What links congenital CMV, Aicardi-Goutiere's Syndrome and Non Megalencephalic Cystic Leukoencephalopathy?

A 3 year old boy came in with the history of neuroregression for the past 6 months. His head size was normal.

His MRI brain was striking. He had cysts in bilateral temporal lobes and multifocal sub cortical white matter changes in frontal and parietal-occipital lobes. 

It decided to relook at all the important leukodystrophies with cysts.

1. Megalencephalic Leukoencephalopathy with subcortical cysts- This has diffuse, extensive white matter changes. The white matter looks positively swollen. The child is usually developing normally and may develop brief deterioration after minor head trauma. In short the MRI brain looks much worse than the child. It's extremely common among the Agarwal community in India. Most importantly they all have a large head which my patient lacked.

2. Congenital CMV disease- Congenital CMV disease also presents with white matter changes and temporal cysts. They often have cortical malformations like polymicrogyria, ventriculomegaly, calcifications and cerebellar atrophy. They are symptomatic since early infancy and have microcephaly.

3. Aicardi Gautiere syndrome- They mimic congenital CMV. They present after a few weeks of life with irritability and sterile pyrexia and chillbalians. The basal ganglia calcifications are striking besides the temporal cysts and white matter changes. 

4. Cystic Leukoencephalopathy without megalencephaly- These children are symptomatic from birth with global developmental delay and very slow to static clinical progression of disease. The head size is normal and MRI brain shows temporal cysts and scattered multifocal subcortical white matte changes, which our patient had.

Congenital CMV, AGS and cystic Leukoencephalopathy without megalencephaly are called interferronopathies.

Normally viral nucleic acids trigger release of interferon. Interferon production can also be upregulated by the presence of excessive nucleic acid residues derived from what are called retro elements. These are remnants of ancient viruses in our DNA which are usually metabolised by various enzymes coded by genes like TREX1, RNAase H2 etc. Mutations in these genes result in excessive nucleic acid residues which activate interferon and cause this group of auto inflammatory disorders like Aicardi Gautieres and cystic Leukoencephalopathy without megalencephaly.  https://doi.org/10.1111/dmcn.14268

This is the key to the uncanny similarity between congenital CMV and AGS.

Undeciphering the mTOR pathway and the Indian scientist who started it all.

 

This 8 year old boy came in with the history of developmental delay and epilepsy. The diagnosis was written on his face. 

The adenoma sebaceum which you see is a misnomer for what are actually angiofibromas. They are a classical skin manifestation of tuberous sclerosis (TS).

Tuberous sclerosis is the classic mTORopathy. Dysregulation in the mTOR pathway is the reason behind the various manifestations including cardiac rhabdomyomas, intracranial hamartomas, subependymal giant astrocytomas and renal angiolipomas.

Overactivation of the mTOR pathway results in giant dysplastic neutrons, abnormal axonogenesis and dendrites, disordered cortical lamination reduced myelination and increased excitatory synaptic currents.

This mechanism has also been implicated in disorders with cortical malformations due to other genes such as STRADa, DEPDC5 and PI3K which act upstream of the mTOR pathway.

Since then there are been great excitement about possible targeted therapy with mTOR inhibitors in TS.

The EXIST-3 was a phase 3 RCT which used Everolimus (an mTOR inhibitor) and showed significant reduction of seizures in patients with TS ( 14.9% in placebo, 29.3% in low dose and 39.6% in high dose group).https://doi.org/10.1016/S0140-6736(16)31419-2

However a recent RCT everolimus failed to improve cognition/ autistic features in children 4-7 years old with TS.

I sat down to understand the mTOR pathway and was pleasantly surprised to find that it all began due to the exemplary work of an Indian scientist Surendra Nath Sehgal. http://www.indianjcancer.com/article.asp?issn=0019-509X;year=2017;volume=54;issue=4;spage=697;epage=698;aulast=Samanta

Surendra Nath Sehgal studied pharmacology from BHU, India; went on to do a PhD from Bristol and finally settled down in a research lab in Canada. He isolated a drug from the soil sample of the exotic Easter Islands in the South Pacific Ocean. 

He called it Rapamycin because the island was called Rapa Nui.

