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402 Laboratory Medicine in Psychiatry and Behavioral Science
Fatty liver disease (continued)
Fuster D, Samet JH: Alcohol use in patients with chronic liver disease.N Engl J Med 379(13):1251–1261, 2018
Juo YY, Livingston EH: Testing for nonalcoholic fatty liver disease. JAMA 322(18):1836, 2019
Neuschwander-Tetri BA: Non-alcoholic fatty liver disease.BMC Med 15(1):45, 2017
Sanyal AJ, Van Natta ML, Clark J, et al: Prospective study of outcomes in adults with nonalcoholic fatty
liver disease.N Engl J Med 385(17):1559–1569, 2021
Sheka AC, Adeyi O, Thompson J, et al: Nonalcoholic steatohepatitis: a review.JAMA 323(12):1175–1183,
2020 [published correction appears in JAMA 323(16):1619, 2020]
Younossi ZM, Felix S, Jeffers T, et al: Performance of the Enhanced Liver Fibrosis Test to estimate advanced
fibrosis among patients with nonalcoholic fatty liver disease.JAMA Netw Open 4(9):e2123923, 2021
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403 Diseases and Conditions
Folate deficiency
Clinical findings Folate (vitamin B
9
) is an essential nutrient that plays a critical role in
the synthesis of DNA, RNA, proteins, and RBCs. Deficiency of folate
affects cell division and can result in the accumulation of toxic metab
-
olites such as homocysteine. Foods that contain folate include leafy
green vegetables, fresh fruit, beans, whole grains, seafood, and eggs.
Folic acid is a synthetic form of folate used in supplements and forti
-
fied foods.
Folate deficiency has well-established associations with malnutrition,
alcohol use disorder, malabsorption syndromes, pregnancy, hemodial
-
ysis treatment, and the use of anticonvulsant drugs. Less well-known
and less common is the association of deficiency with antibodies to the
folate receptor-1 found on the basolateral endothelial surface of the
choroid plexus, which is responsible for transporting folate across the
blood-brain barrier into the CSF. When these antibodies bind to the
receptor, it is unable to transport folate such that cerebral folate defi
-
ciency develops. This deficiency can be present even while peripheral
folate levels are normal. This antibody-mediated cerebral folate defi
-
ciency is well known in infants and young children but also can occur
in adults.
Signs and symptoms of peripheral folate deficiency include the follow-
ing: megaloblastic anemia, dementia, peripheral neuropathy (particu-
larly reduced vibration sense in lower extremities), weakness, ataxia,
positive Romberg testing, and paraplegia with abnormal deep tendon
reflexes and extensor plantar responses. Nausea, vomiting, diarrhea,
headache, and shortness of breath may also be seen. Signs and symp
-
toms of cerebral folate deficiency in adults include cerebral calcifica-
tions, white matter lesions on MRI, pyramidal symptoms (spasticity,
weakness, hyperreflexia), movement disorders (e.g., myoclonus), cer-
ebellar dysfunction, and cognitive impairment.
Folate deficiency has been identified in half of stroke survivors and at
high rates among patients with schizophrenia. Low folate levels pre
-
sent a risk factor for dementia, particularly in the presence of elevated
homocysteine levels. Cerebral folate deficiency has been identified in
patients with treatment-refractory depression in whom serum folate
levels were normal. Notes on unpublished cases indicate that cerebral
folate deficiency can present in adolescents as catatonic schizophrenia
and in adults as myoclonus and dementia. Cerebral folate deficiency
should be included in the differential diagnosis for patients with cog
-
nitive impairment, neurological signs, brain calcifications, and white
matter lesions seen on MRI.
Laboratory testing Reference values for adults:
• Serum folate: 3–13 ng/mL
• RBC folate: 140–628 ng/mL
• CSF 5-MTHF (5-methyltetrahydrofolate): 40–120 nmol/L
Macrocytic anemia
is seen, with hypersegmented neutrophils and
macro-ovalocytes.
Either serum or RBC folate can be assayed; serum folate testing is more
widely available, whereas RBC folate testing more closely reflects tis-
sue levels.
Plasma homocysteine, which is even more sensitive, is increased in
folate deficiency but is nonspecific.
