Wednesday, July 27, 2022

Expanding the phenotype of DNAJC30-associated Leigh syndrome

Zawadzka M, Krygier M, Pawłowicz M, Wilke MVMB, Rutkowska K, Gueguen N, Desquiret-Dumas V, Klee EW, Schimmenti LA, Sławek J, Procaccio V, Płoski R, Mazurkiewicz-Bełdzińska M. Expanding the phenotype of DNAJC30-associated Leigh syndrome. Clin Genet. 2022 Jul 21. doi: 10.1111/cge.14196. Epub ahead of print. PMID: 35861300.


Leigh syndrome (LS) is a progressive neurodegenerative disease, characterized by extensive clinical, biochemical, and genetic heterogeneity. Recently, biallelic variants in DNAJC30 gene, encoding a protein crucial for the repair of mitochondrial complex I subunits, have been associated with Leber hereditary optic neuropathy and LS. It was suggested that clinical heterogeneity of DNAJC30-associated mitochondrial disease may be attributed to digenic inheritance. We describe three Polish patients, a 9-year-old boy, and female and male siblings, aged 17 and 11 years, with clinical and biochemical manifestations of LS. Exome sequencing (ES) identified a homozygous pathogenic variant in DNAJC30 c.152A>G, p.(Tyr51Cys) in the 9-year-old boy. In the siblings, ES identified two DNAJC30 variants: c.152A>G, p.(Tyr51Cys) and c.130_131del, p.(Ser44ValfsTer8) in a compound heterozygous state. In addition, both siblings carried a novel heterozygous c.484G>T, p.(Val162Leu) variant in NDUFS8 gene. This report provides further evidence for the association of DNAJC30 variants with LS. DNAJC30-associated LS is characterized by variable age at onset, movement disorder phenotype and normal or moderately elevated blood lactate level. Identification of a candidate heterozygous variant in NDUFS8 supports the hypothesis of digenic inheritance. Importantly, DNAJC30 pathogenic variants should be suspected in patients with LS irrespective of optic nerve involvement.

Neurodevelopmental outcomes at 1 year in infants of mothers who tested positive for SARS-CoV-2 during pregnancy

 Edlow AG, Castro VM, Shook LL, Kaimal AJ, Perlis RH. Neurodevelopmental Outcomes at 1 Year in Infants of Mothers Who Tested Positive for SARS-CoV-2 During Pregnancy. JAMA Netw Open. 2022 Jun 1;5(6):e2215787. doi: 10.1001/jamanetworkopen.2022.15787. PMID: 35679048; PMCID: PMC9185175.


Importance: Epidemiologic studies suggest maternal immune activation during pregnancy may be associated with neurodevelopmental effects in offspring.

Objective: To evaluate whether in utero exposure to SARS-CoV-2 is associated with risk for neurodevelopmental disorders in the first 12 months after birth.

Design, setting, and participants: This retrospective cohort study examined live offspring of all mothers who delivered between March and September 2020 at any of 6 Massachusetts hospitals across 2 health systems. Statistical analysis was performed from October to December 2021.

Exposures: Maternal SARS-CoV-2 infection confirmed by a polymerase chain reaction test during pregnancy.

Main outcomes and measuresNeurodevelopmental disorders determined from International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnostic codes over the first 12 months of life; sociodemographic and clinical features of mothers and offspring; all drawn from the electronic health record.

Results: The cohort included 7772 live births (7466 pregnancies, 96% singleton, 222 births to SARS-CoV-2 positive mothers), with mean (SD) maternal age of 32.9 (5.0) years; offspring were 9.9% Asian (772), 8.4% Black (656), and 69.0% White (5363); 15.1% (1134) were of Hispanic ethnicity. Preterm delivery was more likely among exposed mothers: 14.4% (32) vs 8.7% (654) (P = .003). Maternal SARS-CoV-2 positivity during pregnancy was associated with greater rate of neurodevelopmental diagnoses in unadjusted models (odds ratio [OR], 2.17 [95% CI, 1.24-3.79]; P = .006) as well as those adjusted for race, ethnicity, insurance status, offspring sex, maternal age, and preterm status (adjusted OR, 1.86 [95% CI, 1.03-3.36]; P = .04). Third-trimester infection was associated with effects of larger magnitude (adjusted OR, 2.34 [95% CI, 1.23-4.44]; P = .01).

