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
What are the clinical features associated with early, middle, and late Huntington dz
Mean age of onset is 45yo; 2/3 present w neurologic manifestations, the other 1/3 with psychiatric manifestations
Early: Clumsiness, Agitation, Irritability, Apathy, Anxiety, Disinhibition, Delusions, Hallucinations, Abnormal eye movements, Depression, Olfactory dysfunction
Middle: Dystonia, Involuntary movements, Trouble w/balance & walking, Chorea, twisting & writhing motions, jerks, staggering, swaying, disjointed gait (can seem like intoxication), Trouble w/activities that require manual dexterity, Slow voluntary movements; difficulty initiating movement, Inability to control speed & force of movement, Slow reaction time, General weakness, Weight loss, Speech difficulties, Stubbornness
Late: Rigidity, Bradykinesia (difficulty initiating & continuing movements), Severe chorea (less common), Significant weight loss, Inability to walk, Inability to speak, Swallowing difficulties; danger of choking, Inability to care for oneself
mean survival time after onset is 15-18yrs avg age of death is 54-55yrs
Describe the abnormalities in movement, cognition, and psychiatric features in Huntington dz
movement: chorea is present in >90% of individuals, increases in severity over the first 10yrs, continuously present and cannot be suppressed voluntarily, worsened by stress; bradykinesia, rigidity, dystonia, impairment in voluntary motor is an early sign, clumsiness, problems in gaze fixation, dysarthria, dysphagia in the late stages; hyperreflexia
cognition: global and progressive decline in cognitive capabilities; forgetfulness, slowness of through process, impaired visuospatial abilities and impaired ability to manipulate acquired knowledge; loss of flexibility; impairment of executive functions; early in the dz the memory deficits in HD are usually much less severe than in Alzheimer’s dz (more similar to frontotemporal dementia)
psych: significant personality changes, affective psychosis, schizophrenic psychosis, depression, hostility, OCD, anxiety, and psychoticism, intermittent explosiveness, apathy, aggression, alcohol abuse, sexual dysfunction and deviations, and increased appetite are frequent; paranoid delusions;
incidence of depression is more than 2x that in the general pop; the critical periods for suicide risk are just prior to receiving a dx and later, when affected individuals experience a loss of independence; sleep and circadian rhythms are disrupted
What are the neurologic images consistent w Huntington dz
intraneuronal inclusions containing huntingtin, the protein expressed from HTT, are also a prominent neuropathologic feature of the dz
significant striatal atrophy in symptomatic individuals, regional and whole brain grey and white matter changes have been detected
What is juvenile HD
defined by onset of symptoms before 20yo and accounts for 5-10% of individuals with HD
severe mental deterioration, prominent motor and cerebellar symptoms, speech and language delay, and rapid decline
epileptic seizures, unique to the youngest-onset group, are present in 30-50% of those w onset of HD before 10yo
in teens, symptoms are more similar to adult HD
What are genotype/phenotype correlations in Huntington dz
juvenile onset–> HTT allele w CAG repeats >60
homozygotes for fully penetrant HD alleles appear to have a similar age of onset to heterozygotes, but may exhibit an accelerated rate of dz progression
more variability in the late age of onset is associated w smaller CAG sizes
What are the genetic modifiers in Huntington dz
cis acting: most common CAG repeat tract has a CAA interruption; uninterrupted CAG repeats are associated w decreased age of onset in HD and increased somatic instability of the repeat; uninterrupted CAG length is more predictive than polyglutamine length in estimating HD age of onset
Describe the anticipation seen in Huntington dz
occurs far more commonly in paternal transmission of the mutated allele
anticipation arises from instability of the CAG repeat during spermatogenesis
most often children w juvenile onset dz inherit the expanded allele from their fathers
What tx is available for Huntington dz
choreic movements can be partially suppressed by neuroleptics (haloperidol)
anti-parkinsonian agents may ameliorate hypokinesia and rigidity, but may increase chorea
psychotropic drugs/ASMs for psychiatric disturbances
valproic acid for tx of myoclonic hyperkinesia
What is the molecular pathogenesis of Huntington dz? What testing should be ordered to dx it
HTT encodes huntingtin protein. A CAG trinucleotide repeat expansion in exon one of HTT is translated into an uninterrupted stretch of glutamine residues in huntingtin. This polyglutamine expansion in huntingtin elicits toxic effects by dysregulating vital cellular processes, which ultimately leads to cell death
GOF mechanism
most repeats can be detected by traditional PCR. However, del of apparent homozygosity for a normal CAG repeat does not rule out the presence of a very large expanded CAG repeat
triplet primed PCR may be able to detect expansions, but repeat size cannot be determined
How is the dx of Friedrich ataxia
established in a proband of biallelic PVs in FXN in intron 1
normal alleles: 5-33 GAA repeats; >80-85% of alleles contain fewer than 12 repeats
mutable normal (premutation) alleles: 34-65 GAA repeats; accounts for fewer than 1% of FXN alleles
full penetrance (dz-causing expanded) alleles: 66 to approx. 1,300 GAA repeats; majority between 600-1200 GAA repeats
Borderline alleles: 44-66 repeats; shortest repeat length associated w dz has not been clearly determined
rare GAA repeats exist that are interrupted by other nucleotides, typically close to the 3’ end of the GAA repeat tract
size of the shorter expanded pathogenic GAA repeat alleles shows better correlation than the larger repeat allele and accounts for ~50% of the variation in age of onset
What testing should be ordered for Friedrich ataxia? How are the test results interpreted?
