For Medical Professionals

Diagnosis

PI4KA-related disorder is a clinically variable disorder characterized by neurologic dysfunction, gastrointestinal manifestations (bowel atresia, inflammatory bowel disease), and immunodeficiency. PI4KA-related disorder should be suspected in individuals with the following clinical, laboratory, and imaging features.

Clinical features

Neurologic
- Peripheral spasticity, often more marked in lower than upper limbs
- Truncal hypotonia
- Global developmental delay
- Intellectual disability (mild to severe)
- Seizures
- Ataxia
- Nystagmus
- Intention tremor
- Dysmetria
- Dystonia
- Arthrogryposis/contractures
- Kyphosis or scoliosis
Gastrointestinal
- Multiple intestinal atresia
- Very early onset or treatment-refractory inflammatory bowel disease
- Nonspecific gastrointestinal symptoms (vomiting, diarrhea, constipation, gastroesophageal reflux disease)
Combined immunodeficiency. Recurrent otitis media; upper and lower respiratory tract infections

Laboratory features

Increased fecal calprotectin
Iron-deficient anemia
Increased C-reactive protein
Hypogammaglobulinemia: variable immunoglobulin defects
Leukopenia: cellular defects ranging from severe T-cell lymphopenia (affecting CD8+ T cells more than CD4+ T cells), moderate B- and NK-cell lymphopenia, to normal lymphocyte counts

Imaging features

Brain MRI. Hypomyelinating leukodystrophy characterized by abnormal white matter signal (diffuse T₂-weighted elevation of white matter signal typically involving the entire supratentorial white matter), often associated with a thin corpus callosum, cerebellar hypoplasia or atrophy, progressive supratentorial atrophy, brain stem atrophy (pons and medulla oblongata), and/or polymicrogyria

Note: Perisylvian polymicrogyria has to date been reported only in individuals with the PI4KA variant p.Asp1854Asn [Pagnamenta et al 2015, Verdura et al 2021].

Gastrointestinal imaging. Intestinal atresia of the small bowel and/or colon may be extensive, affecting the gastrointestinal tract from the pylorus to the anus.
Gastrointestinal endoscopic and histopathologic features. Multiple abnormalities are noted including multiple distinct small lumens, lined by mucosa and surrounding muscularis mucosa, dilatated and narrowed lumen, with areas of mucosal atrophy and foci of acute neutrophilic mucosal inflammation. Endoscopic and histologic findings in individuals with inflammatory bowel disease include lymphoid mucosal infiltration; epithelial damage, ileal/general colonic inflammation; and histologic features of Crohn disease, ulcerative colitis, or unspecified inflammatory bowel disease.

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 PI4KA-related disorder is established in a proband with suggestive clinical features, brain MRI features, and/or intestinal histology, and biallelic pathogenic (or likely pathogenic) variants in PI4KA identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG 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. Reference to “pathogenic variants” in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic PI4KA variants of uncertain significance (or identification of one known PI4KA pathogenic variant and one PI4KA variant of uncertain significance) does not establish or rule out a diagnosis of this disorder. (3) Genetic analysis of PI4KA is complicated by the presence of two non-processed pseudogene partial copies, PI4KAP1 and PI4KAP2, each located <1 Mb from PI4KA.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other neurodevelopmental disorders are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic findings suggest the diagnosis of PI4KA-related disorder, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

Single-gene testing. Sequence analysis of PI4KA is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Typically, if only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications; however to date, no deletions or duplications of PI4KA have been identified as a cause of this disorder.

Note: Targeted analysis for the known founder variant c.4867T>G (p.Tyr1623Asp) can be performed first in individuals of Amish ancestry who present at birth with multiple intestinal atresia with or without immunodeficiency.

Amultigene panel that includes PI4KA and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition 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. (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.

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; 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.

Table 1.

