Final Diagnosis -- Spinal Muscular Atrophy (SMA) type I (Werdnig-Hoffmann Disease)


Spinal Muscular Atrophy (SMA) type I (Werdnig-Hoffmann Disease)


Spinal Muscular Atrophy (SMA) is an autosomal recessive neuromuscular disease that has an incidence of approximately 1 in 6,000 to 10,000 live births and a carrier frequency of about 1 in 50 (Ogino and Wilson, 2004; Rodrigues et al, 1995). It is the second most common lethal autosomal recessive disease in humans, after cystic fibrosis, and the most common fatal neuromuscular disease diagnosed in children under the age of eighteen.

SMA is divided into three main groups based on age of onset and the clinical severity or prognosis of the disease. However, all subtypes are biologically similar and map by linkage analysis to the long arm of chromosome 5. SMA type I (Werdnig-Hoffmann Disease) is the infantile onset form which usually manifests before 6 months of age. Patients with this subtype typically have profound weakness early in life and are sometimes described as "floppy infants" with a loss of deep tendon reflexes and an inability to sit upright or walk. These patients usually have early death due to respiratory failure. There are some reports of babies presumed to have sudden infant death syndrome (SIDS) who were found to have an absence of the SMN1 gene and likely represent infants who died of respiratory failure due to SMA (Ogino and Wilson, 2004). Type II SMA (intermediate or juvenile) usually presents between 6 and 18 months of age, and patients can usually sit unaided, but not walk without assistance. Type II patients usually survive into adolescence or adulthood. Type III SMA (Kugelberg-Welander Disease) is the mildest form of SMA and usually manifests after 12-24 months of age. Patients with this subtype walk independently and typically have normal survival. SMA type IV (adult-type) has been a controversial entity (Brahe et al, 1995; Zerres et al, 1995), but is defined by some as SMA presenting after 30 years of age. The existence of type IV is questioned by some due to the fact that SMN1 is not homozygously absent in some of these patients, and therefore it is unclear if these represent SMN1-unrelated SMA or small intragenic mutations in SMN1.

The separation of SMA into distinct subtypes has also been correlated with SMN2 copy number (Mailman et al, 2002). With a decrease in the number of SMN2 gene copies, there appears to be an increase in the severity of weakness, with more patients presenting with type I SMA if there are one or two SMN2 gene copies (Mailman et al, 2002). Patients with three to four copies of the SMN2 gene appear more likely to have milder disease, such as SMA type III. It is important to realize that all patients with SMA will have at least one copy of SMN2, because the complete loss of SMN would be an embryonic lethal condition and not result in a live birth. Thus, it appears that SMN2 copy number has an important modifying effect on the disease severity and prognosis.

Molecular Pathogenesis:

SMA is most often (about 95% of cases) caused by a homozygous absence of the SMN1 gene. "Absence" can be due to either gene deletion (typically a large deletion that includes the whole gene) or gene conversion to SMN2. There is also a high rate of de novo gene deletions, which could explain the high carrier frequency of SMA (Ogino and Wilson, 2002).

The SMN genes give rise to a 38 kD SMN protein. The protein is thought to have a variety of functions, including splicing, ribosome formation, gene transcription, and possibly motor neuron specific actions, such as a role in neurite outgrowth and axonal transport (Briese et al, 2005). The SMN gene exists as 2 highly homologous copies in an inverted, duplicated region of the gene. The telomeric copy is referred to as SMN1, and the centromeric copy is referred to as SMN2. The 2 copies of SMN differ by a total of 5 nucleotide base pairs (one in exon 7, exon 8, and intron 6; two in intron 7). Although none of the single base pair differences cause a change in the amino acid sequence (i.e. translationally silent), the change in exon 7 influences the splicing pattern, such that it diminishes the ability of the SF2/ASF (serine/arginine rich) protein to bind to SMN2, and thereby reduces the recognition of SMN2 exon 7 by the spliceosome. This results in a truncated SMN protein that is less stable and cannot fully substitute for the full-length SMN protein from the SMN1 gene. The result is that there is insufficient full-length SMN protein for the survival and maintenance of motor neurons.

Molecular diagnosis of SMA can be done via targeted mutation analysis using PCR with restriction fragment length polymorphism (PCR-RFLP), which is able to detect the homozygous absence of SMN1 (van der Steege G. et al, 1995) as described above. Other diagnostic methods include sequencing of the SMN gene copies to find small intragenic mutations and linkage analysis for patients in whom neither a sequence variant nor an SMN1 gene deletion can be identified.

Also as mentioned, one drawback to the PCR-RFLP assay method is that it will not detect SMA carriers. To detect carriers, SMN1 dosage analysis must be done; this is typically determined by quantitative competitive PCR-RFLP using a stable diploid reference gene, such as the cystic fibrosis transmembrane regulator (CFTR) gene (McAndrew et al, 1997).

Recent developments:

Currently, there is no cure for SMA. It is likely that new therapeutic treatments will be available in the near future. Many promising agents are under investigation and going to clinical trials. Many of these therapeutic modalities involve increasing the transcription of the SMN2 gene in order to get more full-length SMN transcript, correcting the splicing defect to include exon 7, stabilizing the SMN protein, and repairing degenerating neurons through stem cell therapy. Some of these therapeutic agents include histone deacetylase inhibitors, sodium butyrate (Chang et al, 2001), short oligonucleotides (Skordis et al, 2003) and gene therapy.

If a cure becomes available or if a therapeutic agent is able to help these patients, it will be important to identify patients early to start treatment before anterior motor neurons degenerate. One group has proposed newborn screening for SMA using DNA extracted from blood spots assessed by real-time multiplex PCR analysis to identify patients with an absence of SMN1 exon 7 (Pyatt and Prior, 2006). This approach delivers an analytical sensitivity and specificity of 100% in pilot studies. A newborn screening test would require automated DNA extraction to screen large number of samples. The proposed test on newborns would not detect compound heterozygotes or deliver dosage analysis for patients who may develop a less severe phenotype because of additional SMN2 gene copies.

Until a cure or treatment is available for these patients, management will continue to involve preventative care with immunizations and early treatment of any respiratory infections due to the risk of severely compromising respiratory function.


This case demonstrates a classical presentation of Spinal Muscular Atrophy (SMA), most likely type I (Werdnig-Hoffmann Disease) due to the age of presentation and severity of weakness. The patient has the typical homozygous deletion of the SMN1 gene copies as detected PCR-RFLP. The management of this patient will require good preventative care and follow-up.


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Contributed by Sara E Monaco, MD and Jeffrey Kant, MD, PhD

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