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404 Laboratory Medicine in Psychiatry and Behavioral Science
Folate deficiency (continued)
Laboratory testing
(continued)
Before folate therapy is initiated, vitamin B
12
deficiency should be ex-
cluded with a normal B
12
level and a normal MMA level. These defi-
ciencies may occur in tandem, and replacement of folate alone may
result in clinical worsening.
To monitor the effectiveness of folate replacement, a CBC should be
performed after 2 weeks to document increase in hemoglobin and de
-
crease in MCV; another CBC should be performed after 8weeks to doc-
ument resolution of anemia.
Long-term folate replacement is not necessary unless the cause persists
(e.g., malnutrition); long-term monitoring is usually not needed.
Workup for cerebral folate deficiency includes measurement of 5-
MTHF and assay of serum for binding and blocking folate receptor
antibodies.
Baroni L, Bonetto C, Rizzo G, et al: Association between cognitive impairment and vitamin B12, folate,
and homocysteine status in elderly adults: a retrospective study. J Alzheimers Dis 70(2):443–453, 2019
Cao B, Wang DF, Xu MY, et al: Lower folate levels in schizophrenia: a meta-analysis.Psychiatry Res
245:1–7, 2016
Masingue M, Benoist JF, Roze E, et al: Cerebral folate deficiency in adults: a heterogeneous potentially
treatable condition.J Neurol Sci 396:112–118, 2019
McPherson RA, Pincus MR: Henry’s Clinical Diagnosis and Management by Laboratory Methods, 24th
Edition Philadelphia, PA, Elsevier, 2022
Pan LA, Martin P, Zimmer T, et al: Neurometabolic disorders: potentially treatable abnormalities in pa-
tients with treatment-refractory depression and suicidal behavior. Am J Psychiatry 174(1):42–50, 2017
Pascoe MC, Linden T: Folate and MMA predict cognitive impairment in elderly stroke survivors: a cross
sectional study. Psychiatry Res 243:49–52, 2016
Pope S, Artuch R, Heales S, Rahman S: Cerebral folate deficiency: analytical tests and differential diagno-
sis. J Inherit Metab Dis 42(4):655–672, 2019
Ramaekers V, Sequeira JM, Quadros EV: Clinical recognition and aspects of the cerebral folate deficiency
syndromes. Clin Chem Lab Med 51(3):497–511, 2013
Reynolds EH: The neurology of folic acid deficiency.Handb Clin Neurol 120:927–943, 2014
Sanvisens A, Zuluaga P, Pineda M, et al: Folate deficiency in patients seeking treatment of alcohol use
disorder. Drug Alcohol Depend 180:417–422, 2017
Sobczynska-Malefora A, Harrington DJ: Laboratory assessment of folate (vitamin B
9
) status. J Clin Pathol
71(11):949–956, 2018
Williams Barnhardt E, Jacque M, Sharma TR: Brief reversible psychosis and altered mental status in a pa-
tient with folate deficiency: a case report. Prim Care Companion CNS Disord 18(1):10.4088/
PCC.15l01839, 2016
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405 Diseases and Conditions
Fragile X syndrome (FXS)
Clinical findings FXS—the most common heritable form of intellectual disability—
results from the expansion of a segment of DNA known as a CGG
(cytosine-guanine-guanine) trinucleotide repeat in the non-coding
region of the fragile X mental retardation 1 gene (FMR1). This excess
DNA gives rise to excess FMR1-mRNA, which is toxic to cells and
disrupts basic cellular functions. The clinical consequences of the
expansion depend on the number of repeats in FMR1: 55–200 repeats
represent a premutation, whereas >200–1,000 repeats represent a full
mutation.
The full mutation results in FXS, a neurodevelopmental disorder
characterized by intellectual disability and autism spectrum disorder
(ASD). Girls are usually less severely affected than boys. In addition to
autistic behaviors and subaverage intellectual function, signs and
symptoms include physical characteristics such as large head circum
-
ference, long narrow face, prominent jaw and forehead, protruding
ears, finger joint laxity, flat feet, and macro-orchidism in boys after
puberty. Anxiety, social avoidance, hyperactivity, ADHD, and seizures
are seen. Specific behaviors include hand flapping, hand biting, and
temper tantrums, as well as (after puberty) impulsivity, distractibility,
and perseverative speech. Affected adults have increased rates of hy
-
pertension, obesity, parkinsonism, GI disorders, and mood disorders.
