Clinical characteristics.

KPTN-related disorder is characterized by mild-to-profound intellectual disability, global developmental delay, neurobehavioral/psychiatric manifestations (anxiety, stereotypies, hyperactivity, repetitive speech, and impaired social communication), hypotonia, postnatal and progressive macrocephaly, and seizures. Generalized megalencephaly is often present on brain imaging. Some individuals have recurrent infections, conductive hearing impairment, strabismus, nystagmus, ketotic hypoglycemia, thyroid dysfunction, and/or mild skeletal manifestations.

Diagnosis/testing.

The diagnosis of KPTN-related disorder is established in a proband with suggestive findings and biallelic pathogenic variants in KPTN identified by molecular genetic testing.

Management.

Treatment of manifestations: Developmental and educational support; standard management for behavioral and psychiatric manifestations; standard treatment with anti-seizure medications by an experienced neurologist; pressure-equalizing tubes and/or tonsillectomy and/or adenoidectomy as needed for recurrent upper respiratory tract infections; standard treatment for ophthalmologic involvement; standard treatment for endocrine manifestations; treatment of skeletal manifestations per orthopedist; social work support and care coordination as needed.

Surveillance: At each visit (at least annually), assess developmental progress, educational needs, mobility and self-help skills, head circumference, seizures, balance problems, oral apraxia, frequency and type of infections, musculoskeletal manifestations, and family needs; annual behavioral assessment; annual audiology evaluation; annual assessment for strabismus and vision deficits; assess for hypoglycemia in neonates and then at each visit or with intercurrent illness; educate parents and caregivers on symptoms of hypoglycemia; annual assessment of thyroid function.

Genetic counseling.

KPTN-related disorder is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a KPTN pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the KPTN pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

KPTN-related disorder should be considered in probands with the following clinical, laboratory, neuroimaging, and family history findings.

Clinical findings

• Mild-to-profound intellectual disability
• Developmental delay
• Postnatal and progressive macrocephaly (onset usually within the first year of life)
• Neurobehavioral/psychiatric manifestations associated with autism spectrum disorder (anxiety, stereotypies, hyperactivity, repetitive speech, impaired social communication)
• Neonatal/childhood hypotonia
• Seizures (generalized tonic-clonic, absence, focal, tonic seizures)
• Recurrent infections (lower respiratory tract infections, otitis media)
• Characteristic facial features in some individuals (frontal bossing, short downslanted palpebral fissures, hypertelorism, depressed nasal bridge, broad nasal tip, tall, broad chin, thick vermilion of the lower lip; see Figure 1)

Figure 1.

Photographs of individuals with KPTN-related disorder. Characteristic facial features include frontal bossing, downslanted palpebral fissures, hypertelorism, depressed nasal bridge, broad nasal tip, thick vermilion of the lower lip, and tall, broad chin. (more...)

Laboratory findings. Ketotic hypoglycemia, hypo- or hyperthyroidism

Neuroimaging. MRI/CT typically shows generalized megalencephaly.

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of KPTN-related disorder is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in KPTN identified by molecular genetic testing (see Table 1).

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

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Note: Targeted analysis for the KPTN founder variants p.Ser259Ter and p.Met241_Gln246dup can be performed first in individuals of Amish and Mennonite ancestry (see Table 7).

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

Clinical Description

KPTN-related disorder is characterized by mild-to-profound intellectual disability, developmental delay, neurobehavioral/psychiatric manifestations (including anxiety and findings associated with autism spectrum disorder such as stereotypies, hyperactivity, repetitive speech, and impaired social communication), postnatal progressive macrocephaly, and seizures. To date, 54 individuals from 32 families have been identified with biallelic pathogenic variants in KPTN [Baple et al 2014, Pajusalu et al 2015, Lucena et al 2020, Pacio Miguez et al 2020, Thiffault et al 2020, Horn et al 2023, Levitin et al 2023, Liaqat et al 2023]. The following description of the phenotypic features associated with this condition is based on these reports.

