Leukodystrophy, Hypomyelinating, 6

A number sign (#) is used with this entry because hypomyelinating leukodystrophy-6 (HLD6) is caused by heterozygous mutation in the TUBB4A gene (602662) on chromosome 19p13.

Mutation in the TUBB4A gene can also cause dystonia-4 (DYT4; 128101).

Description

Hypomyelinating leukodystrophy-6, also known as hypomyelinating leukodystrophy with atrophy of the basal ganglia and cerebellum, is a neurologic disorder characterized by onset in infancy or early childhood of delayed motor development and gait instability, followed by extrapyramidal movement disorders, such as dystonia, choreoathetosis, rigidity, opisthotonus, and oculogyric crises, progressive spastic tetraplegia, ataxia, and, more rarely, seizures. Most patients have cognitive decline and speech delay, but some can function normally. Brain MRI shows a combination of hypomyelination, cerebellar atrophy, and atrophy or disappearance of the putamen. The disorder usually shows sporadic occurrence, but sibs may be affected if a parent is somatic mosaic for the mutation (summary by Simons et al., 2013).

Hypomyelinating leukodystrophies (HLD) comprise a genetically heterogeneous entity in which there is a substantial permanent deficit in myelin deposition within the brain, resulting in neurologic deficits (van der Knaap et al., 2002).

For a general phenotypic description and a discussion of genetic heterogeneity of hypomyelinating leukodystrophy, see 312080.

Clinical Features

In a retrospective study of patients with leukodystrophy, van der Knaap et al. (2002) identified 7 unrelated patients with neurologic impairment associated with a distinct brain MRI pattern characterized by hypomyelination and atrophy of the basal ganglia and cerebellum. Clinical features included onset at 1 to 3 years of delayed motor development, difficulty walking without support with later deterioration of motor skills, spasticity, dystonia, ataxia, tremor, rigidity, choreoathetosis, dysarthria, and learning disability. Two patients were more severely affected with onset at age 2 months, poor vision with optic atrophy, little motor development, seizures, and mental retardation. Electrophysiologic studies indicated generalized EEG slowing, delayed visual evoked responses, and variable delays in auditory evoked potentials. Sural nerve biopsies of 2 patients were normal. Brain MRI in all patients showed a homogeneous picture, with diffuse myelin deficiency, atrophy of the cerebellar vermis, and small or absent putamen. Serial MRI studies showed variable progression. The myelination defect involved the cerebrum as well as the pyramidal tracts through the posterior limb of the internal capsule to the brainstem. Van der Knaap et al. (2002) postulated that the disease involved both the disturbance of normal myelin development and degeneration. None had a family history of the disorder, and none of the parents were consanguineous.

Mercimek-Mahmutoglu et al. (2005) reported 1 additional patient with a phenotype that was similar to that reported by van der Knaap et al. (2002). A 42-month-old girl developed progressive dystonia, spasticity, and oculogyric eye movements at age 3 months. She also was hypotonic but had opisthotonic posturing. Brain MRI showed supratentorial hypomyelination and progressive atrophy of the basal ganglia and cerebellum.

Van der Knaap et al. (2007) reported 11 additional unrelated patients with this disorder. All were sporadic, and the potential mode of inheritance was unclear, but 1 patient had consanguineous parents. Early psychomotor development was normal or delayed, followed by increasing extrapyramidal movement abnormalities, ataxia, and spasticity beginning between 8 months and 7 years. Almost all had very poor speech development and loss of unsupported walking later in life. Mental deficiency ranged from mild to severe. Other variable features included nystagmus, decreased hearing, short stature, and microcephaly. Brain MRI showed diffuse hypomyelination with evidence of further myelin loss or white matter atrophy on serial imaging. The putamen was small or absent, the head of the caudate was decreased in size, and there was cerebellar atrophy. Histopathologic analysis confirmed myelin deficiency and suggested that it was related to both lack of deposition and ongoing loss.

Simons et al. (2013) reported 11 individuals with HLD and atrophy of the cerebellum. Two of the patients had previously been reported (van der Knaap et al., 2002; van der Knaap et al., 2007). The phenotype was characterized primarily by onset in the first years of life of delayed motor development or gait instability, followed by motor deterioration and extrapyramidal signs. Six patients had cognitive decline and 2 had mild intellectual disability, but 3 had normal cognitive development. All patients except 1 had some sort of speech delay and dysarthria.

Miyatake et al. (2014) reported 8 unrelated Japanese patients with HLD6. Patients 1 and 2 had a more protracted clinical course compared to the others and were previously reported by Sasaki et al. (2009) as having an unclassified hypomyelinating leukodystrophy. These 2 patients were the only ones who achieved unsupported but unsteady walking, but they later lost the ability to walk at ages 12 and 25 years, respectively. Patient 4 was previously reported by Wakusawa et al. (2006) as having HABC. The mean age at onset was 9.2 months (range, 1.5-19 months). Some patients showed some initial motor development (rolling over or walking a few steps) followed by regression, whereas 4 had essentially no motor development, including 3 who never even achieved head control. In addition to severely delayed motor development, all patients developed an extrapyramidal disorder with spasticity, dystonia, and rigidity. Some showed choreoathetosis, tremor, and/or ataxia. Five patients had severe intellectual disability with no language acquisition and 1 had a few words. The 2 patients with a more protracted course achieved some language. Four patients had evidence of brainstem dysfunction on auditory testing. Other more variable features included nystagmus, seizures, and optic atrophy. Brain imaging showed hypomyelination and atrophy of the basal ganglia, cerebellum, and corpus callosum. None of the patients had a family history of a similar disorder.