Molecular Genetic Testing Used in PI4KA-Related Disorder

Gene ¹	Method	Proportion of Pathogenic Variants ² Detectable by Method
PI4KA	Sequence analysis ³	100% ⁴
PI4KA	Gene-targeted deletion/duplication analysis ⁵	None reported ⁴

See Table A. Genes and Databasesfor chromosome locus and protein.
See Molecular Geneticsfor information on variants detected in this gene.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice sitevariants; typically, exonor whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
Pagnamenta et al [2015], Salter et al [2021], Verdura et al [2021], and data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]
Gene-targeted deletion/duplication analysisdetects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exondeletions or duplications.

Management

No clinical practice guidelines for PI4KA-related disorder have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PI4KA-related disorder, the evaluations summarized in Table 1 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 1.

Recommended Evaluations Following Initial Diagnosis in Individuals with PI4KA-Related Disorder

System/Concern	Evaluation	Comment
Neurologic	Neurologic eval for spasticity, cerebellar signs, & dystonia Brain MRI EEG (Seizures may be subclinical.)	To evaluate for hypomyelinating leukodystrophy, cerebellar hypoplasia/atrophy, thin or dysplastic corpus callosum, &/or perisylvian polymicrogyria
Neurocognitive development	Assessment by developmental pediatrician of developmental milestones, cognitive function, speech (communication) & feeding (swallowing) Assessment by PT of functional disability & equipment needs
Multiple intestinal atresia	Pediatric gastroenterology assessment Abdominal x-rays Further abdominal imaging as needed	Plain abdominal x-rays may reveal dilatated loops, & MRI may identify multiple strictures. Exploratory laparoscopy or laparotomy will ultimately be required if clinical signs suggest severe obstruction.
Inflammatory bowel disease	Eval by gastroenterologist CBC ± inflammatory markers (CRP) Fecal calprotectin Endoscopic investigations as indicated by symptomatology	There should be a lower threshold for IBD investigation in persons w/moderate-to-severe DD/ID in whom clinical findings could be consistent w/IBD & communication of abdominal symptomology may be challenging.
Immunodeficiency	Immunology assessment Immunophenotyping incl lymphocyte subsets & immunoglobulins Thymic ultrasound	Recommended in all persons w/PI4KA-related disorder as signs & symptoms may be subtle or subclinical Lymphopenia w/disruption of epithelial barrier results in ↑ risk for pathogenic proliferation & sepsis.
Genitourinary anomalies	Consider renal (& pelvic) imaging.	Assess for structural anomalies.
Hearing	Audiologic assessment	Assess for hearing loss.
Vision	Ophthalmologic assessment	Assess for nystagmus, ↓ visual acuity, optic nerve atrophy, strabismus, & ocular motor dyspraxia.
Genetic counseling	By genetics professionals ¹	To inform affected persons & their families re nature, MOI, & implications of PI4KA-related disorder to facilitate medical & personal decision making
Family support & resources	Assess need for: Community or online resources such as Parent to Parent; Social work involvement for parental support; Home nursing referral.

CBC = complete blood count; CRP = C-reactive protein; DD = developmental delay; IBD = inflammatory bowel disease; ID = intellectual disability; MOI = mode of inheritance; PT = physical therapist

Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Treatment of Manifestations

Individualized care by a multidisciplinary team including a pediatrician, neurologist, gastroenterologist, clinical geneticist, physical therapist, occupational therapist, speech-language therapist, ophthalmologist, audiologist, and primary care physician is recommended.

Table 2.

