Clinical characteristics.

TECPR2-related hereditary sensory and autonomic neuropathy with intellectual disability (TECPR2-HSAN with ID) is characterized by developmental delay and subsequent intellectual disability, behavioral abnormalities, neurologic manifestations (muscular hypotonia, sensory neuropathy with lower-limb hypo- or areflexia and ataxic gait), and autonomic dysfunction (including central hypoventilation and apnea, gastrointestinal dysmotility, dysphagia, and gastroesophageal reflux disease with recurrent aspiration). To date, more than 30 individuals with TECPR2-HSAN with ID have been identified.

Diagnosis/testing.

The diagnosis of TECPR2-HSAN with ID is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in TECPR2 identified by molecular genetic testing.

Management.

Treatment of manifestations: Currently there are no specific disease-modifying treatments for TECPR2-HSAN with ID. Supportive care is recommended to improve quality of life, maximize function, reduce complications, and minimize risk for apnea and asphyxia, the two most common causes of death. Supportive care can include multidisciplinary care by pediatric specialists in neurology, development, behavior, feeding, pulmonology, gastroenterology, orthopedics, ethics, and medical genetics.

Surveillance: Routinely monitor existing manifestations, response to supportive care, and emergence of new manifestations.

Agents/circumstances to avoid: Avoid drugs that cause decreased consciousness, hypopnea, and CO₂ retention such as benzodiazepines or antihistamines; or if necessary, use at low doses with close monitoring.

Genetic counseling.

TECPR2-HSAN with ID is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a TECPR2 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. Once the TECPR2 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

TECPR2-HSAN with ID should be suspected in individuals with the following clinical findings and family history.

Clinical findings

• Developmental delay / intellectual disability (mainly in the moderate to severe range)
• Neurologic findings
  • Muscular hypotonia
  • Gait ataxia
  • Hyporeflexia / areflexia of the lower limbs
  • Impaired pain sensitivity
  • Dysarthria
• Autonomic dysfunction
  • Impaired temperature regulation
  • Impaired blood pressure regulation
  • Central nocturnal and/or daytime hypoventilation
  • Dysphagia
  • Abnormal gastrointestinal mobility resulting in gastroesophageal reflux and/or constipation
• Recurrent respiratory infections resulting from aspiration as a result of gastroesophageal reflux and dysphagia
• Behavioral abnormalities (hyperactivity, aggressiveness, autism spectrum disorder)
• Distinctive facial features that may include brachycephaly, synophrys, thick eyebrows, hypotelorism, epicanthus, round or triangular-shaped face, and dental crowding [Heimer et al 2016, Neuser et al 2021]

Brain imaging

• Thin or dysplastic corpus callosum
• Mild ventriculomegaly (often asymmetric)
• Delayed myelination (i.e., delayed appearance of signal changes related to final myelination of white matter pathways in affected children)
• Mild cerebral atrophy or mild atrophy of the cerebellar hemispheres or vermis

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

Establishing the Diagnosis

The diagnosis of TECPR2-HSAN with ID is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in TECPR2 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 biallelic TECPR2 variants of uncertain significance (or of one known TECPR2 pathogenic variant and one TECPR2 variant of uncertain significance) does not establish or rule out the diagnosis.

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

Clinical Description

TECPR2-related hereditary sensory and autonomic neuropathy with intellectual disability (TECPR2-HSAN with ID) is characterized by developmental delay and subsequent intellectual disability, behavioral abnormalities, neurologic manifestations (muscular hypotonia, sensory neuropathy with lower-limb hypo- or areflexia and ataxic gait), and autonomic dysfunction (including central hypoventilation and apnea, gastrointestinal dysmotility, dysphagia, and gastroesophageal reflux disease with recurrent aspiration).

To date, more than 30 individuals with biallelic pathogenic variants in TECPR2 have been identified [Oz-Levi et al 2012, Zhu et al 2015, Heimer et al 2016, Anazi et al 2017, Patwari et al 2020, Neuser et al 2021, Palma et al 2021, Ramsey et al 2022]. The following description of the phenotypic features associated with TECPR2-HSAN with ID is based on these reports and the authors' personal experience with additional unpublished cases.

Developmental delay is usually noted in infancy with motor and later speech delay. Independent walking is delayed and the gait is often apraxic-ataxic. Most individuals achieve independent walking.

Intellectual disability is typically in the moderate to severe range; however, individuals with milder cognitive impairment have been described [Neuser et al 2021].

