Clinical characteristics.

ENTPD1-related neurodevelopmental disorder (ENTPD1-NDD) is characterized by developmental delay / intellectual disability (ranging from borderline/mild to moderate/severe) and onset of progressive spastic paraplegia with progressive gait impairment beginning before age five years. Difficulty with balance and frequent falling are common and can result in loss of independent ambulation and wheelchair dependence in the teenage to young adult years.

Other neuromuscular findings can include abnormal deep tendon reflexes, weakness, neuropathy, epilepsy, dysarthria, and dysphagia. Behavior abnormalities and neurocognitive regression are common. Life span does not appear to be shortened.

Diagnosis/testing.

The diagnosis of ENTPD1-NDD is established in a proband with suggestive clinical findings and biallelic pathogenic variants in ENTPD1 identified by molecular genetic testing.

Management.

Treatment of manifestations: There is no cure for ENTPD1-NDD. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. Multidisciplinary care is recommended by specialists in neurology (including treatment of seizures); developmental pediatrics and education (to address developmental delay / intellectual disability and need for individual education plan); physical medicine and rehabilitation / physical therapy and occupational therapy (including stretching to help avoid contractures and falls, facilitating activities of daily living, and use of positioning and mobility devices); speech-language pathology (to address dysarthria and dysphagia); orthopedics (to address scoliosis); and psychologists, behavioral therapists, and/or psychiatrists (to address behavioral issues with behavioral interventions and/or medications and to address issues associated with neurocognitive decline).

Surveillance: Regular clinic visits with the treating specialists are recommended to monitor existing or progressing manifestations and the individual's response to supportive care.

Genetic counseling.

ENTPD1-NDD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ENTPD1 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 ENTPD1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.

Suggestive Findings

ENTPD1-related neurodevelopmental disorder (ENTPD1-NDD) should be considered in a proband with the following clinical and imaging findings and family history.

Clinical findings

• Developmental delay / intellectual disability
• Abnormal reflexes (hyperreflexia, hyporeflexia, and/or areflexia with gait impairment by age five years)
• Behavioral concerns (attention-deficit/hyperactivity disorder, aggression, autistic features)
• Neurocognitive regression not attributed to progressive spastic paraplegia

Brain MRI. Brain white matter abnormalities were reported in approximately 50% of those individuals for whom brain MRI was obtained [Calame et al 2022]. Nonspecific white matter abnormalities were seen throughout the brain. Abnormal white matter signal intensity ranges from subtle to moderate. A subset of affected individuals had abnormal T₂-signal hyperintensity in the posterior limbs of the internal capsule bilaterally and might be suggestive of a diagnosis of a purine metabolism disorder.

Other findings included thinning of the corpus callosum and cerebellar atrophy; it is unclear if the cerebellar atrophy is static or progressive (see Figure 1).

Figure 1.

Individuals with biallelic pathogenic ENTPD1 variants show white matter abnormalities, thinning of the corpus callosum, cerebellar atrophy, and signal abnormalities in the posterior limb of the internal capsule. Representative MRI of the brain of affected (more...)

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 ENTPD1-NDD is established in a proband with suggestive clinical findings and biallelic pathogenic (or likely pathogenic) variants in ENTPD1 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 ENTPD1 variants of uncertain significance (or of one known ENTPD1 pathogenic variant and one ENTPD1 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) depending on the clinical phenotype of affected individuals. 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).

Clinical Description

To date, 40 individuals from 22 families have been identified with biallelic ENTPD1 pathogenic variants [Novarino et al 2014, Travaglini et al 2018, Mamelona et al 2019, Pashaei et al 2021, Calame et al 2022, Ölmez et al 2022]. The following description of the phenotypic features associated with this condition is based on these reports.

All individuals reported to date had onset younger than age five years. All individuals had developmental delay and intellectual disability, and progressive spastic paraplegia with gait impairment as well as abnormal deep tendon reflexes (hypereflexia, hyporeflexia, and/or areflexia). Additional neuromuscular findings can include weakness, neuropathy, and epilepsy. Other common findings are dysarthria, behavior abnormalities, and neurocognitive regression. Less commonly observed clinical findings include scoliosis and cataracts. At the time of this writing, ENTPD1-related neurodevelopmental disorder (ENTPD1-NDD) does not seem to affect life spa,n as affected individuals are known to have reached adulthood.

Onset. All affected individuals to date had onset before age five years. A common first manifestation is delayed walking or other motor and speech delays. First steps typically occur later than the average (i.e., age one year).

Intellectual disability ranges from borderline/mild to moderate/severe with impaired ability to engage independently in activities of daily living, which is not solely related to progressive spastic paraplegia.

