Tuesday, March 21, 2023

Riboflavin transporter deficiency

Inspired by a patient

Colasuonno F, Marioli C, Tartaglia M, Bertini E, Compagnucci C, Moreno S. New Insights into the Neurodegeneration Mechanisms Underlying Riboflavin Transporter Deficiency (RTD): Involvement of Energy Dysmetabolism and Cytoskeletal Derangement. Biomedicines. 2022 Jun 6;10(6):1329. doi: 10.3390/biomedicines10061329. PMID: 35740351; PMCID: PMC9219947.


Riboflavin transporter deficiency (RTD) is a rare genetic disorder characterized by motor, sensory and cranial neuropathy. This childhood-onset neurodegenerative disease is caused by biallelic pathogenic variants in either SLC52A2 or SLC52A3 genes, resulting in insufficient supply of riboflavin (vitamin B2) and consequent impairment of flavoprotein-dependent metabolic pathways. Current therapy, empirically based high-dose riboflavin supplementation, ameliorates the progression of the disease, even though response to treatment is variable and partial. Recent studies have highlighted concurrent pathogenic contribution of cellular energy dysmetabolism and cytoskeletal derangement. In this context, patient specific RTD models, based on induced pluripotent stem cell (iPSC) technology, have provided evidence of redox imbalance, involving mitochondrial and peroxisomal dysfunction. Such oxidative stress condition likely causes cytoskeletal perturbation, associated with impaired differentiation of RTD motor neurons. In this review, we discuss the most recent findings obtained using different RTD models. Relevantly, the integration of data from innovative iPSC-derived in vitro models and invertebrate in vivo models may provide essential information on RTD pathophysiology. Such novel insights are expected to suggest custom therapeutic strategies, especially for those patients unresponsive to high-dose riboflavin treatments.

Bulas S, Bedoukian EC, O'Neil EC, Krantz ID, Yum SW, Liu GT, Aleman TS. Ocular Biomarkers of Riboflavin Transporter Deficiency. J Neuroophthalmol. 2023 Mar 1;43(1):110-115. doi: 10.1097/WNO.0000000000001678. Epub 2022 Aug 2. PMID: 35921603.


Background: To describe the clinical presentation with a focus on ocular manifestations and response to riboflavin supplementation of 3 patients with riboflavin transporter deficiency (RTD) caused by mutations in SLC52A2 ( SLC52A2- RTD).

Methods: This is a retrospective review of records of 3 children (aged 18, n = 2 and age = 8, n = 1) with SLC52A2- RTD. Patients underwent comprehensive ophthalmic evaluations including color vision testing, pattern visual-evoked potentials (pVEPs, 1 patient) and spectral domain optical coherence tomography (SD-OCT) imaging. Patients received riboflavin supplements from the time of the molecular diagnosis of RTD.

Results: Two unrelated 18-year-old patients with SLC52A2- RTD had a symptomatic onset with sensorineural hearing loss and auditory neuropathy/dys-synchrony since age 3 and 11, respectively. On examination 7 years after symptomatic onset, they showed subnormal visual acuities (20/30 and 20/60, both eyes, respectively), preserved color vision, and a thin but measurable retinal ganglion cell layer (GCL) and nerve fiber (RNFL). The inner and outer nuclear layers were normal. The asymptomatic SLC52A2- positive brother of one of these patients started riboflavin supplementation right after the molecular diagnosis and had normal vision and SD-OCTs 7 years later. Onset of riboflavin supplementation in one of the 2 symptomatic cases resulted in acute improvement of the pattern visual-evoked potential and vision.

Conclusions: Retinal ganglion cells and their axons are uniquely susceptible to RTD compared with other highly energy-dependent retinal neurons, such as photoreceptors, raising the possibility for alternative mechanisms of disease or protection. Riboflavin supplementation results in acute functional improvement of vision and long-term preservation of GCL and RNFL if initiated early.