Speech impairment. Speech delay is universal; speech remains markedly impaired, with a subset of individuals remaining nonverbal.

Neurologic manifestations. Motor manifestations are axial and appendicular hypotonia. Lower-limb spasticity, dystonia, dyskinesia, and Parkinsonian features (especially rigidity) can develop in late childhood/adolescence.

Gait is mostly ataxic; however, crouched gait can develop at later stages. Although most individuals achieve independent walking, regression in the second decade of life with loss of independent walking is possible.

Findings suggestive of a sensory neuropathy typically include hypo- or areflexia in the lower limbs and decreased pain sensitivity.

Epilepsy is uncommon, but a few individuals experienced febrile or unprovoked seizures. EEG findings of nonspecific background slowing and epileptiform discharges may be seen in a minority of individuals.

Autonomic neuropathy, a prominent feature, significantly affects morbidity and mortality. Autonomic dysfunction presents with central daytime and nocturnal hypopnea and apnea, hypercarbia, dysphagia with recurrent aspiration, gastroesophageal reflux, and constipation. The dysphagia can lead to both recurrent aspiration and asphyxia.

Other features of the autonomic neuropathy are temperature and blood pressure instability, hyperhidrosis, and electrolyte disturbances. Anecdotally, disproportionally decreased consciousness can develop in response to intercurrent illness or mild central nervous system depressants such as antihistamines.

Recurrent respiratory infections are common and can occur as early as the first year of life. These are likely a result of recurrent aspiration due to dysphagia and gastroesophageal reflux and can be precipitated by laryngeal clefts or laryngomalacia seen in a subset of individuals with TECPR2-HSAN with ID. Over time, recurrent respiratory infections can result in chronic lung disease complicated by bronchiectasis.

Behavioral dysregulation is common and often significantly affects quality of life. Manifestations range from hyperactivity and restlessness to psychomotor slowing and apathy. There is a tendency for shouting and grabbing objects and, sometimes, aggressive behaviors. Some individuals display features of autism spectrum disorder.

Other findings include the following:

• Microcephaly (usually mild or in the low ranges of normal)
• Short stature (usually mild or in the low ranges of normal)
• Short neck with a retrocollis hyperextension posture
• Kyphosis, scoliosis, and a barrel-shaped chest, usually developing in the second decade of life
• Sensorineural hearing impairment may develop; however, data are insufficient to estimate severity or typical age of onset.
• Various ophthalmologic findings including refractive errors (astigmatism, myopia), strabismus, and abnormal ocular movement (periodic upward gaze deviation, oculomotor apraxia, and nystagmus)

Prognosis. TECPR2-HSAN with ID, a progressive disorder, is associated with reduced life expectancy. Several individuals died in the first or second decade of life [Authors, unpublished data]. The oldest individual known to the authors lived until age 19 years. The leading causes of death are asphyxia from aspiration of solid foods, nocturnal central apnea, and complications of chronic progressive lung disease.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified [Neuser et al 2021].

Nomenclature

TECPR2-HSAN with ID was originally described as a form of hereditary spastic paraplegia (SPG49) when the first affected individuals were diagnosed at a relatively late age and showed lower-limb spasticity and a crouched gate. However, with the characterization of additional affected individuals, it became clear that the hallmark feature associated with biallelic TECPR2 pathogenic variants is sensory and autonomic neuropathy. Hence, the TECPR2-related phenotype was reclassified as a subtype of hereditary sensory and autonomic neuropathy (HSAN9).

Prevalence

TECPR2-HSAN with ID is an ultra-rare disease. A little more than 30 cases have been reported. The calculated incidence ranges from 1:22,500 (Bukharian population) to 1:5,961,640 newborns (general population, based on gnomAD).

About half of affected individuals are born to consanguineous parents.

Two populations with founder variants are identified:

• Individuals of Jewish Bukharian background: c.3416delT; p.Leu1139ArgfsTer75 [Oz-Levi et al 2012]
• Individuals of Jewish Ashkenazi background: c.1319delT; p.Leu440ArgfsTer19 [Heimer et al 2016]

The carrier frequency for the Bukharian Jewish population is 1.33% [Oz Levi et al 2012].

The carrier frequency for the Ashkenazi Jewish population is at least 0.65% [Neuser et al 2021].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with TECPR2-HSAN with ID, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Currently there are no specific disease-modifying treatments for TECPR2-HSAN with ID.

