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Research Publications

Craniofacial features of POLR3-related leukodystrophy caused by biallelic variants in POLR3A, POLR3B and POLR1C. Mirchi A, Guay SP, Tran LT, Wolf NI, Vanderver A, Brais B, Sylvain M, Pohl D, Rossignol E, Saito M, Moutton S, González-Gutiérrez-Solana L, Thiffault I, Kruer MC, Moron DG, Kauffman M, Goizet C, Sztriha L, Glamuzina E, Melançon SB, Naidu S, Retrouvey JM, Lacombe S, Bernardino-Cuesta B, De Bie I, Bernard G. J Med Genet. 2023 Oct;60(10):1026-1034. doi: 10.1136/jmg-2023-109223. Epub 2023 May 16. PMID: 37197783

RNA polymerase III-related or 4H leukodystrophy (POLR3-HLD) is a rare genetic disorder characterized by hypomyelination (inability to produce sufficient myelin, the fatty coating surrounding nerve fibers, at normal levels during development), neurological dysfunction, hypodontia (missing teeth), and hypogonadotropic hypogonadism (delayed puberty). Description of craniofacial features in individuals with POLR3-HLD is currently very limited.

In this study, researchers assessed the craniofacial features of 31 patients with POLR3-HLD. The team also proposed genotype-phenotype correlations based on patients’ facial features.

Results demonstrate that craniofacial abnormalities are common in patients with POLR3-HLD. Authors note that these findings will assist clinicians in diagnosing POLR3-HLD, help to provide care directed to this patient population’s specific needs, and allow future studies characterizing the underlying pathophysiology. 

Exploration of Gross Motor Function in Aicardi-Goutières Syndrome. Gavazzi F, Glanzman AM, Woidill S, Formanowski B, Dixit A, Isaacs D, Kornafel T, Ballance E, Pierce SR, Modesti N, Barcelos I, Cusack SV, Jan AK, Flores Z, Sherbini O, Vincent A, D'Aiello R, Lorch SA, DeMauro SB, Jawad A, Vanderver A, Adang L. J Child Neurol. 2023 Jul 27:8830738231188753. doi: 10.1177/08830738231188753. Epub ahead of print. PMID: 37499181

Aicardi-Goutières syndrome (AGS) is a rare genetic disorder characterized by a spectrum of motor abilities. The AGS Severity Scale is used to measure outcomes in individuals with AGS. However, because of the relatively limited granularity of this tool, there is a need to define tools that can measure function across the AGS spectrum. 

In this study, researchers explored gross motor function as an outcome measure of AGS. The team administered the Gross Motor Function Measure–88 (GMFM-88) and AGS Severity Scale in 71 individuals affected by AGS, characterizing performance variability by genotype. 

Results support the GMFM-88 as a potential clinical outcome assessment in subsets of the AGS population. Authors note the need for additional validation of outcome measures that can reflect the diverse gross motor function observed in individuals with AGS, including low motor function.

SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia. Srivastava S, Shaked HM, Gable K, Gupta SD, Pan X, Somashekarappa N, Han G, Mohassel P, Gotkine M, Doney E, Goldenberg P, Tan QKG, Gong Y, Kleinstiver B, Wishart B, Cope H, Pires CB, Stutzman H, Spillmann RC; Undiagnosed Disease Network; Sadjadi R, Elpeleg O, Lee CH, Bellen HJ, Edvardson S, Eichler F, Dunn TM. Brain. 2023 Jan 30:awac460. doi: 10.1093/brain/awac460. Epub ahead of print. PMID: 36718090.

Hereditary spastic paraplegia (HSP) is a group of neurodegenerative disorders that primarily affect the upper motor neurons. In the nervous system, a diverse family of lipids called sphingolipids play a critical role in structural and signaling functions. The synthesis of sphingolipids is regulated by the protein SPTSSA.

In this study, researchers identified three children with a complex form of HSP. The team used exome sequencing to discover two different disease-causing variants in the SPTSSA gene. Next, they investigated the effects of these variants on sphingolipid synthesis.

