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.

What's Common to McLeod Syndrome & Glycerol Kinase Deficiency?

McLeod syndrome was first described in a trainee dentist, after whom the condition is named. In most cases it occurs due to truncation of the XK gene, present on Xp21. As the protein occurs on red cell membrane as a heterodimer, linked to the Kell antigen, the condition can sometimes be picked up by the Blood Bank due to the absence or attenuation of the Kell blood group antigen.

Mcleod syndrome shares many features with choreo-acanthocytosis, an autosomal recessive condition caused by defects in a protein called chorein. However, the latter does not have the blood group phenotype of McLeod syndrome- i.e. reduced or absent Kell antigen and absent XK antigen (also called Kx antigen).

McLeod Syndrome can occur alone, or as part of the contiguous gene deletion syndrome affecting neighbouring genes on the short arm of X-chromosome, leading to congenital adrenal hypoplasia, Duchenne Muscular Dystrophy (DMD), X-linked Retinitis Pigmentosa, or combinations thereof.

All documented men with McLeod syndrome have a raised CK between 400-4000 IU/l. It happens even in subjects without contiguous gene deletion, and cannot therefore be attributed to DMD.

Here's where it gets interesting. Similar elevations in CK can be seen in subjects with Glycerol Kinase deficiency, which is also coded on Xp21. This has infantile, juvenile and adult forms, and most with the adult form are asymptomatic except for 2 findings- hypertriglyceridaemia and raised CK. The infantile and occasionally, the juvenile form presents with abdominal pain, non-ketotic hypoglycemia and seizures, much like the carnitine disorders presented elsewhere in this blog.

The hypertiglyceridaemia seen in subjects with glycerol kinase deficiency is actually a pseudo-phenomenon. These subjects in fact have markedly raised serum glycerol, which tests positive in assays for triglycerides. Think of this condition when you see raised CK and high triglycerides in an adult male who is otherwise well.

Nobody knows why these two disparate conditions arising from gene defects on Xp21 should have raised CK. This is currently unexplained.

Curiously, subjects with choreo-acanthocytosis due to reduction in chorein also have a raised CK. However, this is an autosomal recessive condition and therefore cannot be attributed to the X-chromosome.