Speech and language development are variable. Some individuals never achieve independent expressive language, whereas others communicate expressively with dysarthric speech.

Ability to engage in activities of daily living varies and depends on the level of intellectual disability, with some individuals requiring around-the-clock care.

Progressive spastic paraparesis manifests as weakness and spasticity of the lower extremities. Although individuals with this disorder learn to walk, albeit oftentimes delayed, progressive spastic paraplegia during childhood leads to progressive gait impairment, described as spastic, unsteady, toe walking, and ataxic. Issues with balance and frequent falling are common, potentially resulting in loss of independent ambulation and wheelchair dependence. Wheelchair dependence typically occurs in the teenage to young adult years.

Abnormal deep tendon reflexes include hyperreflexia, hyporeflexia, and areflexia. In the individuals reported to date, areflexia/hyporeflexia is more common than hyperreflexia. Although it is unclear why some individuals develop hyperreflexia and others develop hyporeflexia or areflexia, it could be a combination of uniform upper motor neuron disease with variable lower motor neuron disease (likely resulting from excitotoxicity due to impaired ATP metabolism). Even within the same individual, abnormal reflexes can vary between upper and lower extremities. Additionally, it is unclear if reflexes become progressively more hyperreflexic or hyporeflexic.

Muscle weakness varies. While the proximal lower extremities are most commonly involved, the upper extremities can also be involved. Amyotrophy was noted in some individuals.

Peripheral neuropathy, which can affect upper and lower limbs, manifests as hyporeflexia or areflexia, impaired sensation, and neuropathic pain. Neuropathic findings, including abnormal reflexes, tend to occur in advance of progressive spasticity.

Electromyography / nerve conduction studies revealed findings consistent with motor axonal neuropathy.

Epilepsy. Epilepsy, occurring in some affected individuals, typically starts in early childhood. Seizures are convulsive and respond well to standard anti-seizure medication such as valproic acid. EEG reveals generalized epileptiform activity.

Dysarthria ranges from nasal speech with mild dysarthria to anarthria (i.e., total inability to articulate speech). Individuals with dysarthria often also have dysphagia.

Dysphagia. Difficulty swallowing liquids and solid food with resultant coughing, choking, and aspiration can occur and tends to progress. Rarely, dysphagia requires gastrostomy tube placement.

Behavior abnormalities include attention-deficit/hyperactivity disorder, aggression, anger, impulsivity, and autism spectrum disorder. Behavior abnormalities range from mild/moderate to severe and can affect early childhood school performance if left untreated. Additionally, aggression, anger, impulsivity, and autistic behaviors affect interpersonal relationships and can be disabling.

Neurocognitive regression can manifest as progressively impaired ability to engage independently in activities of daily living, worsening academic performance, and speech and language impairment. Regression was observed in childhood with progressive difficulties with school performance, followed by slow progression into early adulthood. Longitudinal data are currently insufficient to determine if neurocognitive regression continues throughout the life span of affected individuals.

Other findings

• Hand and foot deformities most commonly included camptodactyly of the hands and feet and spatulated digits. These deformities can affect day-to-day functioning, including fine and gross motor function.
  Pes cavus can be evident early in the disease course and has been reported in young children.
• Scoliosis. At this time it is unclear if scoliosis, present in five of 36 individuals, is progressive. Because scoliosis may be a late finding in neuromuscular disorders and because the individuals with ENTPD1-NDD reported to date are mostly children or adolescents, its frequency may be underestimated. There were no known vertebral anomalies. No individuals are known to have undergone surgical intervention.
• Cataracts. While seen in approximately 10% of affected individuals, no information is available on cataract type or whether surgical intervention was necessary for any of these individuals.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Nomenclature

Pure and complex hereditary spastic paraplegia. Hereditary spastic paraplegia (HSP) has traditionally been classified into "pure" and "complex," each of which constitutes a large group of disorders with diverse molecular etiologies.

• Pure HSP is characterized by progressive spastic paraplegia with gait impairment, corticospinal tract axonopathy, and axonal length-dependent neuropathy [Harding 1993, Blackstone 2018].
• Complex HSP, the HSP category that encompasses ENTPD1-NDD, shares the features of pure HSP in addition to developmental delay / intellectual disability, behavior abnormalities, structural brain abnormalities, ataxia, and epilepsy, among others [Fink 2013, Elsayed et al 2021].

ENTPD1-NDD and other complex HSPs have significant overlap with a vast range of neurodevelopmental disorders, and it is increasingly difficult to assign predominant phenotypic designations. As individuals with ENTPD1-NDD may be diagnosed by general pediatricians, developmental and behavioral pediatricians, child neurologists, physiatrists, and/or neuromuscular specialists, it is reasonable to continue using movement disorder designations (SPG64 and HSP-ENTPD1 [Lange et al 2022]) as well as ENTPD1-NDD to maximize clinical recognition of the condition.