while the risk for phenotypic expression w borderline alleles is increased, it is not possible to offer precise risks; interpretation of test results in an individual w a large GAA expanded allele of full penetrance and a second allele of fewer than 100 GAA repeats may be difficult
single gene testing: targeted for abnormally expanded GAA repeat in intron 1 of FXN; if one abnormally expanded allele is identified, sequence analysis of FXN is performed next, followed by del/dup analysis; next gen cannot identify expanded repeats
What are the clinical features associated w typical Friedrich ataxia
in about 75% of affected individuals; age of onset is 10-15yrs old
neurologic manifestations: progressive ataxia w onset in childhood-early adulthood; starts w poor balance when walking, followed by slurred speech and upper limb ataxia; MRI is often normal in the early stages, w advanced dz atrophy of the cervical spinal cord and cerebellum
gait ataxia is the earliest symptom in the vast majority; ankle and knee jerks are generally absent
within 5yrs, lower extremity weakness, mixed axonal peripheral neuropathy; muscle weakness in hips and abductors; as dz advances, distal limb muscle weakness and wasting become evident
spasticity in the lower limbs; late stage- equinovarus deformity, contractures, pes cavus, restless leg syndrome; scoliosis in 2/3; autonomic disturbance (cold, cyanosed feet); dysarthria (changes in speaking rate and utterance duration); hoarseness, increased strain, altered pitch; dysphagia, HCM in 2/3 (usually in the later stages w higher number of repeats); urinary frequency and urgency; sleep disordered breathing and sleep apnea; DM, optic nerve atrophy which is often asymptomatic; SNHL; motor and mental rxn times can be significantly slowed
What is the progression of Friedrich ataxia
variable; avg time from symptom onset to wheelchair dependence is 10yrs; avg age of death is 37yrs
common causes of death include cardiac issues typically, then pneumonia
anticipation is NOT observed
What clinical features are associated w atypical presentations of Friedrich ataxia
25% have atypical findings
Late onset Friedrich ataxia: age of onset is 26-39yo; in very late onset Friedrich ataxia: age of onset is 40yo
late onset: frequently exhibit <500 GAA repeats in at least 1 of the expanded alleles
very late onset: frequently have <300 GAA repeats in at least one of the expanded alleles
individuals w somatically unstable, borderline alleles often have late onset/very late onset, mild and gradually progressive dz, and normal reflexes/hyperreflexia
What is the most common inherited ataxia
Friedrich ataxia
has not been documented in SE Asians, in sub-Saharan Africans, or among Native Americans
What tx’s are available for Friedrich ataxia
prosthesis, walking aids, wheelchairs, and PT
in pt rehab
OT
speech therapy to maximize communication skills
management of dysphagia: dietary modification, feeding tubs
tx of cardiac dz (close cardiac monitoring for pregnant women w Friedrich ataxia)
antispasmodic agents for bladder dysfunction
What is the molecular pathogenesis of Friedrich ataxia
inactivating PVs in FXN are of 3 types: GAA repeat expansion, nonsense or frameshift resulting in aberrant or premature termination of translation, and LOF missense and splicing variants –> result in loss of frataxin function
What testing should be ordered for Friedrich ataxia
southern blot, short and long PCR
What are the clinical features associated w Amyotrophic Lateral Sclerosis (Lou Gehrig dz)
progressive, fatal neurodegenerative dz primarily affecting motor neurons w additional areas within the frontal and temporal lobes; also affects other systems like bone (Paget dz of the bone) and muscle (inclusion body myopathy)
motor involvement
degeneration of the upper (UMNs) and lower (LMNs) motor neurons which send their axons through the brain stem and the spinal cord
innervate striated muscle leading to weakness, muscle weakness, muscle wasting (atrophy), hyporeflexia, muscle cramps, and fasciculations; asymmetric focal weakness of the extremities (stumbling or poor handgrip) or bulbar findings (dysarthria, dysphagia)
dx feature not seen in other neurodegenerative dz’s is hyperreflexia in segmental regions of muscle atrophy w/out sensory disturbance
neuropsychological involvement
