Biochemical Genetics 3 Flashcards
Mito, LSDs, MPS's, and Peroxisomal disorders
What are the dx criteria for mitochondrial encephalomyopathy, lactic acidosis, and seizure-like episodes (MELAS?)
Two different criteria published:
1. following three must be met (stroke episodes before 40yo, encephalopathy with seizures and/or dementia, mito myopathy is evident by the presence of lactic acidosis and/or ragged-red fibers on muscle bx) AND at least two of the following (normal early psychomotor development, recurrent headaches, and recurrent vomiting episodes)
- at least TWO category A AND TWO category B criteria
A- headaches with vomiting, seizures, hemiplegia, cortical blindness, acute focal lesions on neuroimaging
B- high plasma or CSF lactate, mito abnormalities on muscle bx, a MELAS PV
How can MELAS be dx with molecular genetic testing
typically blood leukocyte DNA is initially tested for the m.3243A>G PV in MT-TL1, present in ~80% of individuals with typical clinical findings
If the above is normal, targeted testing for other specific mito variants in MT-TL1 and in MT-ND5 is considered next
entire mito genome sequencing that includes MT-TL1, MT-ND5, and other mtDNA genes of interest is most likely to identify the genetic cause
What are the clinical features associated with MELAS
Childhood is the typical age on onset with ~75% of affected individuals presenting at or before 20yo
most common initial symptoms are seizures, recurrent headaches, stroke-like episodes, cortical vision loss, muscle weakness, recurrent vomiting, and short stature
stroke-like episodes present clinically with partially reversible aphasia, cortical vision loss, motor weakness, headaches, altered mental status, and seizures with neurologic deficits; dementia, focal and primary generalized seizures, white matter lesions, cortical atrophy, and corpus callosum agenesis or hypogenesis, migraine headaches can precipitate stroke-like episodes, hearing impairment due to SNHL is usually mild, peripheral neuropathy, early psychomotor development is usually normal, psychiatric illnesses (depression, BPD, anxiety, personality changes)
exercise intolerance, recurrent/cyclic vomiting is common, diabetes occurs occasionally
What is the life expectancy of someone with MELAS
Dz progresses over yrs with episodic deterioration related to stroke-like events. Course varies from individual to individual (average is around 35yo)
Describe the causes of phenotypic variability in those with MELAS
Heteroplasmy: the presence of a mixture of mutated and normal mtDNA
Tissue distribution of mutated DNA
Threshold effect: vulnerability of each tissue to impaired oxidative metabolism
mutational load and tissue distribution do vary and may account for the clinical diversity seen
the m.3243A>G PV is associated with diverse clinical manifestations and is the most frequent variant associated with MELAS
penetrance is dependent on mutational load and tissue distribution, which shows random variation within families
What initial evals must someone with MELAS undergo following dx
measurement of height and weight for growth
ophthalmology eval
audiology eval
echo and electrocardiogram for cardiovascular eval
urinalysis and urine aa analysis for renal involvement
PT/OT assessment
neurologic eval, head MRI w MRS, and neuropsychiatric testing
fasting serum glucose, glucose tolerance test to screen for DM
What is the recommended tx for pts with MELAS
Tx is primarily supportive
Arginine therapy: once an individual has the first stroke like episode, arginine should be administered prophylactically to reduce the risk of recurrent stroke like episodes
CoQ10, L carnitine, creatine, traditional anticonvulsant therapy, aerobic exercise, standard therapy for cardio problems, neuropathy, DM
What should be avoided for ppl with MELAS
mito toxins such as: aminoglycoside antibiotics, linezolid, cigarettes, and alcohol
no valproic acid should be avoided in the tx of seizures
