Clinical characteristics.

ATN1-related neurodevelopmental disorder (ATN1-NDD) is characterized by developmental delay / intellectual disability. Other neurologic findings can include infantile hypotonia, brain malformations, epilepsy, cortical visual impairment, and hearing loss. Feeding difficulties, present in some individuals, may require gastrostomy support when severe; similarly, respiratory issues, present in some, may require respiratory support after the neonatal period. Distinctive facial features and hand and foot differences are common. Other variable findings can include cardiac malformations and congenital anomalies of the kidney and urinary tract (CAKUT). To date, 18 individuals with ATN1-NDD have been identified.

Diagnosis/testing.

The diagnosis of ATN1-NDD is established in a proband with suggestive clinical findings and a heterozygous pathogenic (or likely pathogenic) variant in a 16-amino-acid sequence of exon 7 in ATN1 in which histidine is in every other position (His-X; HX motif), identified by molecular genetic testing.

Management.

Treatment of manifestations: There is no cure for ATN1-NDD. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in clinical genetics, neurology, ophthalmology, gastroenterology, cardiology, and general pediatrics.

Surveillance: Regular clinic visits are recommended due to the complexity of the medical and developmental issues. The frequency of visits should be decided on a person-by-person basis, but may need to be greater (e.g., every 3-6 months) in the first two years of life, then stretching to visits every six months to one year when the child is stable.

Agents/circumstances to avoid: In individuals with MRI-confirmed stenosis of the craniocervical junction, caution is required when manipulating the head and neck for airway management.

Genetic counseling.

ATN1-NDD is an autosomal dominant condition typically caused by a de novo pathogenic variant. Risk to future pregnancies is presumed to be low as the proband most likely has a de novo ATN1 pathogenic variant. There is, however, a recurrence risk (~1%) to sibs based on the theoretic possibility of parental germline mosaicism. Given this risk, prenatal and preimplantation genetic testing may be considered.

Suggestive Findings

ATN1-related neurodevelopmental disorder (ATN1-NDD) should be considered in individuals with the following clinical and brain MRI findings.

Establishing the Diagnosis

The diagnosis of ATN1-NDD is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in a 16-amino-acid sequence of exon 7 in ATN1 in which histidine is in every other position (His-X; HX motif), identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous ATN1 variant of uncertain significance does not establish or rule out the diagnosis of this condition.

Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability may begin with chromosomal microarray analysis (CMA). Other options include use of a multigene panel or comprehensive genomic testing.

Note: Single-gene testing (sequence analysis of ATN1, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• An intellectual disability (ID) multigene panel that includes ATN1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition in a person with a nondiagnostic CMA while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of ATN1-NDD, some panels for intellectual disability may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used and yields results similar to an ID multigene panel with the additional advantage that exome sequencing includes genes recently identified as causing ID, whereas some multigene panels may not.
  Genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

ATN1-related neurodevelopmental disorder (ATN1-NDD) is characterized by developmental delay / intellectual disability. Other neurologic findings can include brain malformations, epilepsy, cortical visual impairment, infantile hypotonia, and hearing loss. Feeding difficulties, present in some individuals, may require gastrostomy support when severe; similarly, respiratory issues, present in some, may require respiratory support after the neonatal period. Distinctive facial and limb features are commonly reported. Other variable findings can include cardiac malformations and congenital anomalies of the kidney and urinary tract (CAKUT).

To date, 18 individuals have been identified with ATN1-NDD [Palmer et al 2019, Palmer et al 2021, Shiyue et al 2022]. The following description of the phenotypic features associated with this condition is based on these reports.

Developmental delay (DD) and intellectual disability (ID). Most individuals with ATN1-NDD have profound developmental delay. Most individuals have significant gross motor delay, ranging from lack of head control to the ability to walk a few steps unaided. The exception is one girl (age 26 months) with mild developmental delay [Palmer et al 2021].

Fine motor skills range from inability to grasp toys / small objects or bring hands to the midline to the ability to finger feed. In contrast, the girl with milder features has fine motor skills that are just below average.

While some affected individuals can speak one or two words and communicate in gestures, most are nonverbal with no clear words. To date communication devices have not been reported to be particularly helpful, consistent with a profound developmental delay; however, caregivers thought that two individuals had more advanced receptive skills, and the girl with milder developmental delay was able to talk in short sentences at the age of 26 months.

