Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is a disorder characterized by degeneration of lower motor neurons and occasionally bul- bar motor neurons leading to progressive limb and trunk paraly- sis as well as muscular atrophy. It is a clinically and genetically heterogeneous group of neuromuscular diseases. It is the sec- ond most common lethal autosomal recessive disorder after cystic fibrosis in Caucasian populations with an overall inci- dence of 1 in 10,000 live births and a carrier frequency of approximately 1 in 50.

GENETICS/BASIC DEFECTS

1. Inheritance

a. Autosomal recessive in most cases (SMA1, SMA2, SMA3)

b. Autosomal dominant in both juvenile and adult form, representing 2% of infantile and about 30% of adult SMA

2. Three candidate genes

a. Survival motor neuron (SMN) gene, an SMA deter- mining gene

i.

, the telomeric copy): Up to 95%

of patients suffering from different forms of SMA are homozygously deleted for both telom- eric copies of the SMN gene

ii.

, the centromeric copy)

b. Neuronal apoptosis inhibitory protein gene (NAIP):

more frequently deleted in type I than in the milder forms (types II and III)

c.

found to be associated with SMA1

3. Mutation in all three forms (SMA1, SMA2, and SMA3) mapped to chromosome 5q13 (SMA critical region) 4. SMN deletions

a. High frequency of SMN deletions in SMA patients (92.8%) provides a direct and accurate genetic test for:

i. Diagnostic confirmation of SMA ii. Prenatal prediction of SMA

b. Homozygous deletion of SMN observed in:

i. Atypical forms of SMA associated with congen- ital heart defects

ii. Arthrogryposis

iii. Some cases of congenital axonal neuropathy iv. Some patients affected with adult form of SMA c. Rare cases of homozygous SMN exon 7 deletion or

conversion reported in asymptomatic relatives of hap- loidentical type II or III SMA patients

d. Absence of deletion of the SMN gene or linkage to chromosome 5q in:

i. SMA associated with diaphragmatic involve- ment

ii. SMA with olivopontocerebellar atrophy

iii. Autosomal dominant form of SMA iv. Amyotrophic lateral sclerosis

v. Post-polio syndrome

5. Molecular-phenotype correlation: Phenotype of SMA associated with disease-causing mutations of the SMN gene spans a continuum without a clear delineation of subtypes

CLINICAL FEATURES

1. Existing classification system based on age of onset of symptoms: useful for prognosis and management a. Congenital axonal neuropathy

i. Prenatal onset of SMA ii. Decreased fetal movement iii. Maternal polyhydramnios

iv. Severe muscle weakness (hypotonia) v. Absence of movement

vi. Joint contractures vii. Facial diplegia viii. Ophthalmoplegia

ix. Respiratory failure requiring immediate endotra- cheal intubation and ventilation

x. Death from respiratory failure within days b. Arthrogryposis multiplex congenita-SMA

i. Prenatal onset of SMA ii. Decreased fetal movement iii. Maternal polyhydramnios

iv. Breech presentation

v. Severe muscular weakness (hypotonia) vi. Arthrogryposis multiplex congenita

vii. Absence of movement except for extraocular and facial movement

viii. Death from respiratory failure before one month of age

c. SMA1 (acute infantile spinal muscular atrophy, Werdnig-Hoffman disease)

i. Represents about 30% of all SMA cases ii. Onset before six months of age

iii. The most severe form with fatal outcome iv. Severe generalized muscular weakness (hypotonia)

v. Lack of motor development

vi. Mild joint contractures at the knees and rarely at the elbows

vii. Most severely affected neonates

a) Difficulty in sucking and swallowing b) Abdominal breathing

viii. Facial muscles spared completely with a bright, normal expression

ix. Ocular muscles and the diaphragm not involved until late in the course of the disease

x. Fasciculation of the tongue seen in most but not all cases

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xi. Intercostal paralysis with severe collapse of the chest: the rule

xii. Affected children unable to sit without support xiii. Absence of tendon reflexes (areflexia)

xiv. Normal intelligence

xv. Usually die within two years due to the following:

a) Feeding difficulty b) Breathing difficulty

d. SMA2 (chronic infantile spinal muscular atrophy, Dubowitz disease)

i. Represent about 45% of SMA cases ii. Onset between six and 12 months

iii. The intermediate form (a more slowly pro- gressive generalized disease with a variable prognosis)

iv. Poor muscle tone at birth or within first 2 months of life

v. Slow attainment of motor milestones

a) Not sitting independently by age 9–12 months b) Not standing by age one year

vi. Frequent tongue fasciculations and atrophy vii. Common finger trembling and general flaccidity viii. Diminished or absent deep tendon reflexes