Sanchez JA, Traub R, Trau SP, Howard JF Jr. Electrodiagnostic Findings in Riboflavin Transporter Deficiency Type 2. J Clin Neuromuscul Dis. 2022 Jun 1;23(4):205-209. doi: 10.1097/CND.0000000000000390. PMID: 35608644.


We present the electrodiagnostic findings in a case of a 3-year-old girl presenting with sensory ataxia, gait disturbance, and visual-auditory disturbance with a genetically confirmed diagnosis of riboflavin transporter deficiency type 2 (RTD2). She carries a homozygous mutation in the SLC52A2 gene, c.1016T>C (p.Leu339Pro). Her testing demonstrates a non-length-dependent axonal sensorimotor polyneuropathy affecting predominantly the upper extremities with active denervation of the distal muscles of both arms. It is important to highlight these findings because most genetic neuropathies have a length-dependent pattern of involvement, affecting the distal legs before the arms. The electrodiagnostic findings in RTD2 have not been previously well described. These electrodiagnostic findings are in agreement with the typical clinical phenotype of RTD2, which affects the upper limbs and bulbar muscles more than the lower extremities.

Frederick AL, Yang JH, Schneider S, Quade A, Guidugli L, Wigby K, Cameron M. To Be or No B2: A Rare Cause of Stridor and Weakness in a Toddler. Child Neurol Open. 2021 Aug 5;8:2329048X211030723. doi: 10.1177/2329048X211030723. PMID: 34395718; PMCID: PMC8361551.


We present a case of a young child with a rare metabolic disorder whose clinical presentation resembled that of autoimmune myasthenia gravis. The differential diagnosis was expanded when autoantibody testing was negative and the patient did not respond to standard immunomodulatory therapies. Rapid whole genome sequencing identified 2 rare variants of uncertain significance in the SLC52A3 gene shown to be in compound heterozygous state after parental testing. Biallelic mutations in SLC52A3 are associated with Riboflavin Transporter Deficiency, which in its untreated form, results in progressive neurodegeneration and death. Supplementation with oral riboflavin has been shown to limit disease progression and improve symptoms in some patients. When the diagnosis is suspected, patients should be started on supplementation immediately while awaiting results from genetic studies.

Monday, March 20, 2023

Dravet syndrome and precision medicine

Sullivan J, Wirrell EC. Dravet Syndrome as an Example of Precision Medicine in Epilepsy. Epilepsy Currents. 2023;23(1):4-7. doi:10.1177/15357597221106281


Dravet syndrome (DS) is a drug-resistant, early-onset, developmental and epileptic encephalopathy where there have been many recently approved therapies with many more in development. With the availability of more syndrome specific treatment options coupled with an earlier diagnosis, DS is well-positioned to be an example of how a precise syndromic diagnosis can guide treatment choices and improve overall outcomes and also allow for the development of potential disease modifying therapies to address more than just seizures. In this review we summarize the current state of DS approved therapies and those that are in various stages of development.

From the article:


Dravet syndrome (DS) is a drug-resistant, early-onset, developmental and epileptic encephalopathy that typically presents in the first year of life with prolonged febrile and afebrile, focal (usually hemiclonic) and generalized tonic-clonic seizures. Development is normal at onset but then slows and global delays are usually evident by 2-3 years of age. Other significant comorbidities emerge with time including crouch gait, parkinsonian features, autistic features, attention deficit disorder, growth delay and feeding problems, dysautonomia and sleep problems. The risk of sudden unexpected death in epilepsy (SUDEP) is significantly increased with a reported rate of 9.32 per 1000 person years.
Over 85% of cases are found to have , mostly de novo, pathogenic, loss-of-function SCN1A variants which result in haploinsufficiency of Nav1.1, the alpha-1 subunit of the sodium channel. Both the underlying channelopathy and the recurrent severe seizures contribute to the presence and severity of comorbidities. In a prospective study of 67 children with DS, 15 of whom were studied longitudinally, Nabbout et al found no correlation between epilepsy variables and developmental/intelligence quotient at last evaluation, but noted that those with a documented SCN1A variant exhibited greater delays than those without variants. This work suggests that the SCN1A variant significantly contributes to the encephalopathy. Conversely, other studies have reported that earlier use of appropriate therapies, or avoidance of therapies that exacerbate seizures may improve outcomes. Since 2018, there have been 3 new antiseizure medications approved for seizures associated with Dravet syndrome...

