Thursday, January 30, 2020

Posterior reversible encephalopathy syndrome epidemiology, comorbidities and outcomes

Aravind Thavamani, Krishna Kishore Umapathi, Mammen Puliyel, Dennis Super, Veerajalandhar Allareddy, Abdulla Ghori.  Epidemiology, Comorbidities, and Outcomes of Posterior Reversible Encephalopathy Syndrome in Children in the United States.  Pediatric Neurology.  In press.


Posterior reversible encephalopathy syndrome (PRES) is an increasingly recognized entity with certain identified predisposing factors in children. However, the actual incidence, comorbidities, outcomes, and hospitalization charges among children (aged less than 20 years) in the United States are largely unknown.

We analyzed the Kids' Inpatient Database for incidence of PRES-related hospitalizations, associated diagnoses, in-hospital outcomes, and charges for children in the United States in 2016. We report demographics, risk factors, discharge status, mortality, length of stay, and hospitalization charges.

In 2016, 825 pediatric hospitalizations related to PRES were captured in the Kids' Inpatient Database. Hospital discharges including solid organ transplant, bone marrow transplant, hypertension, renal disorder, primary immunodeficiency, malignancy, sepsis, severe sepsis, systemic connective tissue disorder, blood transfusion, hypomagnesemia, and sickle cell anemia were queried for presence of PRES. The majority of patients were discharged home. We found that PRES-related hospitalizations were significantly associated with increased length of stay and hospitalization charges in 2016 (P < 0.001). A mortality rate of 3.2% was found in PRES-related hospitalizations when compared with 0.4% in non-PRES hospitalizations (P < 0.001).

PRES accounted for 0.04% of the hospitalizations in this database. Hypertension and the presence of a renal disorder are the most significant risk factors found to be associated with PRES. The presence of PRES was associated with a significant increase in hospitalization charges and increased length of stay.

Courtesy of:

Tuesday, January 28, 2020

TUBB4A gene mutations

Inspired by a patient

Joyal KM, Michaud J, van der Knaap MS, Bugiani M, Venkateswaran S. Severe TUBB4A-Related Hypomyelination With Atrophy of the Basal Ganglia and Cerebellum: Novel Neuropathological Findings. J Neuropathol Exp Neurol. 2019 Jan 1;78(1):3-9.

Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a rare hypomyelinating leukodystrophy characterized by infantile or childhood onset of motor developmental delay, progressive rigidity and spasticity, with hypomyelination and progressive atrophy of the basal ganglia and cerebellum due to a genetic mutation of the TUBB4A gene. It has only been recognized since 2002 and the full spectrum of the disorder is still being delineated. Here, we review a case report of a severely affected girl with a thorough neuropathological evaluation demonstrating novel clinical and pathological findings. Clinically, our patient demonstrated visual dysfunction and hypodontia in addition to the typical phenotype. Morphologically, more severe and widespread changes in the white matter were observed, including to the optic tracts; in gray structures such as the caudate nucleus, thalamus, globus pallidus, and substantia nigra; as well as an area of focal cortical dysplasia. Overall this case offers further insight into the broad range of clinical and neuropathological findings that may be associated with H-ABC and related TUBB4A gene mutations.

Otero-Dominguez E, Gomez-Lado C, Fuentes-Pita P, Dacruz D, Barros-Angueira F, Eiris-Punal J. [Hypomyelinating leukodystrophy type 6. Clinical and neuroimaging key features in the detection of a new case]. Rev Neurol. 2018 Nov 1;67(9):339-342.  [Article in Spanish; Abstract available in Spanish from the publisher]

Abstract in English
Hypomyelinating leukodystrophy-6 is a rare and early onset neurodegenerative disease which entails a clinical pattern of pyramidal-extrapyramidal and cerebellar involvement and it comes with a neuroimaging consisting of hypomielination, cerebellar hypoplasia and specific abnormalities in basal ganglia, particularly the absence or nearly absence of putamen and the possible loss of caudate's volume. It is due to an alteration in tubulin and it is determined by mutations in heterocygosis in TUBB4A gene, showing complete penetrance.

An 8-year-old child with history of delayed motor development, tremor, dysathria, ataxia, nystagmus, cognitive deficit and dystonia with pattern of hypomielination, vermis hypoplasia and absence of putamen. These findings, although distinctive, had been underestimated in previous evaluations and their detection determined the analyse and identification of a pathogenic variant in TUBB4A gene.

Progressive deterioration leads the patient to total dependence or death in infancy or youth and there is no specific treatment capable of modifying its natural course. 

Curiel J, Rodríguez Bey G, Takanohashi A, Bugiani M, Fu X, Wolf NI, Nmezi B, Schiffmann R, Bugaighis M, Pierson T, Helman G, Simons C, van der Knaap MS, Liu J, Padiath Q, Vanderver A. TUBB4A mutations result in specific neuronal and oligodendrocytic defects that closely match clinically distinct phenotypes. Hum Mol Genet. 2017 Nov 15;26(22):4506-4518.

Hypomyelinating leukodystrophies are heritable disorders defined by lack of development of brain myelin, but the cellular mechanisms of hypomyelination are often poorly understood. Mutations in TUBB4A, encoding the tubulin isoform tubulin beta class IVA (Tubb4a), result in the symptom complex of hypomyelination with atrophy of basal ganglia and cerebellum (H-ABC). Additionally, TUBB4A mutations are known to result in a broad phenotypic spectrum, ranging from primary dystonia (DYT4), isolated hypomyelination with spastic quadriplegia, and an infantile onset encephalopathy, suggesting multiple cell types may be involved. We present a study of the cellular effects of TUBB4A mutations responsible for H-ABC (p.Asp249Asn), DYT4 (p.Arg2Gly), a severe combined phenotype with hypomyelination and encephalopathy (p.Asn414Lys), as well as milder phenotypes causing isolated hypomyelination (p.Val255Ile and p.Arg282Pro). We used a combination of histopathological, biochemical and cellular approaches to determine how these different mutations may have variable cellular effects in neurons and/or oligodendrocytes. Our results demonstrate that specific mutations lead to either purely neuronal, combined neuronal and oligodendrocytic or purely oligodendrocytic defects that closely match their respective clinical phenotypes. Thus, the DYT4 mutation that leads to phenotypes attributable to neuronal dysfunction results in altered neuronal morphology, but with unchanged tubulin quantity and polymerization, with normal oligodendrocyte morphology and myelin gene expression. Conversely, mutations associated with isolated hypomyelination (p.Val255Ile and p.Arg282Pro) and the severe combined phenotype (p.Asn414Lys) resulted in normal neuronal morphology but were associated with altered oligodendrocyte morphology, myelin gene expression, and microtubule dysfunction. The H-ABC mutation (p.Asp249Asn) that exhibits a combined neuronal and myelin phenotype had overlapping cellular defects involving both neuronal and oligodendrocyte cell types in vitro. Only mutations causing hypomyelination phenotypes showed altered microtubule dynamics and acted through a dominant toxic gain of function mechanism. The DYT4 mutation had no impact on microtubule dynamics suggesting a distinct mechanism of action. In summary, the different clinical phenotypes associated with TUBB4A reflect the selective and specific cellular effects of the causative mutations. Cellular specificity of disease pathogenesis is relevant to developing targeted treatments for this disabling condition.

Monday, January 27, 2020

Medical mayhem 14

Former nurse Genene Jones, suspected for decades of killing more than a dozen children but tried and convicted for only one, pleaded guilty Thursday in San Antonio to the murder of an 11-month-old boy in 1981 and was sentenced to life in prison. Jones’ sudden reversal — she had previously pleaded not guilty to five murder charges filed in 2017 — confirms her place as a serial baby-killer and ends a twisted criminal-justice saga that has played out over four decades.

Jones, 69, unexpectedly sought the plea deal last week, just a month before she was to go to trial in the first of the five murder charges: for the death of Joshua Sawyer on Dec. 12, 1981.

Jones’ crimes reemerged into prominence in recent years after victims’ relatives learned that she was scheduled for mandatory release in March 2018. A San Antonio prosecutor reinvestigated some of the crimes and brought the five indictments in 2017.

The events they cover date back to Jones’ work in the pediatric intensive-care unit at San Antonio’s charity hospital (now called University Hospital) during the years Ronald Reagan occupied the White House. The five victims ranged in age from 3 months to 2 years. Jones’ alleged murder weapons: an array of powerful drugs.

Jones is not expected to be eligible to even apply for possible parole until around 2038. That fulfills the goal of her victims’ aging parents (three have already died), who for years pressed San Antonio prosecutors to bring new murder cases to block Jones’ release.

