Thursday, January 27, 2022
Wednesday, January 26, 2022
Gloss D, Pargeon K, Pack A, Varma J, French JA, Tolchin B, Dlugos DJ, Mikati MA, Harden C; AAN Guideline Subcommittee. Antiseizure Medication Withdrawal in Seizure-Free Patients: Practice Advisory Update Summary: Report of the AAN Guideline Subcommittee. Neurology. 2021 Dec 7;97(23):1072-1081. doi: 10.1212/WNL.0000000000012944. PMID: 34873018.
Objective: To update a 1996 American Academy of Neurology practice parameter.
Methods: The authors systematically reviewed literature published from January 1991 to March 2020.
Results: The long-term (24-60 months) risk of seizure recurrence is possibly higher among adults who have been seizure-free for 2 years and taper antiseizure medications (ASMs) vs those who do not taper ASMs (15% vs 7% per the 1 Class I article addressing this issue). In pediatric patients, there is probably no significant difference in seizure recurrence between those who begin tapering ASMs after 2 years vs 4 years of seizure freedom, and there is insufficient evidence of significant difference in risk of seizure recurrence between those who taper ASMs after 18 months of seizure freedom and those tapering after 24 months. There is insufficient evidence that the rate of seizure recurrence with ASM withdrawal following epilepsy surgery after 1 year of seizure freedom vs after 4 years is not significantly different than maintaining patients on ASMs. An epileptiform EEG in pediatric patients increases the risk of seizure recurrence. ASM withdrawal possibly does not increase the risk of status epilepticus in adults. In seizure-free adults, ASM weaning possibly does not change quality of life. Withdrawal of ASMs at 25% every 10 days to 2 weeks is probably not significantly different from withdrawal at 25% every 2 months in children who are seizure-free in more than 4 years of follow-up.
Recommendations: Fourteen recommendations were developed.
Bacq A, Roussel D, Bonduelle T, Zagaglia S, Maletic M, Ribierre T, Adle-Biassette H, Marchal C, Jennesson M, An I; Genomics England Research Consortium, Picard F, Navarro V, Sisodiya SM, Baulac S. Cardiac Investigations in Sudden Unexpected Death in DEPDC5-Related Epilepsy. Ann Neurol. 2022 Jan;91(1):101-116. doi: 10.1002/ana.26256. Epub 2021 Nov 16. PMID: 34693554.
Objective: Germline loss-of-function mutations in DEPDC5, and in its binding partners (NPRL2/3) of the mammalian target of rapamycin (mTOR) repressor GATOR1 complex, cause focal epilepsies and increase the risk of sudden unexpected death in epilepsy (SUDEP). Here, we asked whether DEPDC5 haploinsufficiency predisposes to primary cardiac defects that could contribute to SUDEP and therefore impact the clinical management of patients at high risk of SUDEP.
Methods: Clinical cardiac investigations were performed in 16 patients with pathogenic variants in DEPDC5, NPRL2, or NPRL3. Two novel Depdc5 mouse strains, a human HA-tagged Depdc5 strain and a Depdc5 heterozygous knockout with a neuron-specific deletion of the second allele (Depdc5c/- ), were generated to investigate the role of Depdc5 in SUDEP and cardiac activity during seizures.
Results: Holter, echocardiographic, and electrocardiographic (ECG) examinations provided no evidence for altered clinical cardiac function in the patient cohort, of whom 3 DEPDC5 patients succumbed to SUDEP and 6 had a family history of SUDEP. There was no cardiac injury at autopsy in a postmortem DEPDC5 SUDEP case. The HA-tagged Depdc5 mouse revealed expression of Depdc5 in the brain, heart, and lungs. Simultaneous electroencephalographic-ECG records on Depdc5c/- mice showed that spontaneous epileptic seizures resulting in a SUDEP-like event are not preceded by cardiac arrhythmia.
Interpretation: Mouse and human data show neither structural nor functional cardiac damage that might underlie a primary contribution to SUDEP in the spectrum of DEPDC5-related epilepsies.
Thursday, January 20, 2022
Szabo SM, Gooch KL, Mickle AT, Salhany RM, Connolly AM. The impact of genotype on outcomes in individuals with Duchenne muscular dystrophy: A systematic review. Muscle Nerve. 2021 Dec 8. doi: 10.1002/mus.27463. Epub ahead of print. PMID: 34878187.
