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torsion dystonia 4 (DYT4) - Clinical Profile, Genes & Research | Kisho | Kisho

Features include common findings: Torticollis and Dysphonia; and sometimes findings: Difficulty swallowing (dysphagia), Limb dystonia, and Hemidystonia. 11 total HPO annotations.

Organ System	Phenotype Count	Example Features
Brain and nerves	6	Difficulty swallowing (dysphagia), Limb dystonia, Gait ataxia
Head and neck	1	Narrow face
Digestive system	1	Difficulty swallowing (dysphagia)
Arms and legs	1	Limb dystonia

GeneReviews

Clinical Guidance

TUBB4A-related neurologic disorders have a heterogeneous presentation and represent a spectrum of disease. Two primary phenotypes have emerged, TUBB4A-related leukodystrophy and DYT-TUBB4A (previously called DYT4 dystonia). TUBB4A-related leukodystrophy typically presents in childhood; age of onset ranges from a few months in more severe forms to later childhood or adulthood in some instances of isolated hypomyelination . The disorder is progressive and the rate of progression varies with disease severity. DYT-TUBB4A, formerly known as whispering dysphonia, is a rare cause of isolated dystonia that ranges from mild to severe with onset from early childhood to the third decade of life. While spasmodic dysphonia and/or craniocervical dystonia are often the presenting signs, progression to limbs and/or generalized dystonia is common . Laryngeal dystonia is the most common feature, present in more than three quarters of affected individuals . Brain MRI is typically normal. To date, at least 200 individuals have been identified with a pathogenic variant in TUBB4A . The following description of the phenotypic features associated with this condition is based on these reports. Table 2. TUBB4A-Related Neurologic Disorders: Comparison of Clinical Manifestations Clinical Manifestations | Frequency of Neurologic Findings TUBB4A-related leukodystrophy1 | DYT-TUBB4A2

Neurodevelopmental delays	95%	0%
Loss of motor abilities (incl independent assisted ambulation)	50%	Loss of ability can occur in setting of severe generalized dystonia.
A peculiar gait dystonia called "hobby horse" gait has been described . Pyramidal involvement

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

No consensus clinical diagnostic criteria for TUBB4A-related neurologic disorders have been published to date.

Suggestive Findings

TUBB4A-related neurologic disorders should be suspected in individuals with the following clinical and brain imaging findings and family history. Neurologic and neurodevelopmental features variably reported in affected individuals include:

Neurodevelopmental delays
Including motor and speech-language delays
Range from mild delays to severe neurodevelopmental impairment with limited acquisition of motor or cognitive milestones
Abnormal movements including focal, multifocal, or generalized dystonia, with both fixed and mobile features.

Source: GeneReviews — "TUBB4A-Related Neurologic Disorders"

GeneReviews

Differential Diagnosis

TUBB4A-related leukodystrophy. Hypomyelinating leukodystrophies with early childhood onset and/or movement disorders should be considered in the differential diagnosis . Table 3. TUBB4A-Related Leukodystrophy: Genetic Differential Diagnosis

Gene(s)	Disorder	MOI	Brain MRI Findings	Features Similar to TUBB4A-Related Leukodystrophy	Features Distinct from TUBB4A-Related Leukodystrophy
Pelizaeus-Merzbacher-like disease 1	AR	Diffuse homogeneous hyperintense T2-weighted signal affecting WM of cerebrum cerebellum; Involvement of corticospinal tracts w/abnormal T2-weighted signal extending into brain stem resulting in extensive brain stem involvement; Thin CC in older children

Genetic testing for TUBB4A is available. Testing is considered confirmatory for diagnosis.

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. TUBB4A-Related Neurologic Disorders: Recommended Surveillance

System/Concern	Evaluation	Frequency
Psychiatric	Assessment for anxiety, ADHD, ASD, aggression, self-injury	At least annually Musculoskeletal
Ophthalmologic involvement	Routine ophthalmology eval	Per treating ophthalmologist(s) Low vision services
Cardiovascular	Cardiovascular eval	Per treating cardiologist Electrocardiogram
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 ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy

Source: GeneReviews — "TUBB4A-Related Neurologic Disorders"

Phenotype severity distribution: 2 common features.

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

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torsion dystonia 4

Overview

Clinical Presentation

Clinical Guidance

Explore clinical features

Genetic Landscape

Penetrance

Diagnosis

Diagnostic Criteria

Suggestive Findings

Differential Diagnosis

Treatment

Management Guidelines

Evaluations Following Initial Diagnosis

Neurologic involvement/ Leukodystrophy

Development

Musculoskeletal

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

torsion dystonia 4

Overview

Clinical Presentation

Clinical Guidance

Explore clinical features

Genetic Landscape

Penetrance

Diagnosis

Diagnostic Criteria

Suggestive Findings

Differential Diagnosis

Treatment

Management Guidelines

Evaluations Following Initial Diagnosis

Neurologic involvement/ Leukodystrophy

Development

Musculoskeletal

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