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hereditary spastic paraplegia 44 - Clinical Profile, Genes & Research | Kisho | Kisho

Features include always present findings: Ataxia, Spastic gait, Lower limb spasticity, and CNS hypomyelination and others; and common findings: Strabismus, Seizure, Urinary incontinence, and Difficulty with thinking and memory (cognitive impairment) and others. 23 total HPO annotations.

Organ System	Phenotype Count	Example Features
Brain and nerves	11	Seizure, Ataxia, Spastic gait
Eyes	3	Strabismus, Nystagmus, Slow saccadic eye movements
Arms and legs	2	Lower limb spasticity, Upper limb spasticity
Kidneys and urinary system	1	Urinary incontinence
Digestive system	1	Constipation
Bones and joints	1	Sideways curvature of the spine (scoliosis)
Ears	1	Inner ear hearing loss (sensorineural hearing impairment)

GeneReviews

Clinical Guidance

Pelizaeus-Merzbacher-like disease 1 (PMLD1) is a slowly progressive leukodystrophy that typically presents in the neonatal period or early infancy with nystagmus, often complicated by hypotonia and developmental delay. Over time the hypotonia may evolve into spasticity, and extrapyramidal movement abnormalities may emerge. Older children often manifest significant motor impairments that can also effect communication. Cognition is relatively preserved. The following detailed description of clinical manifestations is based on findings in individuals with a molecularly proven diagnosis [, , , , , , , , , , ]. Nystagmus (either rotatory or horizontal) appears in early infancy and is not present in all individuals.

Source: GeneReviews — "Pelizaeus-Merzbacher-Like Disease 1"

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

Pelizaeus-Merzbacher-like disease 1 (PMLD1) should be suspected in individuals with the following classic clinical and neuroimaging findings:

Clinical findings

Nystagmus that typically presents during the neonatal period or early infancy
Mainly motor developmental delay and central hypotonia during infancy
Signs of upper motor neuron dysfunction (including spasticity, brisk deep tendon reflexes, and Babinski sign) usually affecting the lower limbs more than the upper limbs
Gait ataxia and other cerebellar signs
Mild choreiform movements and dystonia of the extremities that can become severe and disabling
Dysarthria and swallowing dysfunction

Neuroimaging findings. Findings on brain MRI include the following :

Source: GeneReviews — "Pelizaeus-Merzbacher-Like Disease 1"

GeneReviews

Differential Diagnosis

Pelizaeus-Merzbacher disease

(PMD) is an X-linked disorder caused by a hemizygous pathogenic variant in PLP1. The clinical presentation and radiologic appearance are similar to PMLD1. Most individuals present with neonatal nystagmus, hypotonia, global developmental delay, spasticity, gait ataxia, and choreoathetosis. Diffuse hypomyelination on brain MRI is observed in most individuals. Note that MRI evidence of brain stem involvement is more characteristic of PMLD1 than PMD. Both PMD and PMLD1 can present as an isolated spastic paraparesis; see . Hypomyelination with atrophy of the basal ganglia and cerebellum (see TUBB4A-Related Leukodystrophy) is caused by a heterozygous pathogenic variant in TUBB4A; affected individuals are typically simplex cases (i.e., a single occurrence in a family).

Source: GeneReviews — "Pelizaeus-Merzbacher-Like Disease 1"

Genetic testing for GJC2 is available. Testing is considered confirmatory for diagnosis.

Biomarker and diagnostic research for hereditary spastic paraplegia 44 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 44. The disease remains an area of unmet medical need.

GeneReviews

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Pelizaeus-Merzbacher-like disease 1 (PMLD1), the evaluations summarized (if not performed as part of the evaluation that led to diagnosis) are recommended. Table 3. Recommended Evaluations Following Initial Diagnosis of Pelizaeus-Merzbacher-Like Disease 1

Organ System	Evaluation	Comment
Eyes	Ophthalmology	Assessment for optic atrophy nystagmus
ENT	Audiology	Assessment for sensorineural hearing loss
Gastrointestinal	Consultation w/gastroenterologist	Consideration of swallowing study to assess for swallowing dysfunction mgmt of constipation gastroesophageal reflux
Musculoskeletal	Referral to an orthopedic surgeon for tone mgmt or orthopedic complications as indicated	Exam to assess for evidence of hip dislocation, joint contractures, scoliosis
Neurologic	Consultation w/pediatric neurologist	Eval of movement disorders, tone, seizures Miscellaneous/

