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
Describe the phenotype and progression of Type 3 Gaucher Dz
oculomotor apraxia, saccadic initiation failure, and opticokinetic nystagmus, massive hepatosplenomegaly
dementia and ataxia in later stages of chronic neurologic dz
mild cerebral atrophy
subacute/juvenile onset
Describe the phenotype and progression of the Perinatal-Lethal form of Gaucher Dz
hepatosplenomegaly, pancytopenia, and microscopic skin changes, ichthyosiform or collodion skin abnormalities or as nonimmune hydrops fetalis; arthrogryposis and dysmorphic facial features; hydrocephalus, corneal opacities, deformed toes, GERD, and fibrous thickening of splenic and hepatic capsules
usually stillborn or die shortly after birth
Describe the phenotype and progression of the cardiovascular form of Gaucher Dz
PV in p.Asp448His present with an atypical phenotype dominated by cardio dz with calcification of the mitral valve and aortic valves that develops around puberty
mild splenomegaly, corneal opacities, and supranuclear ophthalmoplegia
What are heterozygotes for Gaucher dz at increased risk for
parkinsonism is higher in obligate carriers for a GBA1 PV
What genotype-phenotype correlations exist in Gaucher dz
level of residual glucocerebrosidase enzyme activity does not correlate with dz type or severity (discordance in phenotype has been reported even in monozygotic twins)
Type 1 Gaucher: individuals who are homozygous for p.Asn409Ser or p.Arg535His variant tend to have milder dz
a founder effect for specific alleles underlies the observed occurrences in some pops: AJ, Spanish, Portuguese (p.Asn409Ser); Swedish (p.Leu483Pro); also other Jenin Arab, Greek, and Albanian pops
What are some DD for Gaucher dz
MPS II, MPS I, Niemann-Pick dz type C, Niemann-Pick dz types A and B
What initial evals should someone with Gaucher dz type 1 undergo
referral to GD tx center/assess for clinical manifestations of bone dz (q6-12mo)
radiographs/bone density assessment by DXA scan
assessment of spleen and liver volume by MRI or u/s (q6-12mo)
hemoglobin concentration and platelet count; platelet function if bleeding/bruising w normal platelet count (q6-12mo)
assess for clinical manifestations of gallstones, u/s of gallbladder (q6-12mo)
assess for clinical manifestations of pulmonary dz; EKG and echo to identify increased pulmonary artery pressure (in adults, q6-12mo)
assess for depression and/or other mood disorder (in adults, q6-12mo)
What initial evals should someone with Gaucher dz type 2 and 3 undergo
gastro/nutrition/feeding team eval
developmental assessment
assess for seizures, consider EEG, assess for bulbar involvement and abnormal ocular movements
radiograph and MRI of symptomatic areas as indicated to assess for bone dx progression
What types of ERT, SRT, and HSCT tx is available for pts with Gaucher dz
INDIVIDUALS WITH TYPE 2 GD (underlying neuropathology is cell death rather than lysosomal storage of GL1) AND THOSE WITH HYDROPS ARE NOT APPROPRIATE CANDIDATES FOR ERT, SRT, OR HSCT
ERT: based on provision of sufficient exogenous enzyme to overcome the block in the catabolic pathway and effect the clearance of the stored substrate, glucosylceramide (GL1); Cerezyme, VPRIV, and Elelyso; safe and effective in reversing features resulting from hematologic and liver/spleen involvement; reduces rate of bone loss in dose-dependent manner; improved health-related quality of life after 24-48mo of ERT; thrombocytopenia may persist
Substrate reduction therapy: aims to restore metabolic homeostasis by limiting the amount of substrate precursor synthesized to a level that can be effectively cleared by the mutated enzyme with residual hydrolytic activity (Miglustat, Eliglustat)
What types of tx is available for pts with Gaucher dz
bone pain: analgesics, joint replacement sx as needed, referral to orthopedist
low bone density: calcium and vitamin D
splenomegaly: partial or total splenectomy
severe anemia/bleeding: transfusion of blood products as needed
cholelithiasis: abdominal sx in those with gallstones
pulmonary dz/pulmonary HTN: tx per pulmonologist/cardiologist
multiple myeloma: tx per oncologist
parkinsonism/seizures: tx per neurologist
What are some genetic counseling considerations to remember when discussing Gaucher dz
a significant purpose of AJ who are homozygous for p.Asn409Ser or p.Arg535His variant may be asymptomatic
of note, bc of the inherent detection limitations of ancestry-based targeted variant testing, sequence analysis is recommended rather than targeted variant analysis for expanded carrier screening
enzyme activity testing does not reliably detect fetal carrier status
What is the molecular pathogenesis of Gaucher dz? What is the mechanism of dz?
