Risdiplam- the oral drug for SMA

 

My patient with SMA type 2 rushed into my OPD very excited that his child was going to receive Risdiplam free as part of a clinical trial. "How safe is it ? Is it effective?"he was bombarding me with questions.

So that night I sat down to read about it, so I could give him a more educated answer.

The FDA approved Risdiplam (Everysdi by Roche) in August 2020 for use in adults and children above 2 months with SMA.

The most exciting fact is that it is given orally unlike Nusirensin which has to be given intrathecally.

The approval is based on 2 clinical studies. 

The first trial was FIREFISH done on symptomatic infants between 2- 7 months. 41% ( 7/17 babies learnt to sit and 90% were alive without ventilation at 12 months.

In the other trial SUNFISH which was a placebo controlled trial in patients between 2-25 years there was a statistically significant improvement in motor function.

How does it work?  Normally the SMN2 is spliced such that in 85% exon 7 is excluded resulting in a small and easily degradable protein. Risdiplam promoted splicing in SMN2 to allow inclusion of exon 7, resulting in a functional protein. This is able to fill the deficiency of SMN1 protein.

Fever, diarrhoea, rashes and oral ulcers are some minor adverse events documented so far.

Hereditary Hyperekplexia: what should we know?

A 3 month old baby born of a third degree consanguineous marriage, came in with the history of recurrent episodes of tonic posturing and stiffness since day 1 of life. Mother noticed that whenever she was tapped on the nose she would become stiff ( The Nose Tap Test). Sometimes the episode was so prolonged, she would get cyanosed. Neuroimaging and EEG were normal. She had also developed an umbilical hernia because of the recurrent stiffening episodes.

The diagnosis was a no-brainer. Hereditary Hyperekplexia however is often misdiagnosed as tonic seizures. I demonstrated the Vigevano manoeuvre to the mother. Forcibly flexing the head and legs towards the abdomen aborts the episode and is life-saving. Response to clonazepam (0.01-0.1 mg/kg) is most gratifying. Combination clobazam ( upto 2 mg/kg) plus clonazepam has been used in refractory cases. Fluoxetine and alcohol has been used in adult. Cannabidiol and ondansetron  are under investigation.

A beautiful analysis of 97 patients with genetically proven hyperekplexia yielded some useful genotype -phenotype correlations:https://doi.org/10.1093/brain/awt207

The commonest genetic variants were seen in the GLRA1 gene

Infantile apnoea were common in SLC6A5 mutations

92% of patients with GLRB mutations had delayed speech, even autism

Both GLRB and SLC6A5 were more likely to have developmental delay than GLRA1.

 

A treatable myopathy- late onset Pompe's

 A 2 year old girl with normal birth and development came in with the history of inability to get up from squatting and difficulty in climbing stairs for the past 4 months. She had no muscle pain or tenderness and no calf muscle hypertrophy. Her CPK was 700 ugm/L and LDH was 1394 U/L, both moderately elevated.

Her EMG was myopathic. Her workup for autoimmune myositis was negative. However her DBS screening for Pompe's disease showed low levels of acid alpha glycosidase (GAA). We decided to do genetic studies to confirm the diagnosis.

Late onset Pompe's is often not in our radar for children presenting with proximal myopathy.

What are the clinical clues to trigger its consideration in a clinicians mind?

It predominantly affects the hip girdle muscles such as the hip adductors and flexors.

A peculiarity is the involvement of the paraspinal muscles. Sometimes they have back pain or a rigid spine. Myotonic discharges from the paraspinal muscles are considered a good clue to the diagnosis.

The relative involvement of the diaphragm and accessory muscles of respiration results clinically in recurrent pneumonias. Nocturnal hypoventilation may present as early morning headaches. You can check for a decline in oxygen saturation and FVC ( > 10% fall) in the supine position which is a good screen for diaphragmatic involvement. 

Unlike the classic Pompe's disease the heart is not involved except for stray reports of WPW syndrome.

Neither do they have hepatomegaly or macroglossia.

Enzme levels range between 1-40% of normal.

Most importantly early use of enzyme replacement makes a significant difference in what would otherwise be progressive decline in muscle function. https://www.aanem.org/mxonline/resources/downloads/products/ED01.pdf

Genetic testing in autism

 

What is the risk of having a second child with autism? It is interesting to know that it is higher (7%) if the first child with autism was a girl than if it was a boy ( 4%). If a couple has 2 children with autism, the risk of having yet autistic child shoots up to 33-50%.

The genetic architecture of autism is complicated. Largely it is due to the presence of 2 or more low or moderate risk variants which are difficult to identify.https://dx.doi.org/10.1590%2FS1679-45082017RB4020

About 10% will have an abnormal chromosomal microarray. Clinical clues are dysmorphism, malformations & a family history of psychiatric disorders.

There are just a handful of monogenic disorders which are associated with autism.

The most important would be the Fragile X syndrome. It may be wise to recommend it in males with autism even in the absence of the classical phenotype and in girls who have a family history of fragile X or premature ovarian failure.

Girls with intellectual delay and autism need to be tested for the MECP2 gene.

Children with a large head > 2.5 SD need evaluation for the PTEN mutation.

If there are seizures, episodic deteriorations you may need to rule out IEM's. Some treatable IEM's like creatine deficiency disorders may be picked up on an MR spectroscopy.

The bottomline is that no single genetic test will make a diagnosis of autism. It is a clinical diagnosis but about 25% may have an underlying genetic disorder.

