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hereditary spastic paraplegia 64 - Clinical Profile, Genes & Research | Kisho | Kisho

Features include always present findings: Spastic paraplegia; and common findings: Microcephaly, Difficulty walking (gait disturbance), Dysarthria, and Aggressive behavior and others. 15 total HPO annotations.

Organ System	Phenotype Count	Example Features
Brain and nerves	9	Moderate intellectual disability, Difficulty walking (gait disturbance), Dysarthria
Bones and joints	1	Skeletal muscle atrophy
Muscles	1	Skeletal muscle atrophy
Head and neck	1	Microcephaly
Eyes	1	Developmental cataract
Hormones	1	Delayed puberty

GeneReviews

Clinical Guidance

To date, 40 individuals from 22 families have been identified with biallelic ENTPD1 pathogenic variants [, , , , , ]. 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.

Source: GeneReviews — "ENTPD1-Related Neurodevelopmental Disorder"

Diagnosis

Drawn from GeneReviews diagnostic guidelines, newborn screening panel status (RUSP), and ClinGen gene-disease validity classifications. Reflects current clinical evidence and consensus where available.

GeneReviews

Diagnostic Criteria

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

Source: GeneReviews — "ENTPD1-Related Neurodevelopmental Disorder"

GeneReviews

Differential Diagnosis

Table 3. Selected Genes of Interest in the Differential Diagnosis of ENTPD1-Related Neurodevelopmental Disorder

Gene	Disorder(s)	MOI	Clinical Findings	Features of Disorder(s) Overlapping w/ENTPD1-NDD
ALDH18A1	SPG9A1 SPG9B2	ADAR	Cataracts; Gastroesophageal reflux; Motor neuronopathy; Dysarthria; Ataxia; Cognitive impairment	Cataracts; Motor neuropathy; Dysarthria; Ataxia; Cognitive impairment

Genetic testing for ENTPD1 is available. Testing is considered confirmatory for diagnosis.

Biomarker and diagnostic research for hereditary spastic paraplegia 64 has been reported in the published literature.

Treatment

Compiled from FDA-approved drug records, orphan drug designations, and FDA Adverse Event Reporting System (FAERS) safety data. GeneReviews management guidance is included where available.

No approved treatments are currently available for hereditary spastic paraplegia 64. The disease remains an area of unmet medical need.

GeneReviews

Management Guidelines

No clinical practice guidelines for ENTPD1-related neurodevelopmental disorder (ENTPD1-NDD) have been published. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with ENTPD1-NDD, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 4. ENTPD1-Related Neurodevelopmental Disorder: Recommended Evaluations

System/Concern	Evaluation	Comment
Intellectual disability	Developmental assessment	To incl motor, adaptive, cognitive, speech-language eval; Eval for early intervention/ special education Neuromuscular
Progressive spastic paraparesis	Neurologic eval	To incl baseline brain MRI (if not already performed)1; Consider EMG/NCS2; To incl assessment of strength, gait, deep tendon reflexes, spasticity Neuropathy Epilepsy
Activities of daily living	Orthopedics/ physical medicine rehab/ PT OT eval	To incl assessment of:; Gross motor fine motor skills; Contractures, scoliosis; Mobility, ADL, need for adaptive devices; Need for PT (to improve or maintain gross motor skills) /or OT (to improve or maintain fine motor skills)
Dysarthria	Speech language assessment	—
Behavioral findings

Source: GeneReviews — "ENTPD1-Related Neurodevelopmental Disorder"

GeneReviews

Clinical Guidance

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).

Source: GeneReviews — "ENTPD1-Related Neurodevelopmental Disorder"

GeneReviews

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.

Source: GeneReviews — "ENTPD1-Related Neurodevelopmental Disorder"

Clinical Trials

View trials for hereditary spastic paraplegia 64

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Prognosis

Based on GeneReviews surveillance recommendations, HPO phenotype frequency and severity annotations, and published prevalence estimates from Orphanet and OMIM.

