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Hypomyelination with atrophy of the basal ganglia and cerebellum

Introduction

In the context of our ongoing studies on unclassified white matter disorders in children, we identified seven patients with a syndrome characterized by hypomyelination and selective atrophy of the neostriatum and cerebellum. This syndrome was called 'Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC)'. The clinical, MR imaging, MR spectroscopic, and laboratory findings in these patients show that they have a distinct nosologic entity (1). Since the first description in 2002, several other patients have been referred to our Center and a few case reports have been publisehd (2,3).

Clinical symptoms

Of the seven patients that were originally described two presented with poor vision and absent motor development when they were a few months old. Over the years, signs of spasticity, particularly extrapyramidal movement abnormalities with rigidity, dystonia, and choreoathetosis increased. Both patients seemed to have better mental function than motor function, and they appeared to have social awareness.
In comparison, the other patients had better early development. Two patients were able to walk unsupported, but their stride was always unstable, and they frequently fell. The remaining three patients were able to walk with support, but one of them had great difficulty walking. Motor deterioration set in after several years, with increasing spasticity; ataxia; and, particularly, extrapyramidal movement abnormalities with dystonia, choreoathetosis, and rigidity. All five patients had learning difficulties and required special education, but further cognitive decline was questionable and, at most, minor.

None of the seven patients had other abnormalities at physical examination.

Diagnosis - MRI

The MR imaging findings in our patients are compatible with diffuse hypomyelination of the cerebral hemispheres. In addition, the myelin deficit specifically involves the pyramidal tracts through the posterior limb of the internal capsule to the brainstem, in which other structures are well myelinated. Considering that no atrophy or further signal intensity change of the pyramidal tracts occur in the brain stem over time, their observed signal intensity abnormalities are unlikely to be secondary to axonal loss. Hypomyelination of the entire pyramidal tracts is unusual. The volume of the cerebral white matter variably decreases over time. Of the basal ganglia, only the neostriatum appears to be affected. In all patients, the putamen was small or absent at the earliest time point. The head of the caudate nucleus initially has a normal or mildly reduced size, and its size decreases further over time until the head of the caudate nucleus becomes entirely flat in severely affected patients. No evidence suggests a reduction in the size of the thalamus or globus pallidus.

click here for enlarged MRI and legend

Genetics

So far all known patients are isolated cases within a family. The parents do not show any of the symptoms and none of the patients have affected siblings. This strongly suggests that this a genetic disease for which a new or so-called sporadic mutation is repsonsible. A sporadic mutation is one that has no known family history. In other words, the patient is most likley to be the only patient in the family. Such sporadic mutations cannot be found through the standard genetic studies that we perform.

For the patients and parents

H-ABC appears to be caused by sporadic mutations. So far, no families with more than one affected child has been reported. Because the gene for this disease is unknown, it is difficult develop possible treatments other than supportive care and management of some of the symptoms. Dopaminergic substances have alleviated some of the symptoms in one patient (4), but treatment of other patients in a similar way has been unsuccessful.

References

1. van der Knaap MS, Naidu S, Pouwels PJ, Bonavita S, van Coster R, Lagae L, Sperner J, Surtees R, Schiffmann R, Valk J. New syndrome characterized by hypomyelination with atrophy of the basal ganglia and cerebellum. AJNR Am J Neuroradiol. 2002; 23: 1466-1474. 

2. Mercimek-Mahmutoglu S, van der Knaap MS, Baric I, Prayer D, Stoeckler-Ipsiroglu S. 
Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). Report of a new case. Neuropediatrics. 2005; 36: 223-226.

3. Matta AP, Ribas MC. Hypomyelination with atrophy of the basal ganglia and cerebellum: case report. Arq Neuropsiquiatr. 2007; 65: 161-163.

4.Wakusawa K, Haginoya K, Kitamura T, Togashi N, Ishitobi M, Yokoyama H, Higano S, Onuma A, Nara T, Iinuma K. Effective treatment with levodopa and carbidopa for hypomyelination with atrophy of the basal ganglia and cerebellum. Tohoku J Exp Med. 2006; 209: 163-167. 

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