caused by deficient glucocerebrosidase activity and the resultant accumulation of its undegraded substrate, GL1, and other glycolipids
GL1 is believed to originate from the turnover of membrane gangliosides, although neuronal cell death may be the basis of neuropathic involvement
mechanism: result in mRNA instability and/or loss of protein, or in an enzyme with altered activity and/or conformation
How is the dx of infantile neurovisceral, chronic neurovisceral, and chronic visceral acid sphingomyelinase deficiency made
sequence analysis of SMPD1 first then gene-targeted del dup analysis although to date, such variants have not been identified as a cause of this disorder
targeted analysis for specific PVs can be performed FIRST in individuals of AJ, North African, Chilean, Saudi Arabian, and Turkish ancestry (3 variants make up 90% of the pathogenic alleles in AJ populations)
measurement of acid sphingomyelinase enzyme activity in peripheral blood lymphocytes, cultured skin fibroblasts, or dried blood spots. Affected individuals typically have less than 10% residual ASM activity
What was the original name of infantile neurovisceral acid sphingomyelinase deficiency
Niemann Pick type A
What was the original name of chronic neurovisceral acid sphingomyelinase deficiency
Nieman Pick type A-B
What was the original name of chronic visceral acid sphingomyelinase deficiency
Niemann Pick type B
What clinical features are associated with infantile neurovisceral acid sphingomyelinase deficiency
severe feeding problems, growth failure, hepatosplenomegaly (by 3mo, can lead to liver failure, coagulopathy, and ascites), lose the ability to suck or swallow, frequent vomiting, constipation and diarrhea, interstitial lung dz, respiratory failure could be a cause of death, macular halo or a cherry-red macula, hypotonia, skills are lost with dz progression, relentless neurologic deterioration, most children succumb before the third year of life
developmental age usually does not progress beyond 10mo for adaptive behavior, 12mo for expressive language, 9mo for gross motor skills, and 10mo for fine motor skills
Describe the clinical features associated with chronic neurovisceral acid sphingomyelinase deficiency
most survive into adulthood even when untreated
hepatosplenomegaly from mild to massive, acute abdominal pain, secondary thrombocytopenia, interstitial lung dz, cerebellar signs, nystagmus, extrapyramidal involvement, ID, psychiatric disorders, delayed skeletal maturation, short stature, low weight, hyperlipidemia, coarse facial features, osteopenia/osteoporosis that can lead to increased fractures
Describe the clinical features associated with chronic visceral acid sphingomyelinase deficiency
most survive into adulthood
hepatosplenomegaly (mild to massive), progressive hypersplenism, worsening atherogenic lipid profile, and gradual deterioration in pulmonary function, liver failure that has required liver transplant, secondary thrombocytopenia, acute abdominal pain, clinical impairment ranges from none to oxygen dependence (for interstitial lung dz), up to 1/3 with macular halo or cherry red macula, most have no evidence of progressive neurologic dz, delayed skeletal maturation, significant short stature in adulthood, hyperlipidemia, early coronary artery dz, osteopenia/osteoporosis
What are some DD for acid sphingomyelinase deficiency
GSD T1, MPSI, MPSII, MPSIII, MPSIVA, Gaucher dz, Tay-Sachs
What evals should someone with acid sphingomyelinase deficiency undergo following initial dx
growth assessment, gastro/nutrition/feeding team eval
DXA scans to assess bone age in children under 18
liver function tests and liver bx
radiologic exam with measurement of liver and spleen size
CBC, chest radiograph, pulmonary function testing
ophthalmologic exam
comprehensive neurologic eval
fasting lipid profile
CT exam of coronary artery status
assess for frequent fractures and/or extremity pain
developmental assessment
What targeted therapies are available for pts with acid sphingomyelinase deficiency
Olipudase alfa (Xenpozyme) ERT helps to reduce accumulation of sphingomyelin in the lung, liver, spleen, and other non-central CNS organs. does not improve neurocognitive issues
HSCT has variable results; can correct metabolic defect, improve blood counts, and reduce increased liver and spleen volumes; morbidity and mortality associated w tx limits its’ use and is likely to become obsolete now that ERT is available
What is the molecular pathogenesis and mechanism of disease for acid sphingomyelinase deficiency (SMPD1)
encodes acid sphingomyselinase, a lysosomal enzyme responsible for hydrolyzing sphingomyelin to ceramide and phosphorylcholine. Results in the accumulation of sphingomyelin in cells and tissues
PVs result in an enzyme with altered activity that leads to decreased hydrolysis of the substrate and its subsequent accumulation in cells, particularly in the monocyte macrophage system. Accumulating lipids can also contribute to pathogenesis
What is the molecular pathogenesis and mechanism of disease for Tay-Sachs
HEXA is necessary for degradation of GM2 ganglioside (only HEX A is able to degrade GM2 ganglioside); without well-functioning enzymes, GM2 ganglioside builds up in the lysosomes of brain and nerve cells
psuedodeficiency alleles leads to false positive enzyme testing results
LOF variants cause decreased to absent beta hexosaminidase activity
How is the dx of Tay Sachs established with enzyme activity