Findings showed that the variants in SPTSSA caused excessive sphingolipid synthesis, leading to HSP. Authors note that these findings provide a better understanding of the elevated sphingolipid synthesis involved in progressive neurodegenerative diseases.

Early-Onset Vascular Leukoencephalopathy Caused by Bi-Allelic NOTCH3 Variants. Stellingwerff MD, Nulton C, Helman G, Roosendaal SD, Benko WS, Pizzino A, Bugiani M, Vanderver A, Simons C, van der Knaap MS. Neuropediatrics. 2022 Apr;53(2):115-121. doi: 10.1055/a-1739-2722. Epub 2022 Jan 13. PMID: 35026854.

Cerebral autosomal dominant arteriopathy with sub-cortical infarcts and leukoencephalopathy (CADASIL) is an inherited disease of the blood vessels that occurs when the thickening of blood vessel walls blocks the flow of blood to the brain. Heterozygous variants of the NOTCH3 gene are known to cause CADASIL, with patients typically presenting in adulthood. In this study, researchers describe three patients from two unrelated families presenting at an early age with a vascular leukoencephalopathy. The team reviewed clinical records, MRI, and CT scans of the patients. Genome sequencing revealed bi-allelic variants in the NOTCH3 gene. These results indicate that bi-allelic loss-of-function NOTCH3 variants may cause a vascular leukoencephalopathy, distinct from CADASIL.

Hematologic abnormalities in Aicardi Goutières Syndrome. Adang LA, Gavazzi F, D'Aiello R, Isaacs D, Bronner N, Arici ZS, Flores Z, Jan A, Scher C, Sherbini O, Behrens EM, Goldbach-Mansky R, Olson TS, Lambert MP, Sullivan KE, Teachey DT, Witmer C, Vanderver A, Shults J. Mol Genet Metab. 2022 Jun 16:S1096-7192(22)00339-0. doi: 10.1016/j.ymgme.2022.06.003. Epub ahead of print. PMID: 35786528.

Aicardi Goutières syndrome (AGS) is an inherited disease that is associated with early onset neurologic disability and systemic inflammation. Cytopenias—conditions in which there are lower-than-normal numbers of blood cells—are a potentially serious, but poorly understood, complication of AGS. As new treatment options are developed, it is important to understand the roles of the disease versus the treatment in hematologic abnormalities, allowing for better management of cytopenia. In this study, researchers identified novel patterns of hematologic abnormalities in AGS. The team collected laboratory data throughout the lifespan from 142 individuals with AGS. Results showed that AGS results in multilineage cytopenias not limited to the neonatal period. Neutropenia, anemia, and thrombocytopenia were common. For patients on the treatment baricitinib, moderate to severe graded events of neutropenia, anemia, and leukopenia were more common, but rarely of clinical consequence. Based on these results, authors recommend careful monitoring of hematologic parameters in children with AGS throughout the lifespan, especially while on therapy. Authors also note that AGS should be considered in children with neurologic impairment of unclear cause and hematologic abnormalities.

Hospitalization Burden and Incidence of Krabbe Disease. Ghabash G, Wilkes J, Barney BJ, Bonkowsky JL. J Child Neurol. 2022 Jan;37(1):12-19. doi: 10.1177/08830738211027717. Epub 2021 Oct 20.

Novel biallelic variants in NRROS associated with a lethal microgliopathy, brain calcifications, and neurodegeneration. Macintosh J, Derksen A, Poulin C, Braverman N, Vanderver A, Thiffault I, Albrecht S, Bernard G. Neurogenetics. 2022 Apr;23(2):151-156. doi: 10.1007/s10048-022-00683-8. Epub 2022 Jan 31. PMID: 35099671.

