Foundations Exam 2 - Hypotonia, SMA, and CHD

based off of the study guide

Hypotonia

Reduced resistance to passive range of motion in joints; impaired ability to sustain postural control and movement against gravity. Needs brain input to generate tone and muscles to maintain it.

Weakness

Reduction in the maximum power that can be generated. Not always permanent; can be age- or injury-related. (Hypotonia is not the same as weakness.)

Extremely common; present in >1000 genetic diagnoses; seen in most children with developmental delay.

How common is hypotonia?

Axial = trunk (and neck/head control). Appendicular = arms/legs. Central hypotonia: axial > appendicular.

Axial vs appendicular tone

Normal strength (or mild weakness), normal-to-increased DTRs, axial > appendicular, poor visual tracking, poor facial expression, global developmental delay. Points to primary neurodevelopmental genetic syndromes.

Central hypotonia: findings

Weakness AND hypotonia, DTRs decreased/absent, alert mental status; proximal (anterior horn cell, NMJ, muscle) or distal (neuropathy) weakness. Points to neuromuscular disease.

Peripheral hypotonia: findings

Combined hypotonia

Central + peripheral involvement.

Localization is a core purpose of the neuro exam (where - CNS, PNS, NMJ - and what tests to run); it guides further diagnostic/genetic workup.

importance of localizing hypotonia

Brain malformations, neurodevelopmental syndromes, brain trauma. Poor visual tracking, poor facial expression, axial > appendicular, normal/hyperactive DTRs, GDD.

Localization: CNS

Trauma; C-spine anatomic/vertebral abnormalities.

Localization: cranio-cervical junction

SMA, amyoplasia. Alert, normal eye movements, proximal weakness, contractures in severe cases (also tongue fasciculations, absent DTRs). Motor neurons are born here.

Localization: anterior horn cells

Peripheral neuropathies. Alert, normal eye movements, DISTAL weakness (length-dependent).

Localization: motor/sensory nerves

Congenital myasthenic syndromes (nerve-muscle chemical signaling). Alert, ABNORMAL eye movements (eye has NMJs), proximal weakness, contractures in severe cases.

Localization: neuromuscular junction

Myopathies (muscle built differently), muscular dystrophies (ongoing active breakdown). Alert, +/- normal eye movements, proximal weakness, contractures in severe cases.

Localization: muscle

Ehlers-Danlos, Marfan (muscle attachment to bone). Alert, normal eye movements, proximal AND distal weakness, contractures in severe cases.

Localization: connective tissue

Skeletal dysplasias. Alert, normal eye movements, +/- mild weakness, abnormal X-rays.

Localization: bone

Neuromuscular junction (muscle may be +/- normal).

Which localization has abnormal eye movements?

Genetic (chromosomal, single gene), teratogenic, and acquired.

Etiologies of hypotonia/weakness: 3 broad categories

Chemical (ETOH, AEDs, street drugs, industrial chemicals); infectious (TORCH, Zika); physical (radiation, hyperthermia); metabolite in excess from mother/fetus (diabetic embryopathy, uncontrolled maternal PKU).

Teratogenic causes of hypotonia

Trauma; vascular/ischemic incident; nutritional (malnutrition, botulism); autoimmune (typically focal weakness).

Acquired causes of hypotonia/weakness

• Horizontal suspension (head drop)

• head lag on traction/pull-to-sit (head and shoulders should travel as a unit)

• vertical suspension (infant slips through at the shoulder girdle).

3 classic low-tone assessments

UMN: spasticity, rigidity. LMN: hypotonia.

Upper vs lower motor neuron: tone

UMN: hyperreflexia; abdominal reflexes absent. LMN: hypo/areflexia; abdominal reflexes present.

Upper vs lower motor neuron: reflexes

UMN: no fasciculations; cortical sensory loss. LMN: fasciculations (particularly tongue); peripheral sensory loss.

Upper vs lower motor neuron: fasciculations and sensory

UMN: cerebral hemispheres, cerebellum, brainstem, spinal cord. LMN: anterior horn cell, nerve roots, peripheral nerves, NMJ, muscles.

Upper vs lower motor neuron: site

UMN: quadriplegia, hemiplegia, diplegia, paraplegia; EMG normal conduction, decreased interference pattern/firing rate. LMN: proximal (myopathy) or distal (neuropathy); EMG abnormal conduction, large motor units, fasciculations/fibrillations.

Upper vs lower motor neuron: weakness pattern and EMG

60-80% of hypotonia cases. Assume central unless other signs point to peripheral (much more common; brain-based).

Central hypotonia prevalence

15-30% of hypotonia cases.