Pharmaceutical Grade Cannabidiol

Pharmaceutical-grade cannabidiol was approved by the FDA in June 2018 for the treatment of seizures associated with DS. Its exact mechanism of action is unknown – it does not significantly activate CB1 or 2 receptors, but rather may enhance neuronal inhibition (through GABAergic channels), modulate intracellular calcium (TRPV, GPR-55 or VDAC) and have an antiinflammatory effect (adenosine)...

Despite improvements in convulsive seizure frequency, no significant benefits were seen on the Quality of Life in Childhood Epilepsy or Vineland Adaptive Behavior Scales comparing cannabidiol and placebo.


In 2000, stiripentol was the first medication to be specifically studied in a small cohort of DS patients where 71% of patients receiving stiripentol had a 50% or greater reduction in generalized tonic-clonic or clonic seizures compared to only 5% of those who received placebo. Impressively, 9 of the 21 who received stiripentol were seizure free during the 2-month treatment period compared to no patients who received placebo. All patients in this study were also on concomitant valproate and clobazam. There are several potential mechanisms of action including direct enhancement of inhibitory GABAergic neurotransmission in addition to inhibiting the CYP1A2, 3A4 and 2C19 metabolism of concomitant anti-seizure medications.


A post-hoc analysis of patients who enrolled in the various fenfluramine trials and received at least 1-year of treatment in the open-label extension study was done to evaluate for clinically meaningful changes on the Behavior Rating Inventory of Executive Function. In the 58 children included in this analysis, 45 (78%) achieved a greater than 50% reduction in seizures and there was clinically meaningful improvement both the emotional regulation index and the cognitive regulation index. These findings support the notion that non-seizure outcomes can improve in this patient population and allows for redefining our treatment goals as we strive to treat all aspects of the syndrome...

Other Agents in Clinical Trials

Additional mechanisms are also being explored with various agents in different stages of clinical trials including soticlestat (a cholesterol 24-hydroxylase inhibitor), as well as clemizole and lorcaserin both of which like fenfluramine, act via the serotonin pathway.

Antisense Oligonucleotide Therapy

The SCN1A gene contains a nonsense-mediated decay exon that is used to regulate the SCN1A transcript and Nav1.1 protein production. If the mRNA transcript contains this exon, it degrades and thus protein is not produced. Targeted augmentation of nuclear gene output (TANGO) technology can target these nonproductive alternative splicing events to decrease nonproductive mRNA and thus boost protein production. As this therapy targets the underlying pathogenesis, it carries the potential benefit to not only reduce seizures, but also attenuate or prevent comorbidities including SUDEP.

STK-001 is an antisense oligonucleotide (ASO), currently in clinical trials, which utilizes TANGO technology to boost Nav1.1 protein expression... 

AAV-9 Based Gene Therapy

Another novel, potential one-time disease-modifying approach to address the underlying Nav1.1 haploinsufficiency is being developed by Encoded Therapeutics. ETX-101 is an AAV-9 delivered gene therapy that expresses an engineered transcription factor under the control of a GABA-ergic cell-selective regulatory element which is designed to promote increased transcription and therefore translation of the SCN1A gene in inhibitory interneurons...
Making an accurate diagnosis of an epilepsy syndrome such as Dravet syndrome has allowed for the study of novel compounds and data to inform syndrome specific treatments. While this may not necessarily be a true precision medicine approach as some of the ASMs that have been approved for the treatment of seizures associated with Dravet syndrome have also demonstrated efficacy in other epilepsy syndromes, having efficacy and safety data does allow for a more systematic treatment approach for these patients.27 Having the precise understanding of the underlying genetic etiology of Dravet syndrome has paved the way for development of true precision medicine approaches. If effective, these could change the overall natural history of the syndrome as we know it and lead to improvement in domains beyond just seizures, thereby further improving the overall outcomes and quality of lives for these patients and their families. 