white matter structural abnormalities in frontal and temporal lobes; 50% have some type of cognitive impairment in their lifetime most common in executive function, verbal fluency, and social cognition
on the severe end of the spectrum (5% as affected), frontotemporal dementia marked by severe atrophy progressively declines in socially appropriate behavior, judgement, and self-control as well as personality changes
What is the clinical course of Amyotrophic Lateral Sclerosis (Lou Gehrig dz)
regardless of initial manifestations, atrophy and weakness eventually spread to other muscles
oculomotor neurons are generally resistant to degeneration in ALS
once all muscles of communication and expression are paralyzed, individual is “locked in”; death from failure of respiratory muscles
males (onset at 55) more commonly affected than females (mid 60s); ~1/2 die within 5yrs of symptom onset; individuals <55 at symptom onset tend to survive longer
10-15% w ALS have genetic ALS; 10% of individuals w ALS have at least 1 other family member affected
How is the dx of Amyotrophic Lateral Sclerosis (Lou Gehrig dz) established
requires characteristic clinical features and specific findings on electrodiagnostic testing
most commonly employed consensus criteria for its dx is the Escorial criteria
electromyographic eval outlined in the Awaji criteria which may establish the dx more quickly than the consensus criteria alone
the gold standard for neuropsychological eval is a neuropsychological exam; includes the Edinburg cognitive and behavioral ALS screen AND the ALS cognitive behavioral screen
What are the notable variants in Amyotrophic Lateral Sclerosis (Lou Gehrig dz)
C9orf72: expansion of a noncoding GGGGCC hexanucleotide repeat is causative w >60 being widely dx
SOD1: p.Ala4Val is the most common N American variant and is associated w death within 12-18mo after symptom onset
UBQLN2 is the only XLR causative gene
What are the findings in simplex Amyotrophic Lateral Sclerosis (Lou Gehrig dz)
~85% do not have a FH
the etiology of simplex ALS is not well understood. It has been long thought to be multifactorial
lifetime risk of developing ALS is estimated at 1 in 350 for men and 1 in 500 for women
How would you evaluate the genetic cause of Amyotrophic Lateral Sclerosis (Lou Gehrig dz)
very rapid progression of symptoms raises suspicion for SOD1 ALS; an absent ankle reflex in the presence of subacute weakness of the leg may be an early sign in SOD1 ALS
multigene panel can help to determine the cause
What GC considerations should be taken place in Amyotrophic Lateral Sclerosis (Lou Gehrig dz)
most individuals w AD ALS have an affected parent
UBQLN2 is the only XLR gene known to be associated w ALS; both hemizygous males and heterozygous females will be affected
What is the recommended management for Amyotrophic Lateral Sclerosis (Lou Gehrig dz)
tx is palliative
riluzole: inhibits the production of glutamate, a neurotransmitter that has been theorized to be the initiator of a series of molecular events that damage neurons
edaravone: used for those who are early in the course of their illness
tofersen: for tx of SOD1 ALS which bind w mRNA to reduce SOD load in people w SOD1 ALS
What are the clinical features associated w Parkinson dz
neurodegenerative disorder; rest tremor, muscle rigidity, slowed movement, postural instability, insomnia, depression, anxiety, REM sleep behavior disorder, fatigue, constipation, dysautonomia, hyposmia (decreased smell)
unilateral onset w bilateral manifestations occurring as dz progresses
dementia and/or psychosis in 30-40%
How is the dx of Parkinson dz established
based on clinical findings of bradykinesia (slowed movement) plus rest tremor and/or rigidity
neuroimaging helps w definitive dx of dopaminergic deficit
the cardinal histopathologic features is the loss of dopaminergic neurons w intracytoplasmic inclusions (alpha synuclein containing Lewy bodies)
15% have a + FH of PD
Describe the onset of juvenile, early, and late onset Parkinson dz
onset is typically around 60yo
juvenile: <20yo
early onset: 20-50yo
late onset: >50yo
What is the etiology of genetic Parkinson dz
5-10% of all Parkinson dz is attributed to PVs in single genes (GBA1, LRRK2, PARK7, PINK1, PRKN)
age of onset in the proband can be useful in distinguishing AD PD from AR PD
almost all w AD PD inherited a PV from a parent
What are the features of juvenile onset Parkinson dz