Dressed in blue scrubs and wearing dark glasses, with short white hair, Jones arrived in the courtroom using a walker. After signing and confirming her guilty plea, she watched, but remained silent and expressionless, as the presiding judge, and then tearful family members, assailed her for her crimes.

State Judge Frank Castro declared that Jones’ life sentence “doesn’t come close to what you did to these families and the tragedy that you caused. You took God’s little precious gift: babies, defenseless, innocent … I truly believe your ultimate judgment is in the next life.”

Connie Weeks, Joshua Sawyer’s mother, told Jones, “I’m glad that you will never see daylight.” Weeks spoke those words while standing just feet away from her child’s killer, delivering her victim impact statement in court, along with four other family members. “I hope you live a long and miserable life behind bars.”

The goal of successfully prosecuting the San Antonio cases long seemed unattainable.

When Jones worked at Bexar County Hospital during the early 1980s, unexpected emergencies and deaths became so frequent that her 3 to 11 p.m. work hours became known among medical staff as “the Death Shift.” But the ICU treated desperately ill children, and ironclad proof she was responsible proved elusive. Instead of alerting criminal authorities to investigate, the hospital — after several secret internal probes — ousted Jones (but gave her a good recommendation) under the cover of upgrading the ICU to an all-RN staff.

Jones then moved on to a small-town pediatric clinic in nearby Kerrville, where, in a single month, eight children with routine medical problems stopped breathing; one of them died. After evidence surfaced that Jones had injected the children in Kerrville with a paralyzing muscle relaxant, Jones was convicted of murdering 15-month-old Chelsea McClellan and received a 99-year prison sentence.

A lengthy criminal investigation in San Antonio included a Centers for Disease Control study that showed patients during a 15-month “epidemic period” were 10 times more likely to die on a shift that Jones worked. Yet the district attorney declined to bring murder charges, reasoning that proof in any single case was too elusive and Jones would never walk free anyway. (A conviction for injuring a child who survived resulted in a concurrent 60-year sentence.)
 “I Really Did Kill Those Babies”
Genene Jones, a Texas nurse long suspected of more than a dozen child murders decades ago but convicted of only one, allegedly confessed. The newly uncovered evidence emerged in a hearing today in which Jones attempted to have five murder charges against her dismissed.

It was decades later that relatives of Jones’ victims realized a Texas law designed to ease prison overcrowding could result in her walking free. Awarding credit for “good time,” it mandated Jones’ release in early 2018, after she had served about a third of her sentence.

Alarmed, Petti McClellan, Chelsea’s mother, working with Houston victims advocate Andy Kahan, led a campaign to press prosecutors to take the only step possible to keep Jones locked up: bringing new murder charges from among the decades-earlier hospital deaths.

That effort went nowhere until the election of a new Bexar County district attorney, Nico LaHood, in November 2014. An aggressive young assistant DA named Jason Goss, who was just 1 year old when Jones committed her crimes, began digging through dusty boxes of courthouse files from the 1980s Jones investigation. Goss and LaHood brought the first of the new murder charges in March 2017, accusing Jones of killing Joshua Sawyer with a massive overdose of the anti-seizure drug Dilantin.

Four more indictments followed, each accompanied by a $1 million bond that assured Jones remained in the Bexar County jail pending trial even after her mandatory release date.

For the families, who had waited decades to attain any measure of justice in the deaths of their loved ones, the case remained an emotional roller coaster.

LaHood’s 2018 defeat in a bitter primary race against his onetime law partner, Joe Gonzales, assured that lead prosecutor Goss would depart, sparking fears the Jones case would be neglected or even abandoned. That concern proved unfounded; Gonzales assigned Catherine Babbitt, his veteran major crimes chief, to lead the trial team. Jones’ lawyers brought motions to throw out the indictments. The judge rejected them.

Through it all, Petti McClellan, by then a retired nurse, provided support to the San Antonio moms: testifying before the grand juries and attending every court hearing and meeting with prosecutors. In June 2019, at age 64, she suddenly died. Six months later, Juanita Villarreal, the mother of one of the five San Antonio babies Jones was charged with murdering — Paul, just 3 months old — also died.

At one point, Jones had appeared willing to plead guilty to lesser charges that would keep her behind bars, but not to murder. Prosecutors told ProPublica that Jones didn’t want to be known as a serial murderer. “In Genene’s mind, she would not be known as a serial killer,” Babbitt said.

But that was months ago, leaving the Sawyer case headed toward a high-profile courtroom showdown — until last week.

That’s when, just two days after receiving a submission listing 200 potential witnesses and 97 different acts the DA’s team might raise during her trial, Jones’ lawyers raised the prospect of a plea deal, according to the lead prosecutor, Babbitt. “I think she realized we meant business,” she said.

Thursday’s agreement provides for dismissal of the four other murder cases, but a condition of the deal was that each of the five families would be able to give a victim impact statement, directly addressing Jones.

The plea agreement will require Jones to serve 20 years before first becoming eligible for parole, with credit for her two years behind bars awaiting trial. That would likely take Jones to 2038, when she would be 87 years old.

“If the parole board wants to deny her every time she comes up and keep her until she takes her dying breath, that’s their prerogative and our preference,” Babbitt said. “Why on earth would she be allowed to walk among us?”

Jones had formally maintained her innocence until Thursday, pleading not guilty to the five murders, even after informally offering semi-confessional statements over the years on at least two occasions. In a 1998 prison interview, detailed at an April 2018 court hearing, a tearful Jones reportedly told a parole officer: “I really did kill those babies.”

And in a 2011 letter to the Texas Board of Nursing, reported by ProPublica in June 2017, Jones professed feeling guilt. Responding to formal proceedings to revoke her suspended nursing license before her potential release, she wrote from prison apologizing “for the damage I did to all because of my crime.” Added Jones: “I look back now on what I did and agree with you that it was heinous, that I was heinous.”

Thursday’s events unfolded in a nearly full courtroom, with players from key events in the decades long case — including Goss and LaHood — in attendance to see it brought to a conclusion.

After the formal proceedings were over, Jones stood up and quickly wheeled herself out a side door of the courtroom.

Courtesy of a colleague

Inborn errors of the glycosylphosphatidylinositiol anchor biosynthetic pathway

McInerney-Leo AM, Harris JE, Gattas M, Peach EE, Sinnott S, Dudding-Byth T, Rajagopalan S, Barnett CP, Anderson LK, Wheeler L, Brown MA, Leo PJ, Wicking C, Duncan EL. Fryns Syndrome Associated with Recessive Mutations in PIGN in two Separate Families. Hum Mutat. 2016 Jul;37(7):695-702.

Fryns syndrome is an autosomal recessive condition characterized by congenital diaphragmatic hernia (CDH), dysmorphic facial features, distal digital hypoplasia, and other associated malformations, and is the most common syndromic form of CDH. No gene has been associated with this condition. Whole-exome sequence data from two siblings and three unrelated individuals with Fryns syndrome were filtered for rare, good quality, coding mutations fitting a recessive inheritance model. Compound heterozygous mutations in PIGN were identified in the siblings, with appropriate parental segregation: a novel STOP mutation (c.1966C>T: p.Glu656X) and a rare (minor allele frequency <0.001) donor splice site mutation (c.1674+1G>C) causing skipping of exon 18 and utilization of a cryptic acceptor site in exon 19. A further novel homozygous STOP mutation in PIGN (c.694A>T: p.Lys232X) was detected in one unrelated case. All three variants affected highly conserved bases. The two remaining cases were negative for PIGN mutations. Mutations in PIGN have been reported in cases with multiple congenital anomalies, including one case with syndromic CDH. Fryns syndrome can be caused by recessive mutations in PIGN. Whether PIGN affects other syndromic and non-syndromic forms of CDH warrants investigation.

Alessandri JL, Gordon CT, Jacquemont ML, Gruchy N, Ajeawung NF, Benoist G, Oufadem M, Chebil A, Duffourd Y, Dumont C, Gérard M, Kuentz P, Jouan T, Filippini F, Nguyen TTM, Alibeu O, Bole-Feysot C, Nitschké P, Omarjee A, Ramful D, Randrianaivo H, Doray B, Faivre L, Amiel J, Campeau PM, Thevenon J. Recessive loss of function PIGN alleles, including an intragenic deletion with founder effect in La Réunion Island, in patients with Fryns syndrome. Eur J Hum Genet.
2018 Mar;26(3):340-349.

