Clinical characteristics.

TUBB4A-related leukodystrophy comprises a phenotypic spectrum in which the MRI findings range from hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) at the severe end to isolated hypomyelination at the mild end. Progressive neurologic findings reflect involvement of the pyramidal tracts (spasticity, brisk deep tendon reflexes, and Babinski sign), extrapyramidal system (rigidity, dystonia, choreoathetosis, oculogyric crisis, and perioral dyskinesia), cerebellum (ataxia, intention tremor, dysmetria), and bulbar function (dysarthria, dysphonia, and swallowing). Cognition is variably affected, usually less severely than motor function. Typically, those with H-ABC present in early childhood (ages 1-3 years) and those with isolated hypomyelination in later childhood or adulthood. The rate of progression varies with disease severity.

Diagnosis/testing.

The diagnosis is established in a proband with characteristic clinical and MRI findings and a heterozygous TUBB4A pathogenic variant identified by molecular genetic testing.

Management.

Treatment of manifestations: Functionally disabling spasticity requires medical management and physical therapy; dystonia requires medical management and – when refractory to medical management – possibly surgical intervention. Swallowing dysfunction may require use of a gastrostomy tube for feeding. Seizures, constipation, and gastroesophageal reflux disease are treated in the routine manner.

Prevention of secondary complications: Calcium and vitamin D supplementation as required to prevent osteoporosis; attention to skin care and frequent repositioning to help prevent pressure sores in individuals with decreased mobility; annual flu vaccination; use of routine fall prevention strategies, adaptive equipment (e.g., wheelchairs and walkers), and physical therapy to help prevent secondary injury.

Surveillance: Routine evaluations of (1) swallowing and feeding to reduce the risk of aspiration; (2) nutrition to prevent malnutrition; (3) orthopedic and joint integrity to detect joint dislocation and scoliosis. At least yearly: (1) medical evaluations to assess weight and medications; (2) evaluations by specialists in occupational therapy, physical therapy, speech therapy, rehabilitation medicine. Annual neurologic assessment to detect emerging complications.

Genetic counseling.

TUBB4A-related leukodystrophy is inherited in an autosomal dominant manner. Most affected individuals have the disorder as the result of a de novo pathogenic variant. The risk to sibs of a proband with clinically unaffected parents is low but greater than that of the general population because of the possibility of germline mosaicism or somatic and germline mosaicism in a parent. Individuals with TUBB4A-related leukodystrophy are not known to reproduce.

Suggestive Findings

TUBB4A-related leukodystrophy should be suspected in individuals with the following clinical and brain MRI findings that define the two hypomyelination phenotypes.

Clinical findings

• Onset during infancy or childhood
• Motor developmental delay
• Presence of pyramidal and extrapyramidal signs
• Gait ataxia and cerebellar dysfunction
• Dysarthria, aphonia, or "whispering" dysphonia

Brain MRI findings

• Hypomyelination with atrophy of basal ganglia and cerebellum (H-ABC) [van der Knaap et al 2002, Sasaki et al 2009, Blumkin et al 2014, Ferreira et al 2014, Hamilton et al 2014, Sagnelli et al 2016, Tonduti et al 2016] is characterized by (Figure 1):
  • Progressive atrophy of the basal ganglia involving the neostriatum (i.e., the putamen and caudate nucleus) predominantly, often with a significant decrease in size of the putamen (which can disappear over time) and to a lesser degree the head of the caudate. The thalamus and globus pallidus are typically spared. Note that although changes in the putamen are evident in many children with the H-ABC phenotype by age two years, in some children the changes may not be evident until later childhood.
  • Diffuse cerebral hypomyelination manifest as mild T₂-weighted hyperintensity involving the supratentorial white matter, corpus callosum, and internal capsule, and typically isointense or mildly hyperintense T₁-weighted signal
  • Cerebellar findings of white matter T₁-weighted signal that is isointense or mildly hyper- or hypointense relative to gray matter structures. Cerebellar atrophy prominently affecting the vermis is a common but not obligatory feature of H-ABC.
• TUBB4A-related isolated hypomyelination is characterized by variable cerebellar involvement and no evident neostriatal involvement [Pizzino et al 2014, Purnell et al 2014].

Figure 1.

MRI findings A. Cerebellar white matter T₁-weighted signal that is isointense or mildly hyper- or hypointense relative to gray matter structures; cerebellar atrophy prominently affects the vermis. There are no specific signal changes to the brain stem (more...)

Establishing the Diagnosis

The diagnosis of a TUBB4A-related leukodystrophy is established in a proband with characteristic clinical and MRI findings and a heterozygous TUBB4A pathogenic variant identified by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel or single-gene testing) and genomic testing (comprehensive genomic sequencing) depending on the phenotype.

Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. Because the phenotype of TUBB4A-related leukodystrophy is broad, children with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a mild phenotype indistinguishable from many other inherited hypomyelinating leukodystrophies are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

TUBB4A-related leukodystrophy typically presents between ages one and three years; onset range is a few months of age in more severe forms [van der Knaap et al 2002] to later childhood or adulthood in some instances of isolated hypomyelination [Hamilton et al 2014, Pizzino et al 2014, Shimojima et al 2015].

The disorder is progressive; rate of progression varies with disease severity. Males and females are similarly affected.

Manifestations can include the following.

Delayed motor development. Some children have a period of normal motor development with subsequent deterioration [van der Knaap et al 2002].

Cognitive dysfunction. Cognition is variably affected but usually less severely than motor function. Learning difficulty is common; social awareness is usually preserved.

Pyramidal involvement. Bilateral or unilateral upper-motor neuron dysfunction (spasticity, brisk deep tendon reflexes, and Babinski signs) typically manifests in early childhood [Mercimek-Mahmutoglu et al 2005, Wakusawa et al 2006].

Of note, some individuals with a heterozygous TUBB4A pathogenic variant and a spastic paraplegia have been described as having mild white matter changes on brain MRI [Kancheva et al 2015], thus expanding the spectrum of TUBB4A-related leukodystrophy. To date, however, molecular genetic testing of individuals with as-yet unclassified hereditary spastic paraplegia has not commonly identified a causative heterozygous TUBB4A pathogenic variant [Kumar et al 2015].

Extrapyramidal involvement due to neostriatal involvement includes rigidity, dystonia, choreoathetosis, oculogyric crisis, and perioral dyskinesia. Extrapyramidal features – in particular hemidystonia – can be the first manifestation of this condition. Extrapyramidal features can be exacerbated by changes in body position or by visual and acoustic stimuli.

Gait dysfunction. Although some individuals achieve independent ambulation, many never do. Gait instability and falls are common.

Cerebellar signs can include ataxia, intention tremor, dysmetria, and nystagmus.

Dysarthria, dysphonia, and swallowing dysfunction. Communication and feeding difficulties emerge over time, necessitating a gastrostomy tube for feeding in many individuals.

Other less common findings (seen in severe cases) can include the following [van der Knaap et al 2002, Sasaki et al 2009, Simons et al 2013, Ferreira et al 2014, Hamilton et al 2014]:

• Microcephaly
• Short stature
• Seizures
• Poor vision
• Hearing loss
• Scoliosis and joint dislocation resulting from a combination of motor dysfunction and improper positioning
• Hypogonadotropic hypogonadism (in 1 individual) [Tonduti et al 2016]

Individuals mosaic for a TUBB4A pathogenic variant. Of note, a few parents of individuals with TUBB4A-related hypomyelination have been asymptomatic and mosaic for a TUBB4A pathogenic variant [Simons et al 2013].

Neurophysiologic studies

• Electroencephalogram is usually normal or demonstrates slow background activity.
• Electromyogram and nerve conduction studies are normal.
• Brain stem evoked potentials are usually delayed.
• Visual evoked potentials are usually normal.
• Somatosensory evoked potentials in some instances show delayed conduction [van der Knaap et al 2002].

Laboratory findings. Cerebrospinal fluid (CSF) analysis is typically normal [van der Knaap et al 2002]. Of note, in some individuals a low level of CSF 5-methyltetrahydrofolic acid was observed with normal plasma folate levels and normal CSF 5-MTHF reductase or decreased CSF homovanillic acid [Tomás-Vila et al 2014, Tonduti et al 2016]; this has not been broadly described [Mercimek-Mahmutoglu & Stockler-Ipsiroglu 2007] and thus is not thought to be a primary metabolic defect.

Genotype-Phenotype Correlations

Four TUBB4A pathogenic variants are consistently associated with specific phenotypes:

• c.745G>A. In the initial study of persons with classic H-ABC MRI findings, all had this TUBB4A pathogenic variant [Simons et al 2013]. Subsequently, individuals with the classic H-ABC phenotype (Table 2) were found to have this pathogenic variant as well as others [Hamilton et al 2015].
• c.730G>A. Individuals with this pathogenic variant have a typical H-ABC phenotype, but with more severe lack of myelin and a more rapidly progressive disease course [Carvalho et al 2015].
• c.785G>A and c.1228G>A. These pathogenic variants have been described in several individuals with hypomyelination without atrophy of the basal ganglia [Ferreira et al 2014, Hamilton et al 2014, Miyatake et al 2014].

Penetrance

The penetrance is not known but appears to be 100%.