the clinical presentation often includes additional signs such as dystonia, spasticity, and dementia
typically AR inheritance
What are the features of typical, late onset Parkinson dz of unknown cause
generally presumed to be multifactorial in origin
cumulative lifetime risk for PD in general is 4%; w a FH of late onset PD of unknown cause is ~2x greater (8%)
What systems does myotonic dystrophy type 1 affect? What are the clinical categories?
affects the skeletal and smooth muscle as well as the eye, heart, endocrine, and CNS
categorized into mild, classic, and congenital phenotypes
What are the features in mild myotonic dystrophy type 1
cataract and mild myotonia (sustained muscle contraction); life span is normal
What are the features in classic myotonic dystrophy type 1
CTG repeats in 100-1000 range; onset is typically in the 20s-30s
muscle weakness and wasting, myopia, cataract (w “Christmas appearance), and often cardiac conduction abnormalities; adults may become physically disabled and may have a shortened life span
brain MRI w mild cortical atrophy and white matter abnormalities
What are the features in congenital myotonic dystrophy type 1
hypotonia, inverted V shaped upper lip, and severe generalized weakness at birth, often with respiratory insufficiency and early death; ID is common
mom is almost always the one to transmit the larger repeat
How is the dx of myotonic dystrophy type 1 established
DM1 is caused by the expansion of a CTG trinucleotide repeat in the noncoding region of DMPK
normal: 5-34 repeats
premutation: 35-49 CTG repeats (no symptoms)
full penetrance: >50 repeats
electromyography (EMG) may have fast runs of single fiber discharges approaching the pattern of myotonic discharges and are suggestive; Serum CK may be slightly elevated; these tests are NOT dx
What tx is recommended for myotonic dystrophy type 1
use of ankle foot orthoses, wheelchairs, or other assistive devices
special ed support
tx of hypothyroidism
management of pain
consultation w a cardiologist for symptoms or EKG evidence of arrhythmia
removal of cataracts if vision is impaired
HRT for males w hypogonadism
sx excision of pilomatrixoma and BCC
What surveillance is recommended for pts w myotonic dystrophy type 1
annual EKG w 24hr Holter monitoring, annual measurement of serum glucose concentration, ophthalmology exam q2yrs, attention to nutritional status, polysomnography for sleep disturbances
Describe the anticipation seen in myotonic dystrophy type 1
transmission of the longer trinucleotide repeat alleles by MOM that may be associated w earlier onset and more severe dz than that observed in the parent
3-8% of expansions contain variant repeats such as CCG and CGG repeats which may be associated w later onset and milder features
What are the cancer risks w classic myotonic dystrophy type 1
may be at increased risk for thyroid, uterine, choroidal melanoma, and possibly colon, testicular, and prostate cancers
risk of skin cancers, especially BCC
What is the pregnancy management of someone w myotonic dystrophy type 1
at risk for complications including SAB rate, premature labor, prolonged labor, retained placenta, placenta previa, and postpartum hemorrhage
should get: u/s exam, eval for placenta previa, anticipation of possible polyhydramnios, prolonged labor, and/or need for delivery by C-section
for fetus: reduced fetal movement and polyhydramnios
What is the molecular pathogenesis for myotonic dystrophy type 1
CTG repeat that is expanded lies in the 3’ UTR of the DMPK gene; abnormal repeat lengths may reach several thousand, particularly in those w congenital DM1
What are the clinical features associated w myotonic dystrophy type 2
myotonia and muscle dysfunction (proximal and axial weakness, myalgia, and stiffness), and less commonly by posterior subcapsular cataracts, cardiac conduction defects (atrioventricular and intraventricular conduction defects, arrhythmias, left ventricular dysfunction, cardiomyopathy, and sudden death), insulin-insensitive type 2 diabetes mellitus, cochlear SNHL, and other endocrine abnormalities
onset in 3rd-4th decade; fluctuating/episodic muscle pain, weakness in elbow extensors and finger flexors, facial weakness, calf hypertrophy
unlike DM1, which can present in adulthood as a degenerative disorder or w variably severe congenital features, DM2 has not been associated w developmental abnormalities and thus does no cause severe childhood symptoms
