3532 PART 13 Neurologic Disorders

Patients receiving high-dose IV glucocorticoids for status asthmaticus, chronic obstructive pulmonary disease, organ transplantation,

or other indications may develop severe generalized weakness (critical

illness myopathy). This myopathy, also known as acute quadriplegic

myopathy, can also occur in the setting of sepsis. Involvement of the

diaphragm and intercostal muscles causes ventilatory muscle weakness

and is usually appreciated when patients are unable to be weaned off a

ventilatory in the intensive care unit. NCS demonstrate reduced compound muscle action potentials in the setting of relatively preserved

sensory potentials. EMG can demonstrate abnormal insertional and

spontaneous activity and early recruitment of myopathic appearing

units in those muscles that can be activated. Muscle biopsy can show

a distinctive loss of thick filaments (myosin) by electron microscopy.

Treatment is withdrawal of glucocorticoids and physical therapy, but

the recovery is slow. Patients require supportive care and rehabilitation.

■ OTHER DRUG-INDUCED MYOPATHIES

Certain drugs produce painless, largely proximal muscle weakness.

These drugs include the amphophilic cationic drugs (amiodarone,

chloroquine, hydroxychloroquine) and antimicrotubular drugs

(colchicine) (Table 449-6). Muscle biopsy can be useful in the identification of toxicity because autophagic vacuoles are prominent pathologic features of these toxins.

■ GLOBAL ISSUES

As previously discussed, certain dystrophies have an increased prevalence in different parts of the world. LGMD2A/LGMDR1 is the most

common LGMD in individuals from Spain, France, Italy, and Great

Britain; LGMD2I/LGMDR9 is more common in those with northern

European ancestry. GNE myopathy is the most common form of distal

myopathy in Japan but is also prevalent in the Ashkenazi population.

OPMD is most common in those with ancestry from Spain and

French-Canada as well as among Ashkenazi. Epidemiologic studies

are lacking regarding other forms of myopathy and their prevalence in

different areas of the world.

■ FURTHER READING

Amato AA, Russell JA (eds): Neuromuscular Disorders, 2nd ed.

New York, McGraw-Hill Education, 2016.

Doughty CT, Amato AA: Toxic myopathies. Continuum (Minneap

Minn) 25:1712, 2019.

Heller SA et al: Emery-Dreifuss muscular dystrophy. Muscle Nerve

61:436, 2020.

Johnson NE: Myotonic muscular dystrophies. Continuum (Minneap

Minn) 25:1682, 2019.

Narayanaswami P et al: Summary of evidence-based guideline: Diagnosis and treatment limb-girdle and distal muscular dystrophies.

Neurology 83:1453, 2014.

Rosow LK, Amato AA: The role of electrodiagnostic testing, imaging,

and muscle biopsy in the investigation of muscle disease. Continuum

(Minneap Minn) 22:1787, 2016.

Sacconi S et al: FSHD1 and FSHD2 form a disease continuum.

Neurology 92:e2273, 2019.

Sansone VA et al: Randomized, placebo-controlled trials of dichlorphenamide in periodic paralysis. Neurology 86:1408, 2016.

Straub V et al: LGMD Workshop Study Group. 229th ENMC international workshop: Limb girdle muscular dystrophies—Nomenclature

and reformed classification Naarden, the Netherlands, 17-19 March

2017. Neuromuscul Disord 28:702, 2018.

Tawil R et al: Evidence-based guideline summary: Evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy:

Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology

and the Practice Issues Review Panel of the American Association

of Neuromuscular & Electrodiagnostic Medicine. Neurology 85:357,

2015.

Wicklund MP: The limb-girdle muscular dystrophies. Continuum

(Minneap Minn) 25:1599, 2019.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a

chronic complex illness with multisystem manifestations and longterm impact on functional impairment comparable to multiple sclerosis, rheumatoid arthritis, and congestive heart failure. The hallmark of

ME/CFS is persistent and unexplained fatigue resulting in significant

impairment in daily functioning along with worsening symptoms

following physical or mental exertion that would have been tolerated

before illness (post-exertional malaise). Besides intense fatigue, many

patients report concomitant symptoms such as pain, cognitive dysfunction, and unrefreshing sleep. Additional symptoms can include

headache, sore throat, tender lymph nodes, muscle aches, joint aches,

feverishness, difficulty sleeping, psychiatric problems, allergies, and

abdominal cramps.

