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.

The Ross Procedure- An Alternative to Mechanical Aortic Valve Replacement in Young Patients

Consider this problem. A young or middle aged patient needs an aortic valve replacement. Perhaps she was born with a bicuspid valve, or perhaps she grew up in the East and had rheumatic heart disease. Regardless, her aortic valve is end stage and must be replaced. She may be pregnant. What do you do?

The current practice is to give these subjects a mechanical aortic valve. Older subjects would get a tissue (bioprosthetic) valve, but the latter have shorter lives and would almost certainly necessitate replacement after 10 years or so.

Therefore, despite the daunting prospect of lifelong anticoagulation, mechanical aortic valves are preferred in younger subjects.

Donald Ross, British cardiac surgeon, thought of an alternative in 1967. Working at Guy's Hospital, London, he replaced a diseased aortic valve with the patient's own pulmonary valve- an autograft. He then put in a homograft (a cadaveric valve of human origin rather than porcine valve) in the vacant pulmonary position to complete the switch.

His rationale was that a living valve would be physiologically more suitable, the pulmonary valve would share many of the aortic valve's attributes, there would be no immunologic rejection and anticoagulation would be avoided. The background to this was that Star & Edwards had pioneered the first mechanical aortic valve prosthesis in 1960 across the pond, and two years later, Ross himself had performed an aortic valve replacement with a cadaveric graft.

He wasn't happy though. The homografts simply did not last long enough in the aortic position.

Over the next few years, the Ross procedure gained acceptance and was performed in thousands of patients. However, it gained a reputation for being a technically challenging procedure and as the new generation of mechanical valves became available, it became less popular despite the fact that 80% of transplant recipients survived 20 years or longer without re-operation.

In the current issue of JAMA Cardiology, Mazine & colleagues publish a mata-analysis that looks back at five decades of the Ross procedure. Comparing around 1500 such procedures with just over 1900 mechanical valve replacements in young to middle aged patients, they found that the Ross procedure led to reduced all cause mortality, longer survival, better quality of life, haemodynamic performance and left ventricular function than mechanical valves. Rates of major bleeding & stroke were less frequent with the Ross procedure. As expected, re-operations were marginally less common with mechanical valves. These days, most such re-operations would be in the nature of modern percutaneous procedures- TAVR.

Despite the generally held view that the Ross procedure is technically more challenging, peri-operative mortality & morbidity did not differ in the 2 groups. Subjects who had mechanical valves were at a higher risk of needing a permanent pacemaker subsequently.

The Ross procedure cannot be performed in all patients. It is best avoided in those with familial aortopathy and in those with hereditary or acquired connective tissue disease.

It took a while, but after half a century, Donald Ross's groundbreaking procedure has been finally vindicated.

Convergent Series in Medicine

There were 160,000 deaths from cardiovascular causes in the UK in 2016. If the number of deaths decreases by 5% every year, year after year, indefinitely, what is the total number of people that would have succumbed to cardiovascular causes?

This is an example of a convergent geometric series.

In general, the sum of a geometric series is given by S= a (1-r^n)/1-r, where S is the sum of the first n numbers, a is the first number in the sequence, and r is the common ratio of the sequence (the factor by which each successive number increases or decreases).

Now, can you predict what would be the sum of the series if n was infinite? Would the sum S be finite or infinite?

The answer is that it depends on the value of r, the common ratio. If r is between -1 & 1, the sum S would be a finite (convergent series), while if r is <-1 or >1, the sum would be infinite (divergent series).

If r is a fraction, the limit of the equation S= a (1-r^n)/1-r, as n approaches infinity, is S = a/1-r.

In the above example, r=0.95, as the death rate falls by 5% every year, the total number deaths in infinite number of years would be 160,000/0.05=32,00,000.

The sum of this geometric series is finite, hence it's a convergent series.

Alcohol, The Herald

Take a look at the following two situations, and see what you make of them.

In the first, a 33-year old man complains of severe left shoulder pain after drinking alcohol. He's lost weight and has night sweats.

Elsewhere, a 30 year old man has rhinorrhoea, breathlessness and wheezing every time he drinks alcohol.

The first man had Hodgkin's lymphoma. The second had Aspirin Exacerbated Respiratory Disease (AERD).

Musculoskeletal pain can be triggered by alcohol in many cancers. In one series, 40% of these were due to Hodgkin's lymphoma.

Similarly, although the usual trigger for upper & lower respiratory symptoms in AERD is aspirin or Cox 1 inhibiting NSAIDs, alcohol is a common trigger as well. The mechanism is not known.

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.