the adjacent acoustic nerve. Alternatively, pinpoint radiation or laser treatment may be able to burn away the tumor while sparing both nerves.

Unlike NF1, NF2 does not cause behavioral, learning, or cognitive impairments. Also, NF2 is inherited on chromosome 22 and, in the vast majority of cases, in an autosomal dominant pattern. (The mnemonic for its inheritance is “Chromosome 22 carries the NF2 mutation.”)

Sturge–Weber Syndrome

Sturge–Weber syndrome, also known as encephalo–trigeminal angiomatosis, consists simply of angioma of both the face (nevus flammeus) and underlying cerebral hemisphere. Unlike other neurocutaneous disorders, Sturge–Weber syndrome is an embryonal developmental disorder rather than a genetic disorder. Thus, it appears sporadically and does not strike multiple family members.

The facial angioma consists of a deep red discoloration (“port-wine stain”) in the distribution of one or more divisions of the trigeminal nerve (Fig. 13-13). Its extent does not correlate with the size of the cerebral abnormality. Clinicians must distinguish it from completely benign, more common skin abnormalities, such as small forehead angiomas (“strawberry nevi”). Also, port-wine stains, even in the trigeminal nerve distribution, are associated with Sturge–Weber syndrome in only 8% of cases. Whether or not facial angiomas are a manifestation of Sturge–Weber syndrome, laser therapy can bleach them.

FIGURE 13-13 The cutaneous angioma (port-wine stain) of Sturge–Weber syndrome encompasses one or more divisions of the distribution of the trigeminal nerve (see Fig. 4-12). The commonest sites are the anterior scalp, forehead, and upper eyelid, i.e., the first division of the trigeminal nerve. One-third of patients have bilateral involvement.

The CNS component of Sturge–Weber syndrome consists of atrophic, calcified layers of cerebral cortex in the hemisphere underlying the facial vascular malformation. As with tubers, plain skull X-rays, CT, and MRI readily reveal the cerebral abnormality, but MRI most readily shows its extent.

Most Sturge–Weber children have focal motor, complex partial, or other seizures that are often refractory to AEDs. Seizures in the first year of life portend mental retardation. Whether or not they have seizures, Sturge–Weber children tend to have learning disabilities and behavioral disturbances. Depending on the lesion site, they also have focal, lateralized neurologic deficits, such as homonymous hemianopsia and spastic hemiparesis. When present, these deficits arise contralateral to the port-wine stain.

In Sturge–Weber syndrome, as in other neurocutaneous disorders, physical and cognitive deficits often worsen. Neurologists usually attribute the deterioration to increasing sclerosis surrounding the cerebral lesions.

Ataxia-Telangiectasia

The cutaneous component of ataxia-telangiectasia consists of aggregations of small, dilated vessels (telangiectasia) on the conjunctiva, bridge of the nose, and cheeks. Neurologic manifestations become evident in children aged 3–5 years when degeneration of the cerebellar vermis – the neurologic component – causes a progressively severe gait ataxia. Subsequently, patients develop cognitive impairment.

Unlike most other neurocutaneous disorders, ataxia-telangiectasia is inherited in a recessive pattern. It is attributable to a genetic abnormality on chromosome 11 that interferes with DNA repair.

Another, almost unique feature of ataxia-telangiectasia is its consistent association with immunodeficiency. Children with ataxia-telangiectasia have both cellular immunity impairment and complete or nearly complete deficiency of immunoglobulin, IgA or IgE. Their immunodeficiency leads to severe sinus and respiratory tract infections, which may represent their first symptoms. It also allows the development of lymphomas and other neoplasms. (The same association of immunodeficiency with lymphoma also occurs in acquired immunodeficiency syndrome [AIDS] and immunosuppression for organ transplantation.)

Autosomal Chromosomal Disorders

Prader–Willi and Angelman Syndromes (Chromosome 15)

Approximately 75% of Prader–Willi syndrome cases are paternally inherited – the rest are sporadic. Children with this disorder have mental retardation and behavior problems, but their identifying symptoms consist of hyperphagia and resultant obesity. However, to say that children with Prader–Willi syndrome have hyperphagia understates their behavior. They eat relentlessly and sometimes aggressively, with no regard for their bodily needs. They eat barely edible food. They grab meals from family members’ plates, break refrigerator locks, and rummage through garbage cans. Whether or not the incessant eating represents a compulsion, obsessive-compulsive symptoms are a manifestation of the illness.