The condition has been known by many names and debate about

the name and case definition continues. The composite name ME/CFS

was adopted by the U.S. Department of Health and Human Services in

recognition of the limitations of either ME (absence of definitive inflammation in brain and spinal cord) or CFS (trivializes an often devastating

illness through confusion with fatigue that everyone experiences).

An alternative name, systemic exertion intolerance disease (SEID),

proposed by the 2015 Institute of Medicine (IOM, now the National

Academy of Medicine) committee reviewing ME/CFS, has not gained

acceptance.

EPIDEMIOLOGY

Determining how frequently ME/CFS occurs and characteristics of

those affected has been complicated by variability in study design and

application of case definitions. In the absence of a simple diagnostic

test, evaluation by an experienced clinician is required for case identification. Clinic-based studies most accurately identify patients with

ME/CFS but overrepresent higher socioeconomic groups with access

to ME/CFS clinics. Population-based surveys that included a clinical

evaluation estimated a prevalence of 0.2–0.7%, suggesting ≥1 million

Americans have ME/CFS. However, these surveys found that ≥80%

of those meeting criteria for ME/CFS had not been diagnosed by a

health care provider. ME/CFS is three to four times more common in

women than men. The highest prevalence of illness is among those

40–50 years of age, but the age range is broad and includes children

and adolescents. Persons of all race and ethnicities are affected, and

there is some evidence that socioeconomically disadvantaged groups

are at increased risk.

RISK FACTORS AND PATHOPHYSIOLOGY

A wide variety of infectious agents have been reported to be associated

with a postinfectious fatiguing illness resembling ME/CFS. These

include both viral and nonviral pathogens, such as Epstein-Barr virus,

Ross River virus, Coxiella burnetti (Q fever), Ebola virus, SARS-CoV-1,

and Giardia. While recovery from these infections is the rule, approximately 10% of those infected remain ill for ≥6 months. Most recently,

published reports suggest that SARS-CoV-2 infection is also associated

Section 4 Myalgic Encephalomyelitis/

Chronic Fatigue Syndrome

450 Myalgic

Encephalomyelitis/

Chronic Fatigue

Syndrome

Elizabeth R. Unger, Jin-Mann S. Lin,

Jeanne Bertolli

3533 Myalgic Encephalomyelitis/Chronic Fatigue Syndrome CHAPTER 450

with prolonged fatiguing illness. Host and pathogen factors associated

with recovery versus persistent disease remain elusive. In addition to

infectious insults, a variety of stressors, including physical trauma,

adverse events, and allostatic load (or “wear and tear” on the body)

have been found to be associated with ME/CFS. Twin studies and family histories suggest a role for shared environment as well as genetic

factors.

Evidence for immunologic dysfunction is inconsistent. Modest

elevations in titers of antinuclear antibodies, reductions in immunoglobulin subclasses, deficiencies in mitogen-driven lymphocyte

proliferation, reductions in natural killer cell activity, disturbances

in cytokine production, and altered T-cell metabolism have been

described. None of these immune findings has been firmly established

and none of these changes appear in most patients. In theory, symptoms of ME/CFS could result from excessive production of a cytokine,

such as interleukin 1 or interferon alpha, which induces fatigue and

other flulike symptoms; however, compelling data in support of this

hypothesis are lacking.

Other studies have reported various nonspecific changes in regional

brain structures estimated by MRI; dysfunction of the autonomic

nervous system; abnormalities in the hypothalamic-pituitary-adrenal

(HPA) axis; altered metabolism; and dysbiosis of the intestinal microbiome. Confirmatory studies are needed and none of the findings are

consistent enough to be used for diagnosis. It is clear that ME/CFS

represents a complex disorder with alterations in multiple interrelated

homeostatic systems. A variety of unifying models for the illness have

been proposed and discoveries about the pathophysiology of ME/

CFS hold promise for elucidating novel mechanisms and interactions

important in other illnesses (Fig. 450-1).

APPROACH TO THE PATIENT

DIAGNOSIS

A diagnosis of ME/CFS is made based on patient-reported symptoms that fit a characteristic profile. After a careful review of the

literature and symptom-based case definitions for ME, CFS, or

ME/CFS, the IOM committee recommended in 2015 a straightforward clinical case definition (Table 450-1). This includes the

symptoms consistently noted in prior consensus case definitions:

fatigue limiting the patient’s ability to participate in his/her usual

pre-illness activities, sleep problems, and post-exertional malaise

(PEM). PEM is a relapse in symptoms triggered by physical, emotional, or cognitive exertion that would not have been problematic

Fatigue

Post-Exertional Malaise

HypothalamicPituitaryAdrenal Axis

Autonomic

Nervous System

Orthostatic

Intolerance

Infection

Pain

Cognitive

Impairment

Sleep

Problems

Central

Nervous

System

Immune

System Metabolism

Diet/Nutrition

Lifestyle

Stress

Genetics

FIGURE 450-1 A multisystem model for ME/CFS. An example of a unifying model for

ME/CFS demonstrating the interactions of multiple organ systems, environmental,

genetic, and behavioral factors contributing to symptoms.