Peripheral hypotonia prevalence

1. History (incl. pregnancy and family)

2. physical/neuro exam (localize central vs peripheral)

3. imaging (brain/spine MRI, X-ray)

4. lab studies (CK, enzymes, metabolic, genetic)

5. EMG/NCV (suspected peripheral, esp. neuropathy)

6. muscle biopsy (rarely done now).

Diagnostic workup of hypotonia

CK reflects the birth process - normal to be high on DOL1 (e.g., 1595 DOL1 -> 63 DOL7 normal). Persistently high CK suggests muscular dystrophy.

CK interpretation in a newborn

Genetic testing (based on exam findings/history). EMG/NCV and muscle biopsy are rarely done. All 50 states screen newborns for SMA.

Which test is tier 1 for SMA?

spinal muscular atrophy

Anterior horn cell disease (peripheral cause of hypotonia): progressive degeneration/loss of anterior horn cells in spinal cord and brainstem nuclei -> motor neurons die -> muscles atrophy -> symmetric muscle weakness and atrophy. Onset from before birth to young adulthood.

Age of onset / best motor milestone (NOT genetics). Phenotype of SMN mutations is really a continuum without clear subtypes.

SMA clinical classification is based on ___

Non-sitters (type 1), sitters (type 2 going into 3), walkers (types 3 and 4).

SMA newer classification

SMA type 0 (1A)

Prenatal/neonatal onset, most severe: born floppy with contractures (movement restricted in utero), respiratory failure at birth, no suck/gag/grasp, minimal spontaneous movement. Usually fatal in days-weeks.

SMA type 1 (Werdnig-Hoffmann)

Onset <6 months; never sits. Severe symmetric hypotonia, mild contractures, tongue fasciculations, absent DTRs, sucking/swallowing difficulty (1-2 mo), respiratory failure; face spared, ocular muscles/diaphragm late. Death or permanent ventilation by ~2 yr untreated.

SMA type 2 (Dubowitz, chronic)

Onset <18 months; sits but never walks. Hypotonia since birth/early months, general flaccidity, postural finger tremor, tongue fasciculations, DTRs absent in ~70%, leans on one arm on traction (no head lag), scoliosis; sitting often lost by mid-teens. Decreased life expectancy (respiratory infections).

SMA type 3 (Kugelberg-Welander, juvenile)

Onset after first year; learns to sit and walk but loses ability to walk. Trouble with stairs at 2-3 yr, proximal weakness (legs > arms), depressed DTRs. Near-normal life expectancy. Prognosis tied to max motor skills attained.

SMA type 4 (adult)

Normal milestones, weakness onset after 30 yr; muscle atrophy, tongue fasciculations, depressed DTRs; very slow progression, no loss of ambulation.

More in severe SMA: respiratory failure/pulmonary disease, feeding difficulty, scoliosis, joint contractures, metabolic acidosis/hypoglycemia/ketosis with acute illness.

SMA: secondary (systemic) complications

Single-gene autosomal recessive. Incidence/prevalence 1/10,000 live births. Carrier frequency 1/50 (panethnic - use for exam). 2nd most common lethal recessive disease after CF.

SMA inheritance and frequencies

ubiquitously, but highest in brainstem and spinal cord

where is SMN expressed?

RNA processing, axonal/dendritic development, autophagy, mitochondrial homeostasis, ubiquitin pathways

roles of SMN

survival of motor neuron. 5q11-q13, 9 exons, 294aa protein. TWO copies in tandem on each chromosome 5.

describe SMN gene

SMN1

THE DISEASE GENE. Telomeric copy. Deleted/mutated -> SMA. Makes only full-length functional protein (no alternative splicing).

SMN2

Strong genetic MODIFIER. Centromeric copy; alters severity of SMA.

By 1 bp in exon 7 (c.840 C (SMN1) -> T (SMN2)) that alters splicing. 85-90% of SMN2 transcripts skip exon 7 (delta7 SMN: truncated/unstable); only 10-15% make stable full-length protein. Exon 7 is needed for a stable protein.

How do SMN1 and SMN2 differ?

1 SMN2 copy = guaranteed type 1

4 SMN2 copies = guaranteed NOT type 1.

SMN2 copy number and phenotype: the 2 definitive predictions

most are type 1, some type 2, fewer type 3

SMN2 copy number: 2 copies

most are type 2, some are type 3, fewer type 1

SMN2 copy number: 3 copies

most type 3 (some type 2)

SMN2 copy number: 4 copies

SMN2 output is ADDITIVE - each copy contributes ~10-15% stable full-length protein, so more copies = more stable SMN = milder phenotype.

Why is it better to have more SMN2 copies if you have SMA?

~95%: homozygous deletion of SMN1 exon 7 (nothing made from SMN1).

~5%: heterozygous SMN1 exon 7 deletion + point mutation on the other allele.

Rarely: homozygous non-deletion mutation.

SMA mutation types

Homozygous absence of SMN1 exon 7.