established in a proband with abnormally low HEX A activity on enzyme testing and biallelic PVs in HEXA
HEX A enzymatic activity testing: identifies absent to near-absent HEX A enzymatic activity in the serum, WBCs, or other tissues in the presence of normal or elevated activity of the beta HEXB enzyme (acute infantile form have no to extremely low HEXA enzymatic activity; subacute juvenile or late onset have some minimal residual HEX A enzymatic activity
How is the dx of Tay Sachs established with molecular genetic testing
sequence analysis of HEXA first (99% of PVs) then gene targeted del/dup
targeted analysis for PVs can be performed first in those with specific ancestry
French Canadian: 7.6kb del in the HEXA promoter and exon 1
AJ: p.Tyr427IlefsTer5; c.1421+1G>C, c.1073+G>A, p.Gly269Ser
Describe the presentation and clinical progression of a pt with infantile Tay Sachs dz
infants generally appear normal at birth
3yo-6mo: progressive weakness, myoclonic jerks, exaggerated startle reaction to sudden stimuli, decreasing visual attentiveness, unusual eye movements, cherry-red macula
8-10mo: seizures become common and become more frequent and severe, vision deteriorates rapidly
12mo: ventriculomegaly
2-3yo: difficulties in swallowing, unresponsive, vegetative state, death from respiratory complications
Describe the presentation and clinical progression of a pt with subacute juvenile Tay-Sachs
children attain normal developmental milestones up until 2yo
abnormal gait, dysarthria, loss of previously acquired skills and cognitive decline
spasticity, dysphagia, and seizures present by the first decade of life; optic atrophy, retinal pigmentation late in dz presentation
vegetative state by 10-15yo followed within a few yrs by death
clinical variability exists
Describe the presentation and clinical progression of a pt with late onset Tay-Sachs
progressive spectrum of neurologic and psychiatric symptoms as older teenagers or YAs
presentation may resemble that of other “neurodegenerative” conditions of adults
neurogenic lower-extremity weakness with atrophy of the quadriceps to dysarthria, incoordination, tremor, mild spasticity, and/or dystonia, acute psychosis
clinical variability IS SIGNIFICANT
What genotype phenotype correlations exist in Tay-Sachs
individuals with two null alleles have the infantile form, individuals with one null allele and one missense allele have the subacute juvenile-onset form, and individuals with two missense alleles have the milder late-onset phenotype
What are the recommended initial evals following dx of acute infantile Tay Sachs
neurology eval
PT and OT eval
Gastro/nutrition/feeding team eval
ophthalmologic exam
evaluate aspiration risk
What are the recommended initial evals following dx of subacute juvenile Tay Sachs
neurology eval
developmental assessment
PT and OT eval
Gastro/nutrition/feeding team eval
ophthalmologic exam
evaluate aspiration risk
What are the recommended initial evals following dx of late-onset Tay Sachs
neurology eval
speech eval
PT and OT eval
neuropsychiatric eval
Describe the tx of pts with acute infantile Tay-Sachs
supportive and directed to providing adequate nutrition and hydration, managing infectious dz, protecting the airway, and controlling seizures
standard tx of seizures with ASM
PT/OT for abnormal tone
gastrostomy tube for feeding difficulties
monitor for constipation
gastrostomy tube, vibrator vest, improved pulm toilet, suppression of saliva production for aspiration risks
Describe the tx of pts with subacute juvenile Tay-Sachs
standard tx of seizures with ASM
stretching, splints, pharmacologic tx for spasticity
IEP for developmental plateau/cognitive decline
gastrostomy tube for feeding difficulties
monitor for constipation
botulinum toxin to salivary glands for saliva pooling/drooling
Describe the tx of pts with late-onset Tay-Sachs
PT/OT for weakness/impairment
symptom-targeted pharmacotherapy for spasticity/tremor
voice therapy for communication needs
tx for psychiatric issues as standard
What should be avoided in pts with each form of Tay-Sachs
acute infantile: positioning that increases aspiration risk, seizure meds that result in excessive sedation
subacute juvenile: situations that increase the likelihood of contractures or pressure sores, circumstances that exacerbate the risk of falls
late-onset: situations that exacerbate fall risk, psychiatric meds that have been associated with dz worsening (haloperidol, risperidone, chlorpromazine)
What genetic counseling issues need to be considered for Tay-Sachs
biochemical testing can be used to assess carrier status but if they want prenatal testing they need to have f/u molecular testing
recent studies suggest full-exon HEXA NGS is equally or more sensitive for the detection of carriers than targeted testing for specific variants and HEX A enzyme testing
What findings on NBS are consistent with a dx of MPS I
quantification of alpha L iduronidase activity measurement on dried blood spots
f/u biochemical testing includes confirmation of deficiency of IDUA enzyme activity in blood and elevation in urinary glycosaminoglycan levels
What prelim lab findings are indicative of an MPS I dx
heparan and dermatan sulfate in urine glycosaminoglycans (GAG)
How is the dx of MPS I established
proband w suggestive clinical findings AND lab findings AND detection of deficiency IUDA enzyme activity or identification of biallelic PVs (sequence analysis then del dup (rare))
Due to IDUA pseudodeficiency, establishment of the dz requires demonstration of BOTH deficiency of IDUA enzyme activity AND elevation of urine GAGs