TABLE 450-1 2015 Institute of Medicine Clinical Case Definition for

ME/CFS

Substantial reduction or impairment in the ability to engage in pre-illness

levels of activity (occupational, educational, social, or personal life) that:

a. lasts for more than 6 months

b. is accompanied by fatigue that is often profound, of new or definite onset (not

lifelong), not the result of ongoing excessive exertion, and is not substantially

alleviated by rest

*

Post-exertional malaise (PEM)—worsening of symptoms after physical, mental,

or emotional exertion that would not have caused a problem before the illness

*

Unrefreshing sleep

*

Cognitive impairment or orthostatic intolerance

*

Frequency and severity of symptoms should be assessed; should be present at

least half of the time and with at least moderate intensity

TABLE 450-2 Additional Symptoms Experienced by Patients with

ME/CFS

Joint pain without swelling or redness

Muscle aches

New headaches

Tender lymph nodes

Sensitivity to sensory stimuli (e.g., light, noise, smells)

Sore throat

Alcohol intolerance

Difficulties with temperature regulation (feeling feverish or chilled)

for the patient before onset of ME/CFS. The relapse lasts more than

a day, and sometimes weeks. In addition, either difficulty thinking

and concentrating (often referred to by patients as “brain fog”) or

orthostatic intolerance should be present.

Patients with ME/CFS may experience a wide range of other

symptoms not specified in the IOM clinical case definition

(Table 450-2). As a result, patients meeting the case definition

could have very different clinical features based on the type,

frequency, and severity of their symptoms. Patients may describe a

precipitating cause for their illness, such as a known or presumed

infection, but frequently no initiating factor is recognized. The

symptoms may occur suddenly within a day or week or may occur

gradually.

While the case definition indicates illness must be present at

least 6 months, the possibility of ME/CFS should be considered

for patients with consistent symptoms persisting >1 month, and

evaluation and supportive care can begin as early as 4–6 weeks after

onset. Listening to patients’ descriptions of what they are experiencing is important. Asking questions can help patients accurately

describe their experience with fatigue and PEM. These include asking about current activity levels compared with before they became

ill, what happens when they are as active as they were pre-illness,

and how long it takes to recover after exertion. Whereas patients

recognize relapses, the relation of relapse to activity level may not be

apparent, and as a result PEM may not be recognized. Patients may

also appear well during an office visit, only to relapse afterwards

from exertion surrounding the consultation.

Although the IOM definition does not list medical or psychological conditions that exclude the diagnosis of ME/CFS, a careful

clinical evaluation is required to identify and treat other illness that

could explain or contribute to the patient’s symptoms. The initial

evaluation also requires reviewing family history; medical history

(including infections, traumas/surgeries, occupational exposure to

environmental toxins); a review of medications and supplements;

physical examination, including lean test for postural orthostatic

tachycardia syndrome (POTS; Chap. 440); mental health assessment (screen for depression and anxiety); and routine screening

laboratory tests (if recent results are not on record). As routine

3534 PART 13 Neurologic Disorders

laboratory tests are usually within normal limits, their role is in

identifying other illnesses and the specific panel of tests should

be adjusted based on the patient’s presentation. Typically the tests

include complete blood count, erythrocyte sedimentation rate,

electrolytes, fasting glucose, renal function tests (blood urea nitrogen, glomerular filtration rate), calcium, phosphate, liver function

(bilirubin, alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma-glutamyl transferase, total protein,

albumin/globulin ratio), C-reactive protein, thyroid function

(thyroid-stimulating hormone, free thyroxine), iron studies to assess

both iron overload and iron deficiency (serum iron, transferrin

saturation, ferritin), celiac disease screening tests, and urinalysis.

DIFFERENTIAL DIAGNOSIS AND COMORBID CONDITIONS

While the differential diagnosis for fatigue is quite broad, further

workups and referrals should be chosen carefully based on the

patient’s history, symptoms (particularly those that are new, worsening, or unusual), and results of initial laboratory tests. Conditions

reported to occur in association with ME/CFS (Table 450-3) should

be kept in mind during the evaluation and follow-up, as management and treatment modalities for these comorbidities could contribute to an improved quality of life.

