Neurogenetics Flashcards
What are the clinical features associated w Walker Warburg syndrome
global developmental delay, ID, generalized severe hypotonia, muscle weakness, seizures, and various eye defects (microphthalmia, microcornea, lens defects, cataract, atrophy of the optic nerve, coloboma, glaucoma, or buphthalmos)
type II cobblestone lissencephaly in all cases
hydrocephalus, encephalocele, cerebellar hypoplasia w possible Dandy-Walker malformation
autosomal recessive; most severe form of congenital muscular dystrophy; lethal in the first few months of life
How is the dx of Walker Warburg made
dx is based on u/s and fetal MRI for ocular and brain abnormalities
elevated creatine kinase and myopathic/dystrophic muscle pathology w altered alpha dystroglycan expression
What is the management/treatment for Walker Warburg syndrome
no specific tx is available; management is only supportive and preventive
sx is required in some pts for the tx of hydrocephalus or encephalocele
How is the dx of Joubert syndrome established
based on the presence of characteristic clinical features and MRI findings
33 genes are AR and one is XLR
molecular dx is established in ~62-94% of individuals
What molecular testing should be ordered for Joubert syndrome
a multigene panel that includes some or all of the 34 genes that cause Joubert syndrome
targeted analysis for PVs in a specific gene can be performed for the following populations: AJ (TMEM216), Dutch (CPLANE1), French Canadian (CPLANE1, CC2D2A, NPHP1, TMEM231), Hutterite (TMEM237, CSPP1), Japanese (CEP290)
What are the three primary findings of Joubert syndrome
distinctive cerebellar and brain stem malformation called the molar tooth sign
hypotonia
developmental delays
What are the general clinical findings in Joubert syndrome
many of the features are evident in infancy
horizontal nystagmus, oculomotor apraxia in childhood, horizontal head titubation (no-no head tumor), apnea and tachypnea generally improves w age, increased risk for sleep apnea, variable cognitive abilities, speech apraxia, abnormal EEG/seizures, inattention, hyperactivity, temper tantrums
scoliosis, pituitary hormone dysfunction, obesity, heart defects (septal defects, aortic valve anomalies, coarctation of the aorta); laterality defects including situs inversus, conductive hearing loss, tongue hypertrophy
Describe the following Joubert syndrome subtype: Joubert syndrome w retinal disease
classic retinitis pigmentosa
retinal dz may not be progressive and is not always present in infancy or early childhood
ptosis, strabismus, and/or amblyopia; third nerve palsy
Describe the following Joubert syndrome subtype: Joubert syndrome w renal disease
two forms: nephronophthisis and cystic dysplasia
progression to ESKD by 13yo; renal changes visible on u/s –> scarred kidneys w increased echogenicity
another type that has been reported is similar to ARPKD
renal dz in 23% of pts
Describe the following Joubert syndrome subtype: Joubert syndrome w oculorenal dz
retinal dz and renal impairment occur together
Describe the following Joubert syndrome subtype: Joubert syndrome w hepatic dz
hepatic fibrosis is usually progressive but rarely symptomatic at birth
enlarged, abnormally shaped liver, relatively well preserved hepatocellular function leading to splenomegaly
often associated w chorioretinal colobomas and sometimes w renal dz
Describe the following Joubert syndrome subtype: Joubert syndrome w oral-facial-digital features
midline upper lip cleft, midline groove of tongue, hamartomas of the alveolar ridge, cleft palate, oral frenulae, tongue lobulations or hamartomas, wide spaced eyes (telecanthus), hypoplastic alae nasi, micrognathia
postaxial polydactyly, mesaxial polydactyly (extra digit occurs between the central digits)
Describe the following Joubert syndrome subtype: Joubert syndrome w acrocallosal features
agenesis of the corpus callosum that can present with or without polydactyly and hydrocephalus
What are the tx recommendations for someone w Joubert syndrome
Respiratory
supportive therapy may include stimulatory meds such as caffeine or supplementary O2, particularly in the newborn period
anesthetic management during sx procedures
aggressive tx of middle ear infections is indicated to avoid conductive hearing loss
hypotonia/therapeutic interventions
therapy of oromotor dysfunction, nasogastric tub/gastrostomy tube placement, EIP, periodic neuropsychologic and developmental testing
other CNS malformations
neurosx consultation is indicated for those w hydrocephalus, rarely requires shunting
encephalocele may require primary sx closure
anti seizure meds
ophthalmologic