Beyond their striking obesity and other physical anomalies (Fig. 13-14), Prader–Willi children have low normal to below normal IQ. They comprise about 1% of children with mental retardation. They also tend toward affective disorders that may, after adolescence, be accompanied by psychotic features. The severity of the obesity does not correlate with either the nature or severity of the neuropsychiatric disturbances, but, like obesity in general, it carries the comorbidities of hypoventilation, hypersomnia, hypertension, diabetes, stroke, and osteoporosis.

FIGURE 13-14 An 8-year-old boy with Prader–Willi syndrome shows the distinctive obesity, which can reach grotesque proportions, small penis and testicles, short stature, small hands, and short feet. Girls with the syndrome, who also have obesity and hypogonadism, usually have small labia majora and no labia minora. Because both boys and girls with Prader–Willi syndrome also have intellectual disabilities, neurologists remember the manifestations of the illness as the “three Hs”: hyperphagia, hypomentia, and hypogonadism.

The immediate cause of the morbid obesity, hyperphagia, does not respond to medicines or behavioral therapy. Currently available bariatric surgical procedures have produced little benefit. However, some studies found that recombinant growth hormone injections increase height and muscle mass, and noninvasive ventilation reduces hypoventilation.

In contrast to Prader–Willi children, those carrying a very closely related microdeletion on the same chromosome show a completely different phenotype – Angelman syndrome. This disorder, which is usually inherited from the mother, comprises severe mental retardation with prominent deficiency of language skills; epilepsy; microcephaly; stereotypies (involuntary repetitive, patterned, and purposeless movements); jerky-ataxic voluntary movements and ataxic gait; a smiling face; and paroxysms of unprovoked laughter. The jerky movements and superficially happy appearance have given rise to the term “happy puppet syndrome.” Affected adults generally continue to display the same laughter, require assistance with their daily activities, and suffer from refractory epilepsy.

Until genetic testing is completed, girls with Angelman syndrome may appear to have Rett syndrome because of their mental retardation, language impairment, microcephaly, and involuntary movements (see later). They may also appear to have idiopathic autism because of their language impairment, inappropriate behavior and stereotypies; however, their preserved social skills weigh against that diagnosis.

Down Syndrome (Trisomy 21)

At 1 in 600 births, Down syndrome is the most frequently occurring disorder in this group. Affected children have distinctive physical features (Fig. 13-15) and mild to moderate mental retardation, with a median IQ of 40–50. They are also plagued by hearing loss, congenital cardiac anomalies, and gastrointestinal disease, and, as adults, the development of hypothyroidism and leukemia.

FIGURE 13-15 Children with Down syndrome are short with low-set ears that have small lobes. Their eyes’ epicanthal folds are widened and the lids appear to slant upward – thus the outdated term “mongolism.” The bridge of the nose is depressed. The tongue, characteristically large, tends to protrude over a slack jaw. Children’s palms are broad with a single midline crease, and their fingers are short and stubby.

Another, almost uniform complication is that, by age 50 years, Down syndrome leads to an Alzheimer-like dementia (see Chapter 7). In fact, one theory holds that both Down syndrome and Alzheimer disease result from a common genetic abnormality on chromosome 21.

Down syndrome children retain social skills that partly compensate for their mental retardation. Although they do not have psychotic or autistic behavior, they occasionally have behavior that fulfills criteria for ADHD. Beginning when they are young adults, depression becomes comorbid. Curiously, severely affected children may have orofacial dyskinesias unrelated to neuroleptic exposure.

The cause in most children is chromosome 21 trisomy, but a translocation of that chromosome causes some cases. Nevertheless, because all these patients share the same phenotype, clinicians still call the translocation variety “trisomy 21.”

The incidence of Down syndrome correlates with increasing maternal age (especially after 40 years), but babies born to very young mothers also have an increased incidence of the disorder. Its incidence also increases, but not to the same degree, with increasing paternal age. Because a chromosome analysis of amniotic fluid cells can identify a fetus with Down syndrome, obstetricians urge women older than 40 years to undergo amniocentesis. Even though it is obviously genetic, neurologists do not classify Down syndrome as an inherited disorder of mental retardation because it is not transmitted from generation to generation. (This distinction allows neurologists to state that fragile X syndrome [see later] is the most common form of inherited mental retardation.)

Williams Syndrome (Chromosome 7)

Lifelong neuropsychologic oddities and a distinctive, “elfin” facial appearance (Fig. 13-16) characterize Williams syndrome. Children with this disorder are slow to acquire motor milestones, have strikingly poor sense of visuospatial relationships, and cannot perform construction or copying tasks. The majority have ADHD, phobias, or both. In general, they perform in the mild to moderate intellectual disability range on testing, with an average IQ of approximately 65 points. As adults, Williams syndrome individuals rarely find steady employment and develop memory impairment at a greater rate than controls.