Fryns syndrome (FS) is a multiple malformations syndrome with major features of congenital diaphragmatic hernia, pulmonary hypoplasia, craniofacial dysmorphic features, distal digit hypoplasia, and a range of other lower frequency malformations. FS is typically lethal in the fetal or neonatal period. Inheritance is presumed autosomal recessive. Although no major genetic cause has been identified for FS, biallelic truncating variants in PIGN, encoding a component of the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway, have been identified in a limited number of cases with a phenotype compatible with FS. Biallelic variants in PIGN, typically missense or compound missense with truncating, also cause multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1). Here we report six further patients with FS with or without congenital diaphragmatic hernia and recessive loss of function PIGN alleles, including an intragenic deletion with a likely founder effect in La Réunion and other Indian Ocean islands. Our results support the hypothesis that a spectrum of phenotypic severity is associated with recessive PIGN variants, ranging from FS at the extreme end, caused by complete loss of function, to MCAHS1, in which some residual PIGN function may remain. Our data add FS resulting from PIGN variants to the catalog of inherited GPI deficiencies caused by the disruption of the GPI-anchor biosynthesis pathway.

Reynolds KK, Juusola J, Rice GM, Giampietro PF. Prenatal presentation of Mabry syndrome with congenital diaphragmatic hernia and phenotypic overlap with Fryns syndrome. Am J Med Genet A. 2017 Oct;173(10):2776-2781.

We report on a family in which initial features were compatible with Fryns syndrome. The first sibling was a stillborn female with a left diaphragmatic hernia (DH). Her clinical features overlapped with Fryns syndrome. The second pregnancy, a male fetus, was followed for polyhydramnios, hypoplastic mandible, mild enlargement of the fetal bladder, hydronephrosis, and rocker bottom foot deformities. He had facial features similar to his sibling and a large cleft of the secondary palate, small jaw, and secundum atrial septal defect. He underwent surgical repair of imperforate anus, intestinal malrotation, and placement of mucous fistula for biopsy positive Hirschsprung disease. An elevated alkaline phosphatase level of 1569 U/L was reported. Whole exome sequencing performed on the second child demonstrated compound heterozygosity for the PIGV gene with the p.A341E and p.A418D variants in trans. Hyperphosphatasia with mental retardation syndrome (HPMRS) is caused by mutations in PIGV and includes hyperphosphatasia as a diagnostic hallmark. Our patient exhibited hyperphosphatasia but without any storage material in his skin cells. His features remain similar to his sister's, but includes seizures and lacks diaphragmatic hernia. Until now, HPMRS and Fryns syndrome, despite overlapping features, were considered mutually exclusive as HPMRS involves hyperphosphatasia and Fryns typically exhibits DH. Recent identification of PIGN mutations associated with several cases of Fryns syndrome point to a common pathogenetic etiology involving inborn errors of the glycosylphosphatidylinositiol anchor biosynthetic pathway. A diagnosis of HPMRS should be considered when DH is encountered on prenatal ultrasound.

Holtz AM, Harrington AW, McNamara ER, Kielian A, Soul JS, Martinez-Ojeda M, Levy PT. Expanding the phenotypic spectrum of Mabry Syndrome with novel PIGO gene variants associated with hyperphosphatasia, intractable epilepsy, and complex gastrointestinal and urogenital malformations. Eur J Med Genet. 2019 Nov 5:103802. doi: 10.1016/j.ejmg.2019.103802. [Epub ahead of print]

Mabry syndrome is a glycophosphatidylinositol (GPI) deficiency characterized by intellectual disability, distinctive facial features, intractable seizures, and hyperphosphatasia. We expand the phenotypic spectrum of inherited GPI deficiencies with novel bi-allelic phosphatidylinositol glycan anchor biosynthesis class O (PIGO) variants in a neonate who presented with intractable epilepsy and complex gastrointestinal and urogenital malformations.

Zehavi Y, von Renesse A, Daniel-Spiegel E, Sapir Y, Zalman L, Chervinsky I, Schuelke M, Straussberg R, Spiegel R. A homozygous PIGO mutation associated with severe infantile epileptic encephalopathy and corpus callosum hypoplasia, but normal alkaline phosphatase levels. Metab Brain Dis. 2017 Dec;32(6):2131-2137.

We describe two sisters from a consanguineous Arab family with global developmental delay, dystrophy, axial hypotonia, epileptic encephalopathy dominated by intractable complex partial seizures that were resistant to various anti-epileptic treatments. Dysmorphic features comprised low set ears, hypertelorism, upslanting palpebral fissures, a broad nasal bridge, and blue sclera with elongated eyelashes. Brain MRI in both children showed a corpus callosum hypoplasia that was evident already in utero and evolving cortical atrophy. Autozygosity mapping in combination with Whole Exome Sequencing revealed a homozygous missense mutation in the PIGO gene [c.765G > A, NM_032634.3] that affected a highly conserved methionine in the alkaline phosphatase-like core domain of the protein [p.(Met255Ile), NP_116023.2]. PIGO encodes the GPI-ethanolamine phosphate transferase 3, which is crucial for the final synthetic step of the glycosylphosphatidylinositol-anchor that attaches many enzymes to their cell surfaces, such as the alkaline phosphatase and granulocyte surface markers. Interestingly, measurement of serum alkaline phosphatase activities in both children was normal or only slightly elevated. Quantification of granulocyte surface antigens CD16/24/59 yielded reduced levels only for CD59. Phenotype analysis of our and other published patients with PIGO mutations reveals a more severe affectation and predominantly neurological presentation in individuals carrying a mutation in the alkaline phosphatase-like core domain thereby hinting towards a genotype-phenotype relation for PIGO gene mutations.

Tuesday, January 21, 2020

Diagnostic criteria for small fibre neuropathy in clinical practice and research

Devigili G, Rinaldo S, Lombardi R, Cazzato D, Marchi M, Salvi E, Eleopra R, Lauria G. Diagnostic criteria for small fibre neuropathy in clinical practice and research. Brain. 2019 Dec 1;142(12):3728-3736.

The diagnostic criteria for small fibre neuropathy are not established, influencing the approach to patients in clinical practice, their access to disease-modifying and symptomatic treatments, the use of healthcare resources, and the design of clinical trials. To address these issues, we performed a reappraisal study of 150 patients with sensory neuropathy and a prospective and follow-up validation study of 352 new subjects with suspected sensory neuropathy. Small fibre neuropathy diagnostic criteria were based on deep clinical phenotyping, quantitative sensory testing (QST) and intraepidermal nerve fibre density (IENFD). Small fibre neuropathy was ruled out in 5 of 150 patients (3.3%) of the reappraisal study. Small fibre neuropathy was diagnosed at baseline of the validation study in 149 of 352 patients (42.4%) based on the combination between two clinical signs and abnormal QST and IENFD (69.1%), abnormal QST alone (5.4%), or abnormal IENFD alone (20.1%). Eight patients (5.4%) had abnormal QST and IENFD but no clinical signs. Further, 38 patients complained of sensory symptoms but showed no clinical signs. Of those, 34 (89.4%) had normal QST and IENFD, 4 (10.5%) had abnormal QST and normal IENFD, and none had abnormal IENFD alone. At 18-month follow-up, 19 of them (56%) reported the complete recovery of symptoms and showed normal clinical, QST and IENFD findings. None of those with one single abnormal test (QST or IENFD) developed clinical signs or showed abnormal findings on the other test. Conversely, all eight patients with abnormal QST and IENFD at baseline developed clinical signs at follow-up. The combination of clinical signs and abnormal QST and/or IENFD findings can more reliably lead to the diagnosis of small fibre neuropathy than the combination of abnormal QST and IENFD findings in the absence of clinical signs. Sensory symptoms alone should not be considered a reliable screening feature. Our findings demonstrate that the combined clinical, functional and structural approach to the diagnosis of small fibre neuropathy is reliable and relevant both for clinical practice and clinical trial design.

Courtesy of:

Monday, January 20, 2020

Infantilisation of disability

What exactly is infantilisation of disability?

Infantilising a disabled person means you are treating them like a child. It may not be intentional (though perhaps in some cases it is). It happens when you see or find out that the person you are interacting with has a disability of some kind.

It is a form of ableism that is part of the social structures that we live in.

Infantilisation of disabled people can take many forms.

As in the story above [see at link], you may talk to someone as though they are a child, i.e., baby talk. This way of interacting with disabled people happens because you believe that the disabled person is either cute, younger than they are, or has lower cognitive development than yourself.