Conclusions and relevance: This cohort study of SARS-CoV-2 exposure in utero found preliminary evidence that maternal SARS-CoV-2 may be associated with neurodevelopmental sequelae in some offspring. Prospective studies with longer follow-up duration will be required to exclude confounding and confirm these associations.

Tuesday, July 26, 2022

Decompressive craniectomy vs standard medical care at 24 months

Kolias AG, Adams H, Timofeev IS, Corteen EA, Hossain I, Czosnyka M, Timothy J, Anderson I, Bulters DO, Belli A, Eynon CA, Wadley J, Mendelow AD, Mitchell PM, Wilson MH, Critchley G, Sahuquillo J, Unterberg A, Posti JP, Servadei F, Teasdale GM, Pickard JD, Menon DK, Murray GD, Kirkpatrick PJ, Hutchinson PJ; RESCUEicp Trial Collaborators. Evaluation of Outcomes Among Patients With Traumatic Intracranial Hypertension Treated With Decompressive Craniectomy vs Standard Medical Care at 24 Months: A Secondary Analysis of the RESCUEicp Randomized Clinical Trial. JAMA Neurol. 2022 Jul 1;79(7):664-671. doi: 10.1001/jamaneurol.2022.1070. PMID: 35666526; PMCID: PMC9171657.


Importance: Trials often assess primary outcomes of traumatic brain injury at 6 months. Longer-term data are needed to assess outcomes for patients receiving surgical vs medical treatment for traumatic intracranial hypertension.

Objective: To evaluate 24-month outcomes for patients with traumatic intracranial hypertension treated with decompressive craniectomy or standard medical care.

Design, setting, and participants: Prespecified secondary analysis of the Randomized Evaluation of Surgery With Craniectomy for Uncontrollable Elevation of Intracranial Pressure (RESCUEicp) randomized clinical trial data was performed for patients with traumatic intracranial hypertension (>25 mm Hg) from 52 centers in 20 countries. Enrollment occurred between January 2004 and March 2014. Data were analyzed between 2018 and 2021. Eligibility criteria were age 10 to 65 years, traumatic brain injury (confirmed via computed tomography), intracranial pressure monitoring, and sustained and refractory elevated intracranial pressure for 1 to 12 hours despite pressure-controlling measures. Exclusion criteria were bilateral fixed and dilated pupils, bleeding diathesis, or unsurvivable injury.

Interventions: Patients were randomly assigned 1:1 to receive a decompressive craniectomy with standard care (surgical group) or to ongoing medical treatment with the option to add barbiturate infusion (medical group).

Main outcomes and measures: The primary outcome was measured with the 8-point Extended Glasgow Outcome Scale (1 indicates death and 8 denotes upper good recovery), and the 6- to 24-month outcome trajectory was examined.