metformin bc of its propensity to cause lactic acidosis
dichloroacetate bc of onset or worsening of peripheral neuropathy
How should someone with MELAS be managed if they become pregnant
infertility may preclude pregnancy in some affected individuals
affected or at risk women should be monitored for the development of DM and respiratory insufficiency, which may require therapeutic interventions
interpretation of prenatal testing is complex bc 1. the mutational load in mom’s tissue and in fetal tissues sampled may not correspond to that of other fetal tissues, 2. mutational loas in tissues sampled prenatally may shift in utero or after birth as a result of random mitotic segregation, 3. prediction of phenotype, age of onset, severity, or rate of progression is not possible
What is the molecular pathogenesis of MELAS
the inability of dysfunctional mitochondria to generate sufficient energy to meet the energy demands of various organs results in the multiorgan dysfunction observed in MELAS syndrome
PVs in mito tRNA genes result in impaired mito protein synthesis. PVs in ETC structural subunits result in impaired ATP synthesis via oxidative phosphorylation
What makes up the mitochondrial genome
mtDNA encodes 22 tRNAs that are essential for mitochondrial protein synthesis
What are the laboratory findings that would be suggestive of MERRF
lactic acidosis both in the blood and in the CSF, pyruvate commonly elevated
Elevated CSF protein concentration
decreased activity of respiratory chain complexes containing mtDNA-encoded subunits, biochemical studies may also be normal
What are the histopathologic features on muscle bx indicative of MERRF and what electrophysiologic features may be present
ragged red fibers are seen
brain MRI often shows brain atrophy and basal ganglia lesions
How is the dx of MERRF established
the clinical dx is based on the following 4 “canonic” features:
1. myoclonus, 2. generalized epilepsy, 3. ataxia, 4. ragged red fibers in the muscle bx
PV in MT-TK (>90%) or other mito genes
How is MERRF identified on molecular genetic testing
serial single gene testing can be considered
targeted analysis- typically, blood leukocyte DNA is initially screened for PVs in MT-TK using targeted analysis for the m.8344A>G PV, which is present in more than 80% of individuals with typical clinical findings
What are the clinical features that can be seen in individuals with MERRF
Myoclonus, epilepsy, normal early development, ragged red fibers, SNHL, lactic acidosis, FH of MERRF, exercise intolerance, dementia, neuropathy, short stature, impaired sensation, optic atrophy, cardiomyopathy/arrythmias, pigmentary retinopathy, pyramidal signs, ophthalmoparesis, lipomatosis, and DM
Describe the neurologic and cardiac manifestations seen in individuals with MERRF
myopathy: exercise intolerance, muscle weakness, and elevated blood creatine kinase level
generalized myoclonic seizures, commonly migraines, SNHL, peripheral neuropathy, early development is typically normal, depressive mood episodes have been reported
cardiomyopathy (both dilated and hypertrophic)
lipomatosis can be seen in adulthood. average age of onset is in the 40s with lipomas being infiltrative, progressive, and massive in size
What are the initial evals recommended after dx of MERRF
measurement of height and weight, neurologic eval, Head MRI w MRS, EEG, neuropsychiatric testing, audiologic eval, ophthalmologic eval, PT/OT assessment, cardiac eval w echo, electrocardiogram, fasting serum glucose, glucose tolerance test
What is the recommended tx for MERRF
overall dz process: ubiquinol, carnitine, alpha lipoic acid, vitamin E, vitamin B complex, creatine
anticonvulsant therapy for seizures
levetiracetam or clonazepam for myoclonus
cochlear implants or hearing aids for hearing loss
What should be avoided in individuals with MERRF? How should someone be monitored during pregnancy if mom is affected?