Blumkin et al. (2014) reported a 9-year-old boy, born of unrelated parents, with a somewhat attenuated form of HLD6 showing slow progression. He had mildly delayed psychomotor development and developed lower limb spasticity with an unstable gait, toe walking, and frequent falls. He had hip and knee flexion, Achilles tendon shortening, hyperreflexia of the lower limbs, and extensor plantar responses. He also had signs and symptoms of cerebellar atrophy, including lack of smooth pursuit, dysarthria, tremor, and dysmetria. Mild dystonic posturing appeared during action and at rest. Language delay, mild intellectual disability, and severe attention deficit with hyperactivity were also noted. Brain MRI showed incomplete myelination of the cerebral hemispheric deep and subcortical white matter, and cerebellar atrophy. The patient had been treated with colchicine since age 5 years due to genetically confirmed familial Mediterranean fever (FMF; 249100).

Purnell et al. (2014) reported a 4-year-old girl with HLD6. She was first noted to have hypotonia and rotary nystagmus at age 2 months. She had delayed psychomotor development with lack of speech, but had not developed spasticity, dystonia, or choreoathetoid movements by age 4 years. She also had difficulty swallowing foods, and received a gastrostomy tube. The nystagmus resolved by 1 year of age. Brain MRI showed hypomyelination of the dorsal midbrain, cerebellum, and corpus callosum with mild atrophy of the brainstem and cerebellum. The basal ganglia were normal.

Pizzino et al. (2014) reported 5 patients, including 2 adult sibs, with HLD6 confirmed by genetic analysis. All carried a de novo heterozygous TUBB4A mutation, including the 2 adult sibs whose parents did not carry the mutation in peripheral blood, suggesting low-level mosaicism in 1 of the parents. All patients had onset of motor disabilities in early childhood, sometimes with cognitive impairment. Brain imaging showed hypomyelination in all patients, but only 1 had cerebellar atrophy, and the 2 adults had global atrophy. The remaining 2 patients had isolated hypomyelination. None of the patients had severe basal ganglia involvement as evidenced by lack of putamen atrophy even after 5 decades of disease progression. The findings expanded the neuropathologic phenotype associated with TUBB4A, and indicated that some patients may have isolated hypomyelination without additional brain abnormalities.

Kancheva et al. (2015) reported a consanguineous Roma Gypsy family from Bulgaria in which 5 sibs had HLD6. The patients presented in the first year of life with delayed motor development. Three patients learned to walk but lost independent ambulation later in childhood or during the teenage years, and 2 never achieved ambulation. Symptoms included spastic paraparesis, hyperreflexia, weakness of the lower limbs, broken eye pursuit, and dysmetria. Three patients had cerebellar ataxia; nerve conduction studies performed in 2 patients showed axonal motor and sensory polyneuropathy. Two patients who underwent brain imaging showed periventricular hypomyelination and mild cerebellar atrophy. None of the patients had dystonia or cognitive impairment.

Inheritance

HLD6 usually results from de novo mutations and occurs sporadically. However, Simons et al. (2013) reported 2 sibs with the disorder who inherited the mutation from an unaffected mother who was somatic mosaic for the mutation.

Molecular Genetics

In 9 unrelated patients with hypomyelinating leukodystrophy-6, Simons et al. (2013) identified the same de novo heterozygous mutation in the TUBB4A gene (D249N; 602662.0002). Two sibs with the disorder inherited the mutation from their unaffected mother, who was found to be somatic mosaic for the mutation. The D249N mutation was found by exome sequencing, confirmed by Sanger sequencing, and was not found in several large control exome databases. TUBB4A is highly expressed in neurons, and Simons et al. (2013) suggested that the mutation may result in a dominant-negative effect on tubulin dimerization, microtubule polymerization, or microtubule stability in neurons with a secondary involvement of glial cells.

In a 9-year-old boy with slowly progressive HLD6, Blumkin et al. (2014) identified a de novo heterozygous missense mutation in the TUBB4A gene (E410K; 602662.0004). The mutation was found by whole-exome sequencing; functional studies of the variant were not performed.

In a 4-year-old girl with HLD6, Purnell et al. (2014) identified a de novo heterozygous missense mutation in the TUBB4A gene (R156L; 602662.0005). The mutation was found by whole-exome sequencing; functional studies of the variant were not performed.

In 8 unrelated Japanese patients with HLD6, Miyatake et al. (2014) identified heterozygous missense mutations in the TUBB4A gene (see, e.g., 602662.0002; 602662.0004; 602662.0006-602662.0007). The mutations, which were found by whole-exome sequencing, occurred de novo in all cases with available parental samples. Structural modeling suggested that the mutations could affect microtubule assembly, structure, or interaction with other proteins, but functional studies were not performed.

In 5 sibs with HLD6 from a consanguineous Roma Gypsy family, Kancheva et al. (2015) identified a heterozygous missense mutation in the TUBB4A gene (H190Y; 602662.0008). Functional studies of the variant were not performed.