How can IUDA enzyme activity be measured
measured in most tissues
all individuals with MPSI have no or very little IDUA enzyme activity detected by the standard methods used for diagnostics
the overlapping range of residual IUDA enzyme activity noted in fibroblasts of individuals with severe and attenuated disease precludes this measure from being clinically useful
What features are commonly seen in pts with severe MPS I
coarse facial features, macrocephaly, hepatosplenomegaly, dysostosis multiplex, ophthalmologic issues, cardiac involvement, hearing loss, upper airway involvement, hydrocephalus (~25%), ID
appear normal at birth, inguinal or umbilical hernias. Mean age at dx is ~10mo; death due to cardiorespiratory failure usually occurs within the first 10yrs of life
coarsening of the facial features apparent within the first 2yrs; macrocephaly, facial and body hypertrichosis, spinal nerve entrapment, acute spinal injury, endochondral growth plates are thickened and disordered, debilitating hip deformity, characteristic claw hand deformity , CORNEAL CLOUDING, severe visual impairment, open-angle glaucoma, night blindness caused by retinal degeneration, optic nerve compression and atrophy; progressive thickening and stiffening of the valve leaflets can lead to mitral and aortic regurgitation and stenosis, sudden death from arrythmia, coronary artery dz, hearing loss from frequent middle-ear infections, chronic recurrent rhinitis and persistent nasal discharge, upper airway complications, narrowed trachea, thickened vocal cods, enlarged tongue, deep and gravelly voice, DD is obvious by 18mo, limited language skills
IN CONTRAST TO OTHER MPS’s, PLACID RATHER THAN AGGRESSIVE BEHAVIOR; by the time of death at 8-10yo, most children are severely intellectually disabled
What features are commonly seen in pts with attenuated MPS I
hepatosplenomegaly, dysostosis multiplex, ophthalmologic issues, cardiac involvement, hearing loss (50%), upper airway involvement
if development is normal by 24mo and have mild hepatomegaly, normal joint range of motion, mild dysostosis, and mild corneal clouding, they have attenuated form
onset between 3-10yo, short neck, wide mouth, square jaw, variable growth restriction, kyphosis, scoliosis, and severe back pain common; characteristic claw hand deformity, carpal tunnel syndrome, corneal clouding. Glaucoma, retinal degeneration, and optic atrophy can occur, cardiac valvular thickening, moderate to severe hearing loss, rhinorrhea and sleep apnea common, hernias, progressive pulmonary disease (leading cause of death), may have detectable learning disabilities, death in the second to third decade, to a normal life span
What initial evaluations should someone with MPS I undergo as a newborn
consultation with metabolic physician/specialist metabolic dietician
molecular testing for IDUA variants
developmental assessment
What initial evals should someone with MPS I undergo
complete skeletal survey
ophthalmologic exam to assess for corneal clouding and other abnormalities
cardiac eval with echo
hearing assessment
ENT assessment incl sleep study
eval for hernias, stooling issues, and assessment of diet
cranial imaging, incl assessment of possible hydrocephalus, assessment of spinal cord and peripheral nerve involvement, assessment dor carpal tunnel syndrome
developmental assessment
What targeted tx is available for pts with MPS I
HSCT: Considered standard of care for children before 2yo for improved survival and reduction in symptoms
Laronidase (Aldurazyme) ERT: currently used widely in tx non-CNS malformations
PT, surgical release for carpal tunnel may be most beneficial, have major anesthetic risks, including death, corneal transplantation is successful for individuals with attenuated dz although donor grafts eventually become cloudy, cardiac valve replacement should be considered early, shunting procedure for hydrocephalus, tonsillectomy and adenoidectomy for hearing loss is recommended
What is the molecular pathogenesis and mechanism of dz for MPS I
IDUA encodes alpha-L-iduronisase, a glycosidase that removes nonreducing terminal a-L-iduronide residues during lysosomal degradation of heparan sulfate and dermatan sulfate
LOF
How is the dx of MPS II established
established in a male proband with absent or reduced iduronate 2-sulfatase enzyme activity in WBCs, fibroblasts, or plasma; identification of a hemizygous PV in IDS (sequence analysis first then del/dup; rare sporadic cases in females can occur
can also have complex rearrangements
Describe the clinical manifestations of MPS II
“early progressive” dz :progressive cognitive deterioration combined with progressive airway and cardiac dz, usually results in death in the first or second decade of life; delay in global developmental milestones typically first indication of brain involvement
“slow progressive” dz: survival into early adult yrs with normal intelligence is common
appearance of both is normal; coarsening of facial features, macroglossia, rounded cheeks and thick lips, develop ivory-colored skin lesions on the upper back and sides of the upper arms (pathognomonic), short stature, macrocephaly, discreate corneal lesions NO CLOUDING, retinopathy, retinal degeneration leading to poor peripheral vision and night blindness, hypertrophic adenoids and tonsils, progressive swallowing impairment, hoarse voice, conductive and SNHL, recurrent ear infections, joint contractures, generalized thickening of most long bones, hip dysplasia, frequent upper-respiratory infections, airway obstruction, hepatosplenomegaly, sleep apnea, valvar dz, umbilical/inguinal hernia, sleep disturbance, developmental regression between 6-8yo, behavioral and cognitive problems, hydrocephalus, seizures may occur, carpal tunnel syndrome, spinal stenosis, growth velocity decreases with age