Developmental delay is a variable feature. Early motor development is characterized by hypotonia in 55% of affected individuals (21/38), with delayed motor milestones in 60% (30/50). The average age at walking was two years (range: 1-5 years). Language development is highly variable and ranges from normal speech development to nonverbal (8/54 individuals were nonverbal); speech delay is observed in 93% (50/54).

Movement coordination abnormalities include balance problems and oral apraxia, which may lead to infant feeding difficulties.

Intellectual disability (ID) is seen in all affected individuals to date, although severity is highly variable, from mild to profound. Overall severity of ID, as reported by treating clinicians, is as follows: mild ID in approximately 30% (14/47) of affected individuals, moderate ID in 53% (25/47), severe ID in 15% (7/47), and profound ID in 2% (1/47). Generally, the severity of ID is related to the presence and control of seizures. Detailed psychometric tests were carried out in six Amish individuals and identified a moderate level of ID with impairment in all cognitive domains, except relative sparing of narrative memory function [Levitin et al 2023]. Dyslexia and dysgraphia have been reported in affected individuals.

Neurobehavioral/psychiatric manifestations are a common but variable feature. Anxiety was reported in 57% (25/44) of affected individuals, including panic attacks and phobias. Stereotypies were reported in 52% (24/46) of individuals, including hand flapping/clapping/rubbing, picking, head banging, and rocking. Impaired social interactions were reported in 50% (24/48) of individuals, hyperactivity in 31% (14/45), repetitive speech in 28% (11/39), and a single individual had a tic disorder.

Macrocephaly. An occipitofrontal circumference (OFC) more than two standard deviations (SD) above the mean was identified in 49% (23/47) of individuals with KPTN-related disorder, although 96% (45/47) had a larger-than-average OFC. OFC range is between 0.44 SD below the mean and 6.11 SD above the mean. Macrocephaly develops postnatally, within the first year of life. Data on birth OFC was available for 22/54 individuals; of these, only one individual was macrocephalic at birth, and 45% (10/22) had an OFC below average at birth. A single individual had macrocephaly associated with raised intracranial pressure requiring shunt insertion. The proportion of individuals with macrocephaly increases with age: 31% (5/16) between birth and age 6 years, and 53% (9/17) in adulthood. Delayed anterior fontanelle closure has been observed in four individuals. Wide metopic suture was reported in a single individual. Note: A single affected Amish individual was reported to have sagittal craniosynostosis [Baple et al 2014], but it has subsequently been shown that this was caused by a separate unrelated inherited condition in this family.

Epilepsy is reported in 44% (24/54) of individuals with KPTN-related disorder. Age of onset of seizures varies between ages three months and 32 years, with a mean age of seizure onset of 7.4 years. Seizure types include generalized tonic-clonic seizures (100%, 24 individuals), with additional absence (33%, 8 individuals), focal / impaired awareness (29%, 7 individuals), and tonic seizures (1 individual). Development of seizures and seizure frequency appear to increase with age and correlate with severity of ID, with seizures often becoming refractory to multiple anti-seizure medications (ASMs). In four individuals generalized tonic-clonic seizures resolved in childhood or early adulthood, following optimization of ASMs (with ongoing absence seizures in one individual). No ASM has been identified as having greater or specific efficacy for seizure treatment in individuals with KPTN-related disorder. EEG findings in six individuals show similar features of mild generalized slowing indicative of diffuse cerebral dysfunction, with multifocal epileptiform discharges and frequent bifrontal spike and slow wave.