Of note, a few parents of individuals with TUBB4A-related hypomyelination have been asymptomatic and mosaic for a TUBB4A pathogenic variant [Simons et al 2013].

Prevalence

The exact prevalence is unknown; 71 affected individuals have been reported to date.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a TUBB4A-related leukodystrophy, the following evaluations are recommended [Van Haren et al 2015]:

• Evaluation by a pediatric neurologist for evidence of developmental delay, spasticity, and extrapyramidal movement disorders
• Assessment of developmental milestones and cognitive function
• Assessment of functional disability and equipment needs by a physiotherapist
• Assessment of speech (communication) and feeding (swallowing)
• Audiologic assessment
• Orthopedic evaluation for evidence of scoliosis and/or joint deformity, particularly in individuals with significant dystonia
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Although there is no curative treatment for TUBB4A-related leukodystrophies, quality of life can be improved in the following ways.

• Spasticity that is functionally disabling can lead to joint contractures and scoliosis; both require physical therapy (stretching and positioning) and medical management. Oral GABA agonists such as baclofen and diazepam can be used. In some instances intrathecal baclofen pumps can be considered. For focal spasticity, intramuscular botulinum toxin may be helpful.
• Dystonia can be managed with:
  • Baclofen or intramuscular botulinum toxin when associated with spasticity;
  • Trihexyphenidyl or tetrabenazine;
  • High doses of levodopa and carbidopa [Wakusawa et al 2006, Tonduti et al 2016].
• When dystonia is refractory to medical management, a baclofen pump may be considered. Of note, to date deep brain stimulation has not been studied in TUBB4A-related leukodystrophy.
• Swallowing dysfunction may result in use of a gastrostomy tube for feeding to reduce the risk of aspiration.
• Dysarthria may warrant augmentative communication tools.
• Anticonvulsant medications should be used when seizures are present.
• Constipation, commonly due to neurologic dysfunction and poor intestinal motility, can be treated with diet, laxatives, and stool softeners.
• Gastroesophageal reflux disease is common and should be considered in the evaluation of pain.
• Functional ability can be improved by use of walkers or wheeled mobility devices and other necessary equipment.
• Accommodations in school such as an individual educational plan are often needed. With such accommodations many children with the classic H-ABC phenotype perform at or near grade level for many years, although cognitive decline may be seen later.
• Family support and advocacy groups can provide needed psychosocial support for affected individuals.

Prevention of Secondary Complications

The following recommendations – based on consensus – have been developed for all leukodystrophies [Van Haren et al 2015].

• Calcium and vitamin D supplementation as required to prevent osteoporosis
• Skin care and frequent repositioning to help prevent pressure sores in individuals with decreased mobility
• Annual flu vaccination
• Fall prevention strategies, adaptive equipment (e.g., wheelchairs and walkers), and physical therapy (to increase strength) to help prevent secondary injury

Surveillance

The following are appropriate:

• Routine evaluations of swallowing and feeding to reduce the risk of aspiration, and nutrition to prevent malnutrition
• At least yearly:
  • Medical evaluation including physical examination to assess weight and medications
  • Evaluations by specialists in occupational therapy, physical therapy, speech therapy, and rehabilitation medicine
  • Evaluation by orthopedists to assess for scoliosis and joint dislocation
• Annual neurologic evaluation to assess symptoms and any emerging complications

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

TUBB4A-related leukodystrophy is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most probands with TUBB4A-related leukodystrophy have the disorder as the result of a de novo pathogenic variant.
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include molecular genetic testing.
• If the TUBB4A pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or mosaicism in a parent [Simons et al 2013].
• If the parent is the individual in whom the TUBB4A pathogenic variant first occurred, he or she may have germline mosaicism or somatic and germline mosaicism for the variant and be asymptomatic [Simons et al 2013].

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• Because TUBB4A-related leukodystrophy has occurred as the result of a de novo pathogenic variant in most cases reported to date, the risk to the sibs of a proband is presumed to be low but greater than that of the general population because of the possibility of germline mosaicism or somatic and germline mosaicism in a parent.
  Sib recurrence was reported in a family in which the asymptomatic mother was found to be mosaic for a TUBB4A pathogenic variant [Simons et al 2013].

Offspring of a proband. Each child of an individual with TUBB4A-related leukodystrophy would have a 50% chance of inheriting the TUBB4A pathogenic variant; however, individuals with TUBB4A-related leukodystrophy are not known to reproduce.

Other family members. Given that most probands with TUBB4A-related leukodystrophy reported to date have the disorder as a result of a de novo TUBB4A pathogenic variant, the risk to other family members is presumed to be low.

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 parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the TUBB4A pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Revision History

• 3 November 2016 (bp) Review posted live
• 2 January 2016 (av) Original submission

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