avoid mito toxins such as aminoglycoside antibiotics, linezolid, cigs, alcohol; valproic acid should be avoided
should be monitored for DM and respiratory insufficiency, which may require therapeutic interventions
What is mitochondrial replacement therapy for tx of MERRF and other mito conditions
replacement of a woman’s abnormal mito DNA with health mito DNA drom a donor
not approved in the US
How is the dx of LHON established
established in a proband with: bilateral subacute vision failure that develops during young adult life, optic disc atrophy, disk hyperemia, edema of the peripapillary retinal nerve fiber layer, retinal telangiectasia, increased vascular tortuosity, optic nerve dysfunction AND/OR
one of three common mtDNA PVs identified by molecular genetic testing
How can LHON be detected with molecular genetic testing
targeted analysis for the three common mtDNA PVs observed in ~90% of individuals with LHON should be performed first
heteroplasmy occurs in just 10-15% of individuals with LHON
affected individuals generally have more than 70% mutated mtDNA in leukocytes
What are the stages of LHON? What are the clinical features associated with each stage
typically presents in YA as bilateral painless subacute visual failure; 95% lose their vision and do so before 50yo; males are 5x more likely to be affected than females; other: postural tumor, peripheral neuropathy, nonspecific neuropathy, movement disorders, Leigh syndrome
Presymptomatic phase: peripapillary telangiectatic vessels, retinal nerve fiber layer edema, loss of color vision, reduced contrast sensitivity
Acute phase: develop visual blurring affecting the central visual field in one eye; at least 97% of affected individuals have bilateral involvement within one yr
chronic phase: optic atrophy (typically develops within 6wks of the onset of visual loss), centrocecal scotoma
recovery of visual function- if it does occur- is usually incomplete
What penetrance considerations need to be taken into account when seeing pts with LHON
characterized by reduced penetrance and penetrance can vary markedly
the 2 most important risk factors are age and sex:
50% of males and 90% of females do not develop blindness; the 95th centile for age at onset in a male is 50yo for all three primary PVs
smoking has been associated with an increased risk for vision loss
What is the recommended initial evals following dx of LHON
Measurement of best corrected visual acuity
assessment of visual fields
measurement of retinal nerve fiber layer thickness
EKG although cardio manifestations are often a rare finding
screening for possible associated neurologic complications
How are pts with LHON tx
management of individuals remains mostly supportive and includes provision of visual aids, occupational rehab, and registration with the relevant local social services
What should ppl with LHON avoid
strongly advised not to smoke and to moderate their alcohol intake; avoidance of other environmental factors that have been implicated in precipitating visual loss in LHON (head trauma, industrial toxins, drugs w mito toxic effects, etc)
What is the de novo and inherited rate of PVs in LHON
in ~60% of families, a hx of visual loss affecting maternal relatives is present
up to 40% of individuals with LHON have no known FH
What are some related genetic counseling issues when seeing a pt with suspected LHON or a FH of the condition
identification of the familial LHON related PV confers a lifetime risk; the most impt factors determining risk are sex and age
for ex: a male age 18yo has a lifetime risk of ~50% for LHON AFTER a + test result. the risk declines with age but never falls to zero (bc loss of sight can occur at any age)
What are the common clinical features seen in individuals with CPEO (Chronic progressive external ophthalmoplegia)
external ophthalmoplegia (paralysis of the extraocular muscles), bilateral ptosis, mild myopathy
What three features define a dx of Kearns-Sayre syndrome? What other features can they have?
subtype of chronic progressive external ophthalmoplegia (CPEO)
1. onset before the age of 20
2. pigmentary retinopathy (can mimic retinitis pigmentosa; characteristic “salt-and-pepper” pattern of pigment clumping
3. CPEO
have at least one of the following: complete heart block (predisposes to sudden death or stroke), high CSF fluid protein, cerebellar ataxia, short stature, SNHL, endocrine abnormalities
demonstrates ragged red fibers on muscle bx
What causes KSS? How can it be dx?