sx as needed for symptomatic ptosis, strabismus, amblyopia; interventions for the visually impaired when congenital blindness or progressive retinal dystrophy are present
renal
ESKD resulting from nephronophthisis frequently requires dialysis and/or kidney transplantation during the teenage yrs or later
hepatic fibrosis
liver failure and/or fibrosis for sx intervention such as portal shunting for esophageal varices and portal HTN; some individuals have needed orthotopic liver transplantation
other
sx tx for polydactyly
consult w endocrinologist for menstrual irregularities and for pituitary hormone deficiency
What prenatal u/s findings can be used to possibly detect Joubert syndrome
first tri dx for pregnancies at 25% risk has been reported using u/s exam to identify structural brain abnormalities such as encephalocele
exam posterior fossa and/or kidneys for cysts and/or hyperechogenic kidneys, and digits for polydactyly as early as the second tri
visualization of the molar tooth sign is difficult in earlier gestation
What are the common features among cilliopathies
renal disease, retinal dystrophy, and polydactyly
What is the molecular pathogenesis of Joubert syndrome
all genes localize to the primary cilium and/or basal body and centrosome where they may play a role in the formation, morphology, and/or function of these organelles. The cilia are membrane-bound, hair like projections anchored to the basal body
How is the dx of Fragile X syndrome established
through the use of specialized molecular testing; typical multigene panels and comprehensive genomic testing are useful only when no CGG repeat expansion is detected by FXS is still suspected
caused by CGG trinucleotide repeat expansion in the 5’UTR of exon 1 of FMR1 w abnormal gene methylation for most alleles w more than 200 repeats
What is the significance of the allele sizes in Fragile X syndrome
Stability of alleles <90 repeats is heavily influenced by the # of AGG interspersions within the CGG repeat sequence, both w respect to risk for size change in intermediate alleles and small premutations and expansion to a full mutation in premutation alleles larger than ~60 repeats
normal (5-44 repeats); highest % of individuals w ~29-31 repeats
intermediate (45-54 repeats); 14% of intermediate alleles are unstable and may expand into the premutation range when transmitted by the mother; offspring are NOT at risk for FXS
premutation (55-200 repeats): increased risk for FXATS and FXPOI; women w alleles in this range are considered to be at risk of having children w FXS, although this risk is heavily dependent on the # of AGG interspersions for small premutation alleles
full mutation (>200 repeats): associated w aberrant hypermethylation of the FMR1 promoter; almost always, extensive somatic variation of repeat number
What are the clinical criteria associated w FXTAS
Definite: one major radiologic sign+1 major clinical sign or presence of FXTAS inclusions
Probable: either 1 major radiologic sign+ 1 minor clinical sign or 2 major clinical signs
Possible: 1 minor radiologic sign + 1 major clinical sign
radiologic sign
major: MRI white matter lesions in middle cerebellar peduncles
minor: MRI white matter lesions in cerebral white matter; moderate to severe generalized brain atrophy; MRI white matter lesions of the corpus callosum
clinical signs
major: intention tremor, cerebellar gait ataxia
minor: parkinsonism, moderate to severe short term memory deficiency, executive function deficit, neuropathy in the lower extremities
a major criterion is FXTAS intranuclear eosinophilic inclusions that are ubiquitin positive
What are the diagnostic criteria for FXPOI
Based on hypergonadotropic hypogonadism in women younger than 40yo who carry a premutation allele
- has to experience four to six months of amenorrhea
- has two serum menopausal level FSH values obtained at least one month apart
What testing should be ordered for Fragile X syndrome
PCR is used to size the CGG trinucleotide repeat region of FMR1 w high sensitivity; repeat primed PCR allows detection and location of AGG interspersions
Southern blot analysis detects all FMR1 alleles in addition to determining methylation status of the FMR1 promoter region; abnormal hypermethylation of FMR1 is the cause of transcriptional silencing and is critical to assess for full-mutation alleles
PCR w newer and more sensitive assays is now adequate for dx and size determination for the premutation, as well as for identification of the full mutation. Southern blot is currently only used to determine the methylation status for the full mutation and the X inactivation ratio for females w a premutation or full mutation