Though initially evaluated as an anti-fungal it was subsequently found to have immunosuppressive actions.

His persistent efforts to further characterize its properties led to the discovery of its significant anti cancer effects. Incidentally, I suppose that's why the commonest side effect of the mTOR inhibitors like everolimus is stomatitis.

Intense research into its mechanisms revealed that it acts on a target (to be later called mTOR) which plays a key role in cell proliferation and cell growth. This pathway is switched on by many oncogenic signalling pathways.

Ironically, Surendra Sehgal developed metastatic colon cancer in 1998 and he was treated with Rapamune which helped him survive till 2003.

 

Allan-Herndon-Dudley Syndrome: a medical chimera

 A 10 month old boy came to me with the history of axial hypotonia, scissoring of lower limbs and dyskinetic movements for the past 6 months. 

His birth weight was 3.75 kg but despite a good appetite had poor weight gain and excessive sweating. His parents also noticed that the anterior fontanelle had closed by 6 months. 

His TSH was normal but he had an elevated fT3 and normal fT4. His free T3/T4 ratio was 4.13

This combination of developmental delay with dyskinesias in a boy with a free T3/T4 > 0.75 is classical of   Allan-Herndon-Dudley syndrome (AHDS).

The problem in AHDS is in the MCT8 gene. It codes for a protein which transports thyroid hormones across the blood brain barrier. In its absence T3 is unable to enter the brain and just a minuscule amount of T4 enters via another transporter coded by OATP1C1.

There is an excess of peripheral conversion of T4 to T3. What results is a peripheral thyrotoxicosis. But alas the brain is starving for thyroid hormones.

This lack of thyroid hormone inside the brain results in hypomyelination, developmental delay and dyskinesias. Systemically there is tachycardia, sweating and weight loss.

I sat down to see what is new in the therapy of this fascinating disease.

Merely giving T4 supplements aggravates the hyperthyroidism and is to be avoided.

Trials of a combination of T4 with propylthiouracil (PTU) stabilises the peripheral hyperthyroidism, allows a little T4 to enter the brain and improves weight gain. Unfortunately it does not improve the neurological functions significantly. Its drawback is the long term risk of agranulocytosis and liver failure with PTU.

A recent review of advances in therapeutics of AHDS describes the use of T3 analogs which don't require MCT8 to cross the BBB. Trials are on with three drugs- DITPA, TRIAC and sobetirome.

Work is also on with gene therapy and pharmacological chaperones ( Frontiers in Neurology April 2020) .https://doi.org/10.3389/fnins.2020.00380

An interesting study used intranasal T4 to bypass the block due to MCT8 deficiency but failed to raise thyroid hormone levels in the brain (PLOS ONE July 2020). https://doi.org/10.1371/journal.pone.0236113

Cardiomyopathy in DMD - what should we know?

A 10 year old child with Duchene muscular dystrophy came for follow up after 6 months, delayed because of the lockdown during the COVID pandemic.

The lockdown had deprived him of any regular physiotherapy and medications were also irregular because of erratic supplies in his village. He had stopped walking the last 2 months. He had some tachycardia.

We got an echocardiogram (ECHO) done. It revealed moderate LV dysfunction with an LV ejection fraction of 39%.

It was a good opportunity to review the literature on what is optimal therapy for cardiomyopathy in DMD today and what is new( https://doi.org/10.1542/peds.2018-0333I)