MANAGEMENT

While there are no approved drugs to treat or cure ME/CFS,

patients benefit from receiving a diagnosis and an individualized

plan that addresses the symptoms that are most problematic

for the patient. Some symptoms, in particular, disturbed sleep

(Chap. 31) and pain (Chap. 13), may improve with nonpharmacologic therapies (such as sleep hygiene, massage, acupuncture,

hot or cold packs) or medications. Any medications should be

started at lower doses than usual and only slowly increased. Patients

with ME/CFS have been reported to be more sensitive to medications than the general population, and benefits with fewer toxicities

may be achieved at lower doses. Narcotics should be avoided, and

referral to sleep centers or other specialists may be required.

Controlled therapeutic trials have not established significant benefit for patients with ME/CFS from acyclovir, fludrocortisone, galantamine, modafinil, and IV immunoglobulin, among other agents.

These studies have been limited by small numbers and lack power

to investigate benefit in patient subgroups. Preliminary small studies

reported the possible effectiveness of the B-cell targeting anti-CD20

monoclonal antibody rituximab in ME/CFS, but a subsequent large,

well-designed prospective double-blind study found no benefit.

Numerous anecdotes circulate regarding other traditional and nontraditional therapies. It is important to guide patients away from

therapeutic modalities that are toxic, expensive, or unreasonable.

Educating the patient and family about PEM can be helpful in

avoiding the harmful cycle of overexertion during “good days”

followed by relapse that can negate any functional gains. This is

often referred to as “push and crash.” Recognizing limits and using

activity management (pacing) can help limit PEM. It is important

to maintain tolerated activity levels to minimize deconditioning.

Activity may be advanced very gradually as tolerated.

TABLE 450-3 ME/CFS Comorbid Conditions

Chronic overlapping pain conditions: fibromyalgia (FM), chronic migraine,

temporomandibular joint disease (TMJ), irritable bowel syndrome (IBS),

endometriosis, vulvodynia, urologic chronic pelvic pain syndromes (UCPPS)

Postural orthostatic tachycardia syndrome (POTS)

Allergies

Sjögren’s syndrome

Ehlers-Danlos syndrome

Mast-cell activation syndrome (MCAS)

Dysautonomia

Multiple chemical sensitivities

Counseling may help patients and their families cope with the

long-term consequences of living with a chronic illness. Consultation with a physical or occupational therapist may identify energysaving strategies for activities of daily living as well as needed

accommodations, such as a wheelchair for activities that require

walking longer distances or prolonged standing.

COURSE AND PROGNOSIS

The illness severity varies from mild or moderate, with patients

retaining varying degrees of pre-illness function, to severe, with

patients essentially homebound. Most patients experience some

improvement and stabilize, although return to their prior level of

function is unusual. A continued decline in function should prompt

evaluation for other illnesses. Patients should be re-evaluated at

scheduled intervals to adjust treatments and detect any intercurrent

disease. New or changing symptoms should be worked up to identify any new illnesses. Given the social isolation and loss of hope

associated with a debilitating chronic illness, serious depression and

an increased risk of suicide is reported for patients with ME/CFS.

Clinicians should be prepared to screen for this and refer patients

as needed.

■ FURTHER READING

Bateman L et al: Myalgic encephalomyelitis/chronic fatigue syndrome:

Essentials of diagnosis and Management. Mayo Clin Proc 2021.

https://doi.org/10.1016/j.mayocp.2021.07.004

Centers for Disease Control and Prevention: Myalgic

Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Available

from https://www.cdc.gov/me-cfs/index.html. Accessed March 15, 2021.

Institute of Medicine: Beyond Myalgic Encephalomyelitis/Chronic

Fatigue Syndrome: Redefining an Illness. Washington, DC: The

National Academies Press, 2015.

Komaroff AL: Advances in understanding the pathophysiology of

chronic fatigue syndrome. JAMA 322:499, 2019.

Lapp CW: Initiating care of a patient with myalgic encephalomyelitis/

chronic fatigue syndrome (ME/CFS). Front Pediatr 6:415, 2019.

Rowe PC et al: Myalgic encephalomyelitis/chronic fatigue syndrome

diagnosis and management in young people: A primer. Front Pediatr 5:

121, 2017.

Psychiatric disorders are central nervous system diseases characterized

by disturbances in emotion, cognition, motivation, and socialization.