What ADDITIONAL testing could be ordered for Fragile X syndrome if other tests are normal
<1% of individuals w FXS have a sequence variant, a partial deletion, or a full deletion of FMR1
can order a multigene panel w FMR1 and other genes of interest
What are the clinical features found in males w Fragile X syndrome
medical problems in infancy/childhood: hypotonia, GERD, strabismus, seizures, sleep disturbances, joint laxity, pes planus, scoliosis, recurrent ear infections
normal growth but large head size
delayed developmental milestones (sit alone, 10mo; walk, 20mo; first clear words, 20mo)
ID
Behavioral issues in males and some females at all ages (ADHD, self-injurious behavior like hand biting, anxiety and irritable behaviors)
ASD in 50-70% associated w more severe behavioral issues and increased rate of seizures
distinct craniofacies; subset of individuals have typical physical features and presence is not reliable for dx
mitral valve prolapse, aortic root dilatation
macroorchidism in all males after completion of puberty
What are the clinical features in females heterozygous for full mutation alleles
physical/behavioral features in males w FXS have been reported in females but with lower frequency and milder involvement
Describe the clinical features of fragile X associated tremor/ataxia syndrome
late onset progressive cerebellar ataxia and intention tremor who have FMR1 premutation between 60-65yo
first sign is tremor followed by ataxia and cognitive impairment
executive function impairment
working memory and info processing speed; 1/2 meet criteria for dementia
other: short term memory loss, parkinsonism, peripheral neuropathy, neuropathic pain, autonomic dysfunction
psychiatric disorders
penetrance in those >50yo is lower in females (17%) than males (46%)
prevalence for females is about 16-20% of premutation carriers
Describe the clinical features associated with fragile X associated primary ovarian insufficiency
hypergonadotropic hypogonadism before 40yo in 20% of women w premutation allele
ovarian insufficiency, primary amenorrhea, delayed puberty, high rates of infertility, menopausal type symptoms; in contrast to menopause, ovarian function in women w POI is more erratic and unpredictable
dx of POI does not eliminate the possibility of subsequent conception; long term health sequelae including osteoporosis and cardiovascular disease; increased risk for developing thyroid dz
women w full mutation alleles are not at increased risk for FXPOI, nor do they have signs of diminished ovarian reserve
What are the clinical features seen in a premutation carrier of Fragile X syndrome
males and females have normal intellect and appearance; subset of individuals w a premutation may have subtle intellectual or behavioral symptoms including learning difficulties or social anxiety
higher repeat size is associated w greater motor impairment, more severe peripheral neuropathy, higher number of intranuclear inclusions in the brain, MRI abnormalities, and earlier age of onset
21% of women who carry a premutation develop FXPOI; women w 80-99 repeats are at greatest risk for FXPOI
What are the clinical features seen in full mutation carriers of Fragile X syndrome
males who have a full mutation generally have moderate to severe ID and may or may not have a distinctive appearance
50% of females who have a full mutation are ID but usually less severely affected than males; many q IQ in the normal range will have substantial issues w learning disability, ADHD, anxiety, and/or social emotional dysfunction
mosaicism of FMR1 variants is common; repeat size mosaicism AND methylation mosaicism such individuals are usually ID
Describe the anticipation seen in Fragile X syndrome
occurs when less severely affected individuals with a premutation or mosaic mutation transmit unstable FMR1 alleles to their offspring
the form of anticipation in FXS is increasing numbers of individuals w FXS w advancing generations
What is the significance of AGG trinucleotide repeats in Fragile X syndrome
and position of AGG trinucleotide repeats are known to be important in the overall stability of the CGG repeat sequence; presence of interruption confers reduced risk of transmission to a full mutation
CGG region is interrupted by an AGG triplet q9-10 CGG repeats
# and position of trinucleotide repeats are known to be important in the overall stability of CGG repeat sequence; presence confers reduced risk of transmission to full mutation
impact of AGG interruptions on the clinical outcomes in individuals w a premutation is unknown
What is the most common known single gene cause of ASD
