Spinal Muscular Atrophy III (Kugelberg-Welander Disease)

In more chronic SMA III, also referred to as Kugelberg-Welander Syndrome, weakness usually initially occurs between the ages of 18 months and late teens. Motor milestones may be delayed in infancy. Proximal weakness is observed with the pelvic girdle being more affected than the shoulder girdle (86). There is an exaggerated lumbar lordosis and anterior pelvic tilt owing to hip extensor weakness. There is also a waddling gait pattern with pelvic drop and lateral trunk lean over the stance phase side, secondary to hip abductor weakness. If ankle plantar flexion strength is sufficient, the patients may show primarily forefoot or toe contact and no heel strike similar to patients with Duchenne dystrophy. This is a compensatory measure for knee extensor weakness to maintain a stabilizing knee extension moment at the knee. The patient may exhibit a Gower's sign when arising from the floor; stair climbing is difficult due to hip flexor weakness. Facial weakness is sometimes noted. Fasciculations are noted in about half of the patients (166) and are more common later in the disease course. Fasciculations in the limb muscles and thoracic wall muscles are common. Calf pseudohypertrophy has been occasionally noted, but wasting of affected musculature is more prominent. DTRs are diminished and often become absent over time. Contractures are generally mild as long as patients remain ambulatory. Scoliosis may be observed in SMA III, but it occurs less frequently and is less severe than scoliosis and SMA II. While no survival data exists for patients with SMA III, cases have been followed into the eighth decade without mechanical ventilation (86,167). Ventilatory failure due to neuromuscular restrictive lung disease is a rare event in SMA III, occurring only in adulthood (86,184).

Zerres and Rudnik-Schoneborn (167) have proposed further subtypes, including SMA Ilia (walks without support; age of onset less than 3 years) and SMA Illb (walks without support; age of onset 3-30 years). In their series, only 44% of SMA "Ilia" patients remained ambulatory 20 years after onset of weakness, whereas 89% of "Illb" patients remained ambulatory after a similar 20-year duration.

Therapeutic Strategies in Predominantly Proximal SMA. Single nucleotide polymorphisms (SNPs) in exon 7 of SMN2 cause a high proportion of exon 7 skipping during pre-mRNA splicing leading to an unstable truncated SMN protein. As a result, small levels of functional SMN protein are produced by the SMN2 gene. Restoring the splicing to achieve exon 7 inclusion has the potential to produce sufficient quantities of functional protein to compensate for the defect of SMN protein (185,186). Splice intervention therapies to promote exon 7 retention and increase amounts of full-length SMN2 transcript offer great potential as a treatment for SMA patients. Several splice silencing motifs in SMN2 have been identified as potential targets for antisense oligonucleotide mediated splice modification. A strong splice silencer is located downstream of exon 7 in SMN2 intron 7. Intrathecal antisense oligonucleotides targeting this motif have promoted SMN2 exon 7 retention in the mature SMN2 transcripts, with increased SMN expression detected in SMA fibroblasts. Systematic optimization of phosphorodi-amidate morpholino oligonucleotides (PMOs) promotes exon 7 retention to levels that rescue the phenotype in a severe mouse model of SMA after intracerebroventricular (ICV) delivery. Furthermore, the PMO gives the longest survival reported to date after a single dosing by ICV (187,188). Clinical trials in humans with SMA are under way. Results of an open-label, escalating dose study to assess the safety, tolerability, and dose range finding of a single intrathecal dose of ISIS-SMN^ in patients with SMA, showed that ISIS-SMN„ was well tolerated when administered intrathecally as a single dose directly into the spinal fluid and that no safety concerns related to the drug were identified. Concentrations of ISIS-SMN^ measured in cerebral spinal fluid were consistent with levels predicted from preclinical studies, indicating that the drug half-life in nervous system tissues is very long and that dosing once every six to nine months is feasible. Although the study was not designed to provide evidence of functional activity, clinically significant, dose-dependent improvements in the Hammersmith Functional Motor Scale-Expanded (HFMSE), a measure of muscle function, were observed in these children.