Source: GeneReviews — "Pelizaeus-Merzbacher-Like Disease 1"

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 — "Pelizaeus-Merzbacher-Like Disease 1"

Clinical Trials

View trials for hereditary spastic paraplegia 44

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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

Table 6. Recommended Surveillance for Individuals with Pelizaeus-Merzbacher-Like Disease 1

Organ System	Evaluation	Frequency/Comment
Constitutional	Monitoring of general health growth; immunizations	Annually
Eyes	Ophthalmology	Biannually unless symptoms develop
Neurologic	Pediatric neurology assessment for disease progression, symptom control, review of medications	Annually Miscellaneous/
Other	Physiatrist physical/occupational therapy assessments for functional capacity equipment needs	Annually w/more frequent treatment visits once eval completed Assessment of communication abilities

Source: GeneReviews — "Pelizaeus-Merzbacher-Like Disease 1"

Phenotype severity distribution: 11 always present features, 9 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 44.

16 publications have been identified in PubMed for hereditary spastic paraplegia 44. Research spans Epidemiology / Natural History (31%), Diagnostic / Biomarker (19%), and Case Report / Case Series (19%).

Research Type	Count	% of Total
Disease patterns and progression	5	31%
Testing and diagnosis research	3	19%
Patient case studies	3	19%
Clinical study results	2	13%
Laboratory research	2	13%
Research summaries	1	6%

Recent Publications

Panza E (2026). [PMID: 41885189](https://pubmed.ncbi.nlm.nih.gov/41885189/). *Annals of clinical and translational neurology*. [Review / Meta-Analysis]
Esmaeil Lashgarian H (2026). [PMID: 41625348](https://pubmed.ncbi.nlm.nih.gov/41625348/). *Iranian journal of medical sciences*. [Case Report / Case Series]
Fathi M (2025). [PMID: 40594583](https://pubmed.ncbi.nlm.nih.gov/40594583/). *Scientific reports*. [Epidemiology / Natural History]
Al-Hedaithy A (2025). [PMID: 39747233](https://pubmed.ncbi.nlm.nih.gov/39747233/). *Scientific reports*. [Diagnostic / Biomarker]
Gioiosa V (2025). [PMID: 41402561](https://pubmed.ncbi.nlm.nih.gov/41402561/). *Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology*. [Case Report / Case Series]
Lallemant-Dudek P (2025). [PMID: 39704400](https://pubmed.ncbi.nlm.nih.gov/39704400/). *European journal of neurology*. [Epidemiology / Natural History]
Ten Martin D (2025). [PMID: 39613968](https://pubmed.ncbi.nlm.nih.gov/39613968/). *The EMBO journal*. [Basic Science / Preclinical]
Doronzio PN (2025). [PMID: 40498122](https://pubmed.ncbi.nlm.nih.gov/40498122/). *Journal of neurology*. [Epidemiology / Natural History]
Özdemir TR (2025). [PMID: 40445718](https://pubmed.ncbi.nlm.nih.gov/40445718/). *Annals of Indian Academy of Neurology*. [Diagnostic / Biomarker]
Di Folco C (2025). [PMID: 40832806](https://pubmed.ncbi.nlm.nih.gov/40832806/). *Movement disorders : official journal of the Movement Disorder Society*. [Basic Science / Preclinical]

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hereditary spastic paraplegia 44

Overview

Clinical Presentation

Clinical Guidance

Explore clinical features

Genetic Landscape

Clinical Guidance

Diagnosis

Diagnostic Criteria

Suggestive Findings

Differential Diagnosis

Pelizaeus-Merzbacher disease

Treatment

Management Guidelines

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 44

Overview

Clinical Presentation

Clinical Guidance

Explore clinical features

Genetic Landscape

Clinical Guidance

Diagnosis

Diagnostic Criteria

Suggestive Findings

Differential Diagnosis

Pelizaeus-Merzbacher disease

Treatment

Management Guidelines

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