The protein NRROS (negative regulator of reactive oxygen species) is expressed by microglia (immune cells of the central nervous system) and perivascular macrophages (brain macrophages, or immune cells, characterized by a close association with the cerebral vasculature). To date, 9 individuals have been reported with biallelic (affecting both alleles of a gene) NRROS variants. In this study, researchers used exome sequencing to identify 2 novel NRROS variants—a missense variant and a premature stop codon—in an individual with a severe neurodegenerative phenotype. Through pathological examination, they found both extensive grey and white matter involvement, dystrophic calcifications, and infiltration of foamy macrophages. Authors state that this is the first reported case of NRROS variants with a mitochondrial ultrastructure abnormality noted on electron microscopy analysis of post-mortem tissue.

Presymptomatic Lesion in Childhood Cerebral Adrenoleukodystrophy: Timing and Treatment. Mallack EJ, Van Haren KP, Torrey A, van de Stadt S, Engelen M, Raymond GV, Fatemi A, Eichler FS. Neurology. 2022 May 24:10.1212/WNL.0000000000200571. doi: 10.1212/WNL.0000000000200571. Online ahead of print.

Restless Legs Syndrome in X-linked adrenoleukodystrophy. Winkelman JW, Grant NR, Molay F, Stephen CD, Sadjadi R, Eichler FS. Sleep Med. 2022 Mar;91:31-34. doi: 10.1016/j.sleep.2022.02.008. Epub 2022 Feb 16. PMID: 35245789; PMCID: PMC9035065.

X-linked adrenoleukodystrophy (ALD) is a neurodegenerative disease that causes progressive gait and balance problems. Leg discomfort, sleep disturbances, and pain contribute to daily disability. In this study, researchers investigated the prevalence and severity of restless legs syndrome (RLS) in 32 adults with ALD. The team gathered data from questionnaires, telephone interviews, neurological examinations, functional gait measures, and laboratory assessments. Results suggest a high prevalence of RLS in adults with ALD. Researchers also found that ALD patients with RLS have more neurological signs and symptoms, and RLS is more common in females with ALD than in males. Authors note that increased awareness of RLS in patients with ALD would allow for more effective treatment.

Sensorimotor outcomes in adrenomyeloneuropathy show significant disease progression. Keller JL, Eloyan A, Raymond GV, Fatemi A, Zackowski KM. J Inherit Metab Dis. 2022 Mar;45(2):308-317. doi: 10.1002/jimd.12457. Epub 2021 Dec 9. PMID: 34796974; PMCID: PMC8987487.

Adrenomyeloneuropathy is an X-linked disorder (on the X chromosome) characterized by the disruption in fat metabolism (break down) which leads to the accumulation of very long-chain fatty acids throughout the nervous system, adrenal glands, and testes. As current outcomes used to evaluate the disorder are limited, quantitative outcomes are needed. In this prospective study, researchers aimed to track sensorimotor outcomes in adults with adrenomyeloneuropathy and evaluate differences in progression between men and women. The team analyzed data to detect changes in outcomes over 2 years. Outcomes included postural sway in four static standing conditions, great-toe vibration, hip strength, walking velocity, timed up-and-go, and 6-minute walk distance. They found that participants showed significant worsening in all standing conditions, sensation, and strength. However, they showed more stability in walking, with only velocity significantly declining. For each sex, postural sway declined significantly in all conditions except for eyes closed feet together for women. Strength declined significantly by sex for hip flexion. Sex-specific significant decline was seen in walking for men only. Authors note that quantitative measures of postural sway, sensation strength, and walking are effective measures of adrenomyeloneuropathy progression in 2 years.

The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology points to consider for diagnosis and management of autoinflammatory type I interferonopathies: CANDLE/PRAAS, SAVI and AGS. Cetin Gedik K, Lamot L, Romano M, Demirkaya E, Piskin D, Torreggiani S, Adang LA, Armangue T, Barchus K, Cordova DR, Crow YJ, Dale RC, Durrant KL, Eleftheriou D, Fazzi EM, Gattorno M, Gavazzi F, Hanson EP, Lee-Kirsch MA, Montealegre Sanchez GA, Neven B, Orcesi S, Ozen S, Poli MC, Schumacher E, Tonduti D, Uss K, Aletaha D, Feldman BM, Vanderver A, Brogan PA, Goldbach-Mansky R. Ann Rheum Dis. 2022 May;81(5):601-613. doi: 10.1136/annrheumdis-2021-221814. Epub 2022 Jan 27.