Treatment of Manifestations in Individuals with PI4KA-Related Disorder

Manifestation/Concern	Treatment	Considerations/Other
Limb spasticity & motor delays	PT, OT, use of appropriate mobility aids Medical mgmt may incl baclofen (incl intrathecal baclofen), diazepam, & intramuscular botulinum toxin.	Spasticity may → joint contractures & scoliosis.
Speech impairment	Speech-language therapy; use of communication aids (e.g., talker)
Intellectual disability	Educational support
Seizures	Use of standard anti-seizure medications; dependent on specific seizure type
Dysphagia	Speech-language therapy Gastrostomy as needed
Multiple intestinal atresia (MIA)	There is no known treatment for MIA. Parenteral nutrition Intestinal transplant may be considered but is assoc w/high mortality rate. Since there is no established cure, quality of life is an important consideration. In children w/poor prognosis due to MIA, palliative approaches may be considered.	In one infant w/PI4KA-related MIA, IBD & small bowel stenosis recurred following surgical resection. ^1, 2
Inflammatory bowel disease (IBD)	Standard anti-inflammatory medications & dietary mgmt established for treatment of IBD incl: immunosuppressants, steroids, & antibody therapies Surgery may be required for treatment-resistant disease & to remove obstructions.	Note: Traditional IBD therapies do little to treat intestinal disease in TTC7A-related MIA or very early-onset IBD. ²
Immunodeficiency	Identification of the nature of immune dysfunction should inform clinical mgmt. HSCT may correct immune defects & ↑ survival in persons w/severe immunodeficiency.	Note: HSCT does not appear to improve phenotypes related to intestinal epithelial defects in TTC7A-related disease; graft-vs-host disease & sepsis are potential complications that may exacerbate intestinal disease. ² Decision making should also incl burden of treatment in children w/ID.
Hearing	Standard treatment for hearing issues
Vision	Treatment per ophthalmologist

ID = intellectual disability; HSCT = hematopoietic stem cell transplantation; OT = occupational therapy; PT = physical therapy

Note: Surgical bowel resections in individuals w/TTC7A-related MIA do not prevent the formation of new atresias.
Due to the phenotypic and mechanistic overlap between TTC7A– and PI4KA-related bowel disease, this information may be applicable to PI4KA-related disorder.

Surveillance

To date, no general surveillance guidelines have been developed; monitoring should be individualized.

Table 3.

Recommended Surveillance for Individuals with PI4KA-Related Disorder

System/Concern	Evaluation	Frequency
Neurologic	Neurologic assessment to monitor for progression of limb spasticity, dysphagia, cerebellar signs, dystonia, & seizures	Annually & as indicated by symptomatology
Developmental delay / Intellectual disability	Assessment of developmental milestones by pediatrician	As indicated by clinical presentation
Inflammatory bowel disease	Assessment by gastroenterologist for clinical signs of IBD, which may develop at any age. Consider CBC & inflammatory markers, incl fecal calprotectin, CRP. ± endoscopic investigations if clinical concerns or limited communication due to neurologic manifestations	Annually & as indicated by symptomatology
Immunology	Monitor for clinical signs of infection susceptibility & have a low threshold for repeating immunologic investigations, as immunodeficiency may be difficult to recognize at very early ages & may develop in later in life.	Annually & as indicated by symptomatology
Hearing	Audiology eval	Annually throughout childhood
Vision	Ophthalmology eval	Annually throughout childhood

CBC = complete blood count; CRP = C-reactive protein; IBD = inflammatory bowel disease

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Recent investigation of anti-apoptotic medications in laboratory and animal models of TTC7A-related gastrointestinal defects and immunodeficiency syndrome (OMIM 243150) suggest that leflunomide may be a potential treatment for bowel inflammation and stenosis in this condition [Jardine et al 2020]. Due to the phenotypic and mechanistic overlap between TTC7A– and PI4KA-related bowel disease, this treatment may be applicable to PI4KA-related disorder. To date, however, no data exist to support the efficacy of leflunomide in treating PI4KA-related bowel disease.

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 disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

PI4KA-related disorder is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

The parents of an affected individual are presumed to be heterozygous for a PI4KA pathogenic variant.
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a PI4KA 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, the following possibilities should be considered:
- 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].
- Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

If both parents are known to be heterozygous for a PI4KA 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 inheriting neither of the familial pathogenic variants.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Unless an affected individual’s reproductive partner also has PI4KA-related disorder or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in PI4KA. (Note: Within the Amish community, the founder variant p.Tyr1623Asp is present at an allele frequency of 0.0006.)

Other family members. Each sib of the proband‘s parents is at a 50% risk of being a carrier of a PI4KA pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the PI4KA 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the PI4KA 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.

More information: PI4KA-Related Disorder – GeneReviews® – NCBI Bookshelf (nih.gov)