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Last updated:
6/6/2023
Years published: 2023
NORD gratefully acknowledges Meena Balasubramanian, MBBS, DCH, FRCPCH, MD, Sheffield Children’s NHS Foundation Trust, University of Sheffield, Sheffield, UK, for the preparation of this report.
HNRNPU-related disorder is a rare neurodevelopmental disorder (RNDD) characterized by seizures, early onset epilepsy, low muscle tone (hypotonia), autistic features and intellectual disability. This condition is caused by changes (variants or mutations) in the HNRNPU gene.
HNRNPU-related disorder is characterized by global developmental delay and intellectual disability, typically in the range of moderate to severe, with speech and language delay and/or absent speech. Affected individuals may also display autistic features. There may be feeding difficulties during the neonatal period as well as neonatal hypotonia which will likely remain lifelong. Abnormal physical features have been described but they are non-specific. Affected individuals are likely to experience seizures which are usually tonic-clonic or absence seizures and may be refractory to treatment. Patients are likely to have abnormalities on a brain MRI. Heart abnormalities are less common but may also be present.
Global Developmental Delay 100%
Abnormal Facial Features 97%
Seizures 95%
Intellectual Disability 84%
Hypotonia 79%
Neonatal Feeding Difficulties 57%
Vision Impairment 36%
Autistic Traits 33%
Rapid Breathing and Apnea Rare
Developmental delay and intellectual disability
All patients described in the literature, with sufficient clinical information to ascertain the level of delay in various developmental areas, had developmental delay and intellectual disability. Developmental delay and intellectual disability ranged from mild to very severe. Most individuals also have a speech and language delay.
Autism spectrum disorder (ASD) and other behavioral concerns
An autism diagnosis or autistic behaviours were described in 33% of individuals in the literature. Autistic traits included obsessions, inflexibility and incapacity for change, stereotypies such as hand-flapping and rocking and difficulties with sensory processing. Other behavioral difficulties described included self-stimulatory behaviors and aggression towards caregivers, emotional dysregulation with outbursts of laughter, screaming, aggression or teeth grinding (bruxism).
Seizures
Seizures or epilepsy have been described in 95% of individuals and remains a hallmark of HNRNPU-related disorder. A variety of seizure types have been reported in the literature, including generalized (tonic-clonic and absence) and focal and complex focal seizures. Affected individuals are likely to experience seizures that start before 24 months of age and the most common type of seizures are tonic-clonic or absence. Seizures may be refractory to treatment but evidence in the literature suggests that most seizures associated with HNRNPU-related disorder respond to standard antiepileptic medications including sodium valproate and levetiracetam.
Feeding issues
Feeding difficulties were described in 57% of individuals in the literature. Some children had difficulty gaining weight (failure-to-thrive) in infancy. Feeding difficulties included poor neonatal suck or latch, vomiting, gastroesophageal reflux, food refusal behaviors and requirement for assistance-feeding. Some babies required naso-gastric tube insertion. Feeding difficulties in infancy have been reported to improve with time.
Hypotonia
Generalized muscle weakness (hypotonia) is seen in 79% of individuals reported with HNRNPU-related disorder with nearly half presenting with neonatal hypotonia. This often improves with age.
Facial & other features
Non-specific abnormal facial features have been described in most affected children (97%). There are no specific or defining facial features, but typical features included palpebral fissure abnormalities, thin upper vermillion, frontal bossing, curved fifth finger and long columella. Some patients also had bunions and webbing of the second and third fingers.
Sleep disturbance
Sleep disturbance is a common finding. This included reports of obstructive sleep apnea, poor sleep and easy waking. Other findings have included breath holding episodes and irregular breathing patterns, particularly at night, that coincide with sleep disturbances.
Structural brain abnormalities
Structural brain abnormalities have been described, but MRI brain imaging has not been done routinely unless there is a clinical indication. This may mean an underreporting of structural brain abnormalities in the literature. There were 62 individuals reported in the literature who had brain MRI imaging and 38 (61%) had abnormalities noted. The most common abnormality was large ventricles (ventriculomegaly) followed by thinning of the corpus callosum.
Growth
Proportionate short stature has been observed in about 50% of individuals for whom data has been reported but further studies are required to determine the cause of this. One individual had an abnormally small head (microcephaly).
Heart
Common heart abnormalities include atrial septal defect, ventricular septal defect, patent ductus arteriosus, and in a small number of patients, tricuspid atresia, tetralogy of Fallot, aortic dilatation and transposition of the great arteries.
Eyes
About 30% of affected individuals have crossed eyes (strabismus). Far-sightedness (hypermetropia) has been described in at least two individuals.
