We identified a large North American family with dominantly inherited proximal lower extremity weakness. All affected individuals were recognized in childhood and showed the same pattern of proximal leg weakness with a striking predilection for the quadriceps. The clinical histories we obtained suggest static or very slowly progressive weakness, but our follow-up has been too brief to objectively document this feature.
The EMG findings and myopathology were consistent with a chronic neurogenic etiology, but could not distinguish between loss of anterior horn cells and degeneration of motor axons. On clinical grounds, however, the absence of length-dependent weakness in this family argues against a motor neuropathy and the overall phenotype meets diagnostic criteria for a SMA.20
In further support of classification as a SMA, other families with similar early-onset, proximal neurogenic weakness have historically been considered to have SMA and categorized as childhood/juvenile proximal SMA,21
autosomal dominant SMA III,22
or proximal hereditary motor neuronopathy type IV.23
Therefore, we propose calling this disease spinal muscular atrophy–lower extremity, dominant (SMA-LED) to reflect its likely site of pathology, notable quadriceps involvement, and inheritance pattern.
The SMA-LED phenotype is unusual and can be distinguished from most other reported cases of autosomal dominant proximal SMA24
by the absence of clinically apparent upper extremity involvement. None of the participating SMA-LED family members had detectable upper extremity weakness or atrophy on examination. The proband showed mild, subclinical, chronic denervation in the hand, but his child did not. This finding suggests that upper extremity involvement is related to length of disease or that there is intrafamilial variability. Because upper limb EMG was only available for these 2 family members, we could not distinguish between these 2 possibilities. Lower extremity predominance has been described in several other dominant SMA families,25–27
including the one family with a mutation in TRPV4 on 12q23-q24.15,16,28,29
However, in contrast to SMA-LED, these pedigrees showed more prominent distal leg weakness, high rates of arthrogryposis, and congenital onset. Although the features of SMA-LED are different from most other autosomal dominant SMAs, we cannot exclude the possibility that SMA-LED represents one end of a spectrum shared with these other families. The SMA-LED phenotype most closely resembles 3 previously described small families,27,30,31
matching their age at onset, proximal lower extremity predominance, and mild or absent progression. However, these case descriptions did not include enough clinical information to judge whether pronounced quadriceps involvement was present.
The SMA-LED quadriceps biopsies we analyzed were consistent with chronic denervation. In contrast to the type I muscle fiber predominance typically found in autosomal dominant proximal SMA,27
both SMA-LED biopsies showed prominent type II muscle fiber predominance. Similar type II predominance has been reported in one other family.28
The degree of fiber type predominance we have observed could originate from several potential mechanisms. First, successive rounds of denervation with reinnervation could produce what amounts to severe fiber type grouping. Alternatively, the SMA-LED pathologic process could selectively spare type II motor units or specifically target type I motor units. Finally, some authors have hypothesized that the absence of fiber type grouping, the onset of symptoms in utero or in early infancy, a lack of ongoing denervation, and static or minimally progressive weakness all argue for a defect of motor neuron embryogenesis rather than for motor neuron degeneration.27
In this family, the presence of giant motor units on EMG is most consistent with successive rounds of denervation and reinnervation. We also found perivascular inflammation in one muscle biopsy. This inflammation is of uncertain significance. Perivascular mononuclear cell inflammation is a frequent finding in some hereditary neuromuscular disorders, including fascioscapulohumeral dystrophy32
and the dysferlinopathies,33
but to our knowledge, has not been reported for any SMA. Additional pathologic studies are needed to clarify whether inflammation is a consistent finding in SMA-LED.
By genetic linkage studies we have identified the locus for SMA-LED on 14q32. SMA-LED is the first dominantly inherited SMA to show linkage to this region. Interestingly, a recessively inherited, severe SMA that is accompanied by pontocerebellar hypoplasia (SMA-PCH1 OMIM 607596) also localizes to 14q32. Null mutations in vaccinia-related kinase 1
) were recently identified as the causative genetic defect.34
Although the VRK1
gene is nearby, it is 3.6 Mb outside the minimal genomic interval for SMA-LED. According to the UCSC database, the genomic region we have identified spans 6.1 Mb and contains 73 known or predicted genes. Identification of the causative gene mutation in SMA-LED will have important implications for the pathogenesis of motor neuron diseases.