SMA diagnosis is by ___

Older PCR-based direct SMA test

1-bp difference in exon 7: SMN2 is cut into 2 pieces, SMN1 stays intact. Absence of an intact SMN1 band = SMA (positive in ~95%). Cannot count copies or detect carriers.

SMN copy-number ('carrier') test

Determines SMN1 and SMN2 copy number; labs report SMN2 copy number (modifier).

SMN2 differs from SMN1 by only 1 bp, complicating testing - but this is what makes therapies possible.

Why is SMA testing complicated, and why is that a good thing?

EMG: denervation, diminished motor action potential amplitude (SMA case: absent sensory and motor responses).

Biopsy: denervation, hypertrophic AND atrophic fibers, no dystrophic changes or storage material. Rarely needed.

SMA EMG/NCV and muscle biopsy findings

1. ASO/splicing-modifier approach -> correction at the RNA level with exon inclusion (SMN2 pre-mRNA -> exon 7 included -> more full-length SMN protein).

2. Gene therapy = actual gene replacement (AAV9 delivers functional SMN1 transgene).

SMA treatment: the 2 broad concepts (names not required)

Antisense oligonucleotide (intrathecal) or oral splicing modifier acts on SMN2 pre-mRNA to promote exon 7 inclusion, so SMN2 makes more full-length SMN protein.

SMA ASO approach

AAV9 vector (non-replicating, non-integrating, crosses the blood-brain barrier) delivers a functional SMN1 transgene; one-time IV infusion ('one and done' in theory).

SMA gene therapy

Drugs preserve the motor neurons you have; they do not restore what is lost.

Why is early SMA treatment better?

Myostatin-inhibitor monoclonal antibody - blocks the negative regulator of muscle growth; not specific to SMA.

Third (non-specific) SMA-related treatment (which i think we actually don’t need to know)

98%: both parents are heterozygous carriers.

2%: de novo mutation in one allele (vast majority in the SMN1 copy inherited from father - unequal crossing over during spermatogenesis).

SMA parents of an affected child

~6% of population has 3+ SMN1 copies

5-10% have no SMN2 copy

3-4% of carriers are '2:0' (both SMN1 copies on one chromosome), 3-8x more common in African Americans.

SMA population numbers: carrier breakdown

25% affected, 50% carrier, 25% unaffected non-carrier (each pregnancy).

SMA recurrence risk: both parents carriers

De novo mutation (~2% of cases); parent is a 2:0 carrier; gonadal mosaicism; non-paternity.

Parent of an affected child (homozygous SMN1 deletion) has 2 SMN1 copies on carrier testing. What are possible explanations?

2:0 carrier = 25%.

1:1 (two copies on separate chromosomes; child's deletion de novo) = ~1%.

SMA recurrence: 2:0 carrier vs 1:1

g.27134T>G marker (in cis SMN1 copies - presence increases chance of 2:0 carrier; esp. AJ and Spanish populations); haplotype analysis of family members.

Extra tools to refine 2:0 carrier risk

Copy-number test counts SMN1 copies; a result of 2 copies does not exclude 2:0 carrier status (residual risk). A negative screen lowers but never eliminates risk.

Limits of SMA carrier screening

Pyramidal and extrapyramidal tracts

Pathways by which motor signals are sent from the brain to lower motor neurons.

Pyramidal tracts

Conscious/voluntary control of muscles from the cerebral cortex to muscles of body and face. Fibers cross at the medulla (right brain -> left body). Lesions anywhere along the tract (upper motor neuron) produce pyramidal signs.

Pyramidal signs

Spasticity, increased DTRs (hyperreflexia), +Babinski, weakness.

Extrapyramidal tracts

Involuntary/reflexive/responsive control of muscle tone, balance, posture, locomotion; pathways between basal ganglia and other CNS structures (can be affected by medications).

Extrapyramidal signs

Abnormal involuntary movements: athetosis, chorea, dystonia, myoclonus, stereotypies, tics, tremor.

Allan-Herndon-Dudley syndrome (AHDS)

MCT8 deficiency. Central cause of hypotonia plus some weakness (contrast SMA = peripheral). X-linked recessive: affected males; mothers are carriers.

SLC16A2, a solute carrier gene encoding monocarboxylate transporter 8 (MCT8), which transports thyroid hormone. MCT8 is the primary transporter of thyroid hormone into neurons/brain.

AHDS gene and function

Transport defect: thyroid hormone is made but cannot get into the brain -> brain hypothyroidism with abnormal serum levels (a 'complex form of congenital hypothyroidism'); high T3 causes a peripheral hypermetabolic state.

AHDS pathophysiology

Carrier mothers are unaffected (random X-inactivation).

No de novo cases in the UChicago cohort.

Prenatal diagnosis possible for at-risk male pregnancies (e.g., amnio; planning for C-section due to severe neonatal hypotonia).