Now of course there may be some cute/younger looking disabled people out there — just like there are some cute/younger looking able bodied people out there. Cuteness and youthful looks don’t come from disability. There are also some disabilities that impact cognitive development… but that still doesn’t mean that you should be patronising and use baby talk to speak to disabled people impacted in this way.

Another form of infantilisation is when you address the able bodied person and not the disabled person them self. I cringe when I think of the amount of times this has happened to me. One instance jumps immediately to mind — an installation art piece I was doing for my fine art degree required hay, so I had asked dad to come with me to a farm equipment shop.

Dad was only there to help me get the hay into my car, but the man who served me kept on asking my dad why I needed the hay and how much would I need. My dad, being the legend that he is, told the man that he had no idea why I needed the hay or how much, if he really wanted to know he had better ask me. The man then proceeded to use baby talk with me. I got my hay, but ended up leaving the shop angry, flustered, and never wanting to go back there ever again.

And then there is infantilisation by not affording disabled people the right to express and experience adult behaviours, experiences, and habits. What do I mean by this?

Disabled people are expected to be naive and “pure.”

You might be surprised to learn that the disabled person you are interacting with swears, dates, has sex, drinks alcohol, and likes to go out clubbing. You might censor the person, expressing shock at their adult behaviours, and tell them that they should speak, behave, or act in a certain way. You might believe that all disabled people are asexual (some disabled people might be asexual, we are all on a spectrum after all, but disability and asexuality are not mutually exclusive), and then be surprised to meet a boyfriend or girlfriend or spouse.

What steps can you take to ensure you are not infantilising disabled people?

The most simplest thing is to treat disabled people as you would anyone else. Look them in the eye. Shake their hand (in the case of a limb different person who doesn’t have a hand don’t panic, just skip the whole handshaking bit of introducing yourself).

Don’t ask inappropriate questions. If they have a carer or PA with them introduce yourself to them, but don’t direct all your conversation and questions to them if it is the disabled person you are wanting to talk to.

Don’t simplify your language.

Don’t assume that the man or woman with them is their carer. The person could be their boyfriend, girlfriend, wife, husband, partner, sibling, friend, whatever! Some disabled people have carers, some don’t, just don’t assume.

Don’t reduce the disabled person to their disability. Being disabled is just one aspect of the human lived experience, and as actualised human beings, disabled people live as full lives as able bodied people do.

When I was in my early twenties and working in the newsagent slash post office I didn’t have the confidence to stand up for myself the way that I do now.

As I put the woman’s bank transactions through on the computer I put up with her condescending, pitying look. When I handed back her bank book and she congratulated me on getting the job done I simply smiled back at her.

Inside I was screaming.

It is not helpful in any way shape or form to infantilise disabled people. It perpetuates the stigma and tropes that surround disability. If you treat disabled people this way you are telling others that it is normal and expected. Most importantly you are showing your children that this is the normal way to interact with disabled people.

As a disabled person who is treated like a child by someone nearly every day, I implore you to break this behaviour.

Let us all be the adults that we are and engage as adults in all spheres of community and life.

This will lead to a more open, inclusive, and accepting society for everyone.

Courtesy of a colleague

Vigabatrin and intramyelinic edema

Pearl PL, Poduri A, Prabhu SP, Harini C, Goldstein R, Atkinson RM, Armstrong D, Kinney H. White matter spongiosis with vigabatrin therapy for infantile spasms. Epilepsia. 2018 Apr;59(4):e40-e44.

The histopathology, "white matter spongiosis," defined by electron microscopy (EM) as "intramyelinic edema," has been associated with vigabatrin therapy in various animal models, but its role or significance in clinical studies is unknown. We conducted a neuropathological examination on a 27-month-old boy with bilateral polymicrogyria and epilepsy after sudden unexpected death in epilepsy (SUDEP). The patient was initiated on vigabatrin at 4 months of age, which controlled infantile spasms, and was continued as maintenance therapy. Autopsy showed a combination of developmental and acquired lesions: (1) bilateral gyral malformations of the frontal, parietal, temporal, and insular cortex; (2) agenesis of the olfactory tracts and bulbs; (3) hippocampal abnormalities: dentate gyrus bilamination and granule cell dispersion; and (4) areas of microscopic bilateral, symmetric white matter spongiosis in the brainstem central tegmental tract, amiculum and hilum of the inferior olive, medial longitudinal fasciculus, paragigantocellularis lateralis, optic nerves and chiasm, and hypothalamus. The white matter spongiosis was identical to the histopathologic lesions (which by EM exhibited intramyelinic edema) that were demonstrated in animal models on vigabatrin therapy, indicating that vigabatrin toxicity is not restricted to animal models.

Horton M, Rafay M, Del Bigio MR. Pathological evidence of vacuolar myelinopathy in a child following vigabatrin administration. J Child Neurol. 2009 Dec;24(12):1543-6.

Vigabatrin, a gamma-aminobutyric acid (GABA) aminotransferase- inhibiting drug used for seizure control, has been associated with white matter vacuolation and intramyelinic edema in animal studies. Similar pathological lesions have never been described in the central nervous system of human participants treated with the drug. Described here is a child with quadriparetic cerebral palsy secondary to hypoxic-ischemic brain injury following premature birth, who received vigabatrin for the treatment of infantile spasms at 9 months of age. A severe deterioration of neurologic function immediately followed the initiation of vigabatrin, and the child died 3 weeks later. Neuropathological examination revealed white matter vacuolation and intramyelinic edema. This represents the first reported case of vigabatrin-induced intramyelinic edema in humans. It validates the concerns regarding vigabatrin safety in infants and individuals with preexisting abnormalities of myelin.

Central neurocytoma

A British woman says she was diagnosed with a tennis ball-sized brain tumor after long suffering from migraine and psychosis — symptoms doctors reportedly dismissed as anxiety, depression and possibly bipolar disorder.

"It was frustrating to be told by doctors that my symptoms were caused by mental illness,” 22-year-old Laura Skerritt, of Somerset, told British news agency South West News Service (SWNS). "I sensed that my health problems weren’t being caused by mental illness.”

"I’m quite an emotional person and flip between happy and sad moods, but this is just part of my quirky personality," she added.

By November 2018, Skerritt’s condition was getting worse; she began suffering from seizures and was having trouble walking. Eventually, further testing at Yeovil District Hospital in Somerset revealed the cause of her health issues: a massive brain tumor. Skerritt said it took more than two years to receive a proper diagnosis.

A month later, Skerritt, who teaches swimming and enjoys horseback riding, underwent a 13-hour operation at Southmead Hospital in Bristol to remove 80 percent of the tumor, a central neurocytoma.

A central neurocytoma is a rare, typically non-cancerous tumor that forms in the ventricles, or fluid-filled spaces in the brain, according to the University of Pittsburgh Medical Center.

The surgery was successful, but the 22-year-old said her recovery was the most difficult part of the process. Skerritt told SWNS that she lost nearly 30 pounds and had to re-learn how to talk.

Unfortunately, Skerritt now requires another operation followed by eight weeks of “intensive radiotherapy” after she suffered what she called a “major seizure.”

"It’s going to be really hard going back into hospital but I’m hoping I make it through the treatment,” she said.

Skerritt added that her health ailments have affected her on a deeper level as well.

"My diagnosis changed my outlook on life. I’m not sure whether or not I want kids, for fear of them inheriting the disease or seeing me suffer [from] symptoms,” she said, adding she was forced to give up her driver’s license.

“I lost my independence,” she said.

Sunday, January 19, 2020

PANDAS and PANS revisited

Maybe one day I will see one.

By 2015, when Adam was 8, Elliott began to fear she might have to have him hospitalized. She took him for a full psychological evaluation with Rebecca Daily, an autism specialist at the University of Oklahoma. During the visit, Elliott mentioned that Adam’s problems had all started when he was a toddler, around the time he had had his tonsils and adenoids removed. Doctors had recommended the surgery because he had had so many bouts of strep throat.

“What did you say?” Daily asked.

Elliott repeated what she had said.

She remembers Daily then saying: “This is not autism, this is not ADHD. This is a disease called PANDAS.”

Elliott had never heard of PANDAS, short for ‘pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections.’ But the diagnosis had been gaining traction over the previous two decades. In 1998, Susan Swedo, then a pediatrician at the U.S. National Institutes of Health (NIH), first proposed PANDAS to explain an apparent association between strep throat, obsessive-compulsive disorder (OCD) and tic disorders such as Tourette syndrome. By Swedo’s estimate, the condition affects up to 1 in 200 children, but many experts contest that figure — and even the condition’s very existence.