MRI in adults shows reduced volume of the cerebellar vermis and en-
largement of the caudate nucleus and lateral ventricles.
Fragile X premutation–associated conditions (FXPAC) include the
following:
• Fragile X tremor/ataxia syndrome (FXTAS) is a progressive dis-
ease with onset usually after age 50 years that is characterized by
kinetic tremor and/or cerebellar ataxia, with additional symptoms
including parkinsonism, autonomic dysfunction, proximal leg
muscle weakness, peripheral neuropathy, and cognitive impair-
ment involving memory and executive functions. MRI abnormali-
ties that may be identified well before clinical symptoms include
reduced volume in the cerebellum and brainstem and white matter
changes.
• Fragile X–associated neuropsychiatric disorders (FXAND) are as-
sociated with developmental problems such as ASD, ADHD, de-
pression, OCD, and anxiety disorders. These conditions are seen in
both adults and children. Adults are also observed to have chronic
fatigue, fibromyalgia, autoimmune dysfunction, migraine syn-
dromes, and central pain syndromes. It has been proposed that the
term FXAND be replaced by two terms: fragile X-associated neu-
ropsychiatric conditions (FXANC) and fragile X various associated
conditions (FXVAC) to reflect the non-neuropsychiatric nature of
some of these symptoms.
• Fragile X–associated primary ovarian insufficiency (FXPOI) in its
most severe form is characterized by irregular or absent menstrual
periods and elevated FSH levels before age 40 years, low estrogen
levels, early menopause, and early osteoporosis.
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406 Laboratory Medicine in Psychiatry and Behavioral Science
Fragile X syndrome (FXS) (continued)
Laboratory testing PCR is used to identify expansions of CGG trinucleotide repeat in
FMR1:
• >200–1,000 repeats—full mutation
• 55–200 repeats—premutation
• 59–200 repeats—premutation with risk of FXTAS
Methylation-specific PCR is then performed for CGG repeats >100 to
distinguish premutation from full mutation alleles.
ARUP Laboratories: Fragile X syndrome, in Laboratory Test Directory. Salt Lake City, UT, ARUP Labora-
tories, Test Directory, 2022. Available at: https://arupconsult.com/ati/fragile-x-syndrome. Accessed
January 2022.
Grigsby J, Brega AG, Bennett RE, et al: Clinically significant psychiatric symptoms among male carriers
of the fragile X premutation, with and without FXTAS, and the mediating influence of executive func
-
tioning.Clin Neuropsychol 30(6):944–959, 2016
Hagerman RJ, Hagerman P. Fragile X-associated tremor/ataxia syndrome: features, mechanisms and
management. Nat Rev Neurol 12(7):403–412, 2016
Hagerman RJ, Jackson C, Amiri K, et al: Girls with fragile X syndrome: physical and neurocognitive sta-
tus and outcome. Pediatrics 89(3):395–400, 1992
Hall DA, Berry-Kravis E: Fragile X syndrome and fragile X-associated tremor ataxia syndrome.Handb
Clin Neurol 147:377–391, 2018
Johnson K, Herring J, Richstein J: Fragile X premutation associated conditions (FXPAC).Front Pediatr
8:266, 2020
Salcedo-Arellano MJ, Dufour B, McLennan Y, et al: Fragile X syndrome and associated disorders: clinical
aspects and pathology. Neurobiol Dis 136:104740, 2020
Santos E, Emeka-Nwonovo C, Wang JY, et al: Developmental aspects of FXAND in a man with the FMR1
premutation. Mol Genet Genomic Med 8(2):e1050, 2020
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407 Diseases and Conditions
Frontotemporal dementia (FTD)
Clinical findings FTD refers to a group of neurodegenerative disorders with progressive
deficits in behavior, executive function, and language arising from pa
-
thology in the frontal lobes, anterior temporal lobes, or both. FTD is a
leading cause of early onset dementia and the third-most-common
form of dementia overall. Up to 50% of cases are familial, involving
mutations in chromosome 9 open reading frame 72 (C9orf72), microtu
-
bule-associated protein tau (MAPT), or progranulin (GRN). C9orf72
mutation is the most common, and this and the GRN mutation have
been associated with presentations that look like primary psychiatric
disorders. Several disorders related to FTD—FTD-motor neuron dis
-
ease, progressive supranuclear palsy, and corticobasal syndrome—are
not discussed further in this section.