ix. Intact sensation

x. Loss of the ability to sit independently by the mid-teens

xi. Slow or arrest of clinical progression xii. Severe scoliosis if untreated

xiii. Defect in respiratory ventilation

xiv. Highly variable life expectancy, ranging up to adult life in some cases

e. SMA3 (juvenile spinal muscular atrophy, Kugelberg- Welander disease)

i. Represents about 8% of all SMA cases

ii. Childhood onset after 12 months (usually after 18 months to 30 years of life)

iii. The mild chronic form iv. Motor milestones

a) Ability to walk but frequent fall on walking b) Trouble walking upstairs and downstairs at

age 2–3 years v. Muscle weakness

a) Proximal muscle weakness associated with muscle atrophy

b) Legs more severely affected than the arms vi. Normal sensation

vii. No evidence of upper motor neuron involvement viii. Hypertrophy of the calves in about 25% of cases ix. Prognosis generally correlates with the maxi-

mum motor function attained f. SMA4 (adult SMA)

i. Adult onset (after 20 or 30 years of age) ii. Muscle weakness (after age 30 years)

iii. Clinical features similar to those described for SMA3 with evidence of lower motor neuron involvement

a) Tongue fasciculations b) Muscle atrophy

c) Depressed deep tendon reflexes d) Normal sensation

2. Consider diagnosis of SMA in infants presenting with the following clinical features:

a. During neonatal period i. Severe hypotonia ii. Absent movement

iii. Contractures, usually of a mild degree

iv. Evidence of anterior horn cell (i.e., lower motor neuron) involvement

a) Tongue fasciculations

b) Absence of deep tendon reflexes v. Respiratory failure

vi. Variable cranial nerve involvement usually apparent late in the course

a) Ophthalmoplegia b) Facial diplegia b. After neonatal period

i. Poor muscle tone

ii. Symmetric muscle weakness a) Sparing the ocular muscles

b) Involving the facial muscles and diaphragm late in the course of the disease

iii. Delayed acquisition of motor skills

iv. Evidence of anterior horn (i.e., lower motor neuron) involvement

a) Tongue fasciculations (seen in only 65% of patients)

b) Absence of deep tendon reflexes v. Normal reaction to sensory stimuli vi. Normal intelligence

DIAGNOSTIC INVESTIGATIONS

1. Increased serum creatine phosphokinase (CK) activity in about half of the patients with type III SMA

2. Electromyography (EMG) a. During voluntary effort

i. Spontaneous discharge activity in resting muscle ii. Increased amplitude

iii. Prolonged duration of motor unit potentials b. Severe denervation commonly found in older patients c. Nerve conduction velocity

i. Generally considered normal

ii. Some decrease in velocity in severe case 3. Muscle histology

a. Denervation changes with small groups of atrophic muscle fibers associated with markedly hypertro- phied fibers

b. Small angular fibers randomly intermixed with normal- sized fibers

c. Atrophic fibers arranged in groups

i. Usually of uniform fiber type based on the myosin ATPase reaction

ii. Considered as an extensive collateral reinnerva- tion of previously denervated muscle fibers by sprouts from surviving motor neurons

d. In SMA type III, but not in infantile SMA (type I or II)

i. Markedly hypertrophic fibers

ii. Excessive variation in fiber size

iii. Internal nuclei

iv. Observation of degenerative changes with necro- sis and regenerative fibers associated with prolif- erative interstitial connective tissue

a) Interpreted as “pseudomyopathic” changes b) Usually found in patients with high serum

levels of CK activity suggesting the pres- ence of a myopathic process secondary to neurogenic process

c) These pseudomyopathic changes not observed in other human neurogenic dis- eases, suggesting that they can be specific to the molecular mechanism resulting in or associated with juvenile SMA

4. Neuropathologic features found at autopsy of SMA patients a. Loss of the large anterior horn cells of the spinal cord

(most striking feature)

b. Severe degree of central chromatolysis in the remaining surviving motor neurons, appearing as large ballooned cells without stored substances

c. Other anterior horn cells i. Pyknotic

ii. Presence of occasional figures of neuronophagia associated with astrogliosis

iii. Small anterior roots 5. Molecular diagnosis of SMA

a. The following relatively simple DNA tests enable confirmation of a suspected clinical diagnosis of SMA or prediction of the outcome of a pregnancy in families with a history of SMA.

i. SSCP analysis

ii. PCR followed by restriction enzyme digestion b. Mutation analysis of SMN1 available on clinical basis

i. Used to detect deletion of exons 7 and 8 of SMN1 ii. Homologous deletions of exon 7 of SMN1 in