Pediatric neurologists point out that Tourette syndrome and OCD are highly heritable; if strep plays a role in these conditions at all, it is extraordinarily rare. Strep, by contrast, is common. In one study that followed 814 children for 12 weeks, for example, about half of the children had ongoing strep infections, and they did not show more obsessive-compulsive behaviors or tics than the other children.

Still, PANDAS has attracted a vocal band of proponents who have proposed it as a catchall for a wide range of mental health issues sometimes lumped under the broader term ‘autoimmune encephalopathy.’ The list of purported triggers has grown from strep to include Lyme disease, mononucleosis and herpes. And the range of possible outcomes has expanded to encompass ADHD, anorexia nervosa and autism. The boundaries between these diagnoses can be subjective, and some clinicians and parents are quick to attribute obsessive-compulsive behavior to PANDAS, even when it may stem from autism, OCD or something else. “There’s going to be diagnostic confusion whether a child has a late presentation of autism or if they have PANDAS,” Swedo says.

Daily recommended that Adam take a test developed by a colleague of hers, microbiologist Madeleine Cunningham. Oklahoma-based Moleculera Labs, which Cunningham co-founded, markets the $925 test — called the ‘Cunningham Panel’ — for children who are not responding to treatments for psychiatric conditions and who may instead have “a treatable autoimmune disorder.” One brochure reads: “Could an infection be causing your child’s symptoms?”

Whether they pursue the test or not, parents who suspect their child has PANDAS often end up seeking expensive, unproven and potentially dangerous treatments — including, in rare cases, rituximab, an immunosuppressant typically used for cancer treatment and organ transplants that has serious, sometimes deadly, side effects. Medical quacks and profiteers have thrived, largely unchecked in a marketplace that intersects with the outer fringes of the autism and chronic Lyme communities. One Oklahoma company, for instance, markets donkey milk as a PANDAS treatment. Most parents end up paying out of pocket, but five states have passed laws mandating insurance coverage for treatment of the condition.

The condition’s rising popularity notwithstanding, several experts say the way it is being diagnosed and treated is worrisome. “Allow me to be considered a naysayer,” says Edward Kaplan, an expert in streptococcal infections at the University of Minnesota in Minneapolis. He says there may be a neurological trigger for the behavioral changes in some children diagnosed with PANDAS, but the link to strep is tenuous at best. “This disease is diagnosed by all kinds of people more frequently than perhaps it should be.”…

Swedo then inverted her approach. Rather than seeking out children with rheumatic fever, she began studying children with OCD and Tourette syndrome, and swabbing their throats for evidence of a strep infection. She often found it — which is not surprising because it is a common infection, and many children also carry the bacteria without getting sick. What was surprising, Swedo says, was what happened when she started treating those children.

She recalls one child who refused to swallow his spit, preferring, instead, to stockpile it. “He had three cups under his bed,” she says. When she treated him with penicillin, she says, “he responded beautifully; his obsessive-compulsive symptoms disappeared.” He then had another strep infection, and the OCD-like behavior “came roaring back.” In another child, she tried ‘plasmapheresis,’ a technique to separate the child’s blood cells from the plasma and strip out the germ-fighting antibodies circulating in his system. She says that led to an 80 percent decrease in the boy’s OCD traits, according to his parents…

It was PANDAS that would become Swedo’s legacy. In 1998, Swedo proposed five criteria to diagnose PANDAS: the presence of OCD or a tic disorder, sudden onset prior to puberty, a waxing and waning pattern of trait severity, an association between strep infections and behavioral traits, and neurological abnormalities such as jerking movements or problems with coordination. Despite the clear, testable criteria she laid out, the definition of PANDAS proved elastic in the hands of practitioners. By 2008, one study had found that only 39 percent of children diagnosed with PANDAS actually fit Swedo’s original definition. So many children were diagnosed, in fact, that Stanford University’s multidisciplinary PANDAS clinic — the first of its kind when it opened in 2012 — sees children from within only a seven-county area and only if they agree to participate in research.

Given the surge of interest, the NIH launched a $3 million multicenter study — the largest and most rigorous analysis of the condition.[1] The researchers followed 71 children who met PANDAS diagnostic criteria over two years and compared them with children who had traits of Tourette syndrome or OCD but not PANDAS. Two landmark studies, published in 2008 and 2011, found that in 91 percent of all PANDAS cases, there was no association between the timing of strep infections or presence of strep antibodies and flare-ups of OCD or tics. Even though children with PANDAS were more likely to receive antibiotics than the other children were, the researchers could detect no difference in the number of flare-ups the children experienced…

Cunningham tested whether these five molecules might serve as diagnostic markers for PANDAS and concluded that they did. But in 2008, independent studies at Johns Hopkins University in Baltimore, Maryland, raised doubts about the utility of Cunningham’s biological markers and the link between infection and PANDAS flare-ups.

That did not keep Cunningham’s team from the patent office: In 2011, Cunningham and Craig Shimasaki, a molecular biologist and entrepreneur, founded Moleculera Labs to commercialize the test Cunningham had developed. Their website says that a single elevated enzyme “may indicate a clinically significant autoimmune condition.” This claim clashes with published results showing similar levels of the enzyme in people with and without PANDAS. Moleculera has reported that autistic children may also receive a positive result, raising further questions about the utility of the test…

In one 2017 study, the Cunningham Panel did not distinguish 20 people with psychiatric conditions who met the formal criteria for PANDAS or PANS from 33 who did not.[2[ Susanne Bejerot, professor of psychiatry at Örebro University in Sweden, who led the study, was so disturbed by the findings that she recruited 21 controls — including a fellow doctor with no history of mental illness — to take the test. She found that 86 percent tested positive for at least one of the five markers on the Cunningham Panel. “Parents are very happy about the Cunningham Panel because they always get positive results,” Bejerot says. “That means they can show it to a clinician and get antibiotics or other treatments.”…

[Donald] Gilbert studied philosophy before he became a doctor. He gives lectures on PANDAS that sound more like epistemology than medicine, as he explores the role of inference and the nature of causality. “I’m a skeptic by nature,” he says.

In August 2018, Gilbert gave a talk for primary care physicians with the relatively staid title “PANDAS and PANS: A clinician’s guide to management.” In it, he challenged the anecdotal evidence PANDAS supporters frequently cite. He also recommended that, unless OCD traits make it impossible for a child to attend school, clinicians should not run any tests, offer any treatments or provide any neurology referrals. In his slides, he wrote: “Inoculate the family with education so they do not seek out a PANDAS/PANS clinic.”

After the Cincinnati Children’s Hospital posted a video of the talk online, the PANDAS Network, a nonprofit advocacy organization that is listed as one of the National Institute of Mental Health’s Outreach Partners, shared it on Facebook. All hell broke loose. “Move over you foolish man,” read a comment from the PANDAS Network’s account. “Step away from the podium.”

“His swipes at Dr. Swedo and Cunningham … are so incredibly rude and flat-out unprofessional,” one commenter wrote.

“This man needs to be stopped,” wrote another.

Within a week, the group had issued a “call to action,” directing its members to file complaints against Gilbert with the Ohio State Medical Board and the Accreditation Council for Continuing Medical Education. “[Dr. Gilbert] mocked the disorder, disparaged researchers, misled attendees, encouraged physicians to commit medical malpractice, and generally enjoyed a jolly good time laughing along with his colleagues at desperate parents,” attorney Beth Maloney wrote in a letter to his employer. “The general medical bigotry that was on full display caused me to wonder whether your hospital will next try to take PANDAS children from parents who disagree with its doctors.”

Gilbert says he was upset by the attacks but chose to ignore them at first. When he attended a professional conference a few months later, however, the organizers left his name off the program and advised him to register at the hotel under a false name for his own safety.  While he was there, he says, Swedo, who retired from the NIH last year and now serves as chief science officer for the PANDAS Physicians Network, asked to meet him.

When they met in the conference hotel, Swedo handed him printouts of his slides along with her handwritten responses. Gilbert disagreed with her about the science but says he saw that she wanted him to recognize the rigor in her own work. Swedo says she remains deeply offended that Gilbert compared her to a quack. “I had grounds to sue him, but I chose not to,” she says. She says she tries to warn parents about snake-oil salesmen and shuns healthcare providers she believes are over-diagnosing PANDAS. She lays blame for the explosion in questionable fringe therapies on the PANDAS naysayers such as Gilbert. “The controversy is responsible for the overtreatment of these kids,” Swedo says. “Mainstream medicine has failed to deliver recognition of suffering and a promise that we are going to find out what is happening.”

