Effective Treatment with Levodopa and Carbidopa for Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum
ABSTRACT Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a rare leukoencephalopathy presenting in the infantile period and characterized by diffuse cerebral hypomyelination, and atrophy of the basal ganglia and cerebellum. As patients with H-ABC lack remarkable laboratory findings, the diagnosis is based on brain magnetic resonance imaging findings alone. Only eight cases have been reported in the literature, and thus the natural course and treatment of this disease are not fully understood. We report a 35-month-old boy with H-ABC who had hemidystonia, hypomyelination, and cerebellar ataxia. We diagnosed H-ABC after considering a thorough differential diagnosis, excluding other diseases involving hemidystonia, hypomyelination, and cerebellar ataxia. Furthermore, technetium-99m ethyl cysteinate dimmer-single-photon emission computerized tomography (Tc-ECD-SPECT) and positron emission tomography with fluorodeoxyglucose (18)F (FDG-PET) revealed decreased blood flow and glucose metabolism in the bilateral lenticular nucleus, thalamus, and cerebellum. A peroral levodopa preparation containing carbidopa (levodopa-carbidopa) was effective at ameliorating and stopping the progression of the patient's dystonia (final effective doses: levodopa, 200 mg/day and carbidopa, 20 mg/day). This is the first case report of a Japanese patient with H-ABC and treatment for this disease. Levodopa-carbidopa may be an effective treatment for H-ABC.
Full-textDOI: · Available from: Kazuhiro Haginoya, Sep 28, 2015
- SourceAvailable from: Andrea Poretti
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- "Most patients present with cognitive deficit of variable severity and onset. Since its first description of seven patients in 2002 [van der Knaap et al., 2002], 23 additional patients have been reported [Mercimek-Mahmutoglu et al., 2005; Wakusawa et al., 2006; Matta and Ribas, 2007; Mercimek-Mahmutoglu and Stockler- Ipsiroglu, 2007; van der Knaap et al., 2007; Wakusawa et al., 2007; Narumi et al., 2011; Simons et al., 2013]. More recently, it was discovered that H-ABC is associated with mutations in TUBB4A, encoding for tubulin beta 4A [Simons et al., 2013]. "
ABSTRACT: Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) has recently been associated with a single heterozygous p.D249N mutation in TUBB4A. We describe two novel mutations in this gene. A p.C239F mutation was found in one of the originally described H-ABC patients, for whom we provide follow-up 11 years after the original publication. The second novel mutation, p.R262H, was found in a patient with a typical clinical presentation for H-ABC, but with a novel neuroimaging phenotype, given the absence of atrophy of the putamen and caudate nucleus despite 7 years of follow-up. The recent recognition of TUBB4A mutations as the underlying etiology of H-ABC will likely lead to the identification of subtler clinical and neuroimaging presentations of this disorder, like in our third patient. Thus mutations in this gene should be suspected in any patient with hypomyelination, regardless of the long-term presence of neostriatal atrophy. © 2014 Wiley Periodicals, Inc.American Journal of Medical Genetics Part A 07/2014; 164(7). DOI:10.1002/ajmg.a.36526 · 2.16 Impact Factor
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- "Follow-up studies have shown the progressive nature of the disease, with clinical deterioration and MRI evidence of disappearance of the putamen, further loss of myelin and cerebral atrophy in addition to the cerebellar atrophy (van der Knaap et al., 2007). Since the description of H-ABC in 2002, 21 cases have been reported (van der Knaap et al., 2002, 2007; Mercimek- Mahmutoglu et al., 2005; Wakusawa et al., 2006; Matta and Ribas 2007; Narumi et al., 2011). All cases were isolated and therefore the mode of inheritance was hypothesized to be dominant de novo, precluding the possibility of identifying the mutated gene by conventional genetic linkage analysis. "
ABSTRACT: Hypomyelination with atrophy of the basal ganglia and cerebellum is a rare leukoencephalopathy that was identified using magnetic resonance imaging in 2002. In 2013, whole exome sequencing of 11 patients with the disease revealed that they all had the same de novo mutation in TUBB4A, which encodes tubulin β-4A. We investigated the mutation spectrum in a cohort of 42 patients and the relationship between genotype and phenotype. Patients were selected on the basis of clinical and magnetic resonance imaging abnormalities that are indicative of hypomyelination with atrophy of the basal ganglia and cerebellum. Genetic testing and a clinical inventory were performed, and sequential magnetic resonance images were evaluated using a standard protocol. The heterozygous TUBB4A mutation observed in the first 11 patients was the most common (25 patients). Additionally, 13 other heterozygous mutations were identified, located in different structural domains of tubulin β-4A. We confirmed that the mutations were de novo in all but three patients. In two of these three cases we lacked parental DNA and in one the mutation was also found in the mother, most likely due to mosaicism. Patients showed a phenotypic continuum ranging from neonatal to childhood disease onset, normal to delayed early development and slow to more rapid neurological deterioration. Neurological symptomatology consisted of extrapyramidal movement abnormalities, spasticity, ataxia, cognitive deficit and sometimes epilepsy. Three patients died and the oldest living patient was 29 years of age. The patients' magnetic resonance images showed an absent or disappearing putamen, variable cerebellar atrophy and highly variable cerebral atrophy. Apart from hypomyelination, myelin loss was evident in several cases. Three severely affected patients had similar, somewhat atypical magnetic resonance image abnormalities. The study results were strongly suggestive of a genotype-phenotype correlation. The 25 patients with the common c.745G>A mutation generally had a less rapidly progressive disease course than the 17 cases with other TUBB4A mutations. Overall, this work demonstrates that the distinctive magnetic resonance imaging pattern for hypomyelination with atrophy of the basal ganglia and cerebellum defines a homogeneous clinical phenotype of variable severity. Patients almost invariably have prominent extrapyramidal movement abnormalities, which are rarely seen in patients with hypomyelination of different origin. A dominant TUBB4A mutation is also associated with dystonia type 4, in which magnetic resonance images of the brain seem normal. It is highly likely that there is a disease continuum associated with TUBB4A mutations, of which hypomyelination with atrophy of the basal ganglia and cerebellum and dystonia type 4 are the extremes. This would indicate that extrapyramidal movement abnormalities constitute the core feature of the disease spectrum related to dominant TUBB4A mutations and that all other features are variable.Brain 04/2014; 137(7). DOI:10.1093/brain/awu110 · 9.20 Impact Factor
The Tohoku Journal of Experimental Medicine 01/2008; 213(4):373. DOI:10.1620/tjem.213.373 · 1.35 Impact Factor
- "We have also considered the possibility if our patient with H-ABC (Wakusawa et al. 2006; van der Knaap et al. 2007) had CFD. Since 5-MTHF could not be measured in any laboratory in Japan, we measured 5-MTHF in the CSF of our patient in Zürich, Switzerland. "