2-3% of single gene ASD is caused by Fragile X syndrome
What tx are recommended for Fragile X syndrome
typically a dual approach: psychopharmacologic tx of symptoms as needed in conjunction w therapeutic services, such as behavioral intervention, speech and language therapy, OT, and individualized educational support
individuals w FXS are more sensitive to the adverse effects of psychotropic meds
early ed intervention, special ed, and vocational training should be aimed specifically at the known impediments to learning
routine medical management of strabismus, otitis media, GERD, cardiac issues, musculoskeletal concerns, and seizures is appropriate
management of behavior can involve a multidisciplinary clinical team; should be evaluated for ASD; ABA therapy; OT, avoid stimulation and identify interventions for sensory issues
What tx is recommended for FXTAS/ FXPOI
tx is currently symptomatic and supportive for FXTAS
gynecologic or reproductive endocrinologic eval can provide appropriate treatment and counseling for reproductive considerations and hormone replacement
no fertility tx available to increase spontaneous conception rates; discuss the risks of transmission of the premutation or full mutation to a child
both donor oocyte and donor embryo IVF are reasonable options; IVF in women w POI using autologous oocytes has very low success rate
HRT: at the time of dx, recommended to start HRT and continue until the median age of menopause
What referrals should be made for someone w Fragile X syndrome
eyes, ears, dental, cardiovascular, respiratory, GI, musculoskeletal, neurologic, psychiatric
What is someone at risk for if there is a donor oocyte in IVF
these pregnancies in general carry higher risks for HTN disorders of pregnancy (preeclampsia), prematurity, and small for gestational age babies
How can PGT be used for Fragile X syndrome
PGT cannot currently be used in clinical practice to determine if a premutation has expanded into the full mutation range
What is the molecular pathogenesis for Fragile X syndrome
full mutation alleles are associated w aberrant hypermethylation of the CGG expansion resulting in decrease or silencing of FMR1 transcription and loss of FMRP, the protein encoded by the gene
premutation alleles are not associated w hypermethylation but are associated w increased mRNA levels; Patho mechanism is thought to be due to toxicity from elevated levels of FMR1 mRNA
What genes are associated w isolated lissencephaly
LIS1: part of Miller Dieker, minimal parental recurrence risk (AD)
RELN: 25% recurrence risk (AR)
DCX/ARX: recurrence risk depends on maternal carrier status (they are usually asymptomatic or less severely affected)
How is the dx of Rett syndrome (MECP2 disorder) established
in a female proband w suggestive findings and a heterozygous PV
in a male proband w suggestive findings and a hemizygous PV
What testing should be ordered for Rett syndrome
sequence analysis of MECP2 w del/dup analysis
multigene panels such as Angelman/Rett syndrome panels
What are the clinical features associated w classic Rett syndrome
regression followed by recovery or stabilization; deceleration of head growth (acquired microcephaly); gait abnormalities; seizures; hand stereotypies and loss of purposeful hand skills; absence of speech, high pitched crying; cold extremities, irregular breathing, prolonged QT interval, hearing loss
most individuals are female; males meeting criteria have an 47,XXY karyotype and postzygotic MECP2 variants resulting in somatic mosaicism have been reported
What are the clinical features associated w variant Rett syndrome
regression followed by recovery or stabilization; gait abnormalities; sleep disturbances; seizures; hand stereotypies and loss of purposeful hand skills; irregular breathing; agitation
at the more severe end of the spectrum, development is delayed from very early infancy; congenital hypotonia, infantile spasm
in VERY rare instances, females w a PV MECP2 variant may only exhibit mild learning disabilities or some autistic features, presumably as a consequence of X inactivation
What are the tx for Rett syndrome
DD/ID tx as standard
epilepsy w ASMs
psychiatric/behavioral: risperidone or SSRIs for agitation
musculoskeletal: scoliosis tx per guidelines
poor weight gain/FTT: feeding therapy
spasticity: OT/PT/orthopedics
sleep disorder w melatonin
abnormal vision/strabismus: standard tx per ophthalmologist
hearing aids per ENT
tx for prolonged QTc interval
What is the de novo rate for Rett syndrome
99.5% of affected individuals represent simplex cases
What considerations are needed for possible fetuses affected w Rett syndrome
