TUBB4A-related hypomyelinating leukodystrophy: New insights from a series of 12 patients

Eur J Paediatr Neurol. 2016 Mar;20(2):323-330. doi: 10.1016/j.ejpn.2015.11.006.

Davide Tonduti ¹, Chiara Aiello ², Florence Renaldo ³, Imen Dorboz ⁴, Simon Saaman ⁵, Diana Rodriguez ⁶, Houda Fettah ⁷, Monique Elmaleh ⁸, Roberta Biancheri ⁹, Sabina Barresi ², Loredana Boccone ¹⁰, Simona Orcesi ¹¹, Anna Pichiecchio ¹², Roberta Zangaglia ¹³, Hélène Maurey ¹⁴, Andrea Rossi ¹⁵, Odile Boespflug-Tanguy ³, Enrico Bertini ²

Affiliations

1 Department of Child Neurology, Neurological Institute C. Besta Foundation IRCCS, Milan, Italy; INSERM UMR1141, Paris Diderot University, Sorbonne Paris Cité, DHU PROTECT, France. Electronic address: [email protected].
2 Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesu' Children's Research Hospital, Rome, Italy.
3 INSERM UMR1141, Paris Diderot University, Sorbonne Paris Cité, DHU PROTECT, France; AP-HP, Departement of Neuropediatrics and Metabolic Diseases, National Reference Center for Leukodystrophies, Robert Debré Hospital, Paris, France.
4 INSERM UMR1141, Paris Diderot University, Sorbonne Paris Cité, DHU PROTECT, France.
5 AP-HP, Department of Human Genetic, Molecular Biology Unit, Robert Debré Hospital, Paris, France.
6 INSERM UMR1141, Paris Diderot University, Sorbonne Paris Cité, DHU PROTECT, France; AP-HP, Department of Child Neurology, Hôpital Armand-Trousseau, GHUEP, Paris, France.
7 AP-HP, Departement of Neuropediatrics and Metabolic Diseases, National Reference Center for Leukodystrophies, Robert Debré Hospital, Paris, France; INSERM UMR1141, Paris Diderot University, Sorbonne Paris Cité, DHU PROTECT, France.
8 AP-HP, Department of Child Radiology, Paris, France.
9 Dubowitz Neuromuscular Centre, Great Ormond Street Hospital, London, UK.
10 Genetics and Rare Diseases Unit, II Division of Pediatrics, Ospedale Microcitemico, Cagliari, Italy.
11 Child Neurology and Psychiatry Unit, C. Mondino National Neurological Institute, Pavia, Italy.
12 Department of Neuroradiology, C. Mondino National Neurological Institute, Pavia, Italy.
13 Movement Disorders Unit, C. Mondino National Neurological Institute, Pavia, Italy.
14 AP-HP, Neuropediatric Departement, Reference Center for Leukodystrophies Kremlin Bicêtre Hospital, Paris, France.
15 Department of Child Neurology, Neurological Institute C. Besta Foundation IRCCS, Milan, Italy.

PMID: 26643067 DOI: 10.1016/j.ejpn.2015.11.006

Abstract

Background: Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) was first described in 2002. After the recent identification of TUBB4A mutation as the genetic basis of the disease, the clinical and neuroimaging phenotype related to TUBB4A mutations expanded, ranging from primary dystonia type 4 with normal MRI to severe H-ABC cases.

Patients and methods: The study included patients referred to us for an unclassified hypomyelinating leukodystrophy. We selected patients with deleterious heterozygous TUBB4A mutations. Molecular analysis of TUBB4A was performed on genomic DNA extracted from peripheral blood.

Results: The series included 12 patients (5 females and 7 males). Five patients carried the common mutation c.745G > A (p.Asp249Asn), while the remaining harbored different mutations. Three new mutations were found in 5 patients. Clinical and neuroimaging observations are described. A clear correlation between the clinical presentation and the genotype seems to be absent in our group of 12 patients.

Conclusions: TUBB4A-mutated patients manifest a comparable clinical and neuroimaging picture but they can differ from each other in terms of rate of disease progression. Extrapyramidal signs can be absent in the first stages of the disease, and a careful evaluation of MRI is fundamental to obtain the final diagnosis. From a therapeutic perspective a trial with l-dopa should be considered in all patients presenting extrapyramidal symptoms.

Keywords

Atrophy; Cerebellar; H-ABC; Hypomyelination; Leukodystrophy; TUBB4A.

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