What evals should someone with MPS II after dx
echo
pulmonary function testing
sleep study if sleep apnea is a potential concern
audiologic eval
nerve conduction velocity and nerve u/s exam to assess for carpal tunnel syndrome
head cervical MRI to assess for hydrocephalus and spinal cord compression
ophthalmologic eval
developmental assessment
What tx/ management is available for ppl with MPS II
Idursulfase (Elaprase): ERT, positive effects on functional capacity and urine GAG excretion; not expected to benefit children with the CNS form of the dz
developmental, occupational, and PT
shunting for hydrocephalus
tonsillectomy and adenoidectomy
CPAP/Trach
carpal tunnel release
cardiac valve replacement
Inguinal hernia repair
hip replacement
What is the molecular pathogenesis of MPS II and mechanism of dz
PVs in IDS result in absence or reduced levels of I2S enzyme activity, which decreases the amount of sulfate moiety released from the GAGs dermatan sulfate and heparan sulfate during their degradation, disrupting cellular function and dz
What supportive findings are indicative of a Krabbe dz dx
increased CSF protein
abnormal brain MRI consistent with demyelination
abnormal spine MRI (enhancement of spinal nerve roots)
Abnormal electrophysiologic studies
How is the dx of Krabbe established
for children w infantile onset, elevated levels of psychosine levels in dried blood spots confirms the dx
very low enzyme activity (0-5%) is observed in all individuals with Krabbe disease who are symptomatic
sequence analysis of GALC and targeted analysis for the common GALC 30-kb del is performed
How is the dx of Krabbe established following positive NBS
must be followed up urgently, before 14dys for those who are candidates for early tx with HSCT
low GALC activity in dried blood spots and/or leukocytes in asymptomatic newborns is not sufficiently specific to dx Krabbe
first step: measure concentration of psychosine in the blood
sequence analysis of GALC then del/dup looking for common 30kb deletion (can be tested for by allele specific or breakpoint PCR as part of the first tier sequencing assay
Describe the clinical features of Infantile onset Krabbe dz
Stage 1: normal for the first few months after birth, begins to cry frequently without cause, hands tightly fisted, feeding difficulties, GERD, weight loss leading to emaciation
Stage 2: rapid severe neurologic deterioration, hypertonicity with extended and crossed legs, flexed arms, and trunk hyperextension, staring episodes, minor muscle spasms, optic atrophy, sluggish pupillary rxns
Stage 3: poor control of temp and heart rate, blindness, deafness, and seizures
Stage 4: very low muscle tone, absence of voluntary movement
avg age of death in children is 24mo
Describe the clinical features of late onset Krabbe dz
12mo-3yo can be clinically normal until they manifest gait changes, hemiplegia/diplegia, visual impairment, febrile seizures, and/or tremors, loss of milestones, rapid loss of function, death occurs ~4-6yrs after onset
if manifestations are later then 6yo: ADHD, mood disorders, unilateral upper limb weakness, lower-limb hypoesthesia. Dz progression is usually slower
EEG gradually becomes abnormal, brain MRI detects demyelination in the brain stem and cerebellum
What is associated with infantile onset Krabbe dz
homozygosity for the common GALC 30-kb del
compound heterozygosity for either the common GALC 30-kb del and a severe GALC PV
begins within the large intron 10 and extends beyond the end of the gene, accounts for ~45% of PVs in persons of European ancestry
What initial evals should someone undergo following initial dx of Krabbe dz
neurologic and developmental exam
brain stem auditory evoked response to assess hearing and auditory neuropathy
brain MRI to understand dz progression
nerve conduction velocity to understand peripheral nerve involvement
visual evoked potential to help understand the best approach to visual and developmental therapy
What is the recommended tx for infantile Krabbe dz before 14do
compared to those not tx as babies, those tx early with HSCT can live relatively normal lives with variable motor disabilities until the teen yrs when the dz may progress
outcomes vary widely: some individuals live completely normal lives, whereas others are disabled (ranging from reliance on walkers for mobility to quadriplegia)
individuals with later-onset Krabbe dz dx early enough in the dz course may benefit from HSCT
What should pts with Krabbe dz avoid
atypical antipsychotics and multiple meds for seizures: oversedate pts, further affecting cognition
routine childhood vaccines resulting immune response may accelerate dz progression
prolonged indwelling catheters for urinary retention due to the high risk of infection
How is the dx of metachromatic leukodystrophy established
identification of biallelic PVs in ARSA (sequence analysis then del/dup)
identification of increased urine sulfatides (quantified by high performance liquid chromatography, mass spec)
identification of metachromatic lipid deposits in nervous system tissue following nerve or brain bx (pathognomonic for condition)