90% are sporadic cases caused by a deletion of mito DNA
Dx using NGS of the mito genome in peripheral blood leukocyte samples is the preferred dx modality
How are pts with KSS monitored and tx?
care is primarily supportive
folic acid supplementation in those with low CSF is recommended
HRT for those with endocrinopathies
cardiac pacemaker for pts with cardiac conduction blocks
yrly ECG, echo, and 24-Hr Holter monitoring (no matter pts age), audiometry, and endocrinologic eval
Describe the molecular pathogenesis of PDCD (pyruvate dehydrogenase complex deficiency)
mito disorder of carbohydrate oxidation that mostly affects the brain and leads to decreased ATP production and energy deficits
How can PDCD present prenatally? when is the typical age of dx?
around 45 months (little before 4yo)
on u/s can present with microcephaly, IUGR, structural brain anomalies including: ventriculomegaly, paraventricular psudocysts, cerebellar hypoplasia, delayed gyration, and/or dysgenesis of the corpus callosum
What are the features associated with PDCD deficiency
Neurologic findings
DD, hypotonia, epilepsy, hypertonia, ataxia, peripheral neuropathy, dystonia, spasticity,
facial features that resemble those in FAS (long philtrum, thin upper lip, low set ears)
rare ophthalmologic findings; primary or acquired microcephaly; acquired hip dysplasia
psychiatric manifestations in adolescence and early adulthood (auditory hallucinations, delusional thoughts)
brain MRI findings: cerebral atrophy, asymmetric ventriculomegaly, agenesis/dysgenesis of the corpus callosum
What are the laboratory findings consistent with a dx of PDCD
elevated blood, urine, and CSF lactate and pyruvate
elevated ala and pro
low pyruvate dehydrogenase complex enzyme activity in cultured fibroblasts, lymphocytes, or skeletal muscle
What initial evals should someone with PDCD undergo
consult with metabolic physician and specialist metabolic dietician
STAT blood gas, blood lactic acid and glucose, comprehensive metabolic panel, serum beta hydroxybutyrate (on keto diet), urinalysis, plasma acylcarnitines for metabolic decomp
eval for seizures and structural brain abnormalities
How should pts with PDCD be tx
those with mutations in DLAT, PDHA1, PDHB, PDHX, and PDP1 should follow a keto diet (gold standard tx) and consider thiamine (vitamin B1)
ppl with PDCD do not metabolize carbs efficiently; therefore carbs may precipitate lactic acidosis; supplement with L-carnitine to protect against secondary carnitine deficiency which is associated with long term use of keto diet
those with mutations in DLD need BCAA restriction, dextrose containing IV fluids, riboflavin
All need: benzos for dystonia (botulinum toxin injections if chronic); PT/OT for spasticity; keto diet/standard ASM for seizures; vestibular therapy for ataxia; feeding tube/therapy for inadequate nutrition; bicarb or buffer therapy for acidosis correction; surgical correction/supportive bracing for hip dysplasia; standard psychiatric care for any manifestations
How is PDCD inherited? What are the special genetic counseling manifestations
inherited in XLR (PDHA1) BUT equal frequency of affected males and females; females tend to have indels while males tend to have missense PVs; ~60% of males have a de novo PV; ~85-95% of females have a de novo PV
DLAT, DLD, PDHB, PDHX, PDP1 are inherited in an AR manner
What lab findings are consistent with a dx of Leigh syndrome/NARP
elevated blood lactate, elevated CSF lactate, increased ala, decreased citrulline, elevated 3-hydroxy-isovalerylcarnitine (C5-OH), lactic aciduria, increased Krebs cycle intermediates, increased dicarboxylic acids
What brain imaging findings are associated with Leigh syndrome/NARP
bilateral symmetric hyperintense signal abnormality in the brain stem and/or basal ganglia
magnetic resonance spectroscopy lactate peak (in the absence of acute seizures)
What are the clinical dx criteria for Leigh syndrome
Typical neuroradiologic findings (bilateral symmetric hyperintense signal abnormality in the brain stem and/or basal ganglia) AND one or more of the following characteristic neurologic clinical findings: developmental regression, developmental delay, psychiatric features AND one or more of the following biochemical and/or mitochondrial abnormality: elevated lactate in plasma and/or CSF, MRS lactate peak in absence of acute seizures, respiratory chain enzyme activity deficiency (<30% enzyme activity) in affected tissues (muscle, liver, fibroblasts