They are highly heritable, with genetic risk comprising 20–90% of

disease vulnerability. As a result of their prevalence, early onset, and

persistence, they contribute substantially to the burden of illness

worldwide. All psychiatric disorders are broad heterogeneous syndromes that currently lack well-defined neuropathology and bona

fide biologic markers. Therefore, diagnoses continue to be made solely

from clinical observations using criteria in the Diagnostic and Statistical

Manual of Mental Disorders, Fifth Edition (DSM-5), of the American

Psychiatric Association (see Chap. 452).

Section 5 Psychiatric and Addiction

Disorders

451 Biology of Psychiatric

Disorders

Robert O. Messing, Eric J. Nestler,

Matthew W. State

3535Biology of Psychiatric Disorders CHAPTER 451

There is increasing agreement that the classification of psychiatric

illnesses in DSM does not accurately reflect the underlying biology of

these disorders. Uncertainties in diagnosis complicate efforts to study

the genetic basis and attendant neurobiological mechanisms underlying

mental illness, though recent advances in genomic and neuroscience

technologies along with the consolidation of very large patient cohorts

have, for multiple disorders, led to major progress in these realms. In

addition, there have been efforts to address the limitations of a categorical nosology directly through the development of an alternative diagnostic scheme, termed Research Domain Criteria (RDoC). This system

classifies mental illness on the basis of core behavioral abnormalities

shared across several syndromes—such as psychosis (loss of reality) or

anhedonia (decreased ability to experience pleasure)—and the associated brain circuitry that controls these behavioral domains. It is anticipated that such classifications will assist in defining the biologic basis of

key symptoms. Other factors that have impeded progress in understanding mental illness include the lack of access to pathologic brain tissue

except upon death and the inherent limitations of animal models for disorders defined largely by behavioral abnormalities (e.g., hallucinations,

delusions, guilt, suicidality) that are inaccessible in animals.

Despite these limitations, the past decade has been marked by real

progress. Neuroimaging methods are beginning to provide evidence of

brain pathology; genome-wide association studies and high-throughput

sequencing are reliably identifying genes and genomic loci that confer

risk for severe forms of mental illness; and investigations of better

validated animal models, leveraging a host of new methods to study

molecular, cellular, and circuit-level processes, are offering new insight

into disease pathogenesis. There is also excitement in the utility of neurons, glia, and brain organoids induced in vitro from patient-derived

pluripotent stem cells, providing novel ways to study disease pathophysiology and screen for new treatments. There is consequently

justified optimism that the field of psychiatry will better integrate

behaviorally defined syndromes with an understanding of biological

substrates in a way that will drive the development of improved treatments and eventually cures and preventive measures. This chapter

describes several examples of recent discoveries in basic neuroscience

and genetics that have informed our current understanding of disease

mechanisms in psychiatry.

■ NEUROGENETICS

Because the human brain can only be examined indirectly during life,

genome analyses have been extremely important for obtaining molecular clues about the pathogenesis of psychiatric disorders. Moreover, the

identification of germline risk alleles and mutations provides potential

traction on the question of cause versus effect. In other types of crosssectional studies, it may be impossible to determine whether a phenotype or biomarker observed in affected humans or model systems

reflects an etiologic factor or a compensatory response. In contrast,

germline genetic risk is present before the brain develops—at least

theoretically allowing for experiments to address temporal sequencing.

A wealth of new information has been made possible by recent

technologic developments that have permitted affordable, large-scale

genome-wide association studies and high-throughput sequencing.

As an example of the latter, there has been significant progress in the

genetics of autism spectrum disorders (ASDs), which are a heterogeneous group of neurodevelopmental diseases that share clinical

features of impaired social communication and restricted, repetitive

patterns of behavior. ASDs are highly heritable; concordance rates

in monozygotic twins (~60–90%) are five- to tenfold higher than in

dizygotic twins and siblings, and first-degree relatives show approximately tenfold increased risk compared with the general population.

ASDs are also genetically heterogeneous. More than 100 individual

risk genes, along with dozens of submicroscopic deletions and duplications often containing multiple genes, have been identified, almost

exclusively through the study of rare, large-effect, new (de novo)

mutations (Fig. 451-1). All told, genes and genomic regions vulnerable to these types of mutations account for ~20–30% of formerly

idiopathic cases that present in the clinic, although none individually

accounts for >1%. In addition, ~10% of individuals with ASD have

well-described intellectual disability syndromes including fragile X

syndrome, Rett syndrome, and tuberous sclerosis (Chap. 90). However,

it appears that most of the risk for ASD in the population involves true

polygenic inheritance. There is considerable evidence, for example,

that >50% of the genetic liability is carried in common alleles of very

small individual effect. To date, studies of tens of thousands of cases

have identified five reproducible associations of loci meeting gold

standard genome-wide association statistical thresholds. With continually increasing cohort sizes, and thus power, this number is certain to

grow in the future.