Hypotonia. The majority (11/18) had persistent global hypotonia. Over time, six developed appendicular hypertonia/spasticity in the presence of central hypotonia. Only one child, the girl with mild developmental delay, has continued to have normal tone over time.

Feeding difficulties appear to be secondary to a combination of gastroesophageal reflux disease, low tone, and dysphagia. Eight individuals required gastrostomy feeds as a result of both poor feeding and increased risk of aspiration. Two of the eight were able to start oral feeding, and one other was preparing to try oral feeding. One individual relied on total parenteral nutrition at age one year because of severe gut motility issues.

Cortical visual impairment was present in eight individuals.

Sensorineural hearing loss was present in four of the 16 of individuals evaluated for this finding.

Epilepsy. In its most severe form, ATN1-NDD can be described as a neonatal- or infantile-onset developmental and epileptic encephalopathy characterized by seizures resistant to multiple anti-seizure medications (ASMs) associated with developmental delay and intellectual disability.

One individual had Lennox-Gastaut syndrome.

While seizures were controlled in many individuals with a single ASM, others required two or more ASMs to achieve seizure control.

Respiratory/sleep difficulties can require respiratory support after the neonatal period. Of the 18 individuals who experienced respiratory difficulties, nine had obstructive sleep apnea; of these, three also had central sleep apnea. Three individuals with obstructive sleep apnea required tracheostomy.

Other findings contributing to respiratory difficulty in some individuals included Pierre Robin sequence, micrognathia, laryngomalacia, and asthma.

Neuroimaging. While some individuals have a normal brain MRI, major structural brain abnormalities are common (see Table 3).

Normal brain imaging findings appear to correlate with better neurodevelopmental outcome. In the five individuals with no major structural abnormalities, motor skills in four ranged from crawling, pulling to stand, taking a few steps, or, in one instance, walking unassisted, and at least four were able to grasp objects. Three individuals had no clear words, one had single words, and one speaks in short sentences.

By contrast, of the 13 individuals with major structural abnormalities, two could stand with support, whereas the others had minimal motor skills (range: lack of head control to inability to roll to sitting with support); 12 individuals were nonverbal and one had a few single words.

Other associated features

• Behavioral problems. Sleep disturbances, which likely are multifactorial, are the only behavioral issues reported.
• Growth. While weight gain is suboptimal secondary to feeding issues in some individuals, growth parameters are usually within the normal range.
• Ophthalmologic involvement includes strabismus, hypermetropia, microphthalmia, corneal leukoma, and optic nerve hypoplasia.
• Hearing impairment includes both sensorineural hearing loss and conductive hearing loss. Recurrent otitis media with effusions commonly requires tympanostomy tubes. Hearing impairment ranges from mild/moderate to profound.
• Constipation, a significant issue in six of 18 individuals, has required medical management (see Table 5).
• Musculoskeletal
  • Scoliosis was reported in six of 18 individuals attributed to neuromuscular involvement rather than vertebral anomalies; however, no information is available on need for specific intervention.
  • Hip dysplasia was reported in five of 18 individuals; no information is available on the need for specific intervention.
  • Cervical stenosis was reported in two of six individuals on cervical spine MRI; no information is available on the need for specific intervention other than caution when manipulating the head and neck for airway management (see Agents/Circumstances to Avoid).
  • Orofacial clefting: cleft palate (2 individuals); Pierre Robin sequence (1 individual), micrognathia (1 individual)
  • Arthrogryposis (1 individual)
• Other congenital anomalies
  • Cardiac anomalies, including atrial and ventricular septal defects, anomalous drainage of the great veins, coarctation of the aorta, patent ductus arteriosus and foramen ovale
  • Urogenital anomalies, including unilateral renal hypoplasia or agenesis, vesicoureteric reflux, and cryptorchidism
  • Anorectal anomalies, including anteriorly placed anus

Prognosis. It is unknown whether life span in ATN1-NDD is abnormal. One individual is alive at age 18 years, demonstrating that survival into adulthood is possible [Palmer et al 2021]. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Genotype-Phenotype Correlations

No consistent genotype-phenotype correlations have been identified.

Although more data are required, it is notable that the unique ATN1 variant observed in one individual with a milder phenotype (see Clinical Description) caused a duplication of the amino acids histidine and leucine within the HX repeat motif rather than the typically observed indel or single-nucleotide variant [Palmer et al 2021].

