Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum

69.1 Clinical Features

and Laboratory Investigations A distinct leukoencephalopathy has been described in a few patients, characterized by hypomyelination and atrophy of the basal ganglia and cerebellum (HABC), giving the disease its name. Both males and females are affected. It is highly likely that the disease is inherited. However, since all patients so far have been isolated cases, it is unclear whether the mode of inheritance is autosomal recessive, or whether it is autosomal dominant with all cases representing de novo mutations.

The disease has its onset in infancy or early child- hood. The severity of the disease is highly variable.

The most severely affected patients present soon after birth with poor eye contact and absence of any motor development. Ophthalmological examination reveals pale optic discs, consistent with hypomyelination of the optic nerves. Over the years there are signs of slowly progressive spasticity and extrapyramidal movement abnormalities including rigidity, dystonia, and choreoathetosis. The patients seem to have a bet- ter mental function than motor function and appear to have a social awareness. They may have some seizures. The severely affected patients tend to have a small stature and have a head circumference below the third percentile. Patients with intermediate sever- ity of disease have delayed early development, but achieve grasping and unsupported sitting. In the mildest cases the patients may have normal initial de- velopment and they achieve unsupported walking. In these patients slow deterioration becomes evident in early childhood with increasing spasticity, ataxia, and often prominent extrapyramidal movement abnor- malities consisting of dystonia, choreoathetosis, and rigidity. Some patients are predominantly spastic.

The patients typically have learning problems, but further cognitive decline is at most minor. Occasion- al epileptic seizures may occur. Vision is normal and ophthalmological examination reveals no abnormali- ties. Height and head circumference are normal.

Laboratory examinations, including extensive metabolic studies, are unrevealing. CSF neurotrans- mitters and neurotransmitter metabolites have been studied in several patients and found to be within the normal range. Electroretinogram is normal. Visual evoked responses and somatosensory evoked re- sponses are delayed. Brain stem auditory evoked re-

sponses show a normal latency for waves I and II, whereas the later waves are delayed or not recordable.

Motor and sensory nerve conduction velocities are normal. Sural nerve biopsy is unrevealing.

69.2 Pathology

No autopsy studies are available.

69.3 Pathogenetic Considerations

The disease is most likely inherited, but the mode of inheritance is at present unclear. The disease is char- acterized by a disturbance of normal development and degeneration. From the beginning there is a pic- ture of myelin deficiency. In some patients MRI sug- gests that there is some additional loss of myelin.

There is progressive atrophy of the putamen, caudate nucleus, and cerebellum. The cerebral white matter also shows loss of volume over time. The putamen and caudate nucleus disappear without evidence of remaining scar tissue on MRI, suggesting atrophy by means of apoptosis rather than necrosis. The atrophy is more severe in the clinically more severely affected patients.

69.4 Therapy

At present, no specific therapy exists for patients with HABC. Seizures may require initiation of antiepilep- tic treatment. The severe extrapyramidal symptoms may require use of drugs also used for parkinsonism, including L-dopa. However, the extrapyramidal movement abnormalities tend to be drug-resistant.

Some patients require intrathecal baclofen to reduce the serious hypertonia.

69.5 Magnetic Resonance Imaging

The diagnosis in HABC is MRI-based. Early MRI is characterized by the presence of very little myelin. In some patients, the putamen is already absent within the first year of life and the caudate nucleus is small, making the diagnosis of HABC possible (Fig. 69.1).

However, in other patients the MRI within the first

Hypomyelination with Atrophy

of the Basal Ganglia and Cerebellum

Fig. 69.1. Girl with HABC and a severe phenotype. At the age of 11 months (first row) the signal intensity of all cerebral white matter is high on the T

-weighted image (right), consistent with hypomyelination. The same image shows that the thalamus is of normal size and the globus pallidus is visible, whereas there is no putamen.

The caudate nucleus is very small and lacks the normal intermediate signal intensity. The follow-up images at the age of 10 years (second row) show the atrophy of the cerebellum. The T

-weighted image (right) shows that the white matter still has a high signal and has become seriously atrophic.

