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Hypomyelinating leukodystrophy 6(HABC; HLD6)

MedGen UID:
436642
Concept ID:
C2676244
Disease or Syndrome
Synonyms: LEUKODYSTROPHY, HYPOMYELINATING, WITH ATROPHY OF THE BASAL GANGLIA AND CEREBELLUM; TUBB4A-Associated Leukodystrophy
SNOMED CT: Hypomyelinating leukodystrophy with atrophy of basal ganglia and cerebellum (724283004); H-ABC - hypomyelination, atrophy of basal ganglia and cerebellum (724283004); Hypomyelination with atrophy of basal ganglia and cerebellum syndrome (724283004)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): TUBB4A (19p13.3)
 
Monarch Initiative: MONDO:0012905
OMIM®: 612438
Orphanet: ORPHA139441

Disease characteristics

Excerpted from the GeneReview: TUBB4A-Related Leukodystrophy
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. [from GeneReviews]
Authors:
Norah Nahhas  |  Alex Conant  |  Eline Hamilton, et. al.   view full author information

Additional descriptions

From OMIM
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.  http://www.omim.org/entry/612438
From MedlinePlus Genetics
TUBB4A-related leukodystrophy is a disorder that affects the nervous system. Leukodystrophies are conditions that involve abnormalities of the nervous system's white matter, which consists of nerve fibers covered by a fatty substance called myelin. Myelin insulates nerve fibers and promotes the rapid transmission of nerve impulses. In particular, TUBB4A-related leukodystrophy involves hypomyelination, which means that the nervous system has a reduced ability to form myelin. In some affected individuals, myelin may also break down, which is known as demyelination.

People with TUBB4A-related leukodystrophy have different combinations of signs and symptoms. Some of these combinations are described as separate disorders. However, the features in some affected individuals do not fit into these defined disorders. Researchers now group all of these cases of leukodystrophy, which have the same genetic cause, as TUBB4A-related leukodystrophy.

At the most severe end of the TUBB4A-related leukodystrophy spectrum is a condition called hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). This disorder begins in infancy or early childhood. Most affected individuals have delayed development of motor skills, such as sitting and walking, and some are never able to walk on their own. In other cases, motor skills develop normally and then are lost in early childhood (developmental regression). In addition, individuals with H-ABC have other movement abnormalities, such as involuntary muscle contractions (dystonia), uncontrolled movements of the limbs (choreoathetosis), muscle stiffness (rigidity), and difficulty coordinating movements (ataxia). These individuals also often have impaired speech (dysarthria), a weak voice (dysphonia), and swallowing problems (dysphagia). Some develop seizures. Learning difficulty is common in individuals with H-ABC.

H-ABC is characterized by particular brain abnormalities, including hypomyelination. In addition, tissue in certain regions of the brain breaks down (atrophies), most prominently in a region called the putamen, which is part of a group of structures that help control movement (the basal ganglia). Atrophy of brain tissue in another region involved in movement called the cerebellum is common, and atrophy of the cerebrum, which controls most voluntary activity, language, sensory perception, learning, and memory, can also occur.

At the mildest end of the TUBB4A-related leukodystrophy spectrum is a condition called isolated hypomyelination, which begins at any time from late childhood to adulthood. Individuals at this end of the spectrum have mild hypomyelination and sometimes mild atrophy of the cerebellum, but no problems with the basal ganglia. These individuals can have movement problems, dysarthria, and learning difficulty, although these features are typically milder than in H-ABC.

The features in other individuals with TUBB4A-related leukodystrophy fall in between these two extremes. Affected individuals can have varying degrees of hypomyelination and atrophy or impairment of the basal ganglia or other brain regions. Movement problems can also occur. A small group of affected individuals develop muscle stiffness and paralysis of the lower limbs (spastic paraplegia) that slowly worsen. In addition, these individuals may have mild hypomyelination and ataxia without the other movement or learning problems common in H-ABC.  https://medlineplus.gov/genetics/condition/tubb4a-related-leukodystrophy

Clinical features

From HPO
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Leukodystrophy
MedGen UID:
6070
Concept ID:
C0023520
Disease or Syndrome
Leukodystrophy refers to deterioration of white matter of the brain resulting from degeneration of myelin sheaths in the CNS. Their basic defect is directly related to the synthesis and maintenance of myelin membranes. Symmetric white matter involvement at MRI is a typical finding in patients with leukodystrophies.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
Choreoathetosis
MedGen UID:
39313
Concept ID:
C0085583
Disease or Syndrome
Involuntary movements characterized by both athetosis (inability to sustain muscles in a fixed position) and chorea (widespread jerky arrhythmic movements).
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Poor speech
MedGen UID:
341172
Concept ID:
C1848207
Finding
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Cerebral hypomyelination
MedGen UID:
383084
Concept ID:
C2677328
Finding
Reduced amount of myelin in the nervous system resulting from defective myelinogenesis in the white matter of the central nervous system.
Oculomotor apraxia
MedGen UID:
483686
Concept ID:
C3489733
Disease or Syndrome
Ocular motor apraxia is a deficiency in voluntary, horizontal, lateral, fast eye movements (saccades) with retention of slow pursuit movements. The inability to follow objects visually is often compensated by head movements. There may be decreased smooth pursuit, and cancellation of the vestibulo-ocular reflex.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Specific learning disability
MedGen UID:
871302
Concept ID:
C4025790
Mental or Behavioral Dysfunction
Impairment of certain skills such as reading or writing, coordination, self-control, or attention that interfere with the ability to learn. The impairment is not related to a global deficiency of intelligence.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Rigidity
MedGen UID:
7752
Concept ID:
C0026837
Sign or Symptom
Continuous involuntary sustained muscle contraction. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity.
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Hypometric saccades
MedGen UID:
98065
Concept ID:
C0423082
Finding
Saccadic undershoot, i.e., a saccadic eye movement that has less than the magnitude that would be required to gain fixation of the object.
Visual impairment
MedGen UID:
777085
Concept ID:
C3665347
Finding
Visual impairment (or vision impairment) is vision loss (of a person) to such a degree as to qualify as an additional support need through a significant limitation of visual capability resulting from either disease, trauma, or congenital or degenerative conditions that cannot be corrected by conventional means, such as refractive correction, medication, or surgery.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVHypomyelinating leukodystrophy 6
Follow this link to review classifications for Hypomyelinating leukodystrophy 6 in Orphanet.

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