phenotype is difficult to predict and can range from apparently normal to severely affected
bc parental germline mosaicism for a MECP2 PV has been reported in multiple families, it is appropriate to offer prenatal testing to the parents of a child w a MECP2 disorder whether or not the MECP2 PV has been identified in the leukocyte DNA of either parent
Describe the clinical features associated w Alzheimer’s Disease
dementia that typically begins w subtle and poorly recognized failure of memory and slowly becomes more severe and, eventually, incapacitating
confusion, poor judgement, language disturbance, visual complaints, agitation, withdrawal, hallucinations
death from: general inanition (suffering), malnutrition, pneumonia
typical clinical duration is 8-10yrs
What % of Alzheimer’s Disease is late onset and early onset
late onset: 95%; early onset 5% (<65yo)
How is the clinical dx of Alzheimer’s Disease established
of plaques and tangles must > those in age-matched controls w/out dementia
relies on clinical-neuropathic assessment
findings of beta-amyloid plaques, intraneuronal neurofibrillary tangles (containing tau protein), and amyloid angiopathy remain the gold standard for dx
plaques should be positive for beta amyloid antibodies and negative for prion antibodies
aggregation of alpha synuclein in Lewy bodies may also be found in the amygdala, frequently an accumulation of TDP-43 protein
correct ~80-90% of the time
*single gene testing w sequence analysis followed by del dup is rarely useful and is NOT recommended
What percent of late onset familial cases (defined as 3 or more ppl affected) contribute to Alzheimer’s Disease? Early onset? Down syndrome?
15-25%; <2%; <1%
the rest are combination of environment and genetic interactions
What is the significance of APOE e4 alleles and Alzheimer’s Disease
APOE genotyping is NOT specific or sensitive, little role in predictive testing
gene APOE has three different alleles- e2, e3, e4; presence of e4 alleles in the heterozygous (three fold risk) or homozygous (15 fold risk) state confers a risk for early onset and late onset Alzheimer’s Disease but is not enough to cause the dz
20-25% of the pop are heterozygotes; 10-20% chance for heterozygote to develop AD by 75 while a 25-35% chance for a homozygote
~42% w Alzheimer’s Disease do NOT have an APOE e4 allele
APOE e2 allele seems to have a protective effect
The TREM2 p.Arg47His variant is a statistically significant risk factor for late onset AD, apparent interaction w APOE e4 allele has increased risk for late onset AD
Describe the phenotype and age of onset for early onset familial AD
usually before 65yo
dementia phenotype similar to late onset, sometimes w a long prodrome
APP: onset in 40s-50s
PSEN1: usually 40s-50s; relatively rapid progression over 6-7yrs; often associated w seizures, myoclonus, and language deficits
PSEN2: usually 40s-75; mean duration is 11yrs; reduced penetrance
What risks would you give to a family with Alzheimer’s Disease
late onset nonfamilial and their family members are at empiric risks (typically at a 20-25% risk)
late onset familial and their family members at a 15-25% risk; when both parents have AD (conjugal AD) risk to their children is at least 2x that of the general population
early onset familial: AD dz, bc the onset is typically in early adulthood and the progression is rapid, affected parents are not alive at the time of dx in their children (no de novo PVs have ever been reported)
How is the dx of Huntington disease established
identification of heterozygous abnormal CAG trinucleotide repeat expansion in HTT CANNOT CURRENTLY BE DETECTED BY CLINICAL SEQUENCE-BASED MULTIGENE PANELS, EXOME SEQUENCING, OR GENOME SEQUENCING
normal: 26 repeats or fewer
intermediate: 27-35 repeats; may be at risk for having a child w an allele in the HD causing range
pathogenic alleles: 36 or > repeats (reduced penetrance alleles are 36-39 repeats, at risk for HD but may not develop symptoms OR full penetrance alleles which are 40 or more repeats and is associated with development of HD)
What are the categories associated w Huntington disease classification
presymptomatic: may have changes in imaging, quantitative motor assessments, or other biomarkers; disease modifying tx when safe and available
prodromal: subtle changes in motor skills, cognition, and personality and can occur as early as 15-20yrs before clinical onset; apathy or depression or other behavioral changes; changes in quantitative motor assessment and imaging; disease-modifying tx appropriate
manifest HD: presence of clinical motor and/or cognitive signs and symptoms that have an impact of life; systematic and dz modifying tx appropriate