Results: This study enrolled 408 patients: 206 in the surgical group and 202 in the medical group. The mean (SD) age was 32.3 (13.2) and 34.8 (13.7) years, respectively, and the study population was predominantly male (165 [81.7%] and 156 [80.0%], respectively). At 24 months, patients in the surgical group had reduced mortality (61 [33.5%] vs 94 [54.0%]; absolute difference, -20.5 [95% CI, -30.8 to -10.2]) and higher rates of vegetative state (absolute difference, 4.3 [95% CI, 0.0 to 8.6]), lower or upper moderate disability (4.7 [-0.9 to 10.3] vs 2.8 [-4.2 to 9.8]), and lower or upper severe disability (2.2 [-5.4 to 9.8] vs 6.5 [1.8 to 11.2]; χ27 = 24.20, P = .001). For every 100 individuals treated surgically, 21 additional patients survived at 24 months; 4 were in a vegetative state, 2 had lower and 7 had upper severe disability, and 5 had lower and 3 had upper moderate disability, respectively. Rates of lower and upper good recovery were similar for the surgical and medical groups (20 [11.0%] vs 19 [10.9%]), and significant differences in net improvement (≥1 grade) were observed between 6 and 24 months (55 [30.0%] vs 25 [14.0%]; χ22 = 13.27, P = .001).

Conclusions and relevance: At 24 months, patients with surgically treated posttraumatic refractory intracranial hypertension had a sustained reduction in mortality and higher rates of vegetative state, severe disability, and moderate disability. Patients in the surgical group were more likely to improve over time vs patients in the medical group.

Monday, July 25, 2022

The serotonin theory of depression

Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry. 2022 Jul 20. doi: 10.1038/s41380-022-01661-0. Epub ahead of print. PMID: 35854107. 


The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is associated with lowered serotonin concentration or activity in a systematic umbrella review of the principal relevant areas of research. PubMed, EMBASE and PsycINFO were searched using terms appropriate to each area of research, from their inception until December 2020. Systematic reviews, meta-analyses and large data-set analyses in the following areas were identified: serotonin and serotonin metabolite, 5-HIAA, concentrations in body fluids; serotonin 5-HT1A receptor binding; serotonin transporter (SERT) levels measured by imaging or at post-mortem; tryptophan depletion studies; SERT gene associations and SERT gene-environment interactions. Studies of depression associated with physical conditions and specific subtypes of depression (e.g. bipolar depression) were excluded. Two independent reviewers extracted the data and assessed the quality of included studies using the AMSTAR-2, an adapted AMSTAR-2, or the STREGA for a large genetic study. The certainty of study results was assessed using a modified version of the GRADE. We did not synthesise results of individual meta-analyses because they included overlapping studies. The review was registered with PROSPERO (CRD42020207203). 17 studies were included: 12 systematic reviews and meta-analyses, 1 collaborative meta-analysis, 1 meta-analysis of large cohort studies, 1 systematic review and narrative synthesis, 1 genetic association study and 1 umbrella review. Quality of reviews was variable with some genetic studies of high quality. Two meta-analyses of overlapping studies examining the serotonin metabolite, 5-HIAA, showed no association with depression (largest n = 1002). One meta-analysis of cohort studies of plasma serotonin showed no relationship with depression, and evidence that lowered serotonin concentration was associated with antidepressant use (n = 1869). Two meta-analyses of overlapping studies examining the 5-HT1A receptor (largest n = 561), and three meta-analyses of overlapping studies examining SERT binding (largest n = 1845) showed weak and inconsistent evidence of reduced binding in some areas, which would be consistent with increased synaptic availability of serotonin in people with depression, if this was the original, causal abnormaly. However, effects of prior antidepressant use were not reliably excluded. One meta-analysis of tryptophan depletion studies found no effect in most healthy volunteers (n = 566), but weak evidence of an effect in those with a family history of depression (n = 75). Another systematic review (n = 342) and a sample of ten subsequent studies (n = 407) found no effect in volunteers. No systematic review of tryptophan depletion studies has been performed since 2007. The two largest and highest quality studies of the SERT gene, one genetic association study (n = 115,257) and one collaborative meta-analysis (n = 43,165), revealed no evidence of an association with depression, or of an interaction between genotype, stress and depression. The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations. Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration. 