Time to Transplant in X-Linked Adrenoleukodystrophy. Bonkowsky JL, Wilkes J. J Child Neurol. 2022 Apr;37(5):397-400. doi: 10.1177/08830738221081141. Epub 2022 Mar 3.

Cerebral X-linked adrenoleukodystrophy (cALD) is a disorder characterized by the destruction of myelin (the insulation surrounding nerve fibers) in the brain. Survival and improved outcomes for cALD are associated with hematopoietic stem cell transplantation (HSCT) at earliest evidence of disease on magnetic resonance imaging (MRI). In this study, researchers aimed to determine average duration between diagnosis of cALD and HSCT. Among 27 patients with cALD in the hospitals they evaluated, the team found that time to HSCT was greater than 3 months. They also noted differences in average time by race/ethnicity and by hospital. Authors state that these findings suggest an opportunity to reduce time to transplant in cALD.

Wearable sensors detect impaired gait and coordination in LBSL during remote assessments. Smith Fine A, Kaufman M, Goodman J, Turk B, Bastian A, Lin D, Fatemi A, Keller J. Ann Clin Transl Neurol. 2022 Apr;9(4):468-477. doi: 10.1002/acn3.51509. Epub 2022 Mar 8.

Acquisition of Developmental Milestones in Hypomyelination With Atrophy of the Basal Ganglia and Cerebellum and Other TUBB4A-Related Leukoencephalopathy. Gavazzi F, Charsar BA, Williams C, Shults J, Alves CA, Adang L, Vanderver A. J Child Neurol. 2021 Apr 12:883073821000977. doi: 10.1177/0883073821000977. Online ahead of print.

Adrenal insufficiency updates in children. Ramirez Alcantara J, Halper A. Curr Opin Endocrinol Diabetes Obes. 2021 Feb 1;28(1):75-81. doi: 10.1097/MED.0000000000000591.

Hepatic Involvement in Aicardi-Goutières Syndrome. Gavazzi F, Cross ZM, Woidill S, McMann JM, Rand EB, Takanohashi A, Ulrick N, Shults J, Vanderver AL, Adang L. Neuropediatrics. 2021 Dec;52(6):441-447. doi: 10.1055/s-0040-1722673. Epub 2021 Jan 14.

Interocular Difference in Retinal Nerve Fiber Layer Thickness Predicts Optic Neuritis in Pediatric-Onset Multiple Sclerosis. Waldman AT, Benson L, Sollee JR, Lavery AM, Liu GW, Green AJ, Waubant E, Heidary G, Conger D, Graves J, Greenberg B. J Neuroophthalmol. 2021 Dec 1;41(4):469-475. doi: 10.1097/WNO.0000000000001070.

Late-Onset Aicardi-Goutières Syndrome: A Characterization of Presenting Clinical Features. Piccoli C, Bronner N, Gavazzi F, Dubbs H, De Simone M, De Giorgis V, Orcesi S, Fazzi E, Galli J, Masnada S, Tonduti D, Varesio C, Vanderver A, Vossough A, Adang L. Pediatr Neurol. 2021 Feb;115:1-6. doi: 10.1016/j.pediatrneurol.2020.10.012. Epub 2020 Nov 2.

MRI surveillance of boys with X-linked adrenoleukodystrophy identified by newborn screening: Meta-analysis and consensus guidelines. Mallack EJ, Turk BR, Yan H, Price C, Demetres M, Moser AB, Becker C, Hollandsworth K, Adang L, Vanderver A, Van Haren K, Ruzhnikov M, Kurtzberg J, Maegawa G, Orchard PJ, Lund TC, Raymond GV, Regelmann M, Orsini JJ, Seeger E, Kemp S, Eichler F, Fatemi A. J Inherit Metab Dis. 2021 May;44(3):728-739. doi: 10.1002/jimd.12356. Epub 2021 Jan 9.

