Think of Spinal Muscular Atrophy 3 or 4 in Subjects with Proximal Weakness, Raised CK, Areflexia and Tremor

What is the most common monogenic cause of infant mortality?

You would be surprised to know that it is Spinal Muscular Atrophy (SMA).

SMA has a carrier frequency of 1 in 53 and affects 1 in 11,000 births.

Based on age of onset and severity, it is classified into 5 types- 0,1,2,3 & 4.

Type 0 or the prenatal type, and type 1, the infantile type, are the most severe and affected children die of respiratory failure either at birth or within a few months. Type 1 is also known as Werdnig Hoffman disease.

Type 2, also known as Dubowitz disease, has onset before 18 months and affected subjects can live to 25 years, or rarely longer.

Type 3, known as Welander-Kugelberg syndrome, can start anytime between 18 months and adulthood, while type 4 mostly starts after 35 years of age and accounts for around 5% of cases of SMA. Survival is normal in these last two types and the disease is often non-progressive.

It is SMA types 3 & 4 that I will be dealing with here, as these are the ones who can occasionally present in the Rheumatology clinic.

So what determines the type of SMA?

SMA has autosomal recessive inheritance. The putative gene is called Survival Motor Neuron or SMN, and is loocated on chromosome 5q13. Due to gene duplication, there are two SMNs-SMN1 and SMN2, which are >99% similar. SMN1 sits telomeric to SMN2.

There are rare, non-5q varieties of SMA, but most have "5q disease".

In normal subjects or heterozygotes, SMN1 produces the functional protein. SMN2 is a "defective" gene, due to a single nucleotide substitution- T-->A in exon 7. Thus, SMN2 produces a truncated, non-functional protein due to defective splicing most of the time. However, 15% of SMN2 genes produce some functional protein. There are 4 to 8 copies of SMN2 in an individual.

In SMA, both alleles of SMN1 have deletion of exon 7 in 5q13, and do not produce any functional protein at all. Therefore the small amount of functional protein produced by 15% of SMN2 genes assumes added importance. It will not come as a surprise that the higher the copy number of SMN2 genes that an individual has, the milder is the phenotype of SMA expressed. Thus SMA types 0 or 1 have 1 or 2 copies of SMN2, SMA type 2 has 2 or 3 copies, while SMN3 or 4 have 3-8 copies.

SMA3 and SMA4 present with proximal muscle weakness, complete areflexia (resembling peripheral neuropathy), raised CK and absence of respiratory weakness. They may present with difficulty climbing stairs and sometimes with falls. One unexpected feature is a fine tremor of the extremities. This is the most useful clue to the underlying aetiology.

The diagnosis may be suggested by the presence of neurogenic pattern on EMG- sharp waves and fibrillation potentials, and prolonged, high amplitude motor units. Sequencing of the SMN1 alleles on 5q13 is diagnostic, and the copy number variants of SMN2 will accord with the prognosis and type of SMA.

Recently Nusinersen, an antisense oligonucleotide has won approval for SMA in USA and some countries in Europe. It is currently being assessed by NICE. It works by increasing the amount of functional protein produced by copies of SMN2.

Think of SMA3 or SMA4 in an adult with proximal muscle weakness, raised CK, areflexia, and tremor.

An Important Clue to Protein Losing Enteropathy Causing Hypogammaglobulinaemia

Occasionally one picks up hypogammaglobulinaemia unexpectedly in a young person. Most of them look well and give no history of serious infections. Some will have lymphangiectasia, but most will have a protein losing enteropathy due to malabsorption, caused by either Crohn's disease or coeliac disease.

An important clue in such cases is low IgG and IgA, in combination with a raised IgM. As far as I know, this does not happen in any other form of severe hypogammaglobulinaemia.

Use Both Arms for Bubble Contrast Study in Brain Abscess, Not Just the Right

Subjects with brain abscess without any other risk factors, or relatively young subjects with stroke are often suspected of having a right to left cardiac shunt and undergo a bubble contrast study with agitated saline.

A minority of such subjects have the rarest form of ASD- deroofing of the coronary sinus, accompanied by a left sided superior vena cava (SVC), draining into the coronary sinus. (The coronary sinus collects venous blood from the cardiac muscle and drains into the right atrium, but occasionally, the partition separating the coronary sinus from the left atrium is absent, creating continuity between the coronary sinus and left atrium. Such subjects usually have a left sided SVC, draining into the coronary sinus).

Under such subjects, bubble contrast injected only into the right arm will bypass the left sided sided SVC and will therefore appear in the right atrium long before the left atrium, suggesting an absence of shunt. On the other hand, bubble contrast injected into the left arm will traverse the left subclavian vein and make its way into the left sided SVC, the deroofed coronary sinus and will thus appear immediately in the left atrium, revealing the shunt and thus the cause for the putative brain abscess or stroke.

Persistent left sided SVC is rare, but is still the commonest venous anomaly, affecting 0.3% of subjects in the general population and 10% of subjects with congenital heart disease.