From the article: 

The chemical imbalance theory of depression is still put forward by professionals, and the serotonin theory, in particular, has formed the basis of a considerable research effort over the last few decades. The general public widely believes that depression has been convincingly demonstrated to be the result of serotonin or other chemical abnormalities, and this belief shapes how people understand their moods, leading to a pessimistic outlook on the outcome of depression and negative expectancies about the possibility of self-regulation of mood. The idea that depression is the result of a chemical imbalance also influences decisions about whether to take or continue antidepressant medication and may discourage people from discontinuing treatment, potentially leading to lifelong dependence on these drugs... 

One study in this review found that antidepressant use was associated with a reduction of plasma serotonin, and it is possible that the evidence for reductions in SERT density and 5-HT1A receptors in some of the included imaging study reviews may reflect compensatory adaptations to serotonin-lowering effects of prior antidepressant use. Authors of one meta-analysis also highlighted evidence of 5-HIAA levels being reduced after long-term antidepressant treatment. These findings suggest that in the long-term antidepressants might produce compensatory changes that are opposite to their acute effects. Lowered serotonin availability has also been demonstrated in animal studies following prolonged antidepressant administration. Further research is required to clarify the effects of different drugs on neurochemical systems, including the serotonin system, especially during and after long-term use, as well as the physical and psychological consequences of such effects. 

This review suggests that the huge research effort based on the serotonin hypothesis has not produced convincing evidence of a biochemical basis to depression. This is consistent with research on many other biological markers. We suggest it is time to acknowledge that the serotonin theory of depression is not empirically substantiated. 


Sanfilippo syndrome

Most people think of dementia as an illness that only affects the elderly, but one family is sharing the heartbreaking story of their daughter, who suffers from a childhood version of the debilitating condition. 

In 2020, Haidyn Fowler was diagnosed with Sanfilippo syndrome, a genetic condition that causes the entire body to deteriorate, leading to seizures, movement disorders, immense pain and discomfort and, eventually, the loss of bodily functions. 

The condition is terminal, with a life expectancy between 10 and 20 years.

Haidyn was born with the illness and, although seemingly healthy at birth, her body has slowly started deteriorating — leaving her in near-constant pain and unable to speak at only 7 years old, and with the mental capacity of an 18-month-old. 

“The best way to describe [Sanfilippo syndrome] is that it’s referred to as childhood dementia or childhood Alzheimer’s because it attacks the brain almost identically to Alzheimer’s

disease,” Haidyn’s mom, Carrie,told Good Morning America. “But it is more than just dementia or Alzheimer’s, because not only does it attack the brain, it attacks the central nervous system, and it deteriorates the entire body. 

So anything that you think can go wrong within your body can happen with Sanfilippo syndrome,” she added, admitting that it’s difficult to look back at photos and videos of her daughter when she could still talk and walk unassisted. 

Haidyn has Sanfilippo Syndrome, a neurodegenerative disease that is like Alzheimer's in children. Right: She is shown with her mom Carrie.

Haidyn has Sanfilippo syndrome, a neurodegenerative disease that is like Alzheimer’s in children. Right: She is shown with her mom, Carrie.haidynshope/Instagram

Despite that, Fowler said her daughter still “smiles, laughs, loves and enjoys life” and has inspired her and her husband, Caleb, and older daughter, Braelynne, to work for a cure for the awful disease. 

There is no FDA-approved treatment or cure for Sanfilippo syndrome at the moment, and the Fowler family holds fund-raisers to support further research. 

“She’s taught me so much, but definitely that it’s the little things in life that we take for granted the most,” Carrie told “GMA.” “We love a lot harder. And we fight every day to be really happy for her even despite all the heartbreak that we have to deal with too. We try to focus on being happy for her because she deserves that.” 

Haidyn was “seemingly healthy” at birth. Carrie said it’s hard to look back at photos and videos of Haidyn, now 7, when she could still talk and walk unassisted. Haidyn’s mother said that despite her condition, the little girl continues to “laugh and love. She is slowly losing her ability to walk and speak.


Fowler said they are raising awareness for the illness by advocating in their community and on social media. 