Through chemical screening and optimization, PTC Therapeutics, Inc. and Roche Pharma Research and Early Development have identified orally available small molecules that shift the balance of SMN2 splicing toward the production of full-length SMN2 messenger RNA with high selectivity. Administration of these compounds to A7 mice, a model of severe SMA, led to an increase in SMN protein levels, improvement of motor function, and protection of the neuromuscular circuit. These compounds also extended the life span of the mice. Selective SMN2 splicing modifiers may have therapeutic potential for patients with SMA (189). A clinical trial of the lead compound is being planned.

Adeno-associated virus type 9 (AAV9) is a powerful tool for delivering genes throughout the CNS. To specifically target the CNS, Kaspar and colleagues have explored AAV9 delivery of the SMN gene to CSF. CSF injection efficiently targeted motor neurons, and restricted gene expression to the CNS, providing an alternate delivery route and potentially lower manufacturing requirements for older, larger patients (190). Their findings support the use of AAV9 for gene transfer to the CNS for disorders such as SMA in pediatric populations.

Distal Spinal Muscular Atrophy

Distal SMA is an increasingly recognized group of rare diseases with varied genetic etiologies. Over 20 distinct genetic subtypes have been identified. The patients may be clinically misdiagnosed as having CMT due to the distal weakness of the foot and hand intrinsics. Some subtypes of distal SMA have predominant upper extremity involvement. Other variants of distal SMA may present initially with distal lower extremity weakness. Sensory function is always normal clinically and electrodiagnostically. The course is usually slowly progressive although some patients may experience a prolonged period of stability. Other associated features in some subtypes include vocal cord paralysis and diaphragm weakness. Some subtypes have associated pyramidal signs.

Juvenile Segmental SMA (Benign Focal Amyotrophy; Hirayama Disease)

This disease was originally described by Hirayama as a slowly progressive focal motor neuron disease affecting the upper extremities. Most cases occur on a sporadic basis. The onset of this syndrome is typically between 15 and 25 years with a range of 2 to 30. Wasting and weakness develop segmentally in C8-T1 hand and forearm muscles, unilaterally and often but not always the dominant extremity. Sensation is completely normal. The disease progresses to more proximal upper extremity muscles. The lower extremities are never affected and typically the disease progression plateaus after 2 to 6 years. Symptoms worsen in the cold ("cold paresis"). Tremor may occur due to distal weakness. Hyperhidrosis of the involved limb is a common complaint. Reflexes are typically spared but not brisk. EMG studies are consistent with an anterior horn cell disorder. MRI abnormalities of the cervical spinal cord (segmental atrophy, stenosis, or foraminal narrowing) have been described in a proportion of patients. The disease is more common in Asian populations.

(Fazio-Londe Disease) Progressive Bulbar Paralysis of Childhood

Fazio-Londe disease or progressive bulbar paralysis of childhood is a progressive bulbar paralysis which is probably genetically transmitted. This is a disorder of bulbar motor neurons. Patients present with cranial nerve findings including ptosis, facial weakness, dysphagia, normal hearing, and respiratory stridor. They may show hyper-reflexia. Dominant transmission is rare. One group with recessive inheritance has early onset in infancy and rapid progression with death from respiratory failure less than 2 years from the age of onset. Another group with recessive inheritance shows later onset (3-12 years), less respiratory involvement, but slowly progressive dysarthria; dysphagia and facial weakness. These patients may have progressive motor neuron disease with primary involvement of the anterior horn cells in the cervical and upper thoracic core segments. In addition, there may be widespread degenerative changes in the brainstem. Of cranial nerves, cranial nerve VII is almost always affected. These patients develop dysphagia secondary to cranial nerve XII involvement. The nuclei of cranial nerves III, IV, VI, and X may also be involved; however, clinical impairment of extraocular movement is rare.