What kind of molecular testing can be used to detect Leigh syndrome/NARP
genome sequencing is preferred as it allows analysis of the mito and nuclear genome and typically has the highest diagnostic rate
exome sequencing should be considered in conjunction with mtDNA sequencing, especially in the pediatric pop, given that ~70% of individuals will have nuclear gene-encoded LSS
rare, autosomal recessive or de novo PVs also have occurred
1/4 of probands have de novo PVs
most frequently observed phenotype of pediatric-onset mito disorders
What are the clinical features associated with Leigh syndrome
typical onset in infancy or early childhood of sudden neurodevelopmental regression. Clinically, it is difficult to distinguish between mtDNA and nuclear gene encoded Leigh syndrome
DD, regression, hypotonia, dystonia, ataxia, spasticity, muscle weakness, peripheral neuropathy, dysphagia, epilepsy, respiratory abnormalities, SNHL, ophthalmoplegia, optic atrophy, retinopathy, poor weight gain, gastro manifestations, cardiac manifestations, hepatic manifestations, renal manifestations, endocrine manifestations
What prenatal technologies are currently available for mito disorders
rr assessment and prenatal testing is challenging due to the intricacies of mtDNA transmission such as the mtDNA bottleneck effect, PV-specific selection, and the threshold effect
PGT is currently considered an appropriate reproductive option for females with familial heteroplasmic mtDNA PVs and is likely the best option available for those with moderate recurrence risk
quantification of the heteroplasmy levels in fetal tissue can be obtained by CVS or amnio; major limitation is the potential difficulty in predicting clinical outcome based on fetal genetic testing results
What initial evals should someone with Leigh syndrome undergo
Neurologic eval, Brain MRI and MRS, Plasma and CSF lactate and pyruvate, urine organic acids
pulm assessment for apnea, hyperventilation, or irregular respiration
measurement of growth parameters/ nutrition and feeding eval
developmental and/or cognitive assessment
PT and OT eval
Ophthalmologic eval
BP, EKG, Echo
Liver function tests, consider abdominal u/s
urinalysis, urine aas, serum electrolytes, BUN, creatinine
audiologic eval
CBC to assess for anemia
random glycose for monitoring of DM
assess for anxiety and other psychosocial manifestations
How is the dx of Fabry dz established in a male proband
identification of deficient alpha-galactosidase A enzyme activity in plasma, isolated leukocytes, and/or cultured cells
males w classic form have <1% enzyme activity
males w atypical form have >1% enzyme activity
hemizygous PV in GLA
What clinical features are associated with NARP syndrome
neurogenic muscle weakness, ataxia, and retinitis pigmentosa
can also include mild learning difficulties, night blindness, deafness, DM, migraine, or sudden unexpected death
How is the dx of Fabry dz established in a female proband
although demonstration of markedly decreased alpha gal A enzyme activity is dx of the heterozygous state, some heterozygotes have activity levels in the normal range
heterozygous PV in GLA
What molecular testing is recommended for dx of Fabry dz
sequence analysis of GLA (95%) then del dup (5%)
if person is from Nova Scotia or Chinese ancestry, can do targeted analysis for atypical presentations
What additional testing can be done to aid in the dx of Fabry dz
plasma globotriaosylsphingosine (lyso-Gb3) levels (deacetylated derivative of accumulated substrates):
have been correlated w dz severity and organ involvement
are higher in affected males than females
lower levels at initiation of tx correlate with better long term outcomes of pulmonary airflow limitation and general clinical events
Compare and contrast the age of onset, age of death, and manifested features between classic Fabry and atypical/late-onset Fabry
classic: 4-8yo; 41yo; angiokeratoma, acroparesthesia, hypohidrosis/anhidrosis, corneal/lenticular opacity, LVH/ischemia, TIA/stroke, ESKD, <1% residual alpha Gal A enzyme activity