95% of cases with clinical diagnosis of SMA iii. Compound heterozygotes for deletion of SMN1

exon 7 and an intragenic mutation of SMN1 in 2–5% of patients with a clinical diagnosis of SMA c. Sequence analysis of all SMN1 exons and intron/exon

borders available on clinical basis

i. Used to identify the intragenic SMN1 mutations present in the 2–5% of patients who are com- pound heterozygotes

ii. Limitations

a) Cannot determine whether the point muta- tion is in the SMN1 gene or the SMN2 gene, unless one of these genes is absent

b) Does not detect exonic duplications

c) Cannot detect deletions of whole exons if more than one SMN gene copy is present d. SMA carrier testing (gene dosage analysis) available

clinically

i. Mutation analysis not reliable for carrier detec- tion since it does not quantitate the number of

ii. A PCR-based dosage assay (called SMA carrier testing or SMN gene dosage analysis) allows for the determination of the number of SMN1 gene copies, thus permitting highly accurate carrier detection

iii. Dosage analysis to differentiate carriers from noncarriers

e. Linkage analysis available on clinical basis

i. Available to families in which direct DNA test- ing is not informative

ii. May be used for confirmation of carrier testing results and prenatal testing results

GENETIC COUNSELING

1. Recurrence risk a. Patient’s sib

i. Autosomal recessive inheritance: 25%

ii. Autosomal dominant inheritance: not increased unless a parent is affected

b. Patient’s offspring: only milder forms of SMA likely to reproduce

i. Autosomal recessive inheritance a) All offspring: carriers

b) Recurrence risk not increased unless the spouse is affected or a carrier

ii. Autosomal dominant inheritance: 50%

2. Prenatal diagnosis

a. Possible to detect fetuses at 25% risk when the disease- causing SMN mutations in both parents are known b. Mutation analysis on fetal DNA obtained from CVS

or amniocentesis c. Linkage analysis

i. Many diagnostic laboratories still perform link- age analysis in addition to direct SMN

mutation analysis in families where the previously affected child lacks both copies of SMN

, since there are people in the normal population who lack both copies of SMN

but not clinically affected ii. The only option available to the families where

no deletion has been observed but the clinical findings are consistent with 5q SMA

3. Management

a. Feeding gastrostomy for children with difficult in suck- ing and swallowing

b. Management of respiratory function

i. Noninvasive ventilation support for patients with sufficient orofacial muscle strength

ii. Long-term ventilatory support not usually con- sidered

c. Management of scoliosis in patients with SMA2 and SMA3

i. Orthosis to allow to sit upright rather than bedridden

ii. Option of surgical repair for the severe scoliosis

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Fig. 1. A 2 1/2 week-old white male died of respiratory failure associ- ated with congenital spinal muscular atrophy (Werdnig-Hoffman dis- ease). There was generalized muscle atrophy including respiratory muscle.

Fig. 2. Quadriceps muscle shows many exceedingly atrophic muscle fibers which tend to be in groups (arrow). No degenerative muscle fibers are present (H & E,×100).

Fig. 3. Residual muscle seen in a 14 year old female showed chronic denervative change with presence of scattered target fibers (arrows) (H

& E ×400).

Fig. 4. Biopsy of quadriceps muscle from a 10 month old girl shows a group atrophy involving several entire fascicles (arrow). Both type I (light-stained) and type II (dark-stained) fibers are affected. This is accompanied by a enervative phenomenon (the large muscle fibers all stain pale) (Myosin ATPase, at 9.4,×50).

Fig. 8. A 30-year-old man with Kugelberg-Welander disease showing muscle weakness and had been confined to wheelchair for some time.

He had trouble standing and began to walk at 6 years of age.

Molecular genetic diagnosis revealed homozygous exon 7 deletion and homozygous exon 8 deletion.

Fig. 7. A 5-year-old girl with SMA showing tongue fasciculation.

Fig. 5. A 3-month-old infant boy with Werdnig-Hoffman disease showing generalized hypotonia. He had a small chest with diaphrag- matic breathing, fasciculation of the tongue, and absence of deep ten- don reflexes. Molecular genetic analysis revealed homozygous exon 7 deletion and homozygous exon 8 deletion for the survival motor neu- ron genes (SMN).

Fig. 6. A 27-month-old girl with SMA1. She could not stand holding or independently and had foot drops, absence of deep tendon reflexes, muscle weakness. She was confined to a wheel chair. Molecular genetic analysis revealed homozygous exon 7 deletion and homozygous exon 8 deletion for the SMN gene.