FTD is classified into three subtypes:
• Behavioral variant FTD (bvFTD)
• Nonfluent variant primary progressive aphasia (nfvPPA)
• Semantic variant primary progressive aphasia (svPPA)
svPPA is characterized by impaired object naming and impaired sin-
gle-word comprehension, along with impaired object knowledge (es-
pecially for low-frequency or low-familiarity items), surface dyslexia
or dysgraphia (difficulty reading or spelling words with atypical
sound-letter associations such as “colonel” or “island”), and sparing of
repetition, grammaticality, and motor aspects of speech. A reverse
temporal gradient of recall may be observed, with poor recall of distant
autobiographical memories and spared recent memory. nfvPPA is
characterized by either agrammatism or speech apraxia (effortful, halt
-
ing speech with inconsistent sound errors and distortions) or both,
along with impaired comprehension of syntactically complex sen
-
tences and sparing of single-word comprehension and/or object
knowledge. bvFTD is characterized by early behavioral and executive
deficits. As FTD progresses and brain pathology spreads, these three
variants converge such that global cognitive impairment is seen. Motor
deficits are seen, including motor neuron disease in a subset of pa-
tients. Although the rate of progression varies among patients, death
is expected 7–8 years after onset of symptoms, usually due to intercur-
rent infection such as pneumonia.
bvFTD is characterized by progressive deterioration of behavior and/
or cognition as noted by history or observation. Symptoms of possible
bvFTD include the following:
• Early behavioral disinhibition
• Early apathy or inertia
• Early loss of sympathy or empathy
• Early perseverative, stereotyped, or compulsive/ritualistic be-
havior
• Hyperorality and dietary changes
• Neuropsychological profile of executive/generation deficits with
relative sparing of memory and visuospatial functions
Probable bvFTD can be diagnosed when three or more symptoms of
possible bvFTD are present, functional decline is noted, and neuroim-
aging results are consistent with bvFTD.
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408 Laboratory Medicine in Psychiatry and Behavioral Science
Frontotemporal dementia (FTD) (continued)
Clinical findings Definite bvFTD can be diagnosed with additional histopathological
(continued) evidence of frontotemporal lobar degeneration on biopsy or postmor-
tem exam or in the presence of a known pathogenic mutation.
Among those meeting criteria for possible bvFTD are a subset of pa-
tients who show little progression of behavioral and cognitive impair-
ment. This syndrome—termed bvFTD phenocopy—is difficult to
distinguish clinically from bvFTD at presentation, except that MRI and
PET findings appear normal. Affected individuals are more likely to
be young males lacking motor features and family history of FTD.
These patients tend to have a better prognosis than typical bvFTD pa
-
tients, as if their pathology were on a spectrum midway between
bvFTD and normal.
Patients with C9orf72 mutations present clinically with bvFTD, amyo-
trophic lateral sclerosis (ALS), or a combination of the two, or with
prodromal psychiatric syndromes. C9orf72 mutations give rise to re
-
peat expansions, with carrier status reported to be associated with bi-
polar disorder, OCD, and schizophrenia in the years preceding FTD
diagnosis. In more than half of carriers, delusions and hallucinations
(primarily auditory) are observed
and are often severe. Patients with
GRN mutations may exhibit visual hallucinations and delusions, and
there appears to be an association of these mutations with late-onset
bipolar I disorder that evolves into bvFTD.
Motor symptoms are most often seen in patients with bvFTD, including
early parkinsonism and motor neuron disease, the latter ranging from
mild symptoms to the fully developed syndrome of dysarthria, dyspha
-
gia, pseudobulbar affect, and upper and lower motor neuron signs.