late-onset: >25yo; >60yo; acroparesthesia (can also be without), hypohidrosis/anhidrosis (can also be without), LVH/cardiomyopathy, ESKD or proteinuria, >1% residual alpha Gal A enzyme activity
Describe the general phenotype seen in males with classic Fabry dz
seen in hemizygous males with <1% alpha-Gal-A enzyme activity but may occasionally be seen in heterozygous females
childhood or adolescence with the appearance of angiokeratomas, periodic crises of severe pain in the extremities (acroparesthesia), hypohidrosis (almost a constant finding), and the characteristic corneal and lenticular opacities (cataracts); renal insufficiency usually occurs in the 3rd to 5th decade of life. Death occurs from complications of kidney dz, cardiac involvement, and/or cerebrovascular dz
Describe the angiokeratomas, acroparesthsia, ocular features, cardiac dz, cerebrovascular manifestations, and renal involvement seen in pts with classic Fabry dz
Angiokeratomas: most commonly involve the hips, back, thighs, buttocks, penis, scrotum and tend to be bilaterally symmetric; the number and size of these cutaneous lesions progressively increase with age
Acroparesthesia: episodic crises of agonizing, burning pain in the distal extremities beginning in childhood or early adolescence and signal clinical onset of the dz; lasts from several minutes to several days triggered by exercise, fatigue, emotional stress, or rapid changes in temp and humidity; crises usually decrease in frequency and severity with increasing age; pain can be so excruciating and incapacitating that the individual may contemplate suicide
Ocular features: characteristic corneal opacity; cataracts do not interfere with visual acuity; posterior and anterior cataracts persist and progress despite tx with ERT
cardiac dz: present in most males with the classic phenotype by middle age and is the major cause of morbidity and mortality; left ventricular enlargement and conduction abnormalities are early findings; LVH is progressive and occurs earlier in males than females
cerebrovascular manifestations: (typically a presenting feature of Fabry) thrombosis, transient ischemic attacks, basilar artery ischemia and aneurysm, seizures, hemiplegia, hemianesthesia, aphagia, white matter lesions
renal involvement: renal insufficiency; gradual deterioration of renal function and the development of azotemia occur in the third to fifth decade of life in ~50% of males with classic Fabry dz, rising to almost 90% by the sixth decade; death most often results from ESKD unless chronic hemodialysis or kidney transplant is undertaken
Describe the gastro, pulmonary, vascular, and psychological features seen in pts with classic Fabry dz. How does Fabry present in children?
Gastro: episodic diarrhea, nausea, vomiting, bloating, cramping abdominal pain, and/or intestinal malabsorption
pulmonary: chronic bronchitis, wheezing, or dyspnea
vascular: pitting edema of the lower extremities
psychological: depression
in children: males generally present with the classic phenotype from age 3-5yo. Abdominal pain, acroparesthesia, hearing loss, cataract, skin rash, and fatigue are common features
Describe the general phenotype seen in heterozygous females with classic Fabry dz
variation in clinical manifestations is attributed to random X inactivation
most heterozygous females from families in which affected males have the classic phenotype have a milder clinical course and better prognosis than affected males
have characteristic cornea verticillata, lenticular opacities that do not impair vision; acroparesthesia; angiokeratomas that are usually isolated or sparse; hypohidrosis; and chronic abdominal pain
may develop mild to moderate LVH and valvular dz; isosthenuria (occurs with renal dz; has to do with specific gravity of urine); the presence of erythrocytes, leukocytes, and granular and hyaline casts in the urinary sediment and proteinuria
Describe the general phenotype seen in late-onset variants of Fabry dz
cardiac: asymptomatic during most of their lives and typically present in the 6th to 8th decade of life with LVH, HCM, conduction disturbances, and arrhythmias; females may develop myocardial fibrosis without apparent LVH
renal manifestations: renal variants were identified among individuals of Japanese ancestry on chronic hemodialysis in whom ESKD had been misdiagnosed as chronic glomerulonephritis