Amid the genetic heterogeneity that has so far been identified,

common themes have emerged that inform pathogenesis of ASDs.

For instance, many identified rare mutations are in genes that encode

proteins involved in synaptic function and early transcriptional and

chromatin regulation (Fig. 451-1) and have a clear relationship to

activity-dependent neural responses that can affect the development

of neural systems underlying cognition and social behaviors. One

particularly intriguing hypothesis is that these genes may lead to ASD

risk by changing the balance of excitatory versus inhibitory synaptic

signaling in local and extended circuits and by altering mechanisms

that control brain growth. Some mutations affect genes (e.g., PTEN,

TSC1, and TSC2) that negatively regulate signaling from several

types of extracellular stimuli, including those transduced by receptor tyrosine kinases. Their dysregulation can alter neuronal growth,

resulting in altered brain size, as well as synaptic development and

function. Finally, several recent studies have focused on the question

of when and where multiple functionally diverse risk genes converge

with respect to human brain development. Interestingly, these studies

have thus far tended to overlap with expression patterns of glutamatergic neurons in mid-fetal cortex (Fig. 451-1). Given the pleiotropic

biological effects of the ASD genes identified to date, an understanding

of the developmental or “spatiotemporal” dimensions of risk is likely

to serve as a useful complement to studies of the function of individual

genes. In short, it may turn out that when and where genetic variation

has its impact in the developing brain may be as important as the key

processes that are identified.

With further understanding of pathogenesis and the definition of

specific ASD subtypes, there is reason to believe that effective therapies

will be identified. Work in mouse models has already demonstrated

that some autism-like behaviors can be reversed, even in fully developed adult animals, by modifying the underlying genetic or functional

pathology. These results suggest that key phenotypes arising from

some ASD-related large-effect mutations may well reflect ongoing

functional derangements, offering hope that interventions can be successful well after the initial developmental insult and the emergence of

symptoms. Treatments that target excitation-inhibition imbalance or

altered mRNA translation are one area of early promise. For example,

the genes TSC1, TSC2, and PTEN are negative regulators of signaling

through the target of rapamycin complex 1 (TORC1), which regulates

protein synthesis. Rapamycin, a selective inhibitor of TORC1, can

reverse several behavioral and synaptic defects in mice carrying null

mutations in these genes.

Increasingly, attention has turned to the strategy of targeting the

genetic “lesion” early in development to treat or prevent ASD and

related phenotypes in those cases in which a single, highly penetrant

coding mutation is present. However, even with the relatively large

number of risk genes (>100) that have been identified carrying de novo

putative loss-of-function coding mutations, there is a much smaller

number of potential targets that carry sufficiently high and predictable

risks for severe outcomes to consider directly targeting nucleic acids,

for example, with CRISPR-based therapies or the use of antisense

oligonucleotides (ASOs). Clearly, however, recent successes with very

early intervention in spinal muscular atrophy, using both strategies,

are driving increased interest in their utility in a range of brain-based

disorders. Currently, with regard to neurodevelopmental conditions,

these approaches are being most actively pursued for well-known

intellectual disability syndromes that may also carry elevated risk for

ASD, such as Angelman syndrome, Rett and MECP2 duplication syndrome, and fragile X syndrome. Such efforts could be transformational

3536 PART 13 Neurologic Disorders

FIGURE 451-1 Functional characteristics and developmental convergence of autism spectrum disorder (ASD) associated genes: genes associated with ASD based on

recurrent de novo and transmitted coding mutations are shown in A and B. Those genes encoding proteins with a false discovery rate (FDR) <0.01 in Sanders et al, Neuron

2015, and Satterstrom et al, Cell 2020, are highlighted with respect to their putative functions. Genes meeting the highest confidence criteria in Sanders et al 2015 and

showing either an FDR >0.01 or an FDR >0.3 in Satterstrom are noted (* and **, respectively). Additional interacting and functionally related molecules that do not meet

the above criteria are shown in green. FMR1, TSC1, and TSC2 are syndromic ASD genes included in the figure (A). Multiple gene ontology analyses of ASD genes have

highlighted both pre- and postsynaptic molecules (A) and chromatin modifiers (B) as points of enrichment. In C, an alternative strategy for grouping ASD risk genes is

highlighted (Willsey et al, Cell 2013), based on their spatiotemporal expression patterns as opposed to putative functions. One analytic strategy, illustrated in C, leveraged

only high-confidence ASD genes and examined their developmental expression patterns using the BrainSpan data set. Convergence for ASD risk was identified in deep

layer (V and VI) excitatory neurons in mid-fetal human cortex. Multiple analyses have similarly found glutamatergic neurons in mid-fetal prefrontal cortex as one point of

convergence, with somewhat less agreement on layer specificity and potential additional spatiotemporal points of convergence.