[1] Leckman JF, King RA, Gilbert DL, Coffey BJ, Singer HS, Dure LS 4th, Grantz H, Katsovich L, Lin H, Lombroso PJ, Kawikova I, Johnson DR, Kurlan RM, Kaplan EL. Streptococcal upper respiratory tract infections and exacerbations of tic and obsessive-compulsive symptoms: a prospective longitudinal study. J Am Acad Child Adolesc Psychiatry. 2011 Feb;50(2):108-118.

[2] Hesselmark E, Bejerot S. Biomarkers for diagnosis of Pediatric Acute Neuropsychiatric Syndrome (PANS) - Sensitivity and specificity of the Cunningham Panel. J Neuroimmunol. 2017 Nov 15;312:31-37.


Neurodevelopmental outcomes after mild hypoxic ischemic encephalopathy in the era of therapeutic hypothermia

Finder M, Boylan GB, Twomey D, Ahearne C, Murray DM, Hallberg B. Two-Year Neurodevelopmental Outcomes After Mild Hypoxic Ischemic Encephalopathy in the Era of Therapeutic Hypothermia. JAMA Pediatr. 2019 Nov 11. doi:10.1001/jamapediatrics.2019.4011. [Epub ahead of print]


Therapeutic hypothermia reduces risk of death and disability in infants with moderate to severe hypoxic ischemic encephalopathy (HIE). Randomized clinical trials of therapeutic hypothermia to date have not included infants with mild HIE because of a perceived good prognosis.

To test the hypothesis that children with mild HIE have worse neurodevelopmental outcomes than their healthy peers.

Analysis of pooled data from 4 prospective cohort studies in Cork, Ireland, and Stockholm, Sweden, between January 2007 and August 2015. The dates of data analysis were September 2017 to June 2019. Follow-up was performed at age 18 to 42 months. In this multicenter cohort study, all children were born or treated at the tertiary centers of Cork University Maternity Hospital, Cork, Ireland, or Karolinska University Hospital, Stockholm, Sweden. In all, 690 children were eligible for this study.

At discharge, all children were categorized into the following 5 groups using a modified Sarnat score: healthy controls, perinatal asphyxia (PA) without HIE, mild HIE, moderate HIE, and severe HIE.

Cognitive, language, and motor development were assessed with the Bayley Scales of Infant and Toddler Development, Third Edition (BSITD-III). The BSITD-III scores are standardized to a mean (SD) of 100 (15), with lower scores indicating risk of developmental delay.

Of the 690 children eligible for this study, 2-year follow-up data were available in 471 (mean [SD] age at follow-up, 25.6 [5.7] months; 54.8% male), including 152 controls, 185 children with PA without HIE, and 134 children with HIE, of whom 14 had died. Infants with mild HIE (n = 55) had lower cognitive composite scores compared with controls, with a mean (SD) of 97.6 (11.9) vs 103.6 (14.6); the crude mean difference was -6.0 (95% CI, -9.9 to -2.1), and the adjusted mean difference was -5.2 (95% CI, -9.1 to -1.3). There was no significant difference in the mean cognitive composite scores between untreated children (n = 47) with mild HIE and surviving children with moderate HIE (n = 53) treated with therapeutic hypothermia, with a crude mean difference for mild vs moderate of -2.2 (95% CI, -8.1 to 3.7).

This study's findings suggest that, at age 2 years, the cognitive composite scores of children with a history of mild HIE may be lower than those of a contemporaneous control group and may not be significantly different from those of survivors of moderate HIE treated with therapeutic hypothermia.

Courtesy of:

Saturday, January 18, 2020

Predictors of recurrent febrile seizures during the same febrile illness in children with febrile seizures

Jun Kubota, Norimichi Higurashib, Daishi Hiranob, Hirotaka Isonoa, Haruka Numata, Takayuki Suzukia, Daisuke Kakegawaa, Akira Itoa, Manabu Yoshihashic, Takeru Itoa, Shin-ichiro Hamanod.  Predictors of recurrent febrile seizures during the same febrile illness in children with febrile seizures.  Journal of the Neurological Sciences.  In press.


•Incidence of recurrent febrile seizures during same febrile illness (RFS) was 17.6%.
•Male sex and a body temperature ≤ 39.8 °C were independent predictors of RFS.
•The two predictors combined had high sensitivity, specificity, and negative predictive value.


Febrile seizures (FS) are common in childhood. Of children who experience an FS, 14–24% experience recurrence within 24 h, during the same febrile illness (RFS). The aim of this pilot study was to identify the predictors of RFS among children who experience FS. We conducted a retrospective cohort study of children aged 6–60 months, who visited the emergency department (ED) at Atsugi City Hospital in Japan for treatment of an FS between December 1, 2018 and February 28, 2019. Exclusion criteria included multiple seizures before visiting the ED, diazepam administration before visiting the ED or on departure, seizures lasting >15 min, underlying diseases such as epilepsy, and absence of laboratory test results. The primary outcome was RFS. Fifty-one patients fulfilled the inclusion criteria, of whom nine (17.6%) had RFS. The incidence of RFS was significantly higher in children with a body temperature ≤ 39.8 °C during the ED visit (P = .01). The combination of male sex and a body temperature ≤ 39.8 °C had a sensitivity, specificity and negative predictive value of 88.9%, 76.2%, and 97.0%, respectively. In conclusion, the incidence of RFS was 17.6%. The major predictors of RFS were male sex and a body temperature ≤ 39.8 °C.

Courtesy of:

Thursday, January 16, 2020

IARS2 mutations

Inspired by a colleague's patients

Vona B, Maroofian R, Bellacchio E, Najafi M, Thompson K, Alahmad A, He L, Ahangari N, Rad A, Shahrokhzadeh S, Bahena P, Mittag F, Traub F, Movaffagh J, Amiri N, Doosti M, Boostani R, Shirzadeh E, Haaf T, Diodato D, Schmidts M, Taylor RW, Karimiani EG. Expanding the clinical phenotype of IARS2-related mitochondrial disease. BMC Med Genet. 2018 Nov 12;19(1):196.


IARS2 encodes a mitochondrial isoleucyl-tRNA synthetase, a highly conserved nuclear-encoded enzyme required for the charging of tRNAs with their cognate amino acid for translation. Recently, pathogenic IARS2 variants have been identified in a number of patients presenting broad clinical phenotypes with autosomal recessive inheritance. These phenotypes range from Leigh and West syndrome to a new syndrome abbreviated CAGSSS that is characterised by cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, as well as cataract with no additional anomalies.

Genomic DNA from Iranian probands from two families with consanguineous parental background and overlapping CAGSSS features were subjected to exome sequencing and bioinformatics analysis.

Exome sequencing and data analysis revealed a novel homozygous missense variant (c.2625C > T, p.Pro909Ser, NM_018060.3) within a 14.3 Mb run of homozygosity in proband 1 and a novel homozygous missense variant (c.2282A > G, p.His761Arg) residing in an ~ 8 Mb region of homozygosity in a proband of the second family. Patient-derived fibroblasts from proband 1 showed normal respiratory chain enzyme activity, as well as unchanged oxidative phosphorylation protein subunits and IARS2 levels. Homology modelling of the known and novel amino acid residue substitutions in IARS2 provided insight into the possible consequence of these variants on function and structure of the protein.

This study further expands the phenotypic spectrum of IARS2 pathogenic variants to include two patients (patients 2 and 3) with cataract and skeletal dysplasia and no other features of CAGSSS to the possible presentation of the defects in IARS2. Additionally, this study suggests that adult patients with CAGSSS may manifest central adrenal insufficiency and type II esophageal achalasia and proposes that a variable sensorineural hearing loss onset, proportionate short stature, polyneuropathy, and mild dysmorphic features are possible, as seen in patient 1. Our findings support that even though biallelic IARS2 pathogenic variants can result in a distinctive, clinically recognisable phenotype in humans, it can also show a wide range of clinical presentation from severe pediatric neurological disorders of Leigh and West syndrome to both non-syndromic cataract and cataract accompanied by skeletal dysplasia.

Takezawa Y, Fujie H, Kikuchi A, Niihori T, Funayama R, Shirota M, Nakayama K, Aoki Y, Sasaki M, Kure S. Novel IARS2 mutations in Japanese siblings with CAGSSS, Leigh, and West syndrome. Brain Dev. 2018 Nov;40(10):934-938.