Nomenclature

ATN1-NDD is also referred to as ATN1-related neurodevelopmental condition [Author, personal communication].

Prevalence

To date 18 individuals have been reported with ATN1-NDD. The actual prevalence is unknown. While it is thought to be rare, it is probably underrecognized and underreported, as it has only recently been described and the clinical findings are nonspecific.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ATN1-NDD, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

There is no cure for ATN1-NDD.

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in clinical genetics, neurology, ophthalmology, gastroenterology, cardiology, and general pediatrics (see Table 5).

Surveillance

Regular clinic visits are recommended because of the complexity of the medical and developmental issues associated with ATN1-NDD. The frequency of visits should be decided on a person-by-person basis, but may need to be greater (e.g., every 3-6 months) in the first two years of life, then stretching to visits every six months to one year when the child is stable.

Agents/Circumstances to Avoid

In individuals with MRI-confirmed stenosis of the craniocervical junction, caution is required when manipulating the head and neck for airway management.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this condition.

Mode of Inheritance

ATN1-related neurodevelopmental disorder (ATN1-NDD) is an autosomal dominant condition typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• All probands reported to date with ATN1-NDD whose parents have undergone molecular genetic testing have the condition as a result of a de novo ATN1 pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is known to have the ATN1 pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%.
• If the ATN1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].

Offspring of a proband

• To date, individuals with ATN1-NDD are not known to have had children; however, many are not yet of reproductive age.
• Each child of an individual with ATN1-NDD would have a 50% chance of inheriting the ATN1 pathogenic variant.

Other family members. Given that all probands with ATN1-NDD reported to date have the condition as a result of a de novo ATN1 pathogenic variant, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Risk to future pregnancies is presumed to be low as the proband most likely has a de novo ATN1 pathogenic variant. There is, however, a recurrence risk (~1%) to sibs based on the theoretic possibility of parental germline mosaicism [Rahbari et al 2016]. Given this risk, prenatal and preimplantation genetic testing may be considered.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

ATN1 encodes the protein atrophin-1 (ATN1), a member of a class of evolutionarily conserved transcriptional corepressors involved in nuclear signaling [Palmer et al 2019]. ATN1-related neurodevelopmental disorder (ATN1-NDD) is caused by heterozygous ATN1 pathogenic variants in an evolutionarily conserved region of exon 7 that codes for a histidine-rich amino acid motif of eight HX repeats (in which H represents histidine and X represents any other amino acid). This motif is thought to have specific zinc-binding properties that are disrupted by ATN1 pathogenic variants that affect the spacing of these repeats.

Although the role of ATN1 is incompletely understood, it appears to be a key nuclear transcriptional regulator involved in organ development in which the HX repeat motif plays a critical role [Palmer et al 2019].

Mechanism of disease causation. It is unlikely that ATN1 pathogenic variants cause simple haploinsufficiency of ATN1 given that the databases gnomAD and BRAVO (which exclude individuals with severe childhood-onset conditions) have reports of healthy individuals with heterozygous stop-gain, frameshift, and canonic splice ATN1 variants. Given that the pathogenic variants causing ATN1-NDD cluster in the 16-amino-acid His-X repeat in exon 7, it is likely that disruption of this motif affects critical functioning of the protein.

ATN1-specific laboratory technical considerations. To date, pathogenic variants causing ATN1-NDD have only been reported to affect the 16-amino-acid repeat in exon 7 (His-X).

Author Notes

Dr Elizabeth Palmer (elizabeth.palmer@unsw.edu.au) and Professor Fowzan Alkuraya (falkuraya@kfshrc.edu.sa) are actively involved in clinical research regarding individuals with ATN1-NDD. They would be happy to communicate with persons who have any questions regarding diagnosis of ATN1-NDD or other considerations.

Contact Dr Elizabeth Palmer and Professor Fowzan Alkuraya to inquire about review of ATN1 variants of uncertain significance in patients who do not have the typical features of DRPLA.

Dr Elizabeth Palmer and Professor Alkuraya are also interested in hearing from clinicians treating families affected by CHEDDA (congenital hypotonia, epilepsy, developmental delay, digit abnormalities) in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this condition.

Acknowledgments

We would like to thank the patients, families, and clinicians who have participated in our previous publications delineating this condition.

Revision History

• 25 August 2022 (bp) Review posted live
• 26 May 2022 (ep) Original submission

Literature Cited

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