Neuroimaging (MRI/CT) is normal in more than 80% of individuals with KPTN-related disorder, aside from generalized megalencephaly, which was reported in 20/34 individuals with no structural brain abnormalities. Other subtle neuroanatomic changes in 14 individuals included: mild ventriculomegaly (5 individuals) associated with findings of generalized megalencephaly; pineal cyst (3 individuals); cavum of the septum pellucidum (2 individuals, 1 of whom also had a pineal cyst); nonspecific white matter hyperintensities (2 individuals); raised intracranial pressure (1 individual) requiring treatment with a shunt; calvarial thickening (1 individual) likely related to ASMs; optic nerve tortuosity (1 individual); calcified sylvian artery aneurysm (1 individual).

Additional craniofacial features reported in some individuals with KPTN-related disorder are subtle and include frontal bossing (84%, 38/45), scaphocephaly (15%, 6/39), short downslanted palpebral fissures (37%, 15/41), hypertelorism (33%, 14/42), depressed nasal bridge (17%, 8/48), broad nasal tip, thick vermilion of the lower lip, high-arched palate (8%, 4/48), tall, broad chin (40%, 17/43), and mild retrognathia (see Figure 1).

Recurrent infections, reported in 13/49 individuals, have included lower respiratory tract infections and otitis media. One individual was neutropenic, and another had immunoglobulin A deficiency.

Hearing loss. Conductive hearing loss has been reported in several individuals associated with otitis media.

Ophthalmic abnormalities. Strabismus and/or horizontal nystagmus were reported in 6/49 individuals. Esotropia, amblyopia, and severe astigmatism have also been reported.

Endocrine abnormalities. Ketotic hypoglycemia (often with intercurrent illness) was reported in 4/49 individuals. Additional endocrine abnormalities include hypo- or hyperthyroidism and hyperprolactinemia. Precocious puberty has been reported in three individuals (male and female).

Skeletal abnormalities include joint hypermobility, scoliosis, pectus excavatum/carinatum, short metacarpals, and fifth finger clinodactyly.

Other

• Hepatosplenomegaly (2 individuals)
• Hepatomegaly (1 individual)
• Splenomegaly (1 individual)

Prognosis. Based on current data, life span is not limited by this condition, as several adults have been reported; the oldest individual diagnosed with KPTN-related disorder was age 57 years at last assessment. Data on possible progression of behavior abnormalities or neurologic findings are still limited. It is notable that four of the 54 identified individuals are deceased, one at age nine years from status epilepticus and three individuals in their 3rd or 4th decade from accidental causes or infection. 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

Although no specific genotype-phenotype correlations have been conclusively identified, biallelic predicted loss-of-function variants (e.g., frameshift, nonsense) appear to have a greater degree of severity of ID and increased frequency of seizures when compared with biallelic protein-altering variants (e.g., missense, inframe indels).

Prevalence

KPTN-related disorder is rare, and the prevalence is unknown. To date, 54 individuals from 32 families with KPTN-related disorder have been identified [Baple et al 2014, Pajusalu et al 2015, Lucena et al 2020, Pacio Miguez et al 2020, Thiffault et al 2020, Horn et al 2023, Levitin et al 2023, Liaqat et al 2023].

Two founder KPTN variants have been identified in the Ohio Amish community; p.Ser259Ter accounts for 82.1% of pathogenic variants and p.Met241_Gln246dup accounts for 17.9% of pathogenic variants in the Ohio Amish community, based on studies of >10,000 exomes and genomes from North American Amish and Mennonite individuals [Baple et al 2014]. To date, there have been 14 individuals with KPTN-related disorder identified within the Amish community (population size: approximately 340,000).

Pathogenic variant p.Met241_Gln246dup has been identified in several affected individuals from Europe and the United States and likely represents a European founder variant.

Pathogenic variant p.Ser200IlefsTer55 has been identified in affected individuals from Brazil, Spain, France, Germany, Ireland, and the United Kingdom.

Evaluations Following Initial Diagnosis

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

Treatment of Manifestations

There is currently no cure for KPTN-related disorder. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Current studies of the efficacy of mTOR inhibitors are under way in KPTN-related disorder mouse models. 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.