SHANK2/3

GKAP1

GKAP1

PSD95

CNTNAP2

Homer

PSD95

?+

L1

PTEN

CUL3** CK2

CK2

RBX1

RhoA

CAMKII

CAMKII PI3K

PIKE-L RAC1

cAMP

AKT

MEK

SYNGAP1

TNRC6B**

CAMKII

Ras-GTP

Ras-GDP

CYFIP1

WRC

MINT

CASK

KCT13

AGO1-4

NLGNs

DSCAM

NRNX1

SCN2A

Phos. localizes

Microtubule

GRIN2B SCN2A

Ca2

 + Ch.

NMDARs

DYNC1H1

Ub

NCKAP1**

FMR1

FMR1

CYFIP1

TSC1 TSC2

MAPK mTORC1

TTT-Pontin/

Reptin

complex

WAC

Translation

Ca2

 + Ch. ANK2 Spectrin

 Network

MGluR KCNQ3

GABRB3

GABRB3

SLC6A1

GIGYF1 2EHP

SRPR

SHANK3

∆

Transcription

∆

∆

TCF7L2* POGZ

TBR1*

Actin

Cytoskeleton

FOXP1 DEAF1

MYT1L BCL11A

PAX5 MKX

DYRK1A

MBD5

CTNNB1 CTNNB1

RORB

MED13L

Membrane/

Vessicle Targeting

Kinases

Other

Channels

Ubiquitin Ligases

Cell Adhesion Proteins

Scaffolding Proteins

Phosphatase

Transcription Factors

FDR>0.01

Adaptor Proteins

KATNAL2**

Postsynaptic

Presynaptic

DPYSL2

MAP1A

AP2S1

Nucleus

Endoplasmic

Reticulum

A

H2B

H4 H2A

H3

SUV420H1

KDM5B

KMT2C ASH1L

ARID1B ADNP

CHD8

Ub

WAC

SGRGKGGKGLGKGGAKRHRKVLRDNIQGITKPAIR

RNF20 RNF40

CHD2

SETD5

Lysine demethylase

Other chromatin remodeler

Ubiquitine ligase

Lysine methyltransferase

Methyl group

Reader

FDR > 0.01

RNF168

Ub

TRIP12*

ARTKQTARKSTGGKAPRKQLATKAARKSAPATGGVK

ANKRD11

KDM6B

DNMT3A

SIN3A

TBL1XR1

RAI1

TLK2

B

3537Biology of Psychiatric Disorders CHAPTER 451

for very small numbers of individuals and may well yield important

insights into biology that have impact beyond those carrying rare very

highly penetrant mutations. They will undoubtedly raise significant

practical as well as ethical challenges as treatments for more common

forms of ASD.

The ability to catalog common genetic variants and assay them on

array-based platforms and, more recently, to carry out whole exome

sequencing has allowed investigators to leverage very large patient

cohorts to detect risk loci for schizophrenia and bipolar disorder with

genome-wide significance. In contrast to ASD, where the lion’s share of

early success in gene identification has resulted from the study of rare,

large-effect, de novo mutations, much of gene discovery to date for

these syndromes has resulted from genome-wide association studies of

common inherited polymorphisms. It is noteworthy that there is also

striking overlap among the submicroscopic deletions and duplications,

called copy number variants (CNVs), that have been found to carry

large risks for ASD, schizophrenia, and bipolar disorder, as well as

epilepsy and intellectual disability.

To date, >200 distinct genomic regions, marked by associated single

nucleotide polymorphisms, have been identified in schizophrenia,

some of which show risk as well for bipolar disorder. Several of the

identified genes are parts of molecular complexes, such as voltagegated calcium channels (in particular, CACNA1C and CACNB2) and

the postsynaptic density of excitatory synapses. Genes that promote

risk for addiction and depression have also begun to emerge from

large studies. The best-established susceptibility locus for addiction is

the CHRNA5-A3-B4 nicotinic acetylcholine receptor gene cluster on

chromosome 15 associated with nicotine and alcohol addiction. Recent

genome-wide association studies of depression have required hundreds

of thousands of cases and controls to identify the first statistically

significant loci using state-of-the-art approaches. These findings collectively point to the tremendous heterogeneity of depressive disorders

as well as the very small biologic effects conferred by any individual

common allele.