How is the dx of myotonic dystrophy type 2 established
The diagnosis of DM2 is established in a proband by identification of a heterozygous pathogenic expansion of a CCTG repeat within a complex repeat motif, (TG)n(TCTG)n(CCTG)n in CNBP
normal: < or = 30 uninterrupted CCTG repats OR 11-26 repeats w GCTC/TCTG interruption
unknown: 27-29 CCTG repeats
premutation alleles: 30-54 repeats
unknown: 55-74 repeats
pathogenic: 75-11,000 CCTG repeats
the detection rate of a CNBP CCTG expansion is more than 99% with the combination of routine PCR, Southern blot analysis, and the PCR repeat-primed assay.
If routine PCR analysis detects only one allele, which occurs in 15% of unaffected individuals who are homozygous and in all affected individuals, it is necessary to perform both Southern blot analysis and the PCR repeat-primed assay to determine if the individual is homozygous for the normal-sized allele or has both a normal-sized allele and an expanded allele that fails to amplify by PCR because of its large size (allele sizes are reported in overall bp length rather than CCTG repeat number)
What is the recommended management/tx for myotonic dystrophy type 2
Ankle-foot orthoses, wheelchairs, or other assistive devices as needed for weakness; routine physical activity appears to help maintain muscle strength and endurance and to control musculoskeletal pain; medications used with some success in myalgia management include mexilitene, gabapentin, pregabalin, nonsteroidal anti-inflammatory drugs, low-dose thyroid replacement, and tricyclic antidepressants; myotonia rarely requires treatment but mexilitene or lamotrigine may be beneficial in some individuals; removal of cataracts or epiretinal membrane that impair vision; defibrillator placement for those with arrhythmias; hormone substitution therapy for endocrine dysfunction; prokinetic agents may be helpful for gastrointestinal manifestations; cognitive behavioral therapy and modafinil may be helpful for fatigue and daytime sleepiness; vitamin D supplementation for those with deficiency; hearing aids for sensorineural hearing loss.
What is the recommended surveillance for pts w myotonic dystrophy type 2
Annual evaluation with neurologist, occupational therapist, and physical therapist; annual ophthalmology evaluation for posterior subcapsular cataracts and epiretinal membranes; annual EKG, echocardiogram, and 24-hour Holter monitoring to detect/monitor cardiac conduction defects and cardiomyopathy; cardiac MRI per cardiologist; annual measurement of fasting serum glucose concentration, glycosylated hemoglobin level, thyroid hormone levels, and vitamin D; serum testosterone and FSH per endocrinologist.
What genetic counseling considerations are important myotonic dystrophy type 2
AD; all individuals have had one parent w a CCTG repeat expansion
NO correlation between dz severity/age of onset and CCTG repeat length
repeat length in the pt seems to increase w age, anticipation is not observed
What is another testing option (not molecular) that can help differentiate between type 1 and type 2 muscular dystrophy
muscle bx remains a useful dx tool
type 1 fiber atrophy is a common feature in people w congenital DM1
preferential type 2 fiber atrophy is observed in individuals w DM2
What are the cancer risks associated w myotonic muscular dystrophy type 2
tumor risks are higher in DM1 than DM2
may have increased risks for colon, brain, thyroid, pancreas, ovary, prostate, and endometrial cancer
What is the molecular pathogenesis of myotonic dystrophy type 2
GOF
toxic gain of function RNA process results in missplicing of the chloride channel, cardiac troponin T, and the insulin receptor contributing to the myotonia, cardiac involvement, and insulin insensitivity
How is the dx of DMD/BMD established in a male and female proband
male: diagnosis of a dystrophinopathy is established in a male proband with the characteristic clinical findings and elevated CK concentration and/or by identification of a hemizygous pathogenic
female: usually established in a female proband with characteristic clinical findings and elevated CK concentration and/or by identification of a heterozygous pathogenic
What are the expected CK levels for a male w DMD? BMD? A female w DMD? BMD?