IARS2 encodes isoleucine-tRNA synthetase, which is aclass-1 amino acyl-tRNA synthetase. IARS2 mutations are reported to cause Leigh syndrome or cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysphasia syndrome (CAGSSS). To our knowledge, IARS2 mutations and diseases related to it have only been reported in three families. Here we report a case of two Japanese siblings with Leigh syndrome, some features of CAGSSS, and West syndrome that are found to have compound heterozygous novel IARS2 mutations.

A 7-month-old Japanese girl presented with infantile spasms. Brain magnetic resonance imaging (MRI) revealed diffuse brain atrophy and hyperintensity in the bilateral basal ganglia. Three years later, her younger sister also presented with infantile spasms. MRI revealed diffuse brain atrophy and hyperintensity of the bilateral ganglia, suggesting Leigh syndrome. The siblings were identified with compound heterozygous missense mutations in IARS2, p.[(Phe227Ser)];[(Arg817His)].

This is the first case study reporting Leigh syndrome concomitant with some features of CAGSSS in siblings with novel IARS2 mutations, thereby broadening the phenotypic spectrum of IARS2-related disorders. Further studies are warranted to elucidate the nature of these disorders.

Amish sudden deaths

About 15 years ago, an Amish family in the eastern US was hit by an unexplainable tragedy -- one of their children died suddenly while playing and running around. Just a few months later, the same fate befell another one of their children. Six years later, they lost another child. Two years after that, another one.

The autopsies didn't offer any clues. The children's hearts appeared normal. The family had what they referred to as "the curse of sudden death." And medical examiners couldn't figure out why.

After the deaths of the first two children, a medical examiner who conducted the autopsies got in touch with researchers at the Mayo Clinic Windland Smith Rice Sudden Death Genomics Laboratory in 2004. Researchers at the lab had pioneered the concept of molecular autopsy, using genetic testing to understand the cause of death in sudden unexplained cases, and the examiner wanted to see if they could shed light on the mystery affecting the Amish community.

The team suspected that a gene called RYR2 could be the culprit -- mutations of the gene can cause a cardiac arrhythmic disorder that can lead to exercise-fainting spells, seizures or even sudden cardiac death. But when they analyzed the gene to check for mutations, nothing turned up.

The case remained cold for more than a decade. As the years went by, pediatric cardiologists and genetic counselors from other parts of the country reached out to the lab about other Amish families whose children had also died sudden deaths -- all looking for answers about this heartbreaking phenomenon.

Then last week, researchers at the Mayo Clinic lab reported a breakthrough, published in JAMA Cardiology. With the help of new technology that wasn't around when they first started looking into the case, the team learned that these Amish children had all inherited the same genetic mutation from both of their parents. And out of the 23 young people who had inherited the mutation, 18 had died sudden deaths.

"As we started building out the family structure, it became apparent to us that this was most likely a recessive disorder," David Tester, the lead scientist on the case, told CNN. "With more information and more technological advancement in terms of being able to look at genes, we were able to put this puzzle together."

The children likely had a common ancestor.

Turns out, it was RYR2 -- the gene the researchers had suspected all along. But there wasn't just one mistake in the gene. More than 300,000 base pairs in the gene had been duplicated.

"We finally figured it out that it was an autosomal recessive condition where both bad duplications came from both parents, and those children were unfortunate to get the double dose," Michael Ackerman, director of the Windland Smith Rice Sudden Death Genomics Laboratory, told CNN.
To develop the duplication that causes sudden death, a child has to inherit a mutated gene from each parent -- the chances of which are 25 percent. That four children in one family inherited the mutation and died sudden deaths is incredibly unfortunate, Ackerman said.

The Amish may be more vulnerable to recessive inherited conditions because they are descended from a small number of ancestors and tend to intermarry, Tester said. The two families studied in the report are seemingly unrelated, but because the children all had the exact same duplication in a gene inherited from both parents, Ackerman said that it's likely that they have a common ancestor.

Now that researchers know about this genetic marker, there are steps that medical professionals can take to prevent sudden deaths from occurring in other Amish children, Tester said.

"Having this genetic biomarker, we can now very easily test any individual for the presence of the mutation," he said. "Having that ability can potentially save lives."

Knowing who has the mutation and who doesn't is the first step to preventing tragedies like the ones experienced by the families in the study, Ackerman said. If adults who are carriers for the mutation know that they have it, they can make informed decisions about whether or not they should marry another person who is also a carrier.

There are still challenges ahead. For children who have inherited the mutation and are at risk of sudden death, the only solution to prevent it is an implantable cardioverter defibrillator (ICD), which can be extremely expensive. Ackerman said his team is working on understanding more about what causes the duplication in the gene so that a medication to prevent it can be developed, a treatment that would be much more accessible.

"We're going fast and furious to try to get this figured out for this Amish community," he said.
But for now, Ackerman hopes the discovery will provide some closure to the families who have lost their loved ones.

"We finally have figured out the curse of sudden death for the Amish community and they now have peace of mind as to the reason," he said.

Tester DJ, Bombei HM, Fitzgerald KK, Giudicessi JR, Pitel BA, Thorland EC, Russell BG, Hamrick SK, Kim CSJ, Haglund-Turnquist CM, Johnsrude CL, Atkins DL, Ochoa Nunez LA, Law I, Temple J, Ackerman MJ. Identification of a Novel Homozygous Multi-Exon Duplication in RYR2 Among Children With Exertion-Related Unexplained Sudden Deaths in the Amish Community. JAMA Cardiol. 2020 Jan 8. doi:10.1001/jamacardio.2019.5400. [Epub ahead of print]


The exome molecular autopsy may elucidate a pathogenic substrate for sudden unexplained death.

To investigate the underlying cause of multiple sudden deaths in young individuals and sudden cardiac arrests that occurred in 2 large Amish families.

Two large extended Amish families with multiple sudden deaths in young individuals and sudden cardiac arrests were included in the study. A recessive inheritance pattern was suggested based on an extended family history of sudden deaths in young individuals and sudden cardiac arrests, despite unaffected parents. A family with exercise-associated sudden deaths in young individuals occurring in 4 siblings was referred for postmortem genetic testing using an exome molecular autopsy. Copy number variant (CNV) analysis was performed on exome data using PatternCNV. Chromosomal microarray validated the CNV identified. The nucleotide break points of the CNV were determined by mate-pair sequencing. Samples were collected for this study between November 2004 and June 2019.

The identification of an underlying genetic cause for sudden deaths in young individuals and sudden cardiac arrests consistent with the recessive inheritance pattern observed in the families.

A homozygous duplication, involving approximately 26 000 base pairs of intergenic sequence, RYR2's 5'UTR/promoter region, and exons 1 through 4 of RYR2, was identified in all 4 siblings of a family. Multiple distantly related relatives experiencing exertion-related sudden cardiac arrest also had the identical RYR2 homozygous duplication. A second, unrelated family with multiple exertion-related sudden deaths and sudden cardiac arrests in young individuals, with the same homozygous duplication, was identified. Several living, homozygous duplication-positive symptomatic patients from both families had nondiagnostic cardiologic testing, with only occasional ventricular ectopy occurring during exercise stress tests.

In this analysis, we identified a novel, highly penetrant, homozygous multiexon duplication in RYR2 among Amish youths with exertion-related sudden death and sudden cardiac arrest but without an overt phenotype that is distinct from RYR2-mediated catecholaminergic polymorphic ventricular tachycardia. Considering that no cardiac tests reliably identify at-risk individuals and given the high rate of consanguinity in Amish families, identification of unaffected heterozygous carriers may provide potentially lifesaving premarital counseling and reproductive planning.

Wednesday, January 15, 2020

Moyamoya disease

Moyamoya disease is a cerebrovascular condition characterized by idiopathic chronic progressive steno-occlusive changes of the terminal portions and proximal branches of the internal carotid arteries (ICAs). These changes reduce blood flow through the anterior circulation of the brain causing progressive cerebral ischemia. To compensate for the ischemia, a collateral vascular network of small vessels arising from the carotid artery, leptomeninges, and transdural branches of the external carotid artery (ECA) may form. In the final stages of the disease, the brain’s blood supply is provided almost exclusively by the ECA and the vertebrobasilar systems....

By definition, people with moyamoya disease typically have the pathognomonic arteriographic findings bilaterally with no associated risk factors. In contrast, people with the characteristic moyamoya vasculopathy who also have certain associated conditions (Box 1) are categorized as having moyamoya syndrome. Those with unilateral arteriographic findings are also said to have moyamoya syndrome, even if they have no other associated risk factor. However, approximately 40% of people who initially present with unilateral moyamoya syndrome eventually develop contralateral vasculopathy, such that they will meet the definition of moyamoya disease if they do not have associated conditions. When the term moyamoya is used alone without the distinguishing modifiers syndrome or disease, it refers merely to the findings on cerebral arteriography, regardless of the etiology and/or the laterality...