Prevalence

ENTPD1-NDD is rare. Its prevalence is unknown. To date, 40 affected individuals have been reported (see Clinical Description).

Affected individuals have been reported throughout the world. However, it appears that this disorder is more common in populations with elevated rates of consanguinity.

Additionally, the following recurrent ENTPD1 variants have been identified (see Table 7):

• The variants c.574-6_574-3delTTTC and c.770_771delGG (p.Gly257GlufsTer18) were found in the homozygous state in unrelated consanguineous families from countries with substantial Portuguese ancestry (Brazil and Portugal), which suggests that these variants represent founder variants from the Iberian Peninsula [Calame et al 2022].
• The variants c.1041delG (p.Ile348PhefsTer19) and c.1109T>A (p.Leu370Ter), identified in several Iranian families, may represent founder variants in this population [Calame et al 2022].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ENTPD1-NDD, 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 no cure for ENTPD1-NDD.

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists (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.

Agents/Circumstances to Avoid

While mild-to-moderate physical activity is highly recommended, affected individuals should avoid activity that significantly worsens their symptoms (e.g., worsening weakness, muscle cramps).

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

ENTPD1-related neurodevelopmental disorder (ENTPD1-NDD) 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 an ENTPD1 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an ENTPD1 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 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 an ENTPD1 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.
• Intrafamilial variability has been reported in ENTPD1-NDD. Affected family members with the same biallelic pathogenic variants in ENTPD1 have been reported to have variable ages at disease onset, rate of progression, and clinical features (gait abnormalities, speech impairment, and developmental delay / intellectual disability) [Calame et al 2022].
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with ENTPD1-NDD are obligate heterozygotes (carriers) for a pathogenic variant in ENTPD1.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an ENTPD1 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the ENTPD1 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 individuals known to be carriers, particularly if consanguinity is likely and/or if both partners are of the same ethnic background (see Prevalence).

Prenatal Testing and Preimplantation Genetic Testing

Once the ENTPD1 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

ENTPD1 encodes ectonucleoside triphosphate diphosphohydralase 1 (ENTPD1), a hydralase protein involved in the hydrolysis of adenosine triphosphate (ATP) and adenosine diphosphate (ADP) to adenosine monophosphate (AMP). ENTPD1 is ubiquitously expressed and has important functions in energy metabolism in many tissues throughout the body [Jackson et al 2007, Nardi-Schreiber et al 2017]. Recent evidence suggests that impairment of energy metabolism in individuals with ENTPD1-related neurodevelopmental disorder (ENTPD1-NDD). Affected pathways include amino acid, lipid, carbohydrate, and heme metabolism [Calame et al 2022]. Although ATP is an important neuronal signaling molecule, excess ATP can cause neurotoxicity. Given the wide expression of ENTPD1 and evidence of extraneurologic involvement, the reason why ENTPD1-NDD predominantly causes neurologic symptoms is unknown.

Mechanism of disease causation. All genetic and functional evidence supports loss of function as the mechanism of action in ENTPD1-NDD [Calame et al 2022].

ENTPD1-specific laboratory technical considerations. Assays that may help confirm variants of uncertain significance as pathogenic loss-of-function variants, performed largely on a research basis, include the following [Calame et al 2022]:

• Anti-CD39/ENTPD1 flow cytometry of peripheral blood mononuclear cells
• ATP or ADPase assays using lymphoblastoid cell lines
• Anti-CD39/ENTPD1 immunohistochemistry of sural nerve biopsy

Author Notes

Lupski Laboratory

Daniel Calame, MD, PhD ([email protected]), and Isabella Herman, MD, PhD ([email protected]), are actively involved in basic, translational, and clinical research regarding individuals with ENTPD1-related neurodevelopmental disorder (ENTPD1-NDD). They would be happy to communicate with persons who have any questions regarding diagnosis of ENTPD1-NDD or other considerations.

Dr Calame and Dr Herman are also interested in hearing from clinicians treating families affected by disorders associated with progressive or non-progressive spastic paraplegia or abnormal neurodevelopment in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Contact Dr Calame and Dr Herman to inquire about review of ENTPD1 variants of uncertain significance.

Acknowledgments

We wish to acknowledge all patients with ENTPD1-NDD, their families, and our collaborators. Funding sources for our research include the Muscular Dystrophy Association Development Grant 873841 (DGC), the Chao Physician-Scientist Award (DGC), and the Spastic Paraplegia Foundation (to Dr James R Lupski).

Revision History

• 1 June 2023 (bp) Review posted live
• 14 November 2022 (dc) Original submission

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