Sunday, March 19, 2023

World Down Syndrome Day March 21

A human rights-based approach to disability. The message of With Us Not For Us is key to a human rights-based approach to disability. DSi is committed to moving on from the outdated charity model of disability, where people with disability were treated as objects of charity, deserving of pity and relying on others for support. A human rights-based approach views people with disabilities as having the right to be treated fairly and have the same opportunities as everyone else, working With others to improve their lives.

Our global network calls for all supporters to be With Us Not For Us. The United Nations Convention on the Rights of Persons with Disabilities calls for everyone to have the freedom to make their own choices. But people with Down syndrome often have poor or controlling support. Often their supporters do things For them, not With them.

Our global network calls for all organisations to include people with Down syndrome and being With UsNot For Us. The United Nations Convention on the Rights of Persons with Disabilities calls for full and effective participation of persons with disabilities. But many organisations exclude people with Down syndrome from taking part in their work. They take decisions For them not With them.

Our global network calls for all decision makers to commit to involve organisations representing peoplewith Down syndrome in all decisions, and work With Us Not For Us. Down Syndrome International and its members are Organisations of Persons with Disabilities (OPDs). This means we represent and work With people with Down syndrome, not just For them. The United Nations Committee on the Rights of Persons with Disabilities says that organisations of persons with disabilities should be involved in all policy and decision-making. But organisations that represent people with Down syndrome are often excluded. 

So, what can you do? Speak up with us! Sign up below to hear from the WDSD team. We will give you everything that you need to speak up for ‘With us Not For Us’. 


Dad jokes

“‘Dad, will you hand me my sunglasses?’. ‘As soon as you hand me my dadglasses, Son.’”

A recent study says that despite the embarrassment that "dad jokes" can cause, it might do some kids good in the future.

Humor researcher Marc Hye-Knudsen published a study in British Psychological Society‘s journal this week arguing that "dad jokes" actually have a positive effect on development.

"When considered properly, dad jokes are an intricately multi-layered and fascinating phenomenon that reveals a lot not just about how humour and joke-telling work but also about fathers’ psychology and their relationships with their children," Hye-Knudsen wrote. It’s also what makes dad jokes so susceptible to accusations of being stupid, lame, and unfunny," the study observed.

Hye-Knudsen suggests that when fathers embarrass their children with unfunny jokes, it teaches them how to overcome awkwardness.

"By continually telling their children jokes that are so bad that they’re embarrassing, fathers may push their children’s limits for how much embarrassment they can handle," the article said. "They show their children that embarrassment isn’t fatal."

The study ends by encouraging fathers to continue aiding their children's development by telling embarrassing jokes.

"You’re partaking in a long and proud tradition, and your embarrassingly awful jokes may even do them some good," the paper concludes. "Keep repeating the same old stale puns, year-in and year-out."


See: Hye-Knudsen M. 'Dad jokes? That’s the way eye roll…’ The Psychologist. 14 March 2023  https://www.bps.org.uk/psychologist/dad-jokes-thats-way-eye-roll

Also: Hye-Knudsen M. Dad jokes and the deep roots of fatherly teasing. https://psyarxiv.com/r9mhc/

Monday, March 13, 2023

IVF issues

Worth and cost are two very different things, but once you put a price on something, it’s hard not to feel that you should get what you paid for, even if what was ordered is a baby. The complicated story of Paris Hilton’s desire not just to be a mother in general, but to be the mother of a little girl is case in point. With two daughters of my own, I appreciate the sentiment, but at the heart of this story isn’t only one desired girl, but 20 lost boys.

Today, about two percent of children born each year are conceived in a lab through In Vitro Fertilization (IVF), a "complex series of procedures" in which a woman’s eggs and a man’s sperm are brought together. Yet, Hilton and husband Carter Reum found that seven times was not a charm.

Hilton wanted a girl and the results were 20 boys, snowflake babies now in limbo. IVF has helped some very wonderful people have a family, but there is something profoundly sad about 20 little people found not good enough based on their sex and a business model that commodifies humanity.  