Supportive care to improve quality of life, maximize function, reduce complications, and minimize risk for apnea and asphyxia, which are the two most prevalent causes of death, is recommended. Supportive care can include multidisciplinary care by pediatric specialists in the disciplines of neurology, development, behavior, feeding, pulmonology, gastroenterology, orthopedics, ethics, and medical genetics (see Table 5).

Surveillance

To monitor existing manifestations and response to supportive care and to detect new manifestations, see Table 6.

Agents/Circumstances to Avoid

Avoid drugs that cause decreased consciousness, hypopnea, and CO₂ retention such as benzodiazepines or antihistamines; if necessary, use at low doses with close monitoring.

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 disorder.

Mode of Inheritance

TECPR2-related hereditary sensory and autonomic neuropathy with intellectual disability (TECPR2-HSAN with ID) 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 TECPR2 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a TECPR2 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.

Sibs of a proband

• If both parents are known to be heterozygous for a TECPR2 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. To date, individuals with TECPR2-HSAN with ID 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 TECPR2 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the TECPR2 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 and to the parents of affected children.
• Carrier testing for reproductive partners of known carriers should be considered, particularly if consanguinity is likely and/or the reproductive partner is of Bukharian or Ashkenazi Jewish background, as these population groups have higher carrier frequencies as a result of founder variants (see Prevalence).

Prenatal Testing and Preimplantation Genetic Testing

Once the TECPR2 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

TECPR2 (tectonin beta-propeller repeat containing 2) is a large, multidomain protein comprising an amino-terminal tryptophan-aspartic-acid dipeptide (WD) domain, a middle unstructured region, and a carboxy-terminal TEPCR domain containing six TECPR repeats followed by a functional LC3 interacting region (LIR) motif at the extreme carboxy terminus [Stadel et al 2015]. TECPR2 was identified as an interactor of the ATG8 family proteins, which play key roles in autophagy [Oz Levi et al 2012]. TECPR2 regulates targeting of autophagosomes to lysosomes, a process primarily mediated by its carboxy-terminal TECPR domain. In fibroblasts of individuals with homozygous stop codon TECPR2 variants, formation of mature autophagosome was consistent with the notion that TECPR2 plays an important role in late stages of autophagosome targeting to lysosomes [Fraiberg et al 2021]. Ectopic expression of either full-length TECPR2 or the TECPR domain rescued autophagy in fibroblasts of individuals with TECPR2-HSAN with ID in an LIR-dependent manner.

Animal models supporting a defect in autophagy include:

• Accumulation of autophagosomes in a Tecpr2 knockout mouse [Tamim-Yecheskel et al 2021]. These mice exhibited neuroaxonal dystrophy with development of axonal spheroids in a progressive age-dependent manner in the dorsal column pathway of the brain stem and spinal cord accompanied by sensory pathway defects on behavioral tests, consistent with the hereditary sensory and autonomic neuropathy observed in individuals with TECPR2 deficiency [Heimer et al 2016].
• Observation of similar findings in Spanish water dogs with a homozygous missense variant (p.Arg1337Trp) in a highly conserved position in the TECPR2 C-terminal region [Hahn et al 2015]. Neuronal loss and spheroid formation were accentuated in the gray matter of the cerebral hemispheres, cerebellum, and brain stem; sporadic spheroids were also found in white matter. Interestingly, in the spinal cord this histopathologic process was restricted to sensory pathways.

Mechanism of disease causation. Loss of function; evidence for missense variants is still not sufficient.

TECPR2-specific laboratory technical considerations. The lack of functional data has prevented classification of several novel TECPR2 variants [Neuser et al 2021].

Author Notes

Readers are encouraged to contact the authors for questions about research on TECPR2-related hereditary sensory and autonomic neuropathy with intellectual disability.

• For specific information about clinical features, contact:
  Dr Gali Heimer and Prof Bruria Ben-Zeev
  The Edmond and Lily Safra Children's Hospital
  Emails: galih.md@gmail.com / bruria.benzeev@sheba.health.gov.il
• For inquiries regarding interpretation of molecular genetic test results or functional analyses, contact:
  Dr Sonja Neuser
  Institute of Human Genetics, University of Leipzig Medical Center
  Email: sonja.neuser@medizin.uni-leipzig.de

Acknowledgments

The authors thank all families for their participation in research.

Revision History

• 22 September 2022 (bp) Review posted live
• 13 June 2022 (sn) Original submission

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