“Haidyn is who we are doing it in honor of, but we’re mainly fighting for kids in the future so that there can be a cure,” she said. 

“She fights so hard every day to keep going when most people would have given up long before, and I just … I’m proud of her, so I enjoy letting other people be proud of her.”

“Will’s just doing so well,” a well-intentioned person gushes to me. I smile, happy for the attention and recognition Will receives for his hard work. “I just see him up and walking so much more,” the person continues. “You can really tell he’s getting better!”

I maintain my smile and politely thank the speaker before excusing myself. I take a deep breath and internally sigh. Children with Sanfilippo syndrome do not get better. It’s a progressive, terminal condition with no treatment or cure. What the person is praising is actually part of the toll of the disease.

Very few people see Will daily, and even fewer people understand the reality of living day to day with Sanfilippo. In 2017, we had to purchase an adaptive stroller for Will because he had outgrown traditional stroller options. We paid out of pocket; our insurance at that time wouldn’t cover the stroller because Will was still “mobile within the home” (possibly the worst standard for coverage of a mobility aid, but I digress).

At the time, our desperate need for the stroller wasn’t dictated by his difficulty walking (although walking distances in the Texas heat was always a concern), but by a need for safety.

Will had to be watched constantly. He couldn’t be left unattended. He had no sense of safety and would dart out in a front of a car or put his hand on a hot stove with zero hesitation. Sanfilippo is characterized by extreme hyperactivity, especially in the early years, and it was both terrifying and exhausting.

Holding on to Will and keeping him safe was difficult, especially while also caring for his baby sister. He was strong and would pull and flail to get away when something caught his attention. Cognitively, there was no teaching him to listen and stay put; his brain literally could not comprehend the instruction. Strapping him into a stroller was one of the few ways to ensure he was safe so I could attend to Little Sister, answer a phone call, cook dinner, or even go to the bathroom.

Purchasing the adaptive stroller was both emotionally difficult (it was our first piece of medical equipment) and freeing. With it, Will was now able to stay in child care at my gym, meaning I could exercise while the workers read books and sang songs with him, safely stationary.

We could also do summer camps, with me as his aide, because I could more easily keep him focused on the camp activities instead of him constantly eloping after something that interested him. My husband and I worked hard to give Will the proper amount of exercise out of the chair to maintain muscles while acknowledging that having a safe place to seat him allowed Will more access to socialization and experiences.

However, that meant a lot of people only got to know Will in a chair, and in our society, people often equate chair use with a complete loss of mobility, as they lack awareness of the nuances of mobility aids and support devices.

Will turned 12 last month. Although individual expression of the progression of Sanfilippo varies, we do know the statistics, and we see the changes. Will is slowing down. He’s not constantly trying to elope, which means he can walk around more and sit in regular chairs without needing to be strapped in. While still requiring high levels of supervision, he will now rest on the couch and watch PBS Kids without running around, pulling down toys, and trying to climb shelves every five seconds.

Right now, he’s watching an episode of “Molly of Denali” while I type this at 10 a.m. on a weekday, a situation I would’ve thought impossible just two years ago, when my work time was relegated to 11 p.m. after he was asleep.

He’s changing. And while it may seem like life is getting easier because his behaviors are now less unpredictable, it’s also frightening seeing our ball of constant energy begin to burn out. We know our time is limited. Each moment he slows down reminds us that we are headed toward the inevitable that Sanfilippo brings every child.

So yes, he’s sitting more quietly at camps. And yes, he’s walking around more now. But it’s not because he’s getting better (and I’ll save the commentary on how being still, quiet, and controlled are ableist expectations for a future column). It’s because his body, every day, succumbs a bit more to Sanfilippo.

And although we hold no ill will toward the people who make the comments because they truly do care about our son, it’s difficult to hear praise when we know the truth: the “easier” it becomes to take care of Will, the closer we come to the heartbreak of losing him.