Moyamoya disease can occur at any age, however, the age of presentation follows a bimodal distribution. There is a peak in the first decade of childhood, especially around age 5 years; the second peak is in adulthood around the middle of the fifth decade. Moyamoya disease is more common in women with a 2:1 ratio of women to men in most populations.

Although moyamoya was originally described as predominantly affecting populations with Asian ancestry, it has been identified worldwide, in people of varied ethnic backgrounds, including American and European populations...

The natural history of moyamoya is variable; however, moyamoya progresses in the majority of cases. Progression may have a slow indolent course, an intermittent pattern with rare events, or be fulminant with steep neurologic decline.

It is estimated that up to two-thirds of people with moya-moya disease have symptomatic progression that cannot be halted by medical treatment alone. A large meta-analysis of 1,156 people with moyamoya showed 87% who underwent surgical revascularization had symptomatic benefit in the form of reduction or complete disappearance of symptomatic cerebral ischemia.

The initial neurologic status of an individual is the best predictor of the disease course. Early diagnosis coupled with close follow-up and intervention when appropriate are the major determinants of a favorable long-term outcome...

In all age groups, ischemia (TIA or stroke) is the most common presentation of moyamoya, but adults are 7 times more likely than children to present with intracranial hemorrhage. Manifestations also vary geographically. In the US, ischemic symptoms are the predominant presentation in adults and children, although adults are still 7 times more likely to have intracranial hemorrhage than children (20% vs 2.8%). In contrast, the rate of adults in Asian populations presenting with hemorrhage (42%) is much higher than among those of Asian descent living in the US...

Headache is a frequent presenting symptom and is typically of a migraine-like quality and refractory to medical treatment. Headache is generally believed to be caused by dilatation of the collateral vessels that may stimulate the dural nociceptors.

Choreiform movement is another presenting symptom of moyamoya in children, attributed to dilated collateral vessels in the basal ganglia. Additionally, the morning glory disk is an ophthalmologic finding occasionally seen in moyamoya. It is highly recommended to obtain cerebrovascular imaging to evaluate for moyamoya if this sign is observed on an ophthalmologic examination.

In cerebral ischemia, moyamoya should be included in the differential diagnosis, especially in children, because moya-moya is associated with approximately 6% to 10% of nonperinatal pediatric strokes and TIA...

Although most pediatric moyamoya cases are idiopathic, there are population-based patterns. Historically, Asian ancestry is an increased risk factor for moyamoya, with up to 56% of Asian-Americans with moyamoya harboring a specific mutation of RNF213. In contrast, only 3.6% to 29% of non-Asian individuals with moyamoya harbor RNF213 mutations. Additionally, Caucasians with moyamoya in the US have a higher rate of autoimmune disorders, including type I diabetes (8.5% vs 0.4% in the general population) and thyroid disease (17% vs 8%). Down syndrome (with a 26-fold increased likelihood of moyamoya), neurofibromatosis type I (with a 2%-5% prevalence of moyamoya), sickle cell disease, and other associated conditions are summarized in Box 1.

MRI is the current standard for evaluation of cerebral ischemia. Although protocols may be institution specific, commonly available MRI sequences are generally used, including axial T1-/T2-weighted images to assess structural anatomy and chronic stroke, diffusion-weighted imaging (DWI) and apparent diffusion coefficient values (ADC map) to assess acute stroke, fluid-attenuated inversion recovery (FLAIR) images to assess chronic stroke burden and areas of slow flow (ie, the ivy sign, present in nearly 80% of cases) and MR angiography (MRA) to visualize the circle of Willis. Advances in vessel wall imaging may help to differentiate between vasculitis and moyamoya...

If moyamoya is identified on MRI, DSA should be considered, as this modality has increased diagnostic sensitivity for moyamoya compared with MRI (including the ability to better differentiate vasculitis) and offers valuable data pertinent to preoperative planning. Transdural collaterals visuallzed on DSA are critical biomarkers of disease that can assess angiogenic potential, predict 1-year postoperative radiographic outcomes and, when incorporated into surgical planning, have been demonstrated to reduce perioperative stroke complications by more than 40%, especially in the setting of previous cranial surgery or shunting. The risk of angiogram is generally low, with an approximately 1% complication rate at high volume centers. Contraindications include contrast allergies, aortic stenosis, and unstable general medical conditions that preclude sedation or anesthesia.

When moyamoya is diagnosed in a child, families are frequently concerned about the need to screen other siblings and relatives. Initial screening commonly includes an MRI and MRA, looking for the defining radiographic characteristics of moyamoya.15 Indications for radiographic screening are still to be defined, but because the rate of familial involvement is low (3.4% in a large North American series), initial screening of unaffected family members is generally reserved for first-degree relatives of those who have other first- or second-degree relatives with 1) established moyamoya diagnosis, 2) clinical histories strongly suggestive of moyamoya (eg, TIA, stroke, severe headaches or seizures without identified cause), or 3) identical twins. If an initial screening MRI is normal, it remains unclear what, if any, interval for follow-up imaging is appropriate. There is data, however, to indicate that previously normal scans can later evidence clear (and clinically symptomatic) moyamoya, suggesting that follow up may have utility.

Genetic testing and counseling are also relevant to children and families diagnosed with moyamoya. There is generally high penetrance of the phenotype with most mutations and there is a potential surgical treatment if identified. In North America, only a small minority of pediatric moyamoya cases (<5%) appear to have clear associations with specific mutations, unless the children have Asian heritage (for whom RNF213 mutations exist in 30%-50%). When present, RNF213 mutation with moyamoya has marked significance for familial screening, as data suggest that familial penetrance is approximately 23%. If an individual carries the mutation, there is a near 50% likelihood of manifesting arteriopathy. Other mutations are rarer, but may be detected by specific clinical or radiographic phenotypes (ACTA2 carriers with distinctive stellate arteries branching from a dilated proximal internal carotid, GUCY mutations with achalasia, etc.)...

Key points of surgical management focus on indications for surgery, timing of the operation, selection of specific technique, and expectations of outcome following revascularization. Potential complications of surgery include stroke, infection, and hemorrhage...

Indications include radiographic evidence of moyamoya, including ongoing ischemic symptoms and/or evidence of compromised blood flow or cerebral perfusion reserve. Data also suggest that clinically asymptomatic children who have radiographic or functional evidence of impaired cerebral perfusion should be considered as operative candidates; this position is supported by the American Heart/Stroke Association recommendations. Relative contraindications include very early stage arteriopathy with normal perfusion and/or children with profound medical or neurologic compromise. Of note, the rare data focused on surgical revascularization in individuals with ACTA2 moyamoya suggest that this is a very high-risk population...

If possible, the ability to perform bilateral surgery (if indicated) under a single anesthetic may help to reduce complications and speed up the growth of surgical collaterals, particularly in very young patients...

There is abundant evidence that surgical revascularization improves a wide range of outcome metrics in children with moyamoya. Radiographically, revascularization reverses white matter changes, improves measures of cerebral oxygenation, and increases cerebral blood flow, stabilizing stroke burden, despite progressive arteriopathy. Clinically, surgery decreases ischemic symptoms, headache, and risk of hemorrhage and markedly reduces stroke rates. Surgery reduces stroke risk at years 1 and 5 from 32% and 66% to 90%, respectively, to less than 5% for most populations at both years 1 and 5. Surgery also improves functional and cognitive outcomes. These good outcomes are durable, with recent long-term outcomes (>20 years) demonstrating persistence of the surgical collaterals over decades and the continued protection from stroke while participating in all forms of activity (eg, exercise, advanced educational degrees, and childbirth).

It is increasingly clear that treatment at a high-volume center with a dedicated pediatric cerebrovascular team is among the most important predictors of surgical outcome.

Moyamoya represents a constellation of arteriopathies that vary in genetic and environmental drivers but share a common end-pathway of progressive internal carotid artery narrowing and collateral development that leads to stroke if untreated. Diagnosis is predicated on characteristic radiographic findings observed on MRI and catheter angiogram, with treatment centered on surgical revascularization to reduce the risk of stroke. Surgical treatment is very successful at providing durable substantial reductions in stroke risk particularly when performed at high-volume centers with experienced teams.