Male
DMD: >10X normal
BMD: >5x normal
Female
DMD/BMD: 2-10x normal
What are some explanations for females w clinical features of DMD/BMD
del involving Xp21.2
X chromosome rearrangement involving Xp21.2 or complete absence of an X chromosome
UPD of the X chromosome
compound heterozygosity for two DMD PVs
nonrandom X-chromosome inactivation
What testing should be ordered for suspected DMD/BMD
Because the majority of pathogenic variants involve deletions of one or more exons, gene-targeted deletion/duplication analysis of DMD is performed first and followed by sequence analysis
A multigene panel may be most appropriate for individuals with less severe clinical presentations. Men with the BMD phenotype and most women may not have findings clinically distinct enough to suggest single-gene testing of DMD as the initial test
If no PVs are identified in molecular testing, what other type of testing can be ordered for suspected DMD/BMD
If no DMD pathogenic variant is identified, skeletal muscle biopsy of individuals with suspected DMD or BMD is warranted for western blot and immunohistochemistry studies of dystrophin. Skeletal muscle biopsy continues to be used only rarely in the diagnosis of dystrophinopathies.
How is the distinction between BMD and DMD made
based on the age of wheelchair dependency: before 13yrs in DMD and after age 16yo in BMD
when individuals w atypical dz develop severe cardiomyopathy, it is not possible to distinguish between BMD and DMD-associated DCM
echo is normal, pericardial effusion w cardiac tamponade, precipitating heart failure; subclinical or clinical cardiac involvement in 90% of those w BMD/DMD; cardiac involvement is the cause of death in 20% of individuals w DMD and 50% of those w BMD
What features are associated w DMD-associated DCM
Generally presents w congestive heart failure secondary to an increase in ventricular size and impairment of ventricular function
males- DCM is rapidly progressive w onset in teenage yrs, leading to death from heart failure within 1-2yrs after the diagnosis
DMD-associated DCM may be the presenting findings in individuals w BMD who have little to no clinical evidence of skeletal muscle dz.
Describe the clinical features associated w DMD
delayed motor milestones, general motor delays, persistent toe walking and flat footedness, delays in walking, learning difficulties, speech problems; boys use the Gower maneuver to rise from a supine position, using the arms to supplement weak pelvic girdle muscles; calf muscles are hypertrophic and firm
mean age of dx in boys is 10mo-4yo; rapidly progressive
cardiomyopathy in 1/3 by 14yo, present in all after 18yo but DMD is relatively infrequent cause of DCM; learning disability, ADHD/ASD, anxiety, decreased bone density, increased risk for fracture;
What is the lifespan for DMD
few affected individuals survive beyond the third decade; most do NOT reach reproductive age
What are the clinical features associated w BMD
later onset skeletal muscle weakness, mild end of the spectrum includes men w onset of symptoms after 30yo who remain ambulatory even into their 60s
cardiomyopathy: while skeletal muscle involvement is milder in BMD, heart failure from DCM is common cause of morbidity and the most common cause of death; heart transplant rate in BMD is high within 5yrs after the dx of cardiomyopathy; mean age of death in the 40s
cognitive impairment is not as common or severe compared to DMD
What clinical features can be seen in females w DMD/BMD
In some instances, females can have classic DMD
majority of those who are heterozygous for BMD (81%) and DMD (76%) have NO symptoms
19% (DMD) and 14% (BMD) of females will report muscle weakness, 19% (DMD) and 16% (BMD) report left ventricular dilatation
What is the reading frame rule in DMD/BMD
dels of exons 3-7 are the most extensively investigated del associated w both phenotypes
in frame del/dups are generally correlated w milder BMD phenotype
out of frame del/dups are generally correlated w more severe DMD phenotype
this rule has been able to predict phenotype w 91-92% accuracy
What is the difference that causes DMD to be more severe than BMD
DMD: very large dels lead to absence of dystrophin expression which produces a severely truncated protein
dups are more common in BMD, may result in exceptions to the reading frame rule in a higher proportion of cases (30%)
Dp71 and Dp140 are the shorter isoforms of dystrophin and are highly expressed in fetal brain w gradual increase from the embryonic stage to adult
BMD phenotype occurs when SOME dystrophin is produced, the shorter than normal produce can retain partial function
DMD-associated DCM is caused by PVs that affect the muscle promoter and the first exon, resulting in no dystrophin transcripts being produced in the cardiac muscle
What tx is recommended for pts w DMD/BMD
cardiomyopathy: ACE inhibitor and/or beta blocker; in cases of overt heart failure, other heart failure therapies including diuretics and digoxin; cardiac transplant is offered to those w severe DCM and BMD w limited/no clinical evidence of skeletal muscle dz
scoliosis in DMD/BMD: tx as needed, most pts end up getting a spinal fusion
corticosteroid therapy: improve the muscle strength, remains the tx of choice for affected individuals older than 4yo
Describe the dystrophin restoration therapies available for DMD
Exon skipping therapy in DMD restores the reading frame using synthetic antisense oligonucleotides (ASO) targeted the dystrophin pre-messenger RNA to skip out of frame variants.