Laboratory testing Genetic testing
Up to 50% of bvFTD cases are familial, most involving mutations in
C9orf72, MAPT, or GRN. The C9orf72 mutation is the most common, and
this and the GRN mutation have been associated with presentations that
resemble primary psychiatric disorders. The GRN and MAPT mutations
are seen almost without exception in individuals who have a strong
family history, whereas the C9orf72 mutation is also seen in sporadic
disease. C9orf72 mutations give rise to repeat expansions, with >200 re
-
peats considered pathogenic and ≤30 repeats considered normal.
Recommendations for testing are as follows:
• Genetic testing (all FTD mutations) in patients with probable
bvFTD and at least one first-degree relative with bvFTD, late-onset
primary psychiatric disorder, ALS, or other early onset neurode-
generative disease
• C9orf72 screening in all patients with possible or probable bvFTD,
regardless of family history
• C9orf72 screening in patients with late-onset primary psychiatric
disease and at least one first-degree relative with FTD or ALS
• Strongly consider C9orf72 screening in all patients with suspected
bvFTD that does not meet the full diagnostic criteria if there are
prominent psychiatric symptoms or the patient has a family his-
tory of late-onset primary psychiatric disease.
• GRN screening for patients with primary progressive aphasia, both
familial and sporadic
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409 Diseases and Conditions
Frontotemporal dementia (FTD) (continued)
Laboratory testing
(continued)
Neuroimaging
Structural imaging
• Structural neuroimaging is a requisite component of the workup
for FTD, with MRI preferred to CT.
• In bvFTD, disproportionate atrophy is seen in the frontal (espe-
cially right frontal) and anterior temporal areas, with the severity
dependent on the disease stage.
• In nfvPPA, degeneration is typically seen in the left inferior frontal
gyrus, insula, and premotor areas.
• In svPPA, bilateral anterior temporal atrophy is seen, left more
than right.
Functional imaging
• Functional neuroimaging findings parallel those of structural
imaging, with hypoperfusion (SPECT) or hypometabolism (PET)
in specific areas dependent on subtype of FTD.
• FDG-PET imaging can help distinguish FTD from Alzheimer’s
disease (AD).
• In bvFTD, FDG-PET shows glucose hypometabolism in orbitofron-
tal, dorsomedial, and dorsolateral prefrontal areas, anterior tempo-
ral pole, and basal ganglia. These may be detectable before clinical
criteria are met.
CSF analysis
• Analysis of CSF for amyloid-β
42
, tau, and phosphorylated-tau is
recommended to exclude AD.
• CSF neurofilament light chain assay can help to distinguish bvFTD
from primary psychiatric disorders. Neurofilaments are constitu-
ents of the axonal skeleton, and their presence in CSF is a marker
for neurodegeneration.
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 5th Edition,
Text Revision. Washington, DC, American Psychiatric Association, 2022
Bang J, Spina S, Miller BL: Frontotemporal dementia. Lancet 386(10004):1672–1682, 2015
Ci pr ian i G, Da nt i S, Nut i A, et al: Is th at s chizo ph renia or frontotemporal dementia? Supporting clinicians
in making the right diagnosis. Acta Neurol Belg 120(4):799–804, 2020
Mendez MF, Parand L, Akhlaghipour G: Bipolar disorder among patients diagnosed with frontotemporal
dementia. J Neuropsychiatry Clin Neurosci 32(4):376–384, 2020
Nobili F, Arbizu J, Bouwman F, et al: European Association of Nuclear Medicine and European Academy
of Neurology recommendations for the use of brain 18F-fluorodeoxyglucose positron emission to-
mography in neurodegenerative cognitive impairment and dementia: Delphi consensus.Eur J Neurol
25(10):1201–1217, 2018
Olney NT, Spina S, Miller BL: Frontotemporal dementia.Neurol Clin 35(2):339–374, 2017
Olszewska DA, Lonergan R, Fallon EM, Lynch T: Genetics of frontotemporal dementia. Curr Neurol
Neurosci Rep 16(12):107, 2016
Onyike CU, Huey ED: Frontotemporal dementia and psychiatry.Int Rev Psychiatry 25(2):127–129, 2013
Paquin V, Therriault J, Pascoal TA, et al: Frontal variant of Alzheimer disease differentiated from fronto-
temporal dementia using in vivo amyloid and tau imaging.Cogn Behav Neurol 33(4):288–293, 2020
Power C, Lawlor BA: The behavioral variant frontotemporal dementia phenocopy syndrome: a review.