Duchenne muscular dystrophy (DMD) is associated with progressive muscle weakness, loss of ambulation (LOA), and early mortality. In this review we have synthesized published data on the clinical course of DMD by genotype. Using a systematic search implemented in Medline and Embase, 53 articles were identified that describe the clinical course of DMD, with pathogenic variants categorizable by exon skip or stop-codon readthrough amenability and outcomes presented by age. Outcomes described included those related to ambulatory, cardiac, pulmonary, or cognitive function. Estimates of the mean (95% confidence interval) age at LOA ranged from 9.1 (8.7-9.6) years among 90 patients amenable to skipping exon 53 to 11.5 (9.5-13.5) years among three patients amenable to skipping exon 8. Although function worsened with age, the impact of genotype was less clear for other outcomes (eg, forced vital capacity and left ventricular ejection fraction). Understanding the distribution of pathogenic variants is important for studies in DMD, as this research suggests major differences in the natural history of disease. In addition, specific details of the use of key medications, including corticosteroids, antisense oligonucleotides, and cardiac medications, should be reported.
Courtesy of: https://www.mdlinx.com/journal-summary/the-impact-of-genotype-on-outcomes-in-individuals-with-duchenne-muscular-dystrophy-a-systematic/1XSiLpbG96BTbIQK7QFWRU
Monday, January 17, 2022
Adalia Rose Williams, a 15-year-old YouTuber who was born with a rare genetic disorder called progeria, has died, her family have confirmed.
In a statement posted to Facebook and Instagram, the family said Rose passed away in the evening of January 12, 2022, and that she had finally been "set free from this world."
Rose had amassed nearly three million subscribers on her YouTube channel, with which she documented her life and struggles with her condition.
The family, which had recently moved to San Antonio, Texas, from Austin, said in the statement: "She came into it quietly and left quietly, but her life was far from it. She touched MILLIONS of people and left the biggest imprint in everyone that knew her. She is no longer in pain and is now dancing away to all the music she loves. I really wish this wasn't our reality but unfortunately, it is."
"We want to say thank you to everyone that loved and supported her. Thank you to all her doctors and nurses that worked for YEARS to keep her healthy. The family would now like to mourn this huge loss in private."
What Is Progeria?
Progeria, also known as Hutchinson-Gilford Progeria Syndrome, or HGPS for short, is a very rare genetic disease that essentially causes children to age rapidly.
Children with the condition appear to be healthy at birth but usually begin to show signs of rapid biological aging within the first two years of their life.
The condition is very rare, affecting only around one in 20 million people worldwide, according to the Cleveland Clinic. Progeria is equally common in boys as it is in girls.
The disorder is caused by a mutation in a single gene known as A (LMNA) that makes a protein necessary for holding the center—or nuclei—of cells together.
When this gene is mutated, it produces an abnormal form of the LMNA protein called , which makes cells unstable and results in the rapid aging seen in progeria.
There are no known risk factors—environmental, lifestyle, or others—that may increase the risk of having progeria or giving birth to a child with the condition. Unlike many genetic disorders, progeria does not run through families. In fact, the chances of parents having a second child with the condition are around 2-3 percent, according to the Mayo Clinic.
Signs and symptoms of the condition usually appear in the first year of life, as the child's growth slows significantly, while their motor development and intelligence remains normal.
The main signs and symptoms of the progressive disorder include: slowed growth leading to below average height and weight; a narrowed face, with a small lower jaw, thin lips and beaked nose; a head that is disproportionately large compared to the face; prominent eyes and inability to completely close the eyelids; hair loss, including eyelashes and eyebrows; thinning, spotty and wrinkled skin; visible veins; and a high-pitched voice.
The condition is usually accompanied by several health issues, including severe progressive heart and blood vessel disease; hardening and tightening of skin in some parts of the body; abnormal tooth formation; some hearing loss; loss of fat that lies beneath the skin as well as muscle mass; skeletal abnormalities and fragile bones; stiff joints; and hip dislocation.
The average life expectancy of a child with progeria is around 13 years, according to the Mayo Clinic, although some individuals die younger while others live to around the age of 20. Complications related to cardiovascular issues represent the most common cause of death for people who have progeria.
There is currently no cure for progeria, although the U.S. Food and Drug Administration approved the first ever treatment for the disease in 2020 that provides some improvement in one or several areas of the condition.