AHDS: carriers and family

Genetic testing (SLC16A2 sequencing; case p.A224E pathogenic).

Thyroid hormone labs = strong supporting evidence (exact lab names not required).

AHDS diagnostic testing (2 modalities)

Increased serum free T3 (can't be readily ordered - no pediatric norms)

low-normal or low T4

high-normal TSH

Specialized thyroid panel (UChicago) = functional measure of MCT8 protein (total T4/T3, reverse T3, free T4, index, TSH).

AHDS thyroid lab pattern

Hypotonia (axial > appendicular) with pyramidal signs in legs (spasticity, hyperreflexia, clonus, +Babinski) AND extrapyramidal signs (dystonic hand movements) in the same patient.

AHDS neuro exam clue

AHDS history

Described by Allen, Herndon and Dudley in a 6-generation family of males (24 males); restudied by Stevenson (29 males, 7 generations).

Normal prenatal growth; postnatal microcephaly ~20%; postnatal short stature ~20%; normal stature otherwise, no macroorchidism (not fragile X).

AHDS growth

Hypotonic face with open-mouth posture and tented upper lip, bitemporal narrowing, elongated face, ptosis, cupped/large simple ears, thickened soft tissue of nose and ears, upturned ear lobes.

AHDS craniofacial features

1. Severe congenital hypotonia and weakness

2. decreased muscle bulk and spasticity (first hyperreflexia, retained primitive reflexes, clonus, +Babinski)

3. contractures and dystonic posturing with age.

Paroxysmal dyskinesias, athetoid movements, ataxia

seizures ~25%; minority learn to walk; limited dysarthric speech; severe-profound ID in all.

AHDS neurologic natural history

Tissue-specific (brain) hypothyroidism can't be corrected with physiologic doses of thyroid hormone. Goal: correct thyroid homeostasis systemically AND in the CNS.

AHDS treatment concept

TH analogs that enter cells independent of MCT8 (DITPA, TRIAC)

results: normalize serum thyroid levels, reduce hypermetabolism (weight, HR, labs) but little proven psychomotor benefit. (liver toxicity risk).

Gene therapy in mouse models. (Slc16a2 KO mice lack the neuro phenotype - they have an alternative TH transporter.)

AHDS therapies in trials (concept only)

Right atrium -> right ventricle -> lungs -> left atrium (oxygenated) -> left ventricle -> aorta -> body. Septa separate right from left (atrial defect = hole between atria; ventricular defect = hole between ventricles).

Normal blood flow through the heart

Fetus gets oxygen from mom's placenta; lungs are developing, not oxygenating, so blood bypasses the lungs via the foramen ovale and ductus arteriosus (and the ductus venosus bypasses the liver).

Fetal circulation: why do shunts exist?

Ductus arteriosus (fetal function / response to delivery)

Shunts blood from pulmonary artery to descending aorta (away from lungs). Functionally closes with increased oxygenation and loss of placental prostaglandin E2.

Foramen ovale (fetal function / response to delivery)

Allows blood flow between right and left atria. Closes when systemic pressure exceeds pulmonary pressure.

Ductus venosus

Shunts oxygenated blood from the umbilical vein (placenta) to the IVC, bypassing the semifunctional liver and going toward the heart. Collapses with absent blood flow after birth.

Umbilical artery (after birth)

carries blood from descending aorta to placenta; vasoconstricts with increased oxygenation

umbilical vein (after birth)

placenta → IVC, collapses with absent flow

• Fetal lung fluid resorption

• lung expansion and functional residual capacity

• increased systemic vascular resistance

• decreased pulmonary vascular resistance with increased pulmonary blood flow

• closure of right-to-left shunts.

Requirements for normal fetal -> newborn transition

Congenital anomalies (CHD, diaphragmatic hernia, airway anomalies)

pulmonary hypoplasia

sepsis/pneumonia

persistent pulmonary hypertension

prematurity

IUGR/SGA

LGA.

Problems in fetal-to-newborn transition

Embryonic heart development

Cardiogenic area near the head; endocardial tubes fuse into the primitive heart tube (truncus arteriosus, bulbus cordis, primitive ventricle, primitive atrium) which twists/folds into the 4-chambered heart by ~day 35.

Patent ductus arteriosus (PDA) and patent foramen ovale (PFO).

Embryonic REMNANTS (persistent fetal structures, not true developmental defects)

Ductus fails to close. Oxygen-rich blood flows aorta -> pulmonary artery; extra lung blood raises pulmonary pressure.

Symptoms depend on size (breathing difficulty, poor weight gain; some asymptomatic). Prematurity is a common cause; can be closed surgically. Can be LIFESAVING in tetralogy of Fallot/critical lesions (lets some blood reach lungs).

PDA