GeneReviews

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 6. ENTPD1-Related Neurodevelopmental Disorder: Recommended Surveillance

System/Concern	Evaluation	Frequency
Intellectual disability	Monitor developmental progress educational needs.	At each visit Neurologic
Musculoskeletal	Physical medicine, OT/PT assessment of mobility, self-help skills	Per treating clinicians Scoliosis
Dysarthria	Per treating speech-language pathologist	Per treating speech-language pathologist
Dysphagia	Swallow study speech eval	If clinical concerns for new findings
Neurobehavioral/Psychiatric	Per treating mental health professional	Per treating mental health professional
Neurocognitive	Monitor developmental progress educational needs.	At each visit
Ophthalmologic involvement	Per treating ophthalmologist	Per treating ophthalmologist Per treating low vision services
Family/Community	Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).	At each visit

Source: GeneReviews — "ENTPD1-Related Neurodevelopmental Disorder"

Phenotype severity distribution: 1 always present feature, 7 common features.

Estimated prevalence: <1 in 1,000,000 (VERY_RARE).

Research Landscape

Sourced from ClinicalTrials.gov and PubMed. Publication types are classified using NLM-curated article metadata; research type breakdowns reflect the nature of published work for this disease.

No clinical trials have been registered for hereditary spastic paraplegia 64.

13 publications have been identified in PubMed for hereditary spastic paraplegia 64. Research spans Epidemiology / Natural History (31%), Case Report / Case Series (23%), and Diagnostic / Biomarker (15%).

Research Type	Count	% of Total
Disease patterns and progression	4	31%
Patient case studies	3	23%
Testing and diagnosis research	2	15%
Other research	1	8%
Research summaries	1	8%
Clinical study results	1	8%
Laboratory research	1	8%

Recent Publications

Amprosi M (2026). [PMID: 41586880](https://pubmed.ncbi.nlm.nih.gov/41586880/). *J Neurol*. [Epidemiology / Natural History]
Davarzani A (2026). [PMID: 42120987](https://pubmed.ncbi.nlm.nih.gov/42120987/). *Orphanet J Rare Dis*. [Epidemiology / Natural History]
Erkan DD (2025). [PMID: 40827465](https://pubmed.ncbi.nlm.nih.gov/40827465/). *Int J Dev Neurosci*. [Review / Meta-Analysis]
Doronzio PN (2025). [PMID: 40498122](https://pubmed.ncbi.nlm.nih.gov/40498122/). *J Neurol*. [Epidemiology / Natural History]
Özdemir TR (2025). [PMID: 40445718](https://pubmed.ncbi.nlm.nih.gov/40445718/). *Ann Indian Acad Neurol*. [Diagnostic / Biomarker]
Sequeira S (2025). [PMID: 41552192](https://pubmed.ncbi.nlm.nih.gov/41552192/). *Cureus*. [Case Report / Case Series]
de Lima FD (2025). [PMID: 40993748](https://pubmed.ncbi.nlm.nih.gov/40993748/). *Orphanet J Rare Dis*. [Clinical Trial Publication]
Gioiosa V (2025). [PMID: 41402561](https://pubmed.ncbi.nlm.nih.gov/41402561/). *Neurol Sci*. [Case Report / Case Series]
Mitsutake A (2025). [PMID: 39894496](https://pubmed.ncbi.nlm.nih.gov/39894496/). *Intern Med*. [Epidemiology / Natural History]
Kahawatte S (2025). [PMID: 40009545](https://pubmed.ncbi.nlm.nih.gov/40009545/). *Biochemistry*. [Basic Science / Preclinical]

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hereditary spastic paraplegia 64

Overview

Clinical Presentation

Clinical Guidance

Explore clinical features

Genetic Landscape

Diagnosis

Diagnostic Criteria

Suggestive Findings

Differential Diagnosis

Treatment

Management Guidelines

Clinical Guidance

Therapies Under Investigation

Clinical Trials

Prognosis

Surveillance Guidelines

Research Landscape

Recent Publications

Medical References

External Resources

OMIM

Orphanet

GARD

Questions for Your Care Team

Questions for Your Care Team

hereditary spastic paraplegia 64

Overview

Clinical Presentation

Clinical Guidance

Explore clinical features

Genetic Landscape

Diagnosis

Diagnostic Criteria

Suggestive Findings

Differential Diagnosis

Treatment

Management Guidelines

Clinical Guidance

Therapies Under Investigation

Clinical Trials

Prognosis

Surveillance Guidelines

Research Landscape

Recent Publications

Medical References

External Resources

OMIM

Orphanet

GARD

Related Diseases

Questions for Your Care Team

Questions for Your Care Team