Describe the general symptoms associated with arylsulfatase A deficiency and the different subtypes
age of onset w/in family is similar; all individuals eventually develop complete loss of motor, sensory, and cognitive functions
death most commonly results from pneumonia or other infections
motor symptoms predict a faster deterioration compared to cognitive symptoms
late-infantile: 50-60% of pts; juvenile: 20-40% of pts; adult: 10-20%
describe the features associated with late-infantile form of metachromatic leukodystrophy
age of onset before 30mo, weakness, hypotonia, depressed deep tendon reflexes, coordination difficulties, strabismus, nystagmus, clonus/tremor, cognitive delays, irritability, extreme fatigue, nocturnal awakenings, impairment in hearing and vision
as dz progresses, language, cognitive development, and gross/fine motor skills regress; spasticity, airway obstruction, feeding difficulties, tonic spasms, decerebrate posturing, general unawareness (most children die within 5yrs after the onset of symptoms)
describe the features associated with juvenile form of metachromatic leukodystrophy
age of onset between 30mo-16yo; difficulty with coordination, tremors, abnormal movements, and a regression of fine motor skills, learning difficulties, concentration issues, and behavioral disorders, sleep problems, present initially with behavioral abnormalities
most die before 20yo but survival is variable
describe the features associated with adult form of arylsulfatase A deficiency
first symptoms after sexual immaturity (after 16yo)
initial signs often related to cognitive dysfunction, spasticity, incontinence, peripheral neuropathy, poor decision making, bowl and bladder control are lost, dystonic movements, decorticate posturing, severe contractures, generalized seizures
What is the pathogenesis and mechanism of dz for arylsulfatase deficiency
MLD is a disorder of impaired breakdown of sulfatides, which are found in greatest abundance in nervous tissue, kidneys, and testes; accumulation in the nervous system eventually leads to myelin breakdown (leukodystrophy) and a progressive neurologic disorder
LOF
What SUPPORTIVE findings are consistent with a dx of MPS III
Analysis of urinary glycosaminoglycans (heparan sulfate)
mild dysostosis multiplex on radiographs
white matter alterations, ventriculomegaly, and spinal stenosis on MRI
mitral/aortic valve thickening, mitral valve prolapse on echo (not very common)
How is the dx of MPS III established
multigene panel that includes GNS, HGSNAT, NAGLU, and SGSH
recommended strategy for enzymatic assay is SIMULTANEOUS enzyme panel testing of all for enzymatic deficiencies associated with MPS IIIA (N-sulphoglucosamine sulphohydrolase), MPS IIIB (alpha N acetylglucosaminidase), MPS IIC (heparan alpha glucosaminide N acetyltransferase), MPS IIID (n acetylglucosamine 6 sulfatase)
What are the clinical features associated with MPS III
extreme clinical variability; progressive CNS degeneration causing severe ID, developmental regression, death within second or third decade of life due to neurologic dz or respiratory tract infection
dolichocephaly/macrocephaly, coarse facies that become more evident with GAG accumulation in the soft tissues, macroglossia, coarse and thick hair, synophrys, hirsutism, hepatosplenomegaly, ventriculomegaly, seizure disorders, gait disorders, hyperactive reflexes, spasticity
early childhood development may be normal, DD by 2-6yo, dysphagia, immobility, unresponsiveness, hyperactivity, aggressive and destructive behaviors, early onset dementia, sleep disturbances, joint stiffness, low bone mass, hearing loss, recurrent otitis media, respiratory tract infections, inguinal and umbilical hernias, dysphagia, atrophy of optic nerve and retinal degeneration
What evals should someone with MPS III undergo following initial dx
abdominal u/s, neuro exam, Brain MRI, speech and language eval, developmental assessment, referral to psychiatrist, skeletal survey, DXA and vitamin D for bone marrow degeneration, referral for PT/OT, audiogram, referral to pulm, assessment of swallowing, feeding, nutritional status, echo
What are the recommended txs for someone with MPS III
ASM by neurologist, supportive therapies (PT/OT, speech), create a physically safe home, melatonin for sleep disorders, ear tube insertion or hearing aids, G-tube placement for feeding difficulties that result in malnutrition, consideration of palliative care
How is the dx of MPS IV established
low N-acetylgalactosamine 6-sulfatase (GALNS) enzyme activity in cultured fibroblasts or leukocytes (bc clinical manifestations of type A and B are indistinguishable, customary to measure B-galactosidase enzyme activity at the same time)
biallelic PVs in GALNS (sequence analysis then del dup)
Describe the clinical features seen in MPS IV
severe form present btwn 1-3yo, slowly progressive form may not become evident until late childhood or adolescence; type A accounts for >95% of affected individuals
prominent forehead, pectus carinatum, kyphosis, respiratory compromise, obstructive sleep apnea, valvular heart dz, hearing impairment (mixed hearing loss), corneal clouding, dental abnormalities, hepatomegaly, mild coarse facial features, NORMAL INTELLECT, ligamentous laxity, joint hypermobility, ulnar deviation of the wrist, genu valgum (knock knees)
How should a pt with Morquio be tx
physiatrist to optimize mobility and autonomy
PT/OT
home care
hospice for end of life care
ERT exists but outcome on life is unknown
What is the pathophysiology and mechanism of dz for MPS IV