What is the life expectancy and typical cause of death associated with Fabry dz
life expectancy of males with Fabry is ~60yo compared with ~75yo in general pop
life expectancy of females with Fabry is ~75yo compared with ~80yo in general pop
most common cause of death in both sexes is cardiovascular dz
What are the recommended initial evals following dx of Fabry dz
general: assess for angiokeratomas, acroparesthesia, sweating abnormalities, abdominal pain, and other GI symptoms, pulmonary and vascular manifestations (annually starting at 7yo)
ophthalmologic eval for ocular manifestations
cardiac eval, EKG, echo, cardiac MRI (annually in males at 18yo; q2yrs in females from age 18-35yo)
neurologic eval, brain MRI/MRA (annually beginning at 18)
renal function studies incl BUN, creatinine, and urinalysis (annually beginning at 18)
formal audiologic exam (annually beginning at 18; 2x per yrs in females from 18-35)
assess for mood disturbance, anxiety, and depression (annually beginning in 18yo)
What is the recommended tx for pts with Fabry dz
two ERTs using recombinant or gene-activated human a-Gal A enzyme that have been evaluated are Fabrazyme (approved by FDA) and Replagal
systemic review of ERT in females with Fabry dz suggested that ERT has a beneficial effect on substrate levels, cardiac outcomes, and quality of life. However, there is an emerging consensus that ERT has a limited effect on the long-term outcome of Fabry dz
experts endorse the recommendation that ERT be initiated as early as possible in all males with Fabry dz and in heterozygous females with significant dz
chaperone therapy uses small molecules designed to enhance the residual enzyme activity by protecting the mutated enzyme from misfolding and degradation in the cell (migalastat)
diphenylhydantoin: reducing the frequency and severity of the periodic crises of excruciating pain and constant discomfort (also can do carbamazepine; gabapentin can also improve pain)
aspirin, lipid lowering agents and optimal BP control for cardio dz
anti-platelet agents (clopidogrel) for stroke prophylaxis
renal dz: renal insufficiency is the most serious late complication in males with the classic phenotype/ ACE inhibitors or angiotensin receptor blockers should be used in those with evidence of renal involvement; chronic hemodialysis and kidney transplantation have become lifesaving procedures
How can prenatal molecular genetic testing be used to identify Fabry dz
accurate clinical presentation in a fetus found to have a GLA PV is not possible
If the karyotype is 46,XY, alpha-Gal A enzyme activity can be measured in fetal cells via biochemical analysis
Mechanism of dz: reduced enzyme activity
How is Gaucher dz identified on NBS
primarily based on quantification of glucocerebrosidase enzyme activity on dried blood spots
values below cutoff are considered positive
How is the dx of Gaucher dz established
finding of 0-15% of normal glucocerebroside enzyme activity in peripheral blood leukocytes or by the identification of biallelic PVs in GBA1 on molecular genetic testing
complicated by the presence of a highly homologous pseudogene, GBAP1
sequence analysis first then del dup
Describe the phenotype and progression of Type 1 Gaucher Dz
bone dz in 70-100%, osteopenia, sclerotic lesions, osteonecrosis, acute/chronic bone pain, fractures, joint collapse, degenerative arthritis
“bone crises”, fever, leukocytosis
do NOT have primary CNS dz; neurologic complications CAN occur but secondary to bone dz
hepatosplenomegaly
cytopenias almost universal (anemia, thrombocytopenia, leukopenia, easy bruising or overt bleeding); abnormal platelet aggregation may contribute to bleeding diathesis in the presence of normal platelet counts
cholelithiasis occurs in a significant proportion of adults with GD
Pulmonary arterial HTN
immunologic abnormalities, psychological complications, parkinsonian features (younger age of onset)
INCREASED RISK OF MULTIPLE MYELOMA
Describe the phenotype and progression of Type 2 Gaucher Dz
bulbar signs (stridor, squint, swallowing difficulty) and pyramidal signs (opisthotonos, head retroflexion, spasticity, and trismus) in infancy
dementia and ataxia in later stages of chronic neurologic dz
mild cerebral atrophy
infantile/acute onset