While the heiress plans to keep going, a specific baby order is not for the underfunded. Forbes reports that a single cycle of IVF can cost up to $30K just to get started, and in Hilton’s case, the costs will go even higher as she intends to use a surrogate. "Base pay" for carrying another’s child is $55K and up.

But there are other costs – human costs – as for those unchosen, and parents have three options: destroy them, donate them to science for research, or donate them to someone else.

Creating disposable people on purpose is central to the IVF business model, troubling to many people who remember high school biology where we learned that a new life begins when egg and sperm unite. That didn’t used to be a trick question on a test or a religious point of view.

Preborn people are exactly like us – only smaller and without social media accounts.

Because of the cost, creating far too many preborn than can safely be implanted leads to the kinds of arbitrary life and death decisions usually seen in war movies – a Sophie’s Choice. Some of those children are flushed away after "failing" genetic testing or sex screening, things that lead to accommodation or treatment among the born.

Also troubling is a business model where people are owned by others, and wombs of the young and poor are rented out.

Sophia Vergaro and her former fiancĂ©, Nick Loeb, went twenty-rounds in court before the knockout punch to two children, whose rights to life didn’t count in court because of papers drawn up on their ownership. "In California, which is where the embryos were frozen, they are referred to as products," notes the Daily Mail.

Writing in the New York Times in 2015, Loeb asked, "When we create embryos for the purpose of life, should we not define them as life, rather than as property?"

That contractual power over human property in the world of IVF is absolute, leading even to "Couples are turning extra IVF embryos into jewelry" through companies like Baby Bee Hummingbirds.

If that’s not disturbing enough, the health risks to those involved get little attention.

A Heritage Foundation report found "children born from IVF have higher rates of autism, cancer, and minor birth issues like cleft palate." In fact, about six percent of babies born through IVF have "birth anomalies" compared to four percent of all other babies, and a baby’s risk of dying near birth is "slightly higher’ along with premature birth, which can have severe implications.

The women undergoing the treatments can have an increased risk of heart and pregnancy complications. Overstimulating ovaries to produce many eggs and not just one or two in a cycle "can result in blood clots, kidney failure and death."

Under contract, those problems are endured sometimes by poor young women who provide eggs or take jobs as surrogates in financial arrangements that commodifies their fertility. A woman is born with all the eggs she will ever have, making it an ugly kind of human trafficking as for-profit enterprises advertise for egg "donation." NBC reports that the "fertility industry" is set to pull in $41 billion by 2026.  

What will Hilton’s future little girl feel about her birth story? Will she feel a need to perform up to the expectations that lead to her acquisition? Will she be troubled knowing that her twenty brothers are among one million others in cold storage? Will those boys be born?

When she welcomed her son via surrogate, Hilton told People magazine, "It's always been my dream to be a mother." 

It’s a dream many share, but the science and the contract disputes have far outpaced conversations on the ethics. A National Institutes of Health article noted the business model is riddled with moral dilemmas, and "problems may exist, in part, due to the lack of regulation in the U.S."

Harder choices about how to respect all the women and preborn impacted by this business seem long overdue. Tiny lives hang in the balance … and I don’t mean the balance sheet.


Sunday, March 12, 2023

Fifteen-year outcomes after monitoring, surgery, or radiotherapy for prostate cancer

The blogmaster has a stake in this information

Freddie C. Hamdy, F.R.C.S.(Urol.), F.Med.Sci., Jenny L. Donovan, Ph.D., F.Med.Sci., J. Athene Lane,Ph.D., Chris Metcalfe, Ph.D., Michael Davis, M.Sc., Emma L. Turner, Ph.D., Richard M. Martin, B.M.,B.S., Ph.D., Grace J. Young, M.Sc., Eleanor I. Walsh, M.Sc., Richard J. Bryant, Ph.D., F.R.C.S.(Urol.), Prasad Bollina, M.B., B.S., F.R.C.S.(Urol.), Andrew Doble, F.R.C.S.(Urol), et al. for the ProtecT Study Group. Fifteen-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer. March 11, 2023 DOI: 10.1056/NEJMoa2214122


BACKGROUND Between 1999 and 2009 in the United Kingdom, 82,429 men between 50 and 69 years of age received a prostate-specific antigen (PSA) test. Localized prostate cancer was diagnosed in 2664 men. Of these men, 1643 were enrolled in a trial to evaluate the effectiveness of treatments, with 545 randomly assigned to receive active monitoring, 553 to undergo prostatectomy, and 545 to undergo radiotherapy.