absence of enzyme GALNS leads to intracellular accumulation of the glycoaminoglycans KS and C6S in the lysosomes of multiple tissues. Accumulation in cornea and bone leads to pathognomonic findings of corneal clouding and skeletal dysplasia
LOF
How is XALD identified on NBS
measuring concentration of C26:0-lysophosphatidylcholine
all MALE infants with + screen and confirmed ABCD1 PV need immediate referrals to:
pediatric endo for screening for primary adrenocortical insufficiency and prompt tx
biochemical geneticist/neurologist familiar with targeted tx to develop a plan for routine brain MRI monitoring and neurologic evals for targeted therapy to prevent progression of central nervous system disease
female infants with + NBS do not require immediate f/u since females do not have issues in childhood
How is the dx of XALD established
identification of abnormally elevated VLCFAs on biochemical testing AND identification of hemizygous ABCD1 PV or heterozygous ABCD1 PV in a female (sequence analysis then del dup; leukodystrophy multigene panel is best for identifying genetic cause of condition)
VLCFAs may be determined in serum or plasma; characteristic elevation is in the saturated VLCFAs
Describe the clinical characteristics of X-ALD, childhood cerebral adrenoleukodystrophy (cCALD)
affects the nervous system and the adrenal cortex
ONLY YOUNG MALES
inflammatory cerebral demyelination, commonly between 4-8yo; inattention, deterioration in handwriting skills, difficulty in understanding speech, clumsiness, visual disturbances, aggressive or disinhibited behavior, seizures
dz progression may be rapid, total disability occurring within 6mo-2yrs
Describe the clinical characteristics of X-ALD, adrenomyeloneuropathy
Man in his adult yrs, progressive stiffness and weakness in the legs, abnormalities of the bladder and bowel control, abnormal sensory perception, sexual dysfunction
40-45% with some degree of involvement on brain MRI; 20-63% brain involvement that leads to serious cognitive and behavioral disturbances that may progress to total disability and death
70% with impaired adrenocortical function
Females will present in adulthood with similar phenotype although milder; no sexual involvement, adrenal insufficiency rare, rare cerebral myelin involvement
Describe the clinical characteristics of X-ALD, primary adrenocortical insufficiency
commonly occurs by age 7.5 IN MALES
unexplained vomiting, weakness, coma, increased skin pigmentation
also called Addison dz
What tx is available for pts with XALD at risk for cCALD
boys identified with early changes on brain MRI consistent with cCALD are candidates for targeted therapy to prevent progression of CNS dz (Skysona: working copy of ABCD1 is transfected into the pt’s precursor hematopoietic cells
HSCT has the best outcome when performed on asymptomatic individual with minimal but characteristic findings of cCALD (NOT recommended for those with severe neurologic and neuropsychological dysfunction)
What supportive tx’s are available in males with cCALD
need for 504/IEP for cognitive decline
ASM for seizures
consider alternative means of communication
orthopedics/PT and OT to avoid contractures and falls
speech therapy, OT, discuss gastrostomy tube
corticosteroid replacement therapy (for adrenocortical insufficiency, can be lifesaving in adult males as well)
What is the molecular pathogenesis for XALD? Mechanism of dz? de novo rate?
protein serves as a transporter of certain FAs into the peroxisome; prevents beta oxidation and allows continued elongation of FAs, resulting in accumulation of VLCFAs
LOF
4.1%
How is Zellweger spectrum disorder dx
identification of PVs in one of 13 PEX genes
multigene panel for peroxisome biogenesis that includes these and other genes is most likely to identify the genetic cause
What is the clinical course for pts with Zellweger spectrum disorder in newborn period, older children, and adults
significant morbidity, frequently resulting in death in childhood
newborns: hypotonic, poor feeding, seizures, liver dysfunction (jaundice), distinctive craniofacial features including flat face, broad nasal bridge, large anterior fontanelle, and widely split sutures; bony stippling at the patella, renal cysts
older children: retinal dystrophy, SNHL, DD w hypotonia, liver dysfunction, may develop adrenal insufficiency and osteopenia
adults: sensory deficits but normal neurologic development
What is the clinical features associated with severe Zellweger spectrum disorder
profound hypotonia, characteristic facies, gyral malformations, seizures, inability to feed, renal cysts, hepatic dysfunction, chondrodysplasia punctata, usually die during first yr of life and no developmental progress
What is the clinical features associated with intermediate/mild Zellweger spectrum disorder
generally comes to attention later bc of DD, hearing loss, and/or visual impairment, liver dysfunction that can cause a vitamin K-responsive coagulopathy
many children hypotonic but many learn to walk and talk; some develop progressive degeneration of the CNS myelin (leukodystrophy), leading to loss of previously acquired skills and ultimately death
What is the clinical features associated with atypical Zellweger spectrum disorder
ataxia, peripheral neuropathy, congenital cataracts
screening assays described as having these milder types do NOT show biochemical profile typical of Zellweger spectrum disorder
What is the molecular pathogenesis of Zellweger spectrum disorder? mechanism of dz?