Reliability of the Telemedicine Application of the Gross Motor Function Measure-88 in Patients With Leukodystrophy. Gavazzi F, Adang L, Waldman A, Jan AK, Liu G, Lorch SA, DeMauro SB, Shults J, Pierce SR, Ballance E, Kornafel T, Harrington A, Glanzman AM, Vanderver A. Pediatr Neurol. 2021 Dec;125:34-39. doi: 10.1016/j.pediatrneurol.2021.09.012. Epub 2021 Sep 24. PMID: 34624609; PMCID: PMC8629609.

Leukodystrophies are a group of rare neurological disorders affecting the white matter of the brain that are characterized by severe neuromotor disability. Research on the functional status of people with leukodystrophy is limited by the need for in-person mobility assessments. The Gross Motor Function Measure-88 (GMFM-88) is an assessment tool used to measure change in gross motor function over time. In this study, researchers assessed the reliability of the GMFM-88 using telemedicine compared with standard in-person assessments in patients with leukodystrophy. They found that remote application of the GMFM-88 is a feasible and reliable approach. The authors note that this approach may be of particular value in rare diseases and those with severe neurologic disability that impacts travel ability.

Development of a neurologic severity scale for Aicardi Goutières Syndrome. Adang LA, Gavazzi F, Jawad AF, Cusack SV, Kopin K, Peer K, Besnier C, De Simone M, De Giorgis V, Orcesi S, Fazzi E, Galli J, Shults J, Vanderver A. Mol Genet Metab. 2020 Jun;130(2):153-160. doi: 10.1016/j.ymgme.2020.03.008. Epub 2020 Apr 2.

Janus Kinase Inhibition in the Aicardi-Goutières Syndrome. Vanderver A, Adang L, Gavazzi F, McDonald K, Helman G, Frank DB, Jaffe N, Yum SW, Collins A, Keller SR, Lebon P, Meritet JF, Rhee J, Takanohashi A, Armangue T, Ulrick N, Sherbini O, Koh J, Peer K, Besnier C, Scher C, Boyle K, Dubbs H, Kramer-Golinkoff J, Pizzino A, Woidill S, Shults J. N Engl J Med. 2020 Sep 3;383(10):986-989. doi: 10.1056/NEJMc2001362.

Racial/Ethnic and Insurance Status Disparities in Distance Traveled to Access Children's Hospital Care for Severe Illness: the Case of Children with Leukodystrophies. Grineski SE, Morales DX, Collins T, Wilkes J, Bonkowsky JL. J Racial Ethn Health Disparities. 2020 Oct;7(5):975-986. doi: 10.1007/s40615-020-00722-w. Epub 2020 Feb 24.

Randomized Clinical Trial of First-Line Genome Sequencing in Pediatric White Matter Disorders. Vanderver A, Bernard G, Helman G, Sherbini O, Boeck R, Cohn J, Collins A, Demarest S, Dobbins K, Emrick L, Fraser JL, Masser-Frye D, Hayward J, Karmarkar S, Keller S, Mirrop S, Mitchell W, Pathak S, Sherr E, van Haren K, Waters E, Wilson JL, Zhorne L, Schiffmann R, van der Knaap MS, Pizzino A, Dubbs H, Shults J, Simons C, Taft RJ; LeukoSEQ Workgroup. Ann Neurol. 2020 Aug;88(2):264-273. doi: 10.1002/ana.25757. Epub 2020 Jun 9.

Type II Alexander disease caused by splicing errors and aberrant overexpression of an uncharacterized GFAP isoform. Helman G, Takanohashi A, Hagemann TL, Perng MD, Walkiewicz M, Woidill S, Sase S, Cross Z, Du Y, Zhao L, Waldman A, Haake BC, Fatemi A, Brenner M, Sherbini O, Messing A, Vanderver A, Simons C. Hum Mutat. 2020 Jun;41(6):1131-1137. doi: 10.1002/humu.24008. Epub 2020 Mar 11.