METHODS At a median follow-up of 15 years (range, 11 to 21), we compared the results in this population with respect to death from prostate cancer (the primary outcome) and death from any cause, metastases, disease progression, and initiation of long-term androgen-deprivation therapy (secondary outcomes). 

RESULTS Follow-up was complete for 1610 patients (98%). A risk-stratification analysis showed that more than one third of the men had intermediate or high-risk disease at diagnosis. Death from prostate cancer occurred in 45 men (2.7%): 17 (3.1%) in the active-monitoring group, 12 (2.2%) in the prostatectomy group, and 16 (2.9%) in the radiotherapy group (P=0.53 for the overall comparison). Death from any cause occurred in 356 men (21.7%), with similar numbers in all three groups. Metastases developed in 51 men (9.4%) in the active-monitoring group, in 26 (4.7%) in the prostatectomy group, and in 27 (5.0%) in the radiotherapy group. Long-term androgen-deprivation therapy was initiated in 69 men (12.7%), 40 (7.2%), and 42 (7.7%), respectively; clinical progression occurred in 141 men (25.9%), 58 (10.5%), and 60 (11.0%), respectively. In the active-monitoring group, 133 men (24.4%) were alive without any prostate cancer treatment at the end of follow-up. No differential effects on cancer-specific mortality were noted in relation to the baseline PSA level, tumor stage or grade, or risk-stratification score. No treatment complications were reported after the 10-year analysis.

CONCLUSIONS After 15 years of follow-up, prostate cancer–specific mortality was low regardless of the treatment assigned. Thus, the choice of therapy involves weighing trade-offs between benefits and harms associated with treatments for localized prostate cancer.  (Funded by the National Institute for Health and Care Research; ProtecT Current Controlled Trials number, ISRCTN20141297. opens in new tab; ClinicalTrials.gov number, NCT02044172. opens in new tab.). opens in new tab; ClinicalTrials.gov number, NCT02044172

Sunday, March 5, 2023

Congenital cervical teratoma

 See video: https://photos.app.goo.gl/wCoGPpvc8phuES1F9

S.T. Alharbis, A.S. Alsaadi, A.U. Yosuph, F.D. Abdulhameed, M.M. Arkoubi
Diagnostic imaging and surgical management of a congenital cervical teratoma
J Taibah Med Sci, 13 (2018), pp. 83-86


Congenital cervical teratomas are rare tumours arising from the neck and consist of three major tissue layers of an embryo: the ectodermendoderm, and mesoderm. A great majority of cerviteratomas are benign tumours. However, the clinical significance of these tumours arises from the complications they can cause during pregnancy due to the postnatal mass effect on the airway and oesophagus of the neonate.

Diagnosis of a congenital cervical teratoma is possible during an early prenatal ultrasound evaluation. The appearance depends on the size of the tumour, but it is typically a large neck mass with solid and cystic components that causes hyperextension of the neck and is frequently associated with polyhydramnios. In the postnatal period, ultrasound helps in differentiating cervical teratoma from other common congenital cervical masses. MRI is the modality of choice to evaluate the consistency of the tumour, surrounding soft tissue extent of the tumour, and any mass effect on other cervical structures. In our case report, we present a case of a full-term baby that was delivered with a large cervical mass. MRI was helpful in demonstrating the complex content of the mass, surrounding soft tissue extension, and mass effect on other major cervical structures. The clear demarcation of the mass facilitated complete surgical removal without complications.