HNRNPU-related disorder is caused by pathogenic or likely pathogenic variants in the HNRNPU gene. The majority of variants are new mutations that result in a shortened protein product that does not function properly. Familial cases are increasingly being reported with more easy access to genomic testing.
HNRNPU-related disorder follows an autosomal dominant pattern of inheritance. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
HNRNPU-related disorder has been described all over the world and is not population specific.
HNRNPU-related disorder may be suspected based on the signs and symptoms associated with the disorder. The diagnosis is confirmed with genomic testing that shows a pathogenic variant in the HNRNPU gene.
Multidisciplinary care is recommended and includes management of multiple subspecialty appointments, equipment, medications and supplies. Ongoing assessment for palliative care involvement and/or home nursing is needed.
Developmental delay and intellectual disability should be managed by a developmental pediatrician. Speech and language delay should be managed by appropriate healthcare professionals.
Epilepsy should be treated with antiepileptic drugs (AEDs) by an experienced neurologist. Many different AEDs may be effective; no one AED has been demonstrated effective specifically for this disorder.
Poor weight gain and failure to thrive may require feeding therapy and gastrostomy tube placement for persistent feeding issues.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Taylor J, Spiller M, Ranguin K, et al. Expanding the phenotype of HNRNPU-related neurodevelopmental disorder with emphasis on seizure phenotype and review of literature. Am J Med Genet A. 2022;188(5):1497-1514. doi:10.1002/ajmg.a.62677
Durkin A, Albaba S, Fry AE, et al. Clinical findings of 21 previously unreported probands with HNRNPU-related syndrome and comprehensive literature review. Am J Med Genet A. 2020;182(7):1637-1654. doi:10.1002/ajmg.a.61599
Havrilla JM, Pedersen BS, Layer RM, Quinlan AR. A map of constrained coding regions in the human genome. Nat Genet. 2019;51(1):88-95. doi:10.1038/s41588-018-0294-6
Abou Tayoun AN, Pesaran T, DiStefano MT, et al. Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion.
Hum Mutat. 2018;39(11):1517-1524. doi:10.1002/humu.23626
Bramswig NC, Lüdecke HJ, Hamdan FF, et al. Heterozygous HNRNPU variants cause early onset epilepsy and severe intellectual disability. Hum Genet. 2017;136(7):821-834. doi:10.1007/s00439-017-1795-6
Depienne C, Nava C, Keren B, et al. Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU. Hum Genet. 2017;136(4):463-479. doi:10.1007/s00439-017-1772-0
Leduc MS, Chao HT, Qu C, et al. Clinical and molecular characterization of de novo loss of function variants in HNRNPU. Am J Med Genet A. 2017;173(10):2680-2689. doi:10.1002/ajmg.a.38388
Nozawa RS, Boteva L, Soares DC, et al. SAF-A Regulates Interphase Chromosome Structure through Oligomerization with Chromatin-Associated RNAs. Cell. 2017;169(7):1214-1227.e18. doi:10.1016/j.cell.2017.05.029
Yates TM, Vasudevan PC, Chandler KE, et al. De novo mutations in HNRNPU result in a neurodevelopmental syndrome. Am J Med Genet A. 2017;173(11):3003-3012. doi:10.1002/ajmg.a.38492
Bi HS, Yang XY, Yuan JH, et al. H19 inhibits RNA polymerase II-mediated transcription by disrupting the hnRNP U-actin complex. Biochim Biophys Acta. 2013;1830(10):4899-4906. doi:10.1016/j.bbagen.2013.06.026
Need AC, Shashi V, Hitomi Y, et al. Clinical application of exome sequencing in undiagnosed genetic conditions. J Med Genet. 2012;49(6):353-361. doi:10.1136/jmedgenet-2012-100819
Thierry G, Bénéteau C, Pichon O, et al. Molecular characterization of 1q44 microdeletion in 11 patients reveals three candidate genes for intellectual disability and seizures. Am J Med Genet A. 2012;158A(7):1633-1640. doi:10.1002/ajmg.a.35423
Caliebe A, Kroes HY, van der Smagt JJ, et al. Four patients with speech delay, seizures and variable corpus callosum thickness sharing a 0.440 Mb deletion in region 1q44 containing the HNRPU gene. Eur J Med Genet. 2010;53(4):179-185. doi:10.1016/j.ejmg.2010.04.001
Hasegawa Y, Brockdorff N, Kawano S, Tsutui K, Tsutui K, Nakagawa S. The matrix protein hnRNP U is required for chromosomal localization of Xist RNA. Dev Cell. 2010;19(3):469-476. doi:10.1016/j.devcel.2010.08.006
INTERNET
Balasubramanian M. HNRNPU-Related Neurodevelopmental Disorder. 2022 Mar 10. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK578573/ Accessed June 1, 2023.
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