The thalamus and globus pallidus are of normal size but the putamen and caudate nucleus are not visible.

From Van der Knaap et al. (2002), with permission

Fig. 69.2. Boy with HABC and a milder phenotype at the age of 18 months (first row) and 6 years (second row). The sagittal images (left) show progressive cerebellar atrophy over time. The axial T

-weighted images (right) show per- sistent hypomyelination of the cere- bral white matter. Initially, the basal ganglia have a normal appearance, but on follow-up the putamen has disappeared. Note the normal thalamus and globus pallidus.

From Van der Knaap et al. (2002),

with permission

year of life shows nothing other than myelin deficien- cy; the putamen and caudate nucleus are still present (Fig. 69.2). The severity of the myelin deficit is vari- able. In some patients the cerebral hemispheric white matter has a high signal intensity on T

-weighted im- ages and a low signal intensity on T

-weighted images (Fig. 69.3), indicative of serious hypomyelination. In

other patients the white matter has a moderately high signal intensity on both T

- and T

-weighted images (Fig. 69.4), indicative of diffuse deposition of some myelin (moderate hypomyelination). It is strik- ing that the pyramidal tracts in the brain stem are also hypomyelinated. Over time, the putamen disap- pears (Figs. 69.1–69.5). The caudate nucleus becomes

Fig. 69.3. A 9-year-old boy with HABC. The sagittal T

-weight- ed image (first row, left) shows the prominent cerebellar atro- phy. The cerebral white matter has a high signal intensity on the axial T

-weighted images (first, second, and third rows) and a low signal intensity on T

-weighted images (fourth and

fifth rows), consistent with a serious lack of myelin. On the

T

-weighted images the thalamus and globus pallidus are nor-

mal, whereas there is no putamen and the caudate nucleus is

small

smaller, disappearing in some patients (Figs. 69.1 and 69.5). The thalamus and globus pallidus remain of normal size (Figs. 69.1–69.5). The cerebellum be- comes progressively atrophic (Figs. 69.1 and 69.3).

The atrophy affects the vermis more seriously than the hemispheres. Over the years, variable atrophy of the cerebral white matter occurs, associated with variable dilatation of the lateral ventricles. In some of the patients, there appears to be some additional loss of the little myelin present (Figs. 69.4 and 69.5). The atrophy of cerebral white matter and the basal ganglia is more serious in the clinically severely affected pa- tients.

The full-blown picture of hypomyelination and missing putamen is diagnostic of HABC and does not suggest any other disorder. However, for as long as the putamen is still visible, other disorders leading to hypomyelination should be considered, includ- ing Pelizaeus–Merzbacher disease, Salla disease, and DNA repair disorders.

Proton MRS reveals that within the white matter total N-acetylaspartate and choline are normal, argu- ing against significant neuronal/axonal loss and ac- tive demyelination. Myo-inositol and total creatine are elevated, suggesting significant white matter gliosis.

Fig. 69.3. (continued).

Fig. 69.4.

Fig. 69.4. (continued). A 6-year-old girl with HABC. The cere- bral white matter has a high signal intensity on the axial (first and second rows) and coronal (third row) T

-weighted images and an intermediate to high signal intensity on T

-weighted images (fourth and fifth rows), consistent with moderate hy- pomyelination.The middle cerebellar peduncles and the cere-

bellar white matter are also insufficiently myelinated. The

T

-weighted images show a normal thalamus and globus pal-

lidus, whereas there is no putamen and the caudate nucleus is

very small. Courtesy of Dr. S. Blaser, Department of Diagnostic

Imaging, Hospital for Sick Children, Toronto, Canada

Fig. 69.5. The same girl as in Fig. 69.4, now 8 years old. She is clinically deteriorating. The T

-weighted images (first and sec- ond rows) show white matter atrophy and loss of myelin. The coronal T

-weighted images (third row) show that the caudate

nucleus is no longer visible. Courtesy of Dr. S. Blaser, Depart-

ment of Diagnostic Imaging, Hospital for Sick Children, Toron-

to, Canada