~70% of PVs in DMD are located between exons 45-55
What surveillance is recommended for males w DMD/BMD
DMD: complete cardiac eval (ECG, echo, and cardiac MRI) q2yrs @ beginning of dx, annual complete cardiac eval at 10yo or the onset of cardiac signs
BMD: complete cardiac eval q2yrs, beginning @ dx. Eval should continue at least q2yrs
BOTH: perform baseline pulmonary function testing before confinement to a wheelchair (9-10yo in DMD), 2x yrly eval once any of the following occurs: confinement to a wheelchair, reduction in vital capacity below 80% predicted, age 12yo
What surveillance is recommended for females heterozygous for PVs in DMD
Complete cardiac eval w initial eval to take place in late adolescence or early adulthood, or earlier at the appearance of cardiac signs/symptoms
starting @25-30yo, screening w complete cardiac eval q5yrs
What evals should an at-risk family member undergo for DMD/BMD
serum creatine phosphokinase (CK) testing if the PV is not known
molecular testing of an at risk female if an affected male is not available for testing: del/dup analysis, sequencing, linkage to determine carrier status
BC the markers used for linkage are highly informative and lie both within and flanking the DMD locus, they can be used for most families
What is the molecular pathogenesis for DMD/BMD
in both, partial dels and dups cluster in 2 recombination hot spots, one proximal at the 5’ end of the gene, comprising exons 2-20 (30%) and one more distal, comprising exons 44-53 (70%). Dups cluster near the 5’ end of the gene, w dup of exon 2 being the single most common dups identified
dels of one or more exons may result in in-frame or out of frame transcripts and account for ~60-70% of PVs in individuals w DMD and BMD
PVs that lead to lack of dystrophin expression tend to cause DMD whereas those that lead to abnormal quality or quantity of dystrophin lead to BMD
How is SMA identified on NBS
confirmatory molecular testing including single gene testing for del/dup of SMN1 exon 7; if ONE copy of SMN1 exon is present, perform sequence analysis of SMN1; if exon 7 is present in both copies of SMN1, consider other dx
bc SMN1 sequence analysis cannot determine whether a punitive inactivating variant is in SMN1 or SMN2: establish that the inactivating variant has previously been reported in SMN1 OR sequence a long range PCR product or subclone of SMN1 (Can also do gene del/dup to determine SMN2 copy number)
What are the general clinical features in SMA
muscle weakness and atrophy resulting from progressive degeneration and irreversible loss of the anterior horn cells in the spinal cord and the brain stem nuclei; weakness is symmetric, proximal rather than distal, and progressive
Describe the features, lifespan, and motor milestones associated w SMA 0
Motor milestones: NONE
Lifespan: a few weeks, <6mo
onset: prenatal
Severe neonatal hypotonia
Severe weakness
Areflexia
Respiratory failure at birth
Facial diplegia
↓ fetal movements
Atrial septal defects
Arthrogryposis
Describe the features, lifespan, and motor milestones associated w SMA 1
motor milestones: some head control, sit w support only
lifespan: 8-10mo
onset: <6mo
Loss of head control
Mild joint contractures
Normal or minimal facial weakness
Variable suck & swallow difficulties
Describe the features, lifespan, and motor milestones associated w SMA 2
motor: independent sitting when placed
lifespan: 70% alive by 25yo
onset: 6-18mo
Developmental delay w/loss of motor skills
↓ or absent deep tendon reflexes
Proximal muscle weakness
Postural tremor of fingers
Describe the features, lifespan, and motor milestones associated w SMA 3
motor: independent ambulation
lifespan: normal
onset: >18mo
Proximal muscle weakness (i.e., difficulty w/stairs, running)
Loss of motor skills
Fatigue
Postural tremor of fingers
Loss of patellar reflexes
Puberty may be associated w a more rapid decline in function
Describe the features, lifespan, and motor milestones associated w SMA 4