PEX genes encode proteins required for peroxisome biogenesis
15% with a Zellweger spectrum disorder like phenotype and increased plasma VLCFA have a single enzyme deficiency of peroxisomal beta oxidation and do NOT have a PV in a PEX gene (instead, ACOX1 and HSD17B4)
LOF; alternative splicing and variants in 3’UTR have been reported
What is the recommended tx for someone with Zellweger spectrum disorder
feeding therapy for persistent feeding issues, hearing aids for hearing loss, cataract removal for impaired vision, supplement vitamin K, cholic acid for liver dysfunction, ASM for seizures, DD/ID provide early intervention, adrenal replacement therapy for adrenal insufficiency, vitamin D supplement for osteopenia
What are the signs and symptoms associated with Antley Bixler syndrome
craniosynostosis, frontal bossing, midface hypoplasia, large nose, low nasal bridge, proptosis, low-set, malformed ears, radiohumeral synostosis (arm bones), joint contractures, camptodactyly, rocker bottom feet, bowing and/or fractures of thigh bones, choanal stenosis/atresia, urogenital defects, ID, DD
type 1: includes impaired steroidogenesis and issues with genital defects (severe form of cytochrome P450 oxidoreductase deficiency
type 2: no impaired steroidogenesis and issues with genital defects
How is the dx of antley bixler syndrome made
usually made after birth, sometimes there can be u/s findings
sequencing of POR and/or FGFR2
What tx is available for antley bixler syndrome
tx typically includes sx and is dependent on the severity of the skeletal problems and its associated symptoms
early intervention, PT (to improve range of motion for certain joint contractures), OT, speech
How is the dx of CHILD syndrome/ CK syndrome made
established in male w a hemizygous PV in NSDHL; usually established in a female w a heterozygous PV in NSDHL (sequence analysis then del/dup)
identification of a hypomorphic NSDHL PV that results in partial loss of function protein confirms the dx of CK syndrome
What are the clinical features associated with CHILD syndrome
unilateral distribution of ichthyosiform skin lesions and ipsilateral limb defects (right-sided seen in ~2/3 of individuals); yellow scales and a sharp demarcation in the midline of the body which is evident at birth; onychodystrophy and periungual hyperkeratosis are common
early death of affected females is usually the result of cardio malformations
skeletal features include ipsilateral hypoplasia, scoliosis, joint contractures, unilateral punctate calcifications of cartilaginous structures
CNS anomalies include unilateral hypoplasia or underdevelopment of the brain, lissencephaly, intellect is normal, CHDs, lung hypoplasia causing respiratory compromise and death, unilateral hydronephrosis, renal agenesis
What are the clinical features associated with CK syndrome
X-linked ID, most cannot speak; aggression, ADHD, irritability, seizures in infancy, polymicrogyria, spasticity, tetraparesis, long thin face, plagiocephaly, almond-shaped and upslanted palpebral fissures, prominent nasal bridge, high palate, dental crowding, micrognathia, microcephaly, a thin habitus, long thin fingers and toes, scoliosis, kyphosis, strabismus, optic atrophy
females have normal physical features, intellect, and brain imaging but display behavioral problems including irritability and aggression
What surveillance should pts with CHILD syndrome and CK syndrome undergo
CHILD
regular surveillance for cutaneous manifestations as new lesions may occur in puberty or early adulthood; orthopedic for musculoskeletal deformities like scoliosis and joint contractures; neurologic, cardiologic, or renal involvement
CK
neurologic surveillance of seizures for readjustment of meds if necessary; orthopedic surveillance for scoliosis/kyphosis
What is the mechanism of dz for CHILD syndrome/ CK syndrome
CHILD: variants result in loss of function of the protein and many are null alleles
CK: cause partial loss of enzyme function
What are mtDNA deletion syndromes and what is their recurrence risk
caused by dels in the mito genome: Kearns Sayre, Pearson, CPEO
only a 4% risk for offspring of affected female, but can be 50% risk if the deletion is due to a mutation in a nuclear gene that is involved in mtNDA replication
What are the mitochondrial conditions associated w nuclear DNA variants
Leigh, POLG-related disorders, pyruvate dehydrogenase deficiency, Senger’s syndrome