 

GBS associated with COVID 19 - what should we know?

 

This 5 year old girl came to our hospital with fever and non specific myalgia 8 days back followed 3 days later by progressive ascending quadriparesis.

Her nerve conduction velocities were suggestive of an acute motor axonal neuropathy. However her nasopharyngeal swab for COVID 19 was positive.

What must we know about GBS associated with COVID 19?

Caress et al have reviewed 37 cases of GBS associated with COVID 19 published in literature so far.https://doi.org/10.1002/mus.27024

The time to onset of neurological symptoms after COVID 19 ranged from 3-28 days ( mean 11 days). It appears to be slightly more rapid than usual.

The vast majority (84%) were symptomatic with primary COVID symptoms during the GBS.

Interestingly facial diplegia was seen in almost a quarter of patients.

The requirement for ventilation was 37.8% slightly higher than the routine 20-30% in the garden variety of GBS. It may to some extent be explainable because of the associated respiratory involvement in SARS COV2 infection.

CSF PCR for SARS CoV 2 was negative in all the 18 in whom it was tested so a direct viral damage seems unlikely.

The COVID 19 virus attaches via the spike protein to the ACE 2 receptors and also to gangliosides containing silica acid residues.

So the hypothesis is that anti COVID antibodies in our bodies may inadvertently attack the gangliosides resulting in GBS. However antiganglioside antibodies have been seen in only 12% of the patients in whom they were tested.

 Treatment has been mostly IVIG or PLEX. One must be careful with IVIG since their is an underlying hypercoagulable state in SARS CoV-2 infections. Most people would avoid PLEX because of the possibility of hemodynamic compromise.

The risk of GBS with the COVID19 vaccine also needs to be monitored.

The biochemistry behind Infantile Tremor Syndrome

 

A 9 month old baby came in with progressive hyperpigmentation for 15 days, tremors and altered sensorium for 5 days.

His haemoglobin was 7.7gm/dl with an MCV of 96fl. His MRI brain showed a predominant fronto-temporal atrophy and some mild delay in myelination. His Serum Vitamin B12 was low and serum homocysteine was elevated.

No marks for making the diagnosis of Infantile Tremor Syndrome (ITS). He had been inadequately weaned and was predominantly on breast feeds. His mother was a strict vegetarian. All this tied in very well with the classical picture of ITS. The clouds of doubt about the underlying ethology are slowly dissipating in the face of strong evidence that the culprit is vitamin B12 deficiency.

Studies from PGI Chandigarh in 92 children have shown that though Vitamin B12 levels are documented to be low in about 42%, serum homocysteine is a better marker and is elevated in 96.5 %. An MCV > 95fl is again seen in a mere 42 %.https://doi.org/10.1007/s12098-019-03117-w

If you have inadvertently done an  acylcarnitine profile you may pick up elevated C3/C2 and C3/C16 levels. Urine organic acids will show elevated methylmalonic acid levels.

How does cobalamin deficiency result in such widespread neurological deficits in the brain?

Cobalamine in the brain is in 2 forms - adenosylcobalamine and methylcobalamin. Both have a role to play.

Adenosyl cobalamin converts methylmalonyl CoA  to succinylcholine CoA. In its absence excess of propionyl CoA is formed and subsequently odd chain fatty acids. These C15, C17 fatty acids when incorporated into the myelin are defective. Hence the abnormal myelination and developmental delay.

Methycobalamin deficiency on the other hand impairs conversion of homocysteine to methionine which in turn is the precursor of an important methyl donor for various fatty acids in myelin.

 

Does the herpes virus persist in the brain after encephalitis?

 

An 8 year old girl with cerebral palsy with spastic quadriparesis was admitted with the history of fever, seizures and altered sensorium. This was her MRI brain (seen above)with cystic encephalomalacia and fresh diffusion restriction in bilateral basal ganglia. Her CSF had 7 lymphocytes, elevated proteins and PCR for Herpes was positive with 4000 copies/ml.

In her neonatal period also she had been diagnosed with viral encephalitis and had been treated with acyclovir for presumed herpes infection on the basis of diffusion restriction of bilateral temporal lobes, which is seen the the MRI below. Despite treatment she had been left with significant neurological deficit and had become essentially bedridden.

There have been reports of herpes reactivation several years after an initial encephalitis. In fact it is believed that the virus often remains in a latent state in some tissues in the brain such as the ependymal lining of the ventricles even after treatment with standard doses of acyclovir.

In fact 70% of cases of HSV encephalitis is considered due to reactivation of the virus, though primary infections are more common in children.

During the latent period only the "Latency Associated Transcript" (LAT)of the virus is coded in the neurons. This also interestingly enhances neuronal survival by inhibiting apoptosis. During periods of immune depression such as infections or fever or even trauma, the virus is reactivated and enters the lytic cycle and starts actively damaging neutrons. https://doi.org/10.3389/fncel.2019.00046

There are also cases which have documented a progressive downhill neurological disease due to herpes encephalitis. It is also implicated in certain neurodegenerative disorders such as Alzheimers disease and multiple sclerosis. It is proposed that multiple mild HSV infections involving the brain may result in the same pathology noted in Alzheimers disease.

Acyclovir inhibits active viral replication. It has been suggested that viruses which are not actively replicating may continue to survive in the brain. Various suggestions including longer duration of treatment with acyclovir and repeated courses have ben suggested to overcome the problem of relapsing or chronic HSV brain disease.