motor: normal
lifespan: normal
onset: adulthood
Fatigue
Proximal muscle weakness
Least common form, affected <5% of affected individuals
What are the complications associated w SMA
Poor weight gain w growth failure, restrictive lung dz, scoliosis, joint contractures, and sleep difficulties are common in those who receive supportive care only; severe metabolic acidosis w dicarboxylic aciduria and low serum carnitine concentrations during periods of intercurrent illness or prolonged fasting
respiratory failure is the most common cause of death in SMA I and II
In those w SMA II and III, 50% develop spinal curvatures >50degrees before 10yo
What is the significance of SMN2 in SMA
of copies ranges from 0-5, presence of two copies of SMN2 is ~80% predictive of the SMA I phenotype; presence of 4 or more copies is ~88% predictive of SMA III/IV
Small amounts of full length transcripts generated by SMN2 produce functional protein and result in the milder SMA II or SMA III phenotype
# of copies ranges from 0-5, presence of two copies of SMN2 is ~80% predictive of the SMA I phenotype; presence of 4 or more copies is ~88% predictive of SMA III/IV
a single base substitution (p.Gly287Arg) in exon 7 of SMN2 has been identified as a dz modifier resulting in a milder dz
What tx options are available for SMA
target the underlying mechanism that leads to SMA have become available and have been shown to have a positive effect on dz progression
targeted tx is available for all individuals who have 2 or 3 copies of SMN2
for individuals who have 1 copy of SMN2, targeted tx is left to the distraction of the treating physician
for individuals w 4 or > copies of SMN2, targeted tx can be deferred until symptom onset
Spinraza (antisense oligonucleotide); Zolgensma (gene replacement therapy w viral delivery of SMN1)
What is the de novo rate in SMA
~2% of parents are NOT carriers of an SMN1 PV, as their affected child has a de novo variant. The majority of de novo variants are paternal in origin
How to determine carrier status in SMA
~4% of carriers have 2 SMN1 cis, specifically seen in the Jewish and Black populations
if a child is confirmed to have exon 7 deleted from both SMN1’s
if exon 7 is found to be deleted from one copy of SMN1 in only one parent, the following are possible explanations: 2+0 genotype, child may have a de novo del of exon 7, non-paternity
if child is confirmed to have exon 7 del from one copy of SMN1 and an intragenic PV in the other copy of SMN1, first perform SMN1 dosage analysis on both parents: one parent is found to have the SMN1 del and the other parent should have molecular testing for the intragenic PV on the parent who did not have the del exon 7
if the intragenic SMN1 PV identified in the child is not identified in the parent, possible explanations include: a de novo intragenic SMN1 PV in the child, germline mosaicism, alternate paternity
How would you determine the genetic status of a deceased child w suspected SMA
Muscle bx’s and blood spots often provide enough DNA for molecular testing
If DNA is not available, perform dosage analysis on both parents
previously affected sibs would have similar clinical findings, there can be intrafamilial variability in phenotypic presentation
What is the molecular pathogenesis of SMA
SMN1 produces a full length survival motor neuron protein necessary for lower motor neuron function. SMN2 predominantly produces a survival motor neuron protein that is lacking in exon 7, a less stable protein
SMN region in on chrom 5q12.3-q13.3 w repetitive regions, pseudogenes, retrotranspoable elements, dels, and inverted dups
SMN1 and SMN2 each comprise nine exons and differ only in 8 nucleotides
common exon 7 del is found in 95% of affected individuals
Reduced SMN lowers the capacity of cells to assemble the snRNPs, which leads to defects in splicing,, impaired capacity to produce specific mRNAs necessary for cellular growth and function