J Geriatr Psychiatry Neurol 34(3):196–208, 2021
Pressman PS, Matlock D, Ducharme S: Distinguishing behavioral variant frontotemporal dementia from
primary psychiatric disorders: a review of recently published consensus recommendations from the
Neuropsychiatric International Consortium for Frontotemporal Dementia.J Neuropsychiatry Clin
Neurosci 33(2):152–156, 2021
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410 Laboratory Medicine in Psychiatry and Behavioral Science
Frontotemporal dementia (FTD) (continued)
Saracino D, Ferrieux S, Noguès-Lassiaille M, et al: Primary progressive aphasia associated withGRNmu-
tations: new insights into the nonamyloid logopenic variant. Neurology 97(1):e88–e102, 2021
Seeley WW: Behavioral variant frontotemporal dementia.Continuum (Minneap Minn) 25(1):76–100, 2019
Swift IJ, Sogorb-Esteve A, Heller C, et al: Fluid biomarkers in frontotemporal dementia: past, present and
future.J Neurol Neurosurg Psychiatry 92(2):204–215, 2021
van der Ende EL, Jackson JL, White A, et al: Unravelling the clinical spectrum and the role of repeat length
in C9orf72repeat expansions. J Neurol Neurosurg Psychiatry 92:502–509, 2021
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411 Diseases and Conditions
Generalized anxiety disorder (GAD)
Clinical findings GAD is characterized in DSM-5 by excessive anxiety and worry about
numerous events or activities that occur more days than not for at least
6 months. The individual finds the symptoms difficult to control. The
anxiety and worry are associated with three or more of the following
symptoms:
• Restlessness or feeling “keyed up” or “on edge”
• Easy fatigue
• Difficulty concentrating or “mind going blank”
• Irritability
• Muscle tension
• Sleep disturbance
These symptoms cause significant distress or impairment in social, oc-
cupational, or other areas of function. The disturbance is not attribut-
able to the physiological effects of a substance or another medical
condition and is not better explained by another psychiatric disorder.
The alternative diagnosis of anxiety associated with another medical
condition should be given if the patient’s history, laboratory findings,
or physical examination reveals a specific medical condition judged to
be causative. The alternative diagnosis of substance/medication
-
induced anxiety disorder should be given if a drug of abuse or expo-
sure to a toxin is judged to be causative. These conditions are more
closely associated with panic disorder and anxiety, but several com-
mon abnormalities should be excluded as contributing factors to GAD.
Although the identification of biomarkers of GAD is an active area of
investigation, findings have not yet been adequately validated for clin
-
ical use.
Laboratory testing The basic laboratory workup for GAD includes only TSH and a meta-
bolic panel (BMP or CMP) to check calcium and glucose levels. Further
testing may be indicated to exclude medical conditions causing or con-
tributing to anxiety. Depending on patient characteristics and history,
further evaluation might include one or more of the following:
• ECG, Holter monitoring, cardiac stress testing, and/or echocardio-
gram
• Chest X-ray, pulmonary function tests, and/or arterial blood gases
• GGT with or without CDT for suspicion of covert drinking
• Plasma free metanephrines
• Urine porphyrin precursors
• Pulmonary CT scan
• EEG
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 5th Edition,
Text Revision. Washington, DC, American Psychiatric Association, 2022
Hilbert K, Lueken U, Muehlhan M, Beesdo-Baum K: Separating generalized anxiety disorder from major
depression using clinical, hormonal, and structural MRI data: a multimodal machine learning
study. Brain Behav 7(3):e00633, 2017
Maron E, Nutt D: Biological markers of generalized anxiety disorder.Dialogues Clin Neurosci 19(2):147–
158, 2017
Tomasi J, Lisoway AJ, Zai CC, et al: Towards precision medicine in generalized anxiety disorder: review
of genetics and pharmaco(epi)genetics. J Psychiatr Res 119:33–47, 2019
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