FIGURE 13-16 This 10-year-old girl shows the characteristic elfin (elf-like) appearance of Williams syndrome. She is short. Her forehead is broad and her cheeks are prominent. Her nose has a flat bridge, and its nostrils are full and turned slightly upward. Her teeth are hypoplastic and widely spaced.

On the other hand, they have no gross physical neurologic abnormalities, such as microcephaly, stereotypies, or epilepsy. However, the disorder leads to defects in the elastic qualities of the skin and congenital abnormalities at the root of the aorta, which cause supravalular aortic stenosis.

Most strikingly, the disorder paradoxically seems to enhance certain neuropsychologic functions. For example, remarkably, and so far inexplicably, affected individuals frequently possess unusual talents in music, many showing perfect pitch. Their conversations, although lacking substance and often one-sided, are garrulous and bubbly. Neurologists often call their personal interactions “hypersocial.”

Although some Williams syndrome cases have followed an autosomal dominant inheritance pattern, spontaneous mutations have led to most cases. The genetic abnormality consists of a microdeletion in chromosome 7.

Velocardiofacial (VCF) Syndrome (Chromosome 22)

Neurologists and psychiatrists have come to recognize VCF, along with Prader–Willi, and Williams, and Lesch–Nyhan, as genetic disorders with distinctive, relatively consistent neuropsychiatric manifestations. As its name implies, VCF consists primarily of abnormalities, in various combinations and degrees of severity, of the soft palate (velum palatinum [Latin, velum, veil]), cardiac system, and face.

A cleft palate or velopharyngeal dysfunction is the most obvious characteristic. The deformity causes palate insufficiency that gives the child’s voice a nasal tone. Hearing the nasality, physicians may further suspect the diagnosis by inspection of the palate at rest and during voluntary retraction. In addition, VCF children may have external ear malformations that cause hearing impairment and worsen the speech impediment. The facial appearance of children with VCF has several characteristic, if not pathognomonic, features (Fig. 13-17).

FIGURE 13-17 A, The face of children with velocardiofacial syndrome typically appears long, tapering to a small lower jaw (micrognathia). A tubular nose with a broad tip and small nasal alae, and deformed ears are also typical. B, The cleft palate, another hallmark of the disorder, may not be as overt as in this figure.

Children’s cardiac anomalies, which are congenital, include ventricular septal defects and abnormalities in the pulmonary artery and aorta. They often necessitate open-heart surgery.

Although VCF’s primary components are physical, its neuropsychiatric comorbidities are more likely to determine the child’s life course. Many VCF patients are severely retarded. They score in the borderline to mildly impaired range on IQ testing, e.g., in the 70s. Most importantly, schizophrenia and major depression emerge as many VCF children mature. For example, major depression occurs in up to approximately 40% and psychotic symptoms, which are usually indistinguishable from schizophrenia, occur in up to approximately 30% of adult VCF patients.

VCF, which occurs in 1/3000 children, is an autosomal dominant genetic disorder that stems from microdeletion in chromosome 22. However, with 75% or more cases occurring sporadically, VCF is inherited in only a minority of cases.

Its neuropsychiatric components offer clues to the genetic basis of schizophrenia. The VCF mutation and several others associated with schizophrenia localize to the same region on chromosome 22. Of all of them, the VCF mutation is the statistically most powerful genetic risk factor for schizophrenia. Moreover, unlike many of the other mutations associated with schizophrenia, the VCF mutation is not confined to a single ethnic population.

Sex-Linked Chromosomal Disorders

Fragile X Syndrome

The fragile X syndrome, like many other genetic disorders, consists of mental retardation, behavioral disturbances, and distinctive nonneurologic physical stigmata (Fig. 13-18). About 70% of boys who inherit the entire or “full” mutation have moderate to severe mental retardation. In contrast, most females carrying the full mutation – typically the mother and sisters of affected boys – show none of the syndrome’s physical stigmata. However, about one-third of them have borderline IQs and one-quarter have IQs of 70 or less.

FIGURE 13-18 This fragile X syndrome boy, with the full mutation resulting in an IQ of 65, has the syndrome’s typical features. He has a prominent forehead and jaw; long, thin face; and large, low-set, “seashell-shaped” ears. Although his penis will remain normal in size for his age, his testicles will grow during puberty to a remarkably large size – two- to threefold greater in volume than normal. This macro-orchidism occurs in almost all fragile X syndrome boys and represents the single most consistent physical anomaly.

Fragile X syndrome boys display strikingly abnormal behavior, including stereotypies, particularly flapping or wringing of their hands. Many bite their fingers or hands and engage in other self-injurious behavior. Mostly because of these behaviors, fragile X is the single most common monogenetic cause of autistic spectrum disorders. About 15–30% of fragile X boys have autism. They may have ADHD, anxiety, and other psychiatric disorders, but the mental retardation usually overwhelms those manifestations.

The mutation (FMR1) consists of excessive repetitions of the CGG trinucleotide in the X chromosome.*

Genetic testing can easily detect the mutation in the blood and, during prenatal screening, in amniotic fluid cells. Some neurologists have stated that all children with autism spectrum disorders and mental retardation should undergo genetic testing for fragile X. As with other excessive trinucleotide repeat disorders, the mutation tends to increase in size and its symptoms emerge at an earlier age (anticipation) and are more pronounced in successive generations.

Compared to the normal complement of 5–44 CGG repeats, boys with the full mutation typically have 200 or more repeats. In other words, boys with fragile X syndrome have 200 or more CGG repeats. Those with only 55–200 have the premutation, which leads to a muted version of the disorder.

Occurring in about 1 in 1200 males and half as frequently in females, and responsible for as many as 10% of all cases of mental retardation, fragile X syndrome ranks as the most common cause of inherited mental retardation. Unlike the inheritance in Down syndrome, fragile X syndrome parents regularly and predictably transmit the mutation to one or more of their children. Thus, neurologists often find that the child presenting for fragile X evaluation has a male relative with mild, if not overt, mental retardation.

Unlike boys with the full mutation, those with the premutation (55–200 CGG repeats) lack overt intellectual impairment and physical stigmata. Nevertheless, the premutation has several ramifications. The number of repeats in ova may expand from premutation levels to greater than 200. Thus, an asymptomatic mother who carries the premutation may have children with the syndrome. However, sperm can carry only the premutation. Thus, fathers can transmit only the premutation to their daughters. The premutation also induces developmental problems, including ADHD, depression, and features of autism spectrum disorders. Sometimes the premutation may produce manifestations only after individuals reach 40 years of age. For example, women with the premutation undergo premature ovarian failure and menopause. Also, men with the premutation may develop cerebellar dysfunction (gait ataxia and intention tremor), cognitive impairment, mood disorders, and a wide variety of other psychiatric conditions.

Rett Syndrome

Generally restricted to girls, Rett syndrome symptoms emerge 6–18 months after an initial normal birth and development. Then girls with Rett syndrome regress in virtually all phases of psychomotor development. Over the next several years, they lose their language skills, ability to walk, other learned motor activities, and intellectual abilities. They often deteriorate to a state of profound mental retardation. Moreover, 60–90% of them develop epilepsy, beginning on average at the age of 3 years.

Rett syndrome girls display two striking neurologic abnormalities: stereotypies and acquired microcephaly (Fig. 13-19). Their stereotypies consist of incessant hand movements, particularly hand wringing, hair pulling, clapping, or flapping. As these stereotypies progress, Rett children often lose hand function. In addition, most of them also have stereotypies that do not involve the hands, such as bruxism, mouthing, and body twisting. Stereotypies usually first appear at about 18 months of age. Although different stereotypies emerge, the first one that appears persists through life.

FIGURE 13-19 A 6-year-old girl with Rett syndrome, displaying stereotypies, incessantly moves her hands as though she were washing or clapping. In addition she pulls her hair and has bruxism. In another hallmark of the disease, her head circumference is only 48 cm, which would be normal for a 3-year-old girl, but 2 standard deviations below the mean for her age (51 cm). Because her head circumference had been normal during her first 2–3 years, neurologists determined that she had developed acquired microcephaly. She has also progressively lost her language ability and now cannot speak in a meaningful manner. When her symptoms first appeared, her pediatrician understandably suggested the erroneous diagnosis of autism.

Head growth follows a normal trajectory from birth to about 6 months, but then it decelerates while relatively normal body growth continues. When the head’s size becomes relatively small for the body, neurologists diagnose acquired microcephaly. It contrasts with congenital microcephaly, as found in congenital rubella infections, where the head is small at birth.

Rett syndrome is attributable in about 85% of cases to a mutation in a gene – MECP2 – on the X chromosome. The mutation is presumably lethal to a male fetus, but a male fetus will rarely inherit an attenuated variant of the mutation and survive with a forme fruste of the disorder.

In typical Rett syndrome cases, loss of language, prevalence of epilepsy, and stereotypies mimic autism and Angelman syndrome; however, Rett syndrome children, for practical purposes, are only girls, have microcephaly, and regress in their motor skills. Also, in contrast to children with the common storage diseases, Rett syndrome children do not have either organomegaly or retinal abnormalities.

Turner Syndrome (XO)

Individuals with Turner syndrome have a mutation in or, more usually, absence of one of their sex chromosomes. With a complement of only 45 fully functioning chromosomes, these individuals are usually described as having an “XO” chromosome pattern. From infancy, they are outwardly phenotypically female, but with readily identifiable dysmorphic features (Fig. 13-20). In addition, they do not undergo puberty.

FIGURE 13-20 This 16-year-old girl with Turner syndrome (XO) has mental retardation and the distinctive short stature and webbed neck. As with several other genetic disorders, her ears are low-set (but hidden by a low hairline), her nose is flat, and its bridge spreads into broad epicanthal folds. Because she characteristically failed to undergo puberty, she lacks breast development and other secondary sexual characteristics. Also, her elbows’ carrying angles are relatively straight, which is the male pattern.

A minority (10–20%) of Turner syndrome girls have mild to moderate mental retardation, but the majority – up to 70% – have learning difficulties. In general, they have learning disabilities, attention deficit, and greater impairment on performance than verbal IQ testing. Turner syndrome may be another example – along with Williams syndrome – of preserved verbal ability despite cognitive impairment.

Klinefelter Syndrome (XXY)

With an additional X chromosome, Klinefelter syndrome boys are tall but eunuchoid (Fig. 13-21). As young men, their unusual height and lack of secondary sexual characteristics may draw medical attention, but physicians most often diagnose Klinefelter syndrome only after the boys fail to go through puberty. In fact, physicians sometimes first discover the disorder when an infertility evaluation shows that the man has testicular dysgenesis and lacks sperm.

FIGURE 13-21 After a delayed and then incomplete puberty, this 30-year-old man with Klinefelter syndrome (XXY) has grown taller than 6.5 feet (198 cm), largely due to his disproportionately long legs. His body has assumed a eunuchoid habitus with gynecomastia, sparse facial hair, female pattern of pubic hair, and small testicles. In addition to the XXY syndrome, conditions characterized by excessive height include the XYY and Marfan syndromes and homocystinuria.

Klinefelter syndrome boys have a below average IQ, typically between 80 and 90. However, only about 25% have any degree of intellectual disability and, when present, it is usually mild. While in school, Klinefelter syndrome boys tend to have dyslexia and other learning disabilities. According to some reports, they have a passive personality and decreased libido.

Heavy Metal Exposure

Aside from industrial accidents (such as occurred in Japan’s Minamata Bay), environmental gases and eating certain fish cause most mercury toxicity in neonates and infants. Large sea fish, such as swordfish, shark, king mackerel, and tuna, and certain fresh-water ones, such as pike and bass, have relatively high mercury concentrations. Pregnant women should avoid eating all of them.

Usually consumed in an organic form (methylmercury [CH₃Hg⁺]), a pregnant woman’s gastrointestinal tract absorbs ingested mercury. It readily crosses the placenta and tends to accumulate in fetal brain tissue. Over time, mercury intoxication causes brain damage and eventually cognitive impairment.

On the other hand, the mercury in old-style dental fillings dissolves at such a slow rate that it carries no significant risk. Even dentists who prepared the fillings on a daily basis had no propensity to develop mercury-related illnesses. Removing mercury-containing dental fillings offers no benefits.

Several researchers and many parents proposed an ominous association between autism and the measles, mumps, and rubella (MMR) vaccination because it contained an ethylmercury (C₂H₅Hg⁺) preservative, thimerosal. Because the vaccination may have led to a brief but significant mercury exposure in infants, several studies suggested that it caused autism and other disorders. Although vaccine manufacturers stopped adding mercury preservatives during the 1990s, the incidence of autism continued to climb. That epidemiologic data and many other studies have exonerated both the current and older MMR vaccinations as a cause of autism and other neuropsychologic impairments.

Lead intoxication in infants and children, depending on its intensity, causes mental retardation, learning disabilities, and other signs of cerebral impairment. This intoxication originates in infants and children ingesting lead-based paint chips and environmental pollution. Although acute intoxication causes seizures, the more common low-level exposure leads to subtle cognitive impairment.