• As respiratory support for DMD patients has improved, cardiac contributions to morbidity and mortality are gaining supremacy.
• It is often difficult to pick up cardiac dysfunction clinically in patients with DMD due to their restricted ambulation.
• Early diagnosis and treatment results in improved cardiac remodelling.
• In the new DMD care guidelines, annual cardiac evaluations are recommended from the time of diagnosis. More frequent evaluations are required for those with established cardiomyopathy.
• Cardiac MRI (CMRI) is recommended over ECHO because of suboptimal acoustic windows and inaccurate estimation of systolic function with the latter.
• Subepicardial fibrosis on CMRI is picked up much earlier than changes in ejection fraction/fractional shortening on ECHO.
• The pattern of late gadolinium enhancement is an important biomarker for myocardial fibrosis.
• Strain imaging (on ECHO/CMRI) is a new tool to pick up regional wall abnormalities.
• In the future T1 mapping which evaluates extracellular volume will identify early diffuse fibrosis.
• The NIH working Group recommends starting ACE inhibitors or ARB's by age 10 (Perindopril was used in the trial by Duboc et al)
• For established cardiac involvement (on CMRI/ECHO) the combination of ACEi and aldosterone agonists may have an edge over ACEi alone.
• Decreased ejection fraction is closely linked to ventricular arrhythmias.
• ICD's are recommended for those with a sustained VT/ resuscitated cardiac arrest.
• However preemptive ICD's are still controversial in DMD patients with EF < 35% or ill sustained VT.
• Gene therapies like the exon skipping drugs ( eg Eteplirsen) are less efficacious in the cardiac muscle in animal studies vis a vis skeletal muscle.

Late gadolinium enhancement (LGE) of the inferolateral and anterolateral free wall of the left ventricle is very characteristic of DMD. It is hypothesised to be due to mechanical stress on a structurally damaged myocardium. Viral myocarditis bears an uncanny similarity to this. Interestingly in entero viral myocarditis, the myocardial damage was noted to be due to cleavage of dystrophin.

LGE is picked up before LV dysfunction on ECHO. Anti failure medications started after development of LGE has been shown to delay and probably reverse the remodelling process. (https://www.researchgate.net/deref/http%3A%2F%2Fdx.doi.org%2F10.4330%2Fwjc.v4.i5.173?_sg%5B0%5D=HFeIzFrptTM0CJRLths4NxFgooAeaoZwcCOrOXiu6aW91SJN3M7iAz2Z0tocRGRr6MVGZh4N5NMAeU5l8Qk0_BvyXQ.bHCd8lktPiMjY2ZB4Qnk0UFVzeruLtDHz0iBCXhXk8c4uer4noSbVPFL_ZRiC8H_i6iabfEulTJgx9OvcUBSJQ)

There appears to be a case for CMRI in DMD.

Arrythmias in inborn errors of metabolism

This is the ECG of a 6 year old boy who gave a history of repeated episodes of unexplained hypoglycaemic seizures in the first year of life. His tandem mass spectroscopy suggested a fatty acid oxidation defect. He was advised regular meals, avoidance of fasting, carnitine and biotin supplements and  oral oxcarbamazepine and clobazam on which he became seizure free.

He now came with a short history of fever and on routine examination was noted to have some missed beats. ECG showed bigeminy.

The questions I wanted to answer were 

1. Which are the inborn errors which present with arrhythmias?

2. How can we treat or prevent these?

The common causes of inborn errors of metabolism developing arrhythmias are fatty acid oxidation defects (FAOD), carnitine deficiency and mitochondrial disorders. Arrhythmias also occur in organic acidemias and later stages of storage disorders which affect the heart like Pompes, glycogen storage disorders, Gauchers and mucopolysaccharidosis.

 A beautiful paper in Circulation published in 1999 analysed 107 cases of fatty acid oxidation defects of whom 24 had arrhythmias. While ventricular arrhythmias were present in all types of FAOD's, conduction blocks and atrial arrhythmias were seen only in CPT II and carnitine acyl carnitine translocase. The carnitine transporter, CPT I and MCADs were not associated with arrhythmias. It appears one prime cause of arrhythmias is the accumulation of long chain acyl carnitines which have toxic effects on the phospholipids of the sarcolemma and disrupt various ion channels there. 

Avoidance of fasting and carnitine supplements may have some role in reducing arrhythmias but are not always successful.

A new paper basic science paper published in the International Journal of Molecular Science in April 2020, suggests that resveratrol ( found in grapes and red wine) and  etomoxir ( CPT1 inhibitor) may potentially have a role in preventing arrhythmias in VLCFAOD http://dx.doi.org/10.3390/ijms21072589.

Resveratrol works in (in vitro) in mild phenotypes who have some residual activity of VLCAD by reducing accumulation of very long chain acyl carnitines. Etomoxir works by inhibiting the production of long chain acyl carnitines. Both these drugs have been used to reduce post myocardial infarction related arrhythmias.