A recurrent theme that has emerged from genetic studies of psychiatric disorders is phenotypic pleiotropy, namely, that many genes

are associated with multiple psychiatric syndromes. For example,

mutations in MECP2, FMR1, and TSC1 and TSC2 can cause intellectual disability without ASD, others in MECP2 can cause obsessivecompulsive and attention-deficit/hyperactivity disorders, some alleles

of NRXN1 are associated with symptoms of both ASD and schizophrenia, and common polymorphisms in CACNA1C are strongly associated

with both schizophrenia and bipolar disorder. Likewise, duplication of

chromosome 16p is associated with both schizophrenia and autism,

whereas deletions in the DiGeorge’s (velocardiofacial) syndrome region

are associated with schizophrenia, autism, and bipolar disorder. The

association of genes and genomic regions with multiple syndromes

attests to the complexity of psychiatric disorders, the very large gap

between molecular mechanisms and the current categorical diagnostic schemes, and the influence of additional factors that combine to

specify the ultimate phenotype. The latter might include polygenic

“background,” variations in regulatory regions of the genome that

determine cell-type specificity and timing of gene expression, protective variants, stochastic events, and epigenetic effects. This pleiotropy

of consequences for a given genetic mutation in psychiatry is akin to

the pleiotropy seen for many cancer-causing mutations, where the

same mutation can lead to many different types of cancers across the

population.

■ SIGNAL TRANSDUCTION

Studies of signal transduction have revealed numerous intracellular

signaling pathways that are perturbed in psychiatric disorders, and

such research has provided insight into development of new therapeutic agents. For example, lithium is a highly effective drug for

bipolar disorder and competes with magnesium to inhibit numerous

magnesium-dependent enzymes, including the enzyme GSK3β and

several enzymes involved in phosphoinositide signaling that lead to

activation of protein kinase C. These findings have led to discovery

programs focused on developing GSK3β or protein kinase C inhibitors

as potential novel treatments for mood disorders, although none have

demonstrated clinical efficacy to date.

The observations that tricyclic antidepressants (e.g., imipramine)

inhibit serotonin and/or norepinephrine reuptake and that monoamine

oxidase inhibitors (e.g., tranylcypromine) are effective antidepressants

initially led to the view that depression is caused by a deficiency of

these monoamines. However, this hypothesis has not been substantiated. A cardinal feature of these drugs is that long-term (weeks to

months) administration is needed for their antidepressant effects. This

means that their short-term actions, namely promotion of serotonin

or norepinephrine function, are not per se antidepressant but rather

induce a cascade of adaptations in the brain that underlie their slowly

developing clinical effects. The nature of these therapeutic druginduced adaptations has not been identified with certainty. One

hypothesis holds that, in a subset of depressed patients who display

upregulation of the hypothalamic-pituitary-adrenal (HPA) axis characterized by increased secretion of corticotropin-releasing factor

(CRF) and glucocorticoids, excessive glucocorticoids cause atrophy of

hippocampal neurons, which is associated with reduced hippocampal

volumes seen clinically. Chronic antidepressant administration might

reverse this atrophy by increasing brain-derived neurotrophic factor

(BDNF) or a host of other neurotrophic factors in the hippocampus.

A role for stress-induced decreases in the generation of newly born

hippocampal granule cell neurons, and its reversal by antidepressants

through BDNF or other growth factors, has also been suggested.

A major advance in recent years has been the identification of

several rapidly acting antidepressants with non–monoamine-based

mechanisms of action. The best established is ketamine, a noncompetitive antagonist of N-methyl-d-aspartate (NMDA) glutamate

receptors among other actions, which exerts rapid (hours) and robust

antidepressant effects in severely depressed patients who have not

responded to other treatments. Ketamine, which at higher doses is

psychotomimetic and anesthetic, exerts these antidepressant effects

Convergence of Autism Associated Genes

& Co-expression Network Analysis

Co-expression of Autism

Associated Genes

Map of Gene Expression in the

Developing Human Brain

Mid-fetal Development

Prefrontal and Primary

C Motor-Somatosensory Cortex

FIGURE 451-1 (Continued)