Mode of Inheritance

KPTN-related disorder is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for a KPTN pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a KPTN pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder, although increased head circumference (above the mean for age and sex) is commonly observed.

Sibs of a proband

• If both parents are known to be heterozygous for a KPTN pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder, although increased head circumference (above the mean for age and sex) is commonly observed.

Offspring of a proband. To date, individuals with KPTN-related disorder are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a KPTN pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the KPTN pathogenic variants in the family.

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 young adults who are carriers or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers, particularly if both partners are of the same ancestry. Founder variants have been identified in the Ohio Amish community (see Table 7).

Prenatal Testing and Preimplantation Genetic Testing

Once the KPTN pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

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

KPTN encodes KICSTOR complex protein kaptin (kaptin), a core component of the KICSTOR complex alongside three other proteins, ITFG2 (KICSTOR complex protein ITFG2; also called integrin-alpha FG-GAP repeat-containing protein 2), C12orf66 (KICSTOR subunit 2; also called KICSTOR complex protein C12orf66 or chromosome 12 open reading frame 66), and SZT2 (KICSTOR complex protein SZT2; also called seizure threshold 2 protein homolog) [Wolfson et al 2017]. Kaptin was identified as a key regulator of the mTORC1 (the mechanistic target of rapamycin complex 1) pathway. The KICSTOR complex recruits GATOR1 (GAP activity toward Rags 1) to the lysosomal membrane, which modulates downstream mTORC1 signaling in response to cellular amino acid levels. The serine/threonine protein kinase mTORC1 is within the canonical phosphoinositide 3-kinase (PI3K)-AKT-mTOR signaling cascade. Importantly, loss of KICSTOR components has been shown to inhibit GATOR1 recruitment and increase mTORC1 signaling even under unfavorable metabolic conditions (i.e., when cellular amino acid and nutrient levels are low). Several neurodevelopmental disorders have been associated with hyperactivation of mTORC1, termed "mTORopathies" (e.g., PTEN hamartoma tumor syndrome, tuberous sclerosis complex, and STRADA-related disorders).

Further studies of Kptn^-/- mice and human induced pluripotent stem cell (iPSC) models support the pathogenic mechanism of KPTN-related disorder as likely resulting from hyperactivated mTOR signaling. Levels of phosphorylation of ribosomal protein S6, a downstream target of mTORC1 strongly linked to mTOR pathway activation, were significantly increased in Kptn^-/- mice, and treatment with the mTOR inhibitor rapamycin significantly reduced this increase in phosphorylation of S6 and levels of mTOR activation [Levitin et al 2023]. Transcriptomic studies of both Kptn^-/- mouse and human iPSC models also identified significant dysregulation of gene expression of mTOR pathway regulators [Levitin et al 2023]. These findings are consistent with the proposed role of kaptin as a negative regulator of mTORC1 activity and confirm KPTN-related disorder as an mTORopathy.

Mechanism of disease causation. Loss of function

Author Notes

Further information on our work with the Amish and Mennonite communities can be found at Windows of Hope Project.

Prof Emma Baple and Dr Lettie Rawlins continue to be involved in clinical studies of KPTN-related disorder and in supporting the work of the KPTN Alliance.

Acknowledgments

The authors would like to thank the patients and their families as well as the collaborators who have been involved in describing KPTN-related disorder, with special thanks to Cara Abercrombie and David Freccia, with whom we cofounded the KPTN Alliance. We would also like to thank Dr Olivia Wenger, Dr Ethan Scott, staff at the New Leaf Center Clinic for Special Children, and the Ohio Amish and Mennonite communities for their support of our work on this condition.

This work was supported by the Medical Research Council (MRC), Medical Research Foundation (MRF), National Institutes of Health Javits Award (NIH), Newlife Foundation for Disabled Children (16-17/12), and the National Institute for Health and Care Research Exeter Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.

Revision History

• 1 August 2024